Menno Witter was born in The Netherlands in 1953. He did his PhD with professors Anthony Lohman and Fernando Lopes da Silva at the VU University and VU medical center in Amsterdam, where he published the first detailed anatomical account of the organization of the entorhinal cortex, focusing on its role in hippocampal-cortical interactions (1985). After his Ph.D., he worked with David Amaral and Gary VanHoesen in the US (1985/1986) on the organization of the entorhinal-hippocampal system in primates and continued to work as assistant professor in the department of Anatomy at the Vrije University. In 1989 he published two influential papers on the anatomy of the cortico-hippocampal system, which still are considered 'classics' in the field. In these papers he proposed functional differentiation within the hippocampus and parahippocampus, an issue which is now at the heart of some of the more promising research lines in the hippocampal field. In 1990, together with David Amaral, he initiated the launch of the journal Hippocampus, which, now being in its 19th year, is a major vehicle for communication among scientists in the field. As of 1990, he headed his own research group, focusing on the functional organization of the medial temporal lobe (MTL), in particular in relation to learning and memory and Alzheimer's disease. In 1993, he worked as a visiting scientist and senior consultant with Prof. Dr. G. Matsumoto and Dr. T. Iijima, ETL, Tsukuba, Japan, where he started to use voltage-sensitive dye imaging to study network properties of the hippocampal-parahippocampal system. This powerful approach resulted in the description of networks potentially mediating reverberation, a proposed mechanism for memory storage. This collaboration has continued over the years, focusing on possible interactions between multiple input pathways onto identified neuronal populations.

In 1995, he was appointed as full professor in Anatomy and Embryology at the VU University Medical Center where he continued his work on functional anatomy of the cortico-hippocampal system, combined with in vivo electrophysiology and human functional MRI studies. He contributed significantly to our understanding of parallel input-output pathways between the parahippocampal region and the hippocampus, and the possibility of functional heterogeneity between hippocampal and parahippocampal subfields as well as within the individual subfields. In addition, on the basis of clinical and experimental data, he published a series of influential papers on the role of the midline and intralaminar thalamus in cognition and its contribution to diencephalic amnesia and frontal syndromes. In 1999 he was appointed as scientific director of the Institute for Neuroscience of the VU/VUmc and as director of the Graduate School Neuroscience Amsterdam. He was one of the founding directors of the Center for Neurogenomics and Cognitive Research VU/Vumc (2003).

In 2004 he was appointed as visiting professor in the Centre for the Biology of Memory and the Kavli Institute for Systems Neuroscience at the Norwegian University for Science and Technology (NTNU) in Trondheim. In 2007 he moved to Trondheim, where he continues his work on functional anatomy of the cortico-hippocampal system, relevant to memory processes in particular to spatial memory and navigation. He combines anatomical approaches with in vitro electrophysiology. His current research interests include the study of functional differentiation between cell types and cell layers in the entorhinal cortex, structural and connectional differences between the lateral and medial entorhinal cortex and the development of the entorhinal cortex and its connections. He is also involved in human functional MRI studies that focus on understanding functional heterogeneity within the human MTL.

 

Affiliations

Contact details

Menno Witter, PhD
Professor Neuroscience, Dept. Neuroscience
Kavli Institute for Systems Neuroscience, Centre for the Biology of Memory
MTFS, Norwegian University of Science and Technology (NTNU)
NO-7489 Trondheim, Norway
Phone: +47 73598249
Fax: +47 73598294
Email: menno.witter at(@) ntnu.no

pubmed: witter mp[author]

NCBI: db=pubmed; Term=Witter MP[Author] NCBI pubmed
  • Related Articles Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014 Oct;15(10):655-69 Authors: Strange BA, Witter MP, Lein ES, Moser EI Abstract The precise functional role of the hippocampus remains a topic of much debate. The dominant view is that the dorsal (or posterior) hippocampus is implicated in memory and spatial navigation and the ventral (or anterior) hippocampus mediates anxiety-related behaviours. However, this 'dichotomy view' may need revision. Gene expression studies demonstrate multiple functional domains along the hippocampal long axis, which often exhibit sharply demarcated borders. By contrast, anatomical studies and electrophysiological recordings in rodents suggest that the long axis is organized along a gradient. Together, these observations suggest a model in which functional long-axis gradients are superimposed on discrete functional domains. This model provides a potential framework to explain and test the multiple functions ascribed to the hippocampus. PMID: 25234264 [PubMed - indexed for MEDLINE]

  • Related Articles From details to large scale: The representation of environmental positions follows a granularity gradient along the human hippocampal and entorhinal anterior-posterior axis. Hippocampus. 2014 Aug 25; Authors: Evensmoen HR, Ladstein J, Hansen TI, Møller JA, Witter MP, Nadel L, Håberg AK Abstract In rodents representations of environmental positions follow a granularity gradient along the hippocampal and entorhinal anterior-posterior axis; with fine-grained representations most posteriorly. To investigate if such a gradient exists in humans, functional magnetic resonance imaging data were acquired during virtual environmental learning of the objects' positions and the association between the objects and room geometry. The Objects-room geometry binding led to increased activation throughout the hippocampus and in the posterior entorhinal cortex. Within subject comparisons related specifically to the level of spatial granularity of the object position encoding showed that activation in the posterior and intermediate hippocampus was highest for fine-grained and medium-grained representations, respectively. In addition, the level of fine granularity in the objects' positions encoded between subjects correlated with posterior hippocampal activation. For the anterior hippocampus increased activation was observed for coarse-grained representations as compared to failed encoding. Activation in anterior hippocampus correlated with the number of environments in which the objects positions were remembered when permitting a coarse representation of positions. In the entorhinal cortex, activation in the posterior part correlated with level of fine granularity for the objects' positions encoded between subjects, and activation in the posterior and intermediate entorhinal cortex increased for medium-grained representations. This demonstrates directly that positional granularity is represented in a graded manner along the anterior-posterior axis of the human hippocampus, and to some extent entorhinal cortex, with most fine-grained positional representations posteriorly. © 2014 Wiley Periodicals, Inc. PMID: 25155295 [PubMed - as supplied by publisher]

  • Related Articles Identification of dorsal-ventral hippocampal differentiation in neonatal rats. Brain Struct Funct. 2014 Jul 11; Authors: O'Reilly KC, Flatberg A, Islam S, Olsen LC, Kruge IU, Witter MP Abstract The adult hippocampal formation (HF) is functionally, connectionally, and transcriptionally differentiated along the dorsal-ventral axis. At birth, the hippocampus appears shortened along its dorsal-ventral axis. We therefore questioned at what postnatal age the differentiated dorsal-ventral hippocampus is present. We first established that the ventral tissue in the short postnatal hippocampus remains ventral in the adult-like hippocampus. Second, using anatomical tracing techniques we report that, within the first postnatal week, the main input from the entorhinal cortex (EC) to HF is topographically organized. The terminal distribution of this input along the dorsal-ventral axis of HF was related to a dorsolateral-to-ventromedial axis of origin in EC, thus reflecting adult topography. Finally, we examined gene expression along the dorsal-ventral axis in the developing hippocampus. We found that several genes that were differentially enriched in the adult dorsal and ventral hippocampus were similarly enriched in the dorsal and ventral hippocampal poles at birth. The differentially expressed genes relate to different molecular pathways and biomarkers of disease. Taken together, these data lead us to conclude that the entire dorsal-ventral axis of HF is present at birth showing adult-like functional differentiation. Moreover, our findings indicate that the neonatal ventral hippocampus is enriched with biomarkers associated with mental illnesses. These include schizophrenia, affective and anxiety disorders, disorders previously deemed as ventral hippocampal associated disorders, as well as alcoholism. Our results thus suggest an early developmental susceptibility of the ventral HF to mental illness. PMID: 25012113 [PubMed - as supplied by publisher]

  • Related Articles Grid cells and cortical representation. Nat Rev Neurosci. 2014 Jul;15(7):466-81 Authors: Moser EI, Roudi Y, Witter MP, Kentros C, Bonhoeffer T, Moser MB Abstract One of the grand challenges in neuroscience is to comprehend neural computation in the association cortices, the parts of the cortex that have shown the largest expansion and differentiation during mammalian evolution and that are thought to contribute profoundly to the emergence of advanced cognition in humans. In this Review, we use grid cells in the medial entorhinal cortex as a gateway to understand network computation at a stage of cortical processing in which firing patterns are shaped not primarily by incoming sensory signals but to a large extent by the intrinsic properties of the local circuit. PMID: 24917300 [PubMed - indexed for MEDLINE]

  • Related Articles Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer's disease. J Cereb Blood Flow Metab. 2014 May;34(5):906-14 Authors: Nilsen LH, Witter MP, Sonnewald U Abstract Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer's disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using (1)H- and (13)C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate-glutamine cycle were found in McGill-R-Thy1-APP rats. PMID: 24594625 [PubMed - indexed for MEDLINE]

  • Related Articles Architecture of spatial circuits in the hippocampal region. Philos Trans R Soc Lond B Biol Sci. 2014 Feb 5;369(1635):20120515 Authors: Witter MP, Canto CB, Couey JJ, Koganezawa N, O'Reilly KC Abstract The hippocampal region contains several principal neuron types, some of which show distinct spatial firing patterns. The region is also known for its diversity in neural circuits and many have attempted to causally relate network architecture within and between these unique circuits to functional outcome. Still, much is unknown about the mechanisms or network properties by which the functionally specific spatial firing profiles of neurons are generated, let alone how they are integrated into a coherently functioning meta-network. In this review, we explore the architecture of local networks and address how they may interact within the context of an overarching space circuit, aiming to provide directions for future successful explorations. PMID: 24366129 [PubMed - indexed for MEDLINE]

  • Related Articles Early differences in dorsal hippocampal metabolite levels in males but not females in a transgenic rat model of Alzheimer's disease. Neurochem Res. 2014 Feb;39(2):305-12 Authors: Nilsen LH, Melø TM, Witter MP, Sonnewald U Abstract McGill-R-Thy1-APP rats express the human amyloid precursor protein carrying the Swedish and Indiana mutations. We examined the neurochemical content of the dorsal hippocampus in three-months-old male and female transgenic rats and healthy age- and gender-matched controls using in vivo (1)H MRS in order to assess early metabolite alterations and whether these were similar for both genders. Whereas male and female controls had similar levels of all metabolites, differences were evident between male and female McGill-R-Thy1-APP rats. Compared with McGill-R-Thy1-APP females, McGill-R-Thy1-APP males had lower levels of myo-inositol and N-acetylaspartate (NAA). No differences in metabolite levels were evident when female control and McGill-R-Thy1-APP rats were compared, whereas McGill-R-Thy1-APP males had lower levels of glutamate, NAA and total choline compared with male controls. In addition to metabolite concentrations, metabolite ratios are reported as these are widely used. The results from this preliminary study demonstrate early metabolite alterations in the dorsal hippocampus of males in this rat model of Alzheimer's disease, and imply that very early possible neurochemical markers of the disease are different for males and females. PMID: 24338370 [PubMed - indexed for MEDLINE]

  • Related Articles Organization of multisynaptic inputs to the dorsal and ventral dentate gyrus: retrograde trans-synaptic tracing with rabies virus vector in the rat. PLoS One. 2013;8(11):e78928 Authors: Ohara S, Sato S, Tsutsui K, Witter MP, Iijima T Abstract Behavioral, anatomical, and gene expression studies have shown functional dissociations between the dorsal and ventral hippocampus with regard to their involvement in spatial cognition, emotion, and stress. In this study we examined the difference of the multisynaptic inputs to the dorsal and ventral dentate gyrus (DG) in the rat by using retrograde trans-synaptic tracing of recombinant rabies virus vectors. Three days after the vectors were injected into the dorsal or ventral DG, monosynaptic neuronal labeling was present in the entorhinal cortex, medial septum, diagonal band, and supramammillary nucleus, each of which is known to project to the DG directly. As in previous tracing studies, topographical patterns related to the dorsal and ventral DG were seen in these regions. Five days after infection, more of the neurons in these regions were labeled and labeled neurons were also seen in cortical and subcortical regions, including the piriform and medial prefrontal cortices, the endopiriform nucleus, the claustrum, the cortical amygdala, the medial raphe nucleus, the medial habenular nucleus, the interpeduncular nucleus, and the lateral septum. As in the monosynaptically labeled regions, a topographical distribution of labeled neurons was evident in most of these disynaptically labeled regions. These data indicate that the cortical and subcortical inputs to the dorsal and ventral DG are conveyed through parallel disynaptic pathways. This second-order input difference in the dorsal and ventral DG is likely to contribute to the functional differentiation of the hippocampus along the dorsoventral axis. PMID: 24223172 [PubMed - indexed for MEDLINE]

  • Related Articles Superficially projecting principal neurons in layer V of medial entorhinal cortex in the rat receive excitatory retrosplenial input. J Neurosci. 2013 Oct 2;33(40):15779-92 Authors: Czajkowski R, Sugar J, Zhang SJ, Couey JJ, Ye J, Witter MP Abstract Principal cells in layer V of the medial entorhinal cortex (MEC) have a nodal position in the cortical-hippocampal network. They are the main recipients of hippocampal output and receive inputs from several cortical areas, including a prominent one from the retrosplenial cortex (RSC), likely targeting basal dendrites of layer V neurons. The latter project to extrahippocampal structures but also relay information to the superficial layers of MEC, closing the hippocampal-entorhinal loop. In the rat, we electrophysiologically and morphologically characterized RSC input into MEC and conclude that RSC provides an excitatory input to layer V pyramidal cells. Ultrastructural analyses of anterogradely labeled RSC projections showed that RSC axons in layer V of MEC form predominantly asymmetrical, likely excitatory, synapses on dendritic spines (90%) or shafts (8%), with 2% symmetrical, likely inhibitory, synapses on shafts and spines. The overall excitatory nature of the RSC input was confirmed by an optogenetic approach. Patterned laser stimulation of channelrhodopsin-expressing presynaptic RSC axons evoked exclusively EPSPs in recorded postsynaptic layer V cells. All responding layer V pyramidal cells had an axon extending toward the white matter. Half of these neurons also sent an axon to superficial layers. Confocal imaging of RSC synapses onto MEC layer V neurons shown to project superficially by way of retrogradely labeling from superficial layers confirmed that proximal dendrites of superficially projecting cells are among the targets of inputs from RSC. The excitatory RSC input thus interacts with both entorhinal-cortical and entorhinal-hippocampal circuits. PMID: 24089485 [PubMed - indexed for MEDLINE]

  • Related Articles Transgenically targeted rabies virus demonstrates a major monosynaptic projection from hippocampal area CA2 to medial entorhinal layer II neurons. J Neurosci. 2013 Sep 11;33(37):14889-98 Authors: Rowland DC, Weible AP, Wickersham IR, Wu H, Mayford M, Witter MP, Kentros CG Abstract The enormous potential of modern molecular neuroanatomical tools lies in their ability to determine the precise connectivity of the neuronal cell types comprising the innate circuitry of the brain. We used transgenically targeted viral tracing to identify the monosynaptic inputs to the projection neurons of layer II of medial entorhinal cortex (MEC-LII) in mice. These neurons are not only major inputs to the hippocampus, the structure most clearly implicated in learning and memory, they also are "grid cells." Here we address the question of what kinds of inputs are specifically targeting these MEC-LII cells. Cell-specific infection of MEC-LII with recombinant rabies virus results in unambiguous labeling of monosynaptic inputs. Furthermore, ratios of labeled neurons in different regions are largely consistent between animals, suggesting that label reflects density of innervation. While the results mostly confirm prior anatomical work, they also reveal a novel major direct input to MEC-LII from hippocampal pyramidal neurons. Interestingly, the vast majority of these direct hippocampal inputs arise not from the major hippocampal subfields of CA1 and CA3, but from area CA2, a region that has historically been thought to merely be a transitional zone between CA3 and CA1. We confirmed this unexpected result using conventional tracing techniques in both rats and mice. PMID: 24027288 [PubMed - indexed for MEDLINE]

  • Related Articles Topographic organization of orbitofrontal projections to the parahippocampal region in rats. J Comp Neurol. 2014 Mar;522(4):772-93 Authors: Kondo H, Witter MP Abstract The parahippocampal region, which comprises the perirhinal, postrhinal, and entorhinal cortices, as well as the pre- and parasubiculum, receives inputs from several association cortices and provides the major cortical input to the hippocampus. This study examined the topographic organization of projections from the orbitofrontal cortex (OFC) to the parahippocampal region in rats by injecting anterograde tracers, biotinylated dextran amine (BDA) and Phaseolus vulgaris-leucoagglutinin (PHA-L), into four subdivisions of OFC. The rostral portion of the perirhinal cortex receives strong projections from the medial (MO), ventral (VO), and ventrolateral (VLO) orbitofrontal areas and the caudal portion of lateral orbitofrontal area (LO). These projections terminate in the dorsal bank and fundus of the rhinal sulcus. In contrast, the postrhinal cortex receives a strong projection specifically from VO. All four subdivisions of OFC give rise to projections to the dorsolateral parts of the lateral entorhinal cortex (LEC), preferentially distributing to more caudal levels of LEC. The medial entorhinal cortex (MEC) receives moderate input from VO and weak projections from MO, VLO, and LO. The presubiculum receives strong projections from caudal VO but only weak projections from other OFC regions. As for the laminar distribution of projections, axons originating from OFC terminate more densely in upper layers (layers I-III) than in deep layers in the parahippocampal region. These results thus show a striking topographic organization of OFC-to-parahippocampal connectivity. Whereas LO, VLO, VO, and MO interact with perirhinal-LEC circuits, the interactions with postrhinal cortex, presubiculum, and MEC are mediated predominantly through the projections of VO. PMID: 23897637 [PubMed - indexed for MEDLINE]

  • Related Articles Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Nat Neurosci. 2013 Aug;16(8):1085-93 Authors: Lu L, Leutgeb JK, Tsao A, Henriksen EJ, Leutgeb S, Barnes CA, Witter MP, Moser MB, Moser EI Abstract In the hippocampus, spatial and non-spatial parameters may be represented by a dual coding scheme, in which coordinates in space are expressed by the collective firing locations of place cells and the diversity of experience at these locations is encoded by orthogonal variations in firing rates. Although the spatial signal may reflect input from medial entorhinal cortex, the sources of the variations in firing rate have not been identified. We found that rate variations in rat CA3 place cells depended on inputs from the lateral entorhinal cortex (LEC). Hippocampal rate remapping, induced by changing the shape or the color configuration of the environment, was impaired by lesions in those parts of the ipsilateral LEC that provided the densest input to the hippocampal recording position. Rate remapping was not observed in LEC itself. The findings suggest that LEC inputs are important for efficient rate coding in the hippocampus. PMID: 23852116 [PubMed - indexed for MEDLINE]

  • Related Articles Subicular-parahippocampal projections revisited: development of a complex topography in the rat. J Comp Neurol. 2013 Dec 15;521(18):4284-99 Authors: O'Reilly KC, Gulden Dahl A, Ulsaker Kruge I, Witter MP Abstract The subicular-parahippocampal projection has been proposed as the major output pathway of the hippocampus. This projection shows a striking topographic organization along its three-dimensional axes. Here we aimed to study the development of this projection system. We found that an adult-like topography of subiculum-to-parahippocampal projections is present by postnatal day 7 (P7). The cellular morphology in the subiculum is immature at this age, reaching maturity by P15-19. The density of projections increases from P7 to P15-19 but does so within the constraints of the adult topography. Projections to the entorhinal cortex show a clear arrangement in line with the adult data, in that distal portions of the subiculum project to the medial entorhinal cortex, whereas proximal portions project to the lateral entorhinal cortex. Our results add new details to the proximodistal organization of projections to the pre- and parasubiculum. We show that these projections arise exclusively from the more distal part, sharing their origin with that of medial entorhinal projections. Within this distal portion of the subiculum, a proximodistal gradient of origin maps onto a presubicular termination gradient starting in proximal presubiculum and extending gradually until it covers the proximodistal extent. Proximally located neurons in the distal part of the subiculum target the distal portion of the parasubiculum, and distal subicular neurons target the proximal most portion of parasubiculum. Given the specificity of the known topographic projections this early in development, we expect that these newly described topographic features will be maintained in the adult. PMID: 23839790 [PubMed - indexed for MEDLINE]

  • Related Articles The anterior hippocampus supports a coarse, global environmental representation and the posterior hippocampus supports fine-grained, local environmental representations. J Cogn Neurosci. 2013 Nov;25(11):1908-25 Authors: Evensmoen HR, Lehn H, Xu J, Witter MP, Nadel L, Håberg AK Abstract Representing an environment globally, in a coarse way, and locally, in a fine-grained way, are two fundamental aspects of how our brain interprets the world that surrounds us. The neural correlates of these representations have not been explicated in humans. In this study we used fMRI to investigate these correlates and to explore a possible functional segregation in the hippocampus and parietal cortex. We hypothesized that processing a coarse, global environmental representation engages anterior parts of these regions, whereas processing fine-grained, local environmental information engages posterior parts. Participants learned a virtual environment and then had to find their way during fMRI. After scanning, we assessed strategies used and representations stored. Activation in the hippocampal head (anterior) was related to the multiple distance and global direction judgments and to the use of a coarse, global environmental representation during navigation. Activation in the hippocampal tail (posterior) was related to both local and global direction judgments and to using strategies like number of turns. A structural shape analysis showed that the use of a coarse, global environmental representation was related to larger right hippocampal head volume and smaller right hippocampal tail volume. In the inferior parietal cortex, a similar functional segregation was observed, with global routes represented anteriorly and fine-grained route information such as number of turns represented posteriorly. In conclusion, moving from the anterior to the posterior hippocampus and inferior parietal cortex reflects a shift from processing coarse global environmental representations to processing fine-grained, local environmental representations. PMID: 23806136 [PubMed - indexed for MEDLINE]

  • Related Articles Recurrent inhibitory circuitry as a mechanism for grid formation. Nat Neurosci. 2013 Mar;16(3):318-24 Authors: Couey JJ, Witoelar A, Zhang SJ, Zheng K, Ye J, Dunn B, Czajkowski R, Moser MB, Moser EI, Roudi Y, Witter MP Abstract Grid cells in layer II of the medial entorhinal cortex form a principal component of the mammalian neural representation of space. The firing pattern of a single grid cell has been hypothesized to be generated through attractor dynamics in a network with a specific local connectivity including both excitatory and inhibitory connections. However, experimental evidence supporting the presence of such connectivity among grid cells in layer II is limited. Here we report recordings from more than 600 neuron pairs in rat entorhinal slices, demonstrating that stellate cells, the principal cell type in the layer II grid network, are mainly interconnected via inhibitory interneurons. Using a model attractor network, we demonstrate that stable grid firing can emerge from a simple recurrent inhibitory network. Our findings thus suggest that the observed inhibitory microcircuitry between stellate cells is sufficient to generate grid-cell firing patterns in layer II of the medial entorhinal cortex. PMID: 23334580 [PubMed - indexed for MEDLINE]

  • Related Articles All layers of medial entorhinal cortex receive presubicular and parasubicular inputs. J Neurosci. 2012 Dec 5;32(49):17620-31 Authors: Canto CB, Koganezawa N, Beed P, Moser EI, Witter MP Abstract The medial entorhinal cortex (MEC), presubiculum (PrS), and parasubiculum (PaS) are interconnected components of the hippocampal-parahippocampal spatial-representation system. Principal cells in all layers of MEC show signs of directional tuning, overt in head direction cells present in all layers except for layer II, and covert in grid cells, which are the major spatially modulated cell type in layer II. Directional information likely originates in the head direction-vestibular system and PrS and PaS are thought to provide this information to MEC. Efferents from PaS and PrS show a selective laminar terminal distribution in MEC superficial layers II and III, respectively. We hypothesized that this anatomically determined laminar distribution does not preclude monosynaptic interaction with neurons located in deeper layers of MEC in view of the extensive apical dendrites from deeper cells reaching layers II and III. This hypothesis was tested in the rat using tilted in vitro slices in which origins and terminations of PrS and PaS fibers were maintained, as assessed using anterograde anatomical tracing. Based on voltage-sensitive dye imaging, multipatch single-cell recordings, and scanning photostimulation of caged glutamate, we report first that principal neurons in all layers of MEC receive convergent monosynaptic inputs from PrS and PaS and second, that elicited responses show layer-specific decay times and frequency-dependent facilitation. These results indicate that regardless of their selective laminar terminal distribution, PrS and PaS inputs may monosynaptically convey directional information to principal neurons in all layers of MEC through synapses on their extensive dendritic arbors. PMID: 23223285 [PubMed - indexed for MEDLINE]

  • Related Articles Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1 H MRS study. J Neurochem. 2012 Nov;123(4):532-41 Authors: Nilsen LH, Melø TM, Saether O, Witter MP, Sonnewald U Abstract We investigated metabolite levels during the progression of pathology in McGill-R-Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo (1) H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo (1) H MRS is a powerful tool to investigate disease-related metabolite changes in the brain. PMID: 22943908 [PubMed - indexed for MEDLINE]

  • Related Articles Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012;7(2):e31302 Authors: Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K Abstract Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10-11 months old), human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old), intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression. PMID: 22312444 [PubMed - indexed for MEDLINE]

  • Related Articles Cellular properties of principal neurons in the rat entorhinal cortex. I. The lateral entorhinal cortex. Hippocampus. 2012 Jun;22(6):1256-76 Authors: Canto CB, Witter MP Abstract The lateral entorhinal cortex (LEC) provides a major cortical input to the hippocampal formation, equaling that of the medial entorhinal cortex (MEC). To understand the functional contributions made by LEC, basic knowledge of individual neurons, in the context of the intrinsic network, is needed. The aim of this study is to compare physiological and morphological properties of principal neurons in different LEC layers in postnatal rats. Using in vitro whole cell current-clamp recordings from up to four post hoc morphologically identified neurons simultaneously, we established that principal neurons show layer specific physiological and morphological properties, similar to those reported previously in adults. Principal neurons in L(ayer) I, LII, and LIII have the majority of their dendrites and axonal collaterals alone in superficial layers. LV contains mainly pyramidal neurons with dendrites and axons extending throughout all layers. A minority of LV and all principal neurons in LVI are neurons with dendrites confined to deep layers and axons in superficial and deep layers. Physiologically, input resistances and time constants of LII neurons are lower and shorter, respectively, than those observed in LV neurons. Fifty-four percent of LII neurons have sag potentials, resonance properties, and rebounds at the offset of hyperpolarizing current injection, whereas LIII and LVI neurons do not have any of these. LV neurons show prominent spike-frequency adaptation and a decrease in spike amplitudes in response to strong depolarization. Despite the well-developed interlaminar communication in LEC, the laminar differences in the biophysical and morphological properties of neurons suggest that their in vivo firing patterns and functions differ, similar to what is known for neurons in different MEC layers. PMID: 22162008 [PubMed - indexed for MEDLINE]

  • Related Articles Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex. Hippocampus. 2012 Jun;22(6):1277-99 Authors: Canto CB, Witter MP Abstract Principal neurons in different medial entorhinal cortex (MEC) layers show variations in spatial modulation that stabilize between 15 and 30 days postnatally. These in vivo variations are likely due to differences in intrinsic membrane properties and integrative capacities of neurons. The latter depends on inputs and thus potentially on the morphology of principal neurons. In this comprehensive study, we systematically compared the morphological and physiological characteristics of principal neurons in all MEC layers of newborn rats before and after weaning. We recorded simultaneously from up to four post-hoc morphologically identified MEC principal neurons in vitro. Neurons in L(ayer) I-LIII have dendritic and axonal arbors mainly in superficial layers, and LVI neurons mainly in deep layers. The dendritic and axonal trees of part of LV neurons diverge throughout all layers. Physiological properties of principal neurons differ between layers. In LII, most neurons have a prominent sag potential, resonance and membrane oscillations. Neurons in LIII and LVI fire relatively regular, and lack sag potentials and membrane oscillations. LV neurons show the most prominent spike-frequency adaptation and highest input resistance. The data indicate that adult-like principal neuron types can be differentiated early on during postnatal development. The results of the accompanying paper, in which principal neurons in the lateral entorhinal cortex (LEC) were described (Canto and Witter,2011), revealed that significant differences between LEC and MEC exist mainly in LII neurons. We therefore systematically analyzed changes in LII biophysical properties along the mediolateral axis of MEC and LEC. There is a gradient in properties typical for MEC LII neurons. These properties are most pronounced in medially located neurons and become less apparent in more laterally positioned ones. This gradient continues into LEC, such that in LEC medially positioned neurons share some properties with adjacent MEC cells. PMID: 22161956 [PubMed - indexed for MEDLINE]

  • Related Articles Grid cells without theta oscillations in the entorhinal cortex of bats. Nature. 2011 Nov 3;479(7371):103-7 Authors: Yartsev MM, Witter MP, Ulanovsky N Abstract Grid cells provide a neural representation of space, by discharging when an animal traverses through the vertices of a periodic hexagonal grid spanning the environment. Although grid cells have been characterized in detail in rats, the fundamental question of what neural dynamics give rise to the grid structure remains unresolved. Two competing classes of models were proposed: network models, based on attractor dynamics, and oscillatory interference models, which propose that interference between somatic and dendritic theta-band oscillations (4-10 Hz) in single neurons transforms a temporal oscillation into a spatially periodic grid. So far, these models could not be dissociated experimentally, because rodent grid cells always co-exist with continuous theta oscillations. Here we used a novel animal model, the Egyptian fruit bat, to refute the proposed causal link between grids and theta oscillations. On the basis of our previous finding from bat hippocampus, of spatially tuned place cells in the absence of continuous theta oscillations, we hypothesized that grid cells in bat medial entorhinal cortex might also exist without theta oscillations. Indeed, we found grid cells in bat medial entorhinal cortex that shared remarkable similarities to rodent grid cells. Notably, the grids existed in the absence of continuous theta-band oscillations, and with almost no theta modulation of grid-cell spiking--both of which are essential prerequisites of the oscillatory interference models. Our results provide a direct demonstration of grid cells in a non-rodent species. Furthermore, they strongly argue against a major class of computational models of grid cells. PMID: 22051680 [PubMed - indexed for MEDLINE]

  • Related Articles A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci. 2011 Oct;12(10):585-601 Authors: Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA Abstract The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction. PMID: 21897434 [PubMed - indexed for MEDLINE]

  • Related Articles The retrosplenial cortex: intrinsic connectivity and connections with the (para)hippocampal region in the rat. An interactive connectome. Front Neuroinform. 2011;5:7 Authors: Sugar J, Witter MP, van Strien NM, Cappaert NL Abstract A connectome is an indispensable tool for brain researchers, since it quickly provides comprehensive knowledge of the brain's anatomical connections. Such knowledge lies at the basis of understanding network functions. Our first comprehensive and interactive account of brain connections comprised the rat hippocampal-parahippocampal network. We have now added all anatomical connections with the retrosplenial cortex (RSC) as well as the intrinsic connections of this region, because of the interesting functional overlap between these brain regions. The RSC is involved in a variety of cognitive tasks including memory, navigation, and prospective thinking, yet the exact role of the RSC and the functional differences between its subdivisions remain elusive. The connectome presented here may help to define this role by providing an unprecedented interactive and searchable overview of all connections within and between the rat RSC, parahippocampal region and hippocampal formation. PMID: 21847380 [PubMed]

  • Related Articles Presubiculum layer III conveys retrosplenial input to the medial entorhinal cortex. Hippocampus. 2012 Apr;22(4):881-95 Authors: Kononenko NL, Witter MP Abstract Navigation is mediated by a network of brain areas, and research has focused on the head-direction system in the presubiculum (PrS), the grid cell containing medial entorhinal cortex (EC) (MEC) and place cells in the hippocampus. Less research addressed the interactions of the retrosplenial cortex (RSC) and the navigational system, although it is well established that damage to the RSC leads to navigational deficits. We previously showed that RSC provides a dense input to deep layers of MEC and to superficial layers of PrS. In this study we use confocal microscopical analysis and show that the dense projection from the caudal part of the ventral retrosplenial granular cortex targets neurons in Layer III of PrS, which provide input to superficial layers of MEC. Our high resolution anatomical data indicate that sparsely spiny pyramidal neurons in Layer III of PrS that originate projections to Layer III of MEC are the main target of these retrosplenial projections. Retrosplenial axonal boutons were found to equally contact spines and shafts of basal dendrites in Layer III, but contacts on shafts are more prominent close to the soma, indicating the potential for efficient synaptic transfer. These observations suggest that neurons in Layer III of PrS have an important role in mediating RSC contributions to navigation. PMID: 21710546 [PubMed - indexed for MEDLINE]

  • Related Articles Digital atlas of anatomical subdivisions and boundaries of the rat hippocampal region. Front Neuroinform. 2011;5:2 Authors: Kjonigsen LJ, Leergaard TB, Witter MP, Bjaalie JG Abstract The rat hippocampal region is frequently studied in relation to learning and memory processes and brain diseases. The region is complex, consisting of multiple subdivisions that are challenging to delineate anatomically. Published atlases of the rat brain typically lack the underlying histological criteria necessary to identify boundaries, and textbooks descriptions of the region are often inadequately illustrated and thus difficult to relate to experimental data. An overview of both anatomical features and criteria used to delineate boundaries is required to assign location to experimental material from the hippocampal region. To address this issue, we have developed a web-based atlas application in which images of histological sections are integrated with new and up-to-date criteria for subdividing the rat hippocampus formation, fasciola, and associated parahippocampal regions. The atlas application consists of an interactive image viewer with high-resolution images of an extensive series of sections stained for NeuN, calbindin, and parvalbumin, and an index of structures with detailed descriptions of the criteria used to define the boundaries. Images can be inspected with a graphical overlay of selected subregions. Bi-directional links between images and the index of structures are provided. In summary, we provide a novel content-rich digital atlas resource facilitating identification of morphological features relevant for delineating the anatomical subdivisions of the rat hippocampal region. The atlas application is available at http://www.rbwb.org. PMID: 21519393 [PubMed]

  • Related Articles Spatial representation along the proximodistal axis of CA1. Neuron. 2010 Oct 6;68(1):127-37 Authors: Henriksen EJ, Colgin LL, Barnes CA, Witter MP, Moser MB, Moser EI Abstract CA1 cells receive direct input from space-responsive cells in medial entorhinal cortex (MEC), such as grid cells, as well as more nonspatial cells in lateral entorhinal cortex (LEC). Because MEC projects preferentially to the proximal part of the CA1, bordering CA2, whereas LEC innervates only the distal part, bordering subiculum, we asked if spatial tuning is graded along the transverse axis of CA1. Tetrodes were implanted along the entire proximodistal axis of dorsal CA1 in rats. Data were recorded in cylinders large enough to elicit firing at more than one location in many neurons. Distal CA1 cells showed more dispersed firing and had a larger number of firing fields than proximal cells. Phase-locking of spikes to MEC theta oscillations was weaker in distal CA1 than in proximal CA1. The findings suggest that spatial firing in CA1 is organized transversally, with the strongest spatial modulation occurring in the MEC-associated proximal part. PMID: 20920796 [PubMed - indexed for MEDLINE]

  • Related Articles Hippocampal morphometry in population-based incident Alzheimer's disease and vascular dementia: the HAAS. J Neurol Neurosurg Psychiatry. 2011 Apr;82(4):373-6 Authors: Scher AI, Xu Y, Korf ES, Hartley SW, Witter MP, Scheltens P, White LR, Thompson PM, Toga AW, Valentino DJ, Launer LJ Abstract BACKGROUND: Hippocampal changes may be a useful biomarker for Alzheimer's disease if they are specific to dementia sub-type. We compare hippocampal volume and shape in population-based incident cases of Alzheimer's disease and vascular dementia (VaD). METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study. The following analysis is based on a sub-group of men with mild incident Alzheimer's disease (n=24: age=82.5 ± 4.6) or incident VaD (n=14: age=80.5 ± 4.5). To estimate hippocampal volume, one reader, blinded to dementia diagnosis, manually outlined the left and right formation of the hippocampus using published criteria. We used 3-D mapping methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal width between dementia groups. RESULTS: Hippocampal volume was about 5% smaller in the Alzheimer's disease group compared to the VaD group, but the difference was not significant. Hippocampal shape differed between the two case groups for the left (p<0.04) but not right (p<0.21) hippocampus. The specific region of the hippocampus that most consistently differed between the Alzheimer's disease and VaD cases was in the lateral portion of the left hippocampus. Our interpretation of this region is that it intersects the CA1 sub-region to a great extent but also includes the dentate gyrus (and hilar region) and subiculum. CONCLUSION: As indicated by shape analysis, there are some differences in atrophy localisation between the Alzheimer's disease and VaD cases, despite the finding that volume of the hippocampi did not differ. These findings suggest hippocampal atrophy in Alzheimer's disease may be more focal than in VaD. PMID: 20826877 [PubMed - indexed for MEDLINE]

  • Related Articles Grid cells in pre- and parasubiculum. Nat Neurosci. 2010 Aug;13(8):987-94 Authors: Boccara CN, Sargolini F, Thoresen VH, Solstad T, Witter MP, Moser EI, Moser MB Abstract Allocentric space is mapped by a widespread brain circuit of functionally specialized cell types located in interconnected subregions of the hippocampal-parahippocampal cortices. Little is known about the neural architectures required to express this variety of firing patterns. In rats, we found that one of the cell types, the grid cell, was abundant not only in medial entorhinal cortex (MEC), where it was first reported, but also in pre- and parasubiculum. The proportion of grid cells in pre- and parasubiculum was comparable to deep layers of MEC. The symmetry of the grid pattern and its relationship to the theta rhythm were weaker, especially in presubiculum. Pre- and parasubicular grid cells intermingled with head-direction cells and border cells, as in deep MEC layers. The characterization of a common pool of space-responsive cells in architecturally diverse subdivisions of parahippocampal cortex constrains the range of mechanisms that might give rise to their unique functional discharge phenotypes. PMID: 20657591 [PubMed - indexed for MEDLINE]

  • Related Articles Development of the spatial representation system in the rat. Science. 2010 Jun 18;328(5985):1576-80 Authors: Langston RF, Ainge JA, Couey JJ, Canto CB, Bjerknes TL, Witter MP, Moser EI, Moser MB Abstract In the adult brain, space and orientation are represented by an elaborate hippocampal-parahippocampal circuit consisting of head-direction cells, place cells, and grid cells. We report that a rudimentary map of space is already present when 2 1/2-week-old rat pups explore an open environment outside the nest for the first time. Head-direction cells in the pre- and parasubiculum have adultlike properties from the beginning. Place and grid cells are also present but evolve more gradually. Grid cells show the slowest development. The gradual refinement of the spatial representation is accompanied by an increase in network synchrony among entorhinal stellate cells. The presence of adultlike directional signals at the onset of navigation raises the possibility that such signals are instrumental in setting up networks for place and grid representation. PMID: 20558721 [PubMed - indexed for MEDLINE]

  • Related Articles Chronic activation of the 5-HT(2) receptor reduces 5-HT neurite density as studied in organotypic slice cultures. Brain Res. 2009 Dec 11;1302:1-9 Authors: Dudok JJ, Groffen AJ, Witter MP, Voorn P, Verhage M Abstract The serotonin system densely innervates the brain and is implicated in psychopathological processes. Here we studied the effect of serotonin and serotonin pharmacological compounds on the outgrowth of serotonergic projections using organotypic slice co-cultures of hippocampus and dorsal raphe nuclei. Immunocytochemical analysis showed that several serotonergic neurites had grown into the target slice within 7 days in culture, after which the neurite density stabilized. These projections expressed the serotonin-synthesizing enzyme Tryptophan hydroxylase and the serotonin transporter and contained several serotonin-positive varicosities that also accumulated presynaptic markers. Chronic application of a 5-HT(2) agonist reduced the serotonergic neurite density, without effects on survival of serotonergic neurons. In contrast, application of a 5-HT(1A) agonist or the serotonin transporter inhibitor fluoxetine did not affect serotonergic neurite density. We conclude that serotonergic connectivity was reproduced in vitro and that the serotonin neurite density is inhibited by chronic activation of the 5-HT(2) receptor. PMID: 19728996 [PubMed - indexed for MEDLINE]

  • Related Articles Distinct brain systems underlie the processing of valence and arousal of affective pictures. Brain Cogn. 2009 Dec;71(3):387-96 Authors: Nielen MM, Heslenfeld DJ, Heinen K, Van Strien JW, Witter MP, Jonker C, Veltman DJ Abstract Valence and arousal are thought to be the primary dimensions of human emotion. However, the degree to which valence and arousal interact in determining brain responses to emotional pictures is still elusive. This functional MRI study aimed to delineate neural systems responding to valence and arousal, and their interaction. We measured neural activation in healthy females (N=23) to affective pictures using a 2 (Valence) x 2 (Arousal) design. Results show that arousal was preferentially processed by middle temporal gyrus, hippocampus and ventrolateral prefrontal cortex. Regions responding to negative valence included visual and lateral prefrontal regions, positive valence activated middle temporal and orbitofrontal areas. Importantly, distinct arousal-by-valence interactions were present in anterior insula (negative pictures), and in occipital cortex, parahippocampal gyrus and posterior cingulate (positive pictures). These data demonstrate that the brain not only differentiates between valence and arousal but also responds to specific combinations of these two, thereby highlighting the sophisticated nature of emotion processing in (female) human subjects. PMID: 19665830 [PubMed - indexed for MEDLINE]

  • Related Articles From rapid place learning to behavioral performance: a key role for the intermediate hippocampus. PLoS Biol. 2009 Apr 21;7(4):e1000089 Authors: Bast T, Wilson IA, Witter MP, Morris RG Abstract Rapid place encoding by hippocampal neurons, as reflected by place-related firing, has been intensely studied, whereas the substrates that translate hippocampal place codes into behavior have received little attention. A key point relevant to this translation is that hippocampal organization is characterized by functional-anatomical gradients along the septotemporal axis: Whereas the ability of hippocampal neurons to encode accurate place information declines from the septal to temporal end, hippocampal connectivity to prefrontal and subcortical sites that might relate such place information to behavioral-control processes shows an opposite gradient. We examined in rats the impact of selective lesions to relevant parts of the hippocampus on behavioral tests requiring place learning (watermaze procedures) and on in vivo electrophysiological models of hippocampal encoding (long-term potentiation [LTP], place cells). We found that the intermediate hippocampus is necessary and largely sufficient for behavioral performance based on rapid place learning. In contrast, a residual septal pole of the hippocampus, although displaying intact electrophysiological indices of rapid information encoding (LTP, precise place-related firing, and rapid remapping), failed to sustain watermaze performance based on rapid place learning. These data highlight the important distinction between hippocampal encoding and the behavioral performance based on such encoding, and suggest that the intermediate hippocampus, where substrates of rapid accurate place encoding converge with links to behavioral control, is critical to translate rapid (one-trial) place learning into navigational performance. PMID: 19385719 [PubMed - indexed for MEDLINE]

  • Related Articles The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci. 2009 Apr;10(4):272-82 Authors: van Strien NM, Cappaert NL, Witter MP Abstract Converging evidence suggests that each parahippocampal and hippocampal subregion contributes uniquely to the encoding, consolidation and retrieval of declarative memories, but their precise roles remain elusive. Current functional thinking does not fully incorporate the intricately connected networks that link these subregions, owing to their organizational complexity; however, such detailed anatomical knowledge is of pivotal importance for comprehending the unique functional contribution of each subregion. We have therefore developed an interactive diagram with the aim to display all of the currently known anatomical connections of the rat parahippocampal-hippocampal network. In this Review, we integrate the existing anatomical knowledge into a concise description of this network and discuss the functional implications of some relatively underexposed connections. PMID: 19300446 [PubMed - indexed for MEDLINE]

  • Related Articles A specific role of the human hippocampus in recall of temporal sequences. J Neurosci. 2009 Mar 18;29(11):3475-84 Authors: Lehn H, Steffenach HA, van Strien NM, Veltman DJ, Witter MP, Håberg AK Abstract There is a growing interest in how temporal order of episodic memories is represented within the medial temporal lobe (MTL). Animal studies suggest that the hippocampal formation (HF) is critical for retrieving the temporal order of past experiences. However, human imaging studies that have tested recency discrimination between pairs of previously encoded items have generally failed to report HF activation. We hypothesized that recalling a naturalistic sequence of past events would be particularly sensitive to HF function, attributable to greater involvement of associative processes. To test this prediction, we let subjects watch a novel movie and later, during functional magnetic resonance imaging, asked them to rearrange and "replay" scenes from the movie in correct order. To identify areas specifically involved in retrieval of temporal order, we used a control condition where subjects logically inferred the order of scenes from the same movie. Extensive MTL activation was observed during sequence recall. Activation within the right HF was specifically related to retrieval of temporal order and correlated positively with accuracy of sequence recall. Also, the bilateral parahippocampal cortex responded to retrieval of temporal order, but the activation here was not related to performance. Our study is the first to unequivocally demonstrate that correct sequence recall depends on HF. PMID: 19295153 [PubMed - indexed for MEDLINE]

  • Related Articles Dual transneuronal tracing in the rat entorhinal-hippocampal circuit by intracerebral injection of recombinant rabies virus vectors. Front Neuroanat. 2009;3:1 Authors: Ohara S, Inoue K, Yamada M, Yamawaki T, Koganezawa N, Tsutsui K, Witter MP, Iijima T Abstract Dual transneuronal tracing is a novel viral tracing methodology which employs two recombinant viruses, each expressing a different reporter protein. Peripheral injection of recombinant pseudorabies viruses has been used as a powerful method to define neurons that coordinate outputs to various peripheral targets of motor and autonomic systems. Here, we assessed the feasibility of recombinants of rabies virus (RV) vector for dual transneuronal tracing in the central nervous system. First, we examined whether two different RV-vectors can double label cells in vitro, and showed that efficient double labeling can be realized by infecting targeted cells with the two RV-vectors within a short time interval. The potential of dual transneuronal tracing was then examined in vivo in the entorhinal-hippocampal circuit, using the chain of projections from CA3 pyramidal cells to CA1 pyramidal cells and subsequently to entorhinal cortex. Six days after the injection of two RV-vectors into the left and right entorhinal cortex respectively, double-labeled neurons were observed in CA3 bilaterally. Some double-labeled neurons showed a Golgi-like labeling. Dual transneuronal tracing potentially provides a powerful and sensitive method to study issues such as the amount of convergence and divergence within and between circuits in the central nervous system. Using this sensitive technique, we established that single neurons in CA3 are connected to the entorhinal cortex bilaterally with only one synaptic relay. PMID: 19169410 [PubMed]

  • Related Articles Neurotoxic lesions of the thalamic reuniens or mediodorsal nucleus in rats affect non-mnemonic aspects of watermaze learning. Brain Struct Funct. 2009 Feb;213(3):329-42 Authors: Dolleman-van der Weel MJ, Morris RG, Witter MP Abstract Rats with bilateral neurotoxic reuniens (RE), mediodorsal (MD), hippocampal (HIPP) or sham (SH) lesions were tested in a standard watermaze task, together with unoperated rats. RE-rats and SH-controls readily learned to swim directly to a hidden platform. In contrast, MD-rats displayed a transient deficit characterized initially by thigmotaxis. Like in previous studies, HIPP-rats had long latencies throughout training and displayed more random swims than the other groups. In a memory probe test with the platform removed, SH- and RE-rats approached the correct location relatively directly but, whereas SH-controls persistently searched in the training quadrant, RE-rats switched to searching all over the pool. The MD-group swam in loops to the platform, but then displayed persistent searching in the training quadrant. The HIPP-group performed at chance. These distinct patterns indicate that, although their search strategies were different, RE- and MD-rats had acquired sufficient knowledge about the platform location and could recall information in the probe test. All groups performed well in a subsequent cue test with a visible platform, with RE-rats initially escaping faster than the SH- and HIPP-groups, and MD-rats improving from an initially poorer level of performance to control level. This indicates that there were no sensorimotor or motivational deficits associated with any of the lesions. In conclusion, while the RE and MD nuclei seem not to be critical for the learning and memory of a standard watermaze task, they may contribute to non-mnemonic strategy shifting when animals are challenged in ways that do not occur during training. PMID: 19132385 [PubMed - indexed for MEDLINE]

  • Related Articles Untangling neural networks with dual retrograde transsynaptic viral infection. Front Neurosci. 2009;3(3):344-9 Authors: Ohara S, Inoue K, Witter MP, Iijima T Abstract Using recombinant rabies virus (RV), we developed a dual transsynaptic retrograde tracing technique in the rat central nervous system. Two strains of recombinant RV, injected into two separate loci of the brain, were taken up through axon terminals and carried retrogradely and transsynaptically from neuron to neuron. Each viral strain expresses a unique marker in infected neurons. Therefore, neurons that project transsynaptically to two brain loci can be detected by double-labeling. In this review, we will introduce the advantage of dual viral tracing by recombinant RV, and will also address some potential weaknesses of this technique. Although false negative results may arise due to interference between two strains of RV, the ability of the recombinant RV to visualize the morphology of the infected cell and to infect primates in addition to rodents will make this technique a potential tool to provide new insights into the complex organization of brain networks. PMID: 20198151 [PubMed]

  • Related Articles Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus. 2008;18(12):1200-12 Authors: Brun VH, Solstad T, Kjelstrup KB, Fyhn M, Witter MP, Moser EI, Moser MB Abstract Grid cells are topographically organized in the sense that, within the dorsal part of the medial entorhinal cortex, the scale of the grid increases systematically with anatomical distance from the dorsal border of this brain area. The ventral limit of the spatial map is currently not known. To determine if the grid map extends into the intermediate and ventral parts of the medial entorhinal cortex, we recorded activity from entorhinal principal cells at multiple dorsoventral levels while rats shuttled back and forth on an 18 m long linear track. The recordings spanned a range of more than 3 mm, covering approximately three quarters of the dorsoventral extent of the medial entorhinal cortex. Distinct periodic firing fields were observed at all recording levels. The average interpeak distance between the fields increased from approximately 50 cm in the most dorsal part to approximately 3 m at the most ventral recording positions. The increase in grid scale was accompanied by a decrease in the frequency of theta modulation and the rate of phase precession. The increase in average spacing and field size was approximately linear but this relationship coincided with a substantial increase in the variability of each measure. Taken together, the observations suggest that the spatial scale of the grid representation increases progressively along most of the dorsoventral axis of the medial entorhinal cortex, mirroring the topographical scale expansion observed in place cells in the hippocampus. PMID: 19021257 [PubMed - indexed for MEDLINE]

  • Related Articles Navigating from hippocampus to parietal cortex. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14755-62 Authors: Whitlock JR, Sutherland RJ, Witter MP, Moser MB, Moser EI Abstract The navigational system of the mammalian cortex comprises a number of interacting brain regions. Grid cells in the medial entorhinal cortex and place cells in the hippocampus are thought to participate in the formation of a dynamic representation of the animal's current location, and these cells are presumably critical for storing the representation in memory. To traverse the environment, animals must be able to translate coordinate information from spatial maps in the entorhinal cortex and hippocampus into body-centered representations that can be used to direct locomotion. How this is done remains an enigma. We propose that the posterior parietal cortex is critical for this transformation. PMID: 18812502 [PubMed - indexed for MEDLINE]

  • Related Articles Contacts between medial and lateral perforant pathway fibers and parvalbumin expressing neurons in the subiculum of the rat. Neuroscience. 2008 Oct 15;156(3):653-61 Authors: Wouterlood FG, Boekel AJ, Aliane V, Beliën JA, Uylings HB, Witter MP Abstract The entorhinal cortex (EC) projects via the perforant pathway to all subfields in the hippocampal formation. One can distinguish medial and lateral components in the pathway, originating in corresponding medial and lateral subdivisions of EC. We analyzed the innervation by medial and lateral perforant pathway fibers of parvalbumin-expressing neurons in the subiculum. A neuroanatomical tracer (biotinylated dextran amine, BDA) was stereotaxically injected in the medial or lateral entorhinal cortex, thus selectively labeling either perforant pathway component. Transport was allowed for 1 week. Transported BDA was detected with streptavidin-Alexa Fluor 488. Parvalbumin neurons were visualized via immunofluorescence histochemistry, using the fluorochrome Alexa Fluor 594. Via a random systematic sampling scheme using a two-channel, sequential-mode confocal laser scanning procedure, we obtained image series at high magnification from the molecular layer of the subiculum. Labeled entorhinal fibers and parvalbumin-expressing structures were three dimensionally (3D) reconstructed using computer software. Further computer analysis revealed that approximately 16% of the 3D objects ('boutons') of BDA-labeled fibers was engaged in contacts with parvalbumin-immunostained dendrites in the subiculum. Both medial and lateral perforant pathway fibers and their boutons formed such appositions. Contacts are suggestive for synapses. We found no significant differences between the medial and lateral components in the relative numbers of contacts. Thus, the medial and lateral subdivisions of the entorhinal cortex similarly tune the firing of principal neurons in the subiculum by way of parvalbumin positive interneurons in their respective terminal zones. PMID: 18789377 [PubMed - indexed for MEDLINE]

  • Related Articles What does the anatomical organization of the entorhinal cortex tell us? Neural Plast. 2008;2008:381243 Authors: Canto CB, Wouterlood FG, Witter MP Abstract The entorhinal cortex is commonly perceived as a major input and output structure of the hippocampal formation, entertaining the role of the nodal point of cortico-hippocampal circuits. Superficial layers receive convergent cortical information, which is relayed to structures in the hippocampus, and hippocampal output reaches deep layers of entorhinal cortex, that project back to the cortex. The finding of the grid cells in all layers and reports on interactions between deep and superficial layers indicate that this rather simplistic perception may be at fault. Therefore, an integrative approach on the entorhinal cortex, that takes into account recent additions to our knowledge database on entorhinal connectivity, is timely. We argue that layers in entorhinal cortex show different functional characteristics most likely not on the basis of strikingly different inputs or outputs, but much more likely on the basis of differences in intrinsic organization, combined with very specific sets of inputs. Here, we aim to summarize recent anatomical data supporting the notion that the traditional description of the entorhinal cortex as a layered input-output structure for the hippocampal formation does not give the deserved credit to what this structure might be contributing to the overall functions of cortico-hippocampal networks. PMID: 18769556 [PubMed - indexed for MEDLINE]

  • Related Articles Grid cells in mice. Hippocampus. 2008;18(12):1230-8 Authors: Fyhn M, Hafting T, Witter MP, Moser EI, Moser MB Abstract The medial entorhinal cortex (EC) is a part of the neural network for the representation of self-location in the rat. The key cell type of this system is the grid cell, whose multiple firing fields span the environment in a remarkably regular triangular or hexagonal pattern. The basic properties of grid cells and other cell types have been described, but the neuronal mechanisms responsible for the formation and maintenance of the place code remain elusive. These mechanisms can be investigated by genetic intervention strategies, where specific components of the entorhinal-hippocampal network are activated or silenced. Because of the common use of knockout mice for such targeted interventions, we asked if grid activity is expressed also in the mouse. Principal neurons in the superficial layers of mouse medial EC had stable grid fields similar to those of the rat. Neighboring grid cells shared a common spacing and orientation but had a different spatial phase, such that a small number of grid cells collectively represented all locations in the environment. The spacing of the grid increased with distance from the dorsal border of the medial EC. The lowest values for grid spacing, recorded at the dorsal end, were comparable to those of the rat, suggesting that grid fields do not scale up proportionally with body size. Grid cells were colocalized with head-direction cells and conjunctive place x head-direction cells, as in the rat. The demonstration of grid cells in mice prepares the ground for transgenic analyses of the entorhinal-hippocampal network. PMID: 18683845 [PubMed - indexed for MEDLINE]

  • Related Articles Finite scale of spatial representation in the hippocampus. Science. 2008 Jul 4;321(5885):140-3 Authors: Kjelstrup KB, Solstad T, Brun VH, Hafting T, Leutgeb S, Witter MP, Moser EI, Moser MB Abstract To determine how spatial scale is represented in the pyramidal cell population of the hippocampus, we recorded neural activity at multiple longitudinal levels of this brain area while rats ran back and forth on an 18-meter-long linear track. CA3 cells had well-defined place fields at all levels. The scale of representation increased almost linearly from <1 meter at the dorsal pole to approximately 10 meters at the ventral pole. The results suggest that the place-cell map includes the entire hippocampus and that environments are represented in the hippocampus at a topographically graded but finite continuum of scales. PMID: 18599792 [PubMed - indexed for MEDLINE]

  • Related Articles What is the mammalian dentate gyrus good for? Neuroscience. 2008 Jul 17;154(4):1155-72 Authors: Treves A, Tashiro A, Witter MP, Moser EI Abstract In the mammalian hippocampus, the dentate gyrus (DG) is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers (MF). The MF form a distinct type of synapses, rich in zinc, that appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the DG and to CA3. Computational models have hypothesized that the function of the MF is to enforce a new, well-separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Although behavioral observations support the notion that the MF are crucial for decorrelating new memory representations from previous ones, a number of findings require that this view be reassessed and articulated more precisely in the spatial and temporal domains. First, neurophysiological recordings indicate that the very sparse dentate activity is concentrated on cells that display multiple but disorderly place fields, unlike both the single fields typical of CA3 and the multiple regular grid-aligned fields of medial entorhinal cortex. Second, neurogenesis is found to occur in the adult DG, leading to new cells that are functionally added to the existing circuitry, and may account for much of its ongoing activity. Third, a comparative analysis suggests that only mammals have evolved a DG, despite some of its features being present also in reptiles, whereas the avian hippocampus seems to have taken a different evolutionary path. Thus, we need to understand both how the mammalian dentate operates, in space and time, and whether evolution, in other vertebrate lineages, has offered alternative solutions to the same computational problems. PMID: 18554812 [PubMed - indexed for MEDLINE]

  • Related Articles White matter tract integrity in aging and Alzheimer's disease. Hum Brain Mapp. 2009 Apr;30(4):1051-9 Authors: Damoiseaux JS, Smith SM, Witter MP, Sanz-Arigita EJ, Barkhof F, Scheltens P, Stam CJ, Zarei M, Rombouts SA Abstract The pattern of degenerative changes in the brain white matter (WM) in aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) has been under debate. Methods of image analysis are an important factor affecting the outcomes of various studies. Here we used diffusion tensor imaging (DTI) to obtain fractional anisotropy (FA) measures of the WM in healthy young (n = 8), healthy elderly (n = 22), MCI (n = 8), and AD patients (n = 16). We then applied "tract-based spatial statistics" (TBSS) to study the effects of aging, MCI, and AD on WM integrity. Our results show that changes in WM integrity (that is, decreases in FA) are different between healthy aging and AD: in healthy older subjects compared with healthy young subjects decreased FA was primarily observed in frontal, parietal, and subcortical areas whereas in AD, compared with healthy older subjects, decreased FA was only observed in the left anterior temporal lobe. This different pattern of decreased anatomical connectivity in normal aging and AD suggests that AD is not merely accelerated aging. PMID: 18412132 [PubMed - indexed for MEDLINE]

  • Related Articles Significance of the deep layers of entorhinal cortex for transfer of both perirhinal and amygdala inputs to the hippocampus. Neurosci Res. 2008 Jun;61(2):172-81 Authors: Koganezawa N, Taguchi A, Tominaga T, Ohara S, Tsutsui K, Witter MP, Iijima T Abstract In the rat, a number of sensory modalities converge in the perirhinal cortex (PC). The neural pathway from the perirhinal cortex to the entorhinal cortex (EC) is considered one of the main routes into the entorhinal-hippocampal network. Evidence accumulated recently suggests that EC and PC, far from being passive relay stations, actively gate impulse traffic between neocortex and hippocampus. Using slice preparation maintaining the neurocircuit connecting PC, EC, hippocampal formation and amygdala, we investigated the associative function of PC and EC with respect to sensory and motivational stimuli and the influence of the association on the neurocircuit. In horizontal slices located ventrally to the rhinal sulcus, where we stimulated area 35 and the lateral amygdala, both inputs can be independently conveyed to the dentate gyrus. In slightly more dorsal slices where we stimulated area 36 and the lateral amygdala, the coincidence of the two inputs was needed to activate the hippocampus. This need for association of the two inputs was apparently mediated by the deep layer of EC. In all instances activation of the deep layers of EC was sufficient to activate the dentate gyrus, suggesting the relevance of the deep layers in cortico-hippocampal interactions. PMID: 18407365 [PubMed - indexed for MEDLINE]

  • Related Articles Activation of the human medial temporal lobes by stereoscopic depth cues. Neuroimage. 2008 May 1;40(4):1815-23 Authors: van Strien NM, Scholte HS, Witter MP Abstract The perirhinal cortex (PER) is part of both the medial temporal lobe memory system (MTL) and the ventral visual stream (VVS). In the MTL, PER provides input to the hippocampal formation directly and via the entorhinal cortex (EC), whereas in the VVS, PER is considered to be at the top of the visual processing hierarchy of object information. Because of its position in both networks, PER presumably serves a role in memory and visual perception. PER's perceptual role is thought to be contingent upon the complexity of visual information, i.e., PER only becomes active in visual perception when many higher order visual cues are combined. Using high-resolution functional MRI (fMRI), we investigated the effect of varying the presence of binocular disparity, in complex visual object stimuli. Nineteen subjects were presented with movies of complex objects and a fixation cross, either with or without binocular disparity (referred to as stereo and mono condition respectively). Subjects were instructed to attentively watch the objects, but no instructions were given to memorize them. Group results showed increased activity in the MTL, among which is PER, when comparing the stereo over the mono condition (stereo > mono). Individual analysis showed dominant activation in the stereo > mono contrast in eleven out of nineteen subjects, whereas only three subjects showed dominance in the opposite contrast. We conclude that the MTL is differentially activated by the stereo and mono condition, such that activation is stronger when a complex visual object stimulus with disparity is presented. PMID: 18353684 [PubMed - indexed for MEDLINE]

  • Related Articles Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron. 2008 Jan 24;57(2):290-302 Authors: Brun VH, Leutgeb S, Wu HQ, Schwarcz R, Witter MP, Moser EI, Moser MB Abstract Place-specific firing in the hippocampus is determined by path integration-based spatial representations in the grid-cell network of the medial entorhinal cortex. Output from this network is conveyed directly to CA1 of the hippocampus by projections from principal neurons in layer III, but also indirectly by axons from layer II to the dentate gyrus and CA3. The direct pathway is sufficient for spatial firing in CA1, but it is not known whether similar firing can also be supported by the input from CA3. To test this possibility, we made selective lesions in layer III of medial entorhinal cortex by local infusion of the neurotoxin gamma-acetylenic GABA. Firing fields in CA1 became larger and more dispersed after cell loss in layer III, whereas CA3 cells, which receive layer II input, still had sharp firing fields. Thus, the direct projection is necessary for precise spatial firing in the CA1 place cell population. PMID: 18215625 [PubMed - indexed for MEDLINE]

  • Related Articles Does assimilation into schemas involve systems or cellular consolidation? It's not just time. Neurobiol Learn Mem. 2008 May;89(4):361-5 Authors: Tse D, Langston RF, Bethus I, Wood ER, Witter MP, Morris RG Abstract A comment by Rudy and Sutherland [Rudy, J. R., & Sutherland, R. J. (2008). Is it systems or cellular consolidation? Time will tell. An alternative interpretation of the Morris Group's recent Science Paper. Neurobiology of Learning and Memory] has suggested an alternative account of recent findings concerning very rapid systems consolidation as described in a recent paper by Tse et al [Tse, D., Langston, R. F., Kakeyama, M., Bethus, I., Spooner, P. A., & Wood, E. R., et al. (2007). Schemas and memory consolidation. Science, 316, 76-82]. This is to suppose that excitotoxic lesions of the hippocampus cause transient disruptive neural activity outside the target structure that interferes with cellular consolidation in the cortex. We disagree with this alternative interpretation of our findings and cite relevant data in our original paper indicating why this proposal is unlikely. Various predictions of the two accounts are nonetheless outlined, together with the types of experiments needed to resolve the issue of whether systems consolidation can occur very rapidly when guided by activated neural schemas. PMID: 18055228 [PubMed - indexed for MEDLINE]

  • Related Articles Origin of calretinin-containing, vesicular glutamate transporter 2-coexpressing fiber terminals in the entorhinal cortex of the rat. J Comp Neurol. 2008 Jan 10;506(2):359-70 Authors: Wouterlood FG, Aliane V, Boekel AJ, Hur EE, Zaborszky L, Barroso-Chinea P, Härtig W, Lanciego JL, Witter MP Abstract The entorhinal cortex of the rat (EC) contains a dense fiber plexus that expresses the calcium-binding protein calretinin (CR). Some CR fibers contain vesicular glutamate transporter 2 (VGluT2, associated with glutamatergic neurotransmission). CR-VGluT2 coexpressing fibers may have an extrinsic origin, for instance, the midline thalamic nucleus reuniens. Alternatively, they may belong to cortical interneurons. We studied the first possibility with anterograde and retrograde neuroanatomical tracing methods combined with CR and VGluT2 immunofluorescence and confocal laser scanning. The alternative possibility was studied with in situ hybridization fluorescence histochemistry for VGluT2 mRNA combined with CR immunofluorescence. In the anterograde tracing experiments, we observed many labeled reuniens fibers in EC expressing CR. Some of these labeled fibers contained immunoreactivity for VGluT2 and CR. In the complementary retrograde tracing experiments, we found retrogradely labeled cell bodies in nucleus reuniens of the thalamus that coexpressed CR. We also examined the colocalization of VGluT2 and CR in the entorhinal cortex by using in situ hybridization and CR immunofluorescence. In these experiments, we observed CR-immunopositive cortical neurons that coexpressed VGluT2. For the same sections, with CR as the principal marker and parvalbumin as a control marker, we found that parvalbumin neurons were negative for VGluT2 mRNA. Thus, CR-VGluT2-expressing axon terminals in EC belong to two sources: projection fibers from the thalamus and axon collaterals of local interneurons. VGluT2 expression is linked to the synaptic transmission of the excitatory neurotransmitter glutamate, so these thalamic CR-VGluT2 projection neurons and entorhinal CR-VGluT2 interneurons should be regarded as excitatory. PMID: 18022947 [PubMed - indexed for MEDLINE]

  • Related Articles The CA3 network as a memory store for spatial representations. Learn Mem. 2007 Nov;14(11):732-44 Authors: Papp G, Witter MP, Treves A Abstract Comparative neuroanatomy suggests that the CA3 region of the mammalian hippocampus is directly homologous with the medio-dorsal pallium in birds and reptiles, with which it largely shares the basic organization of primitive cortex. Autoassociative memory models, which are generically applicable to cortical networks, then help assess how well CA3 may process information and what the crucial hurdles are that it may face. The analysis of such models points at spatial memories as posing a special challenge, both in terms of the attractor dynamics they can induce and how they may be established. Addressing such a challenge may have favored the evolution of elements of hippocampal organization observed only in mammals. PMID: 18007017 [PubMed - indexed for MEDLINE]

  • Related Articles Intrinsic and extrinsic wiring of CA3: indications for connectional heterogeneity. Learn Mem. 2007 Nov;14(11):705-13 Authors: Witter MP Abstract Within the framework of a special issue on CA3, it was deemed relevant to summarize what is known about the extrinsic and intrinsic wiring of CA3 as a basis for other contributions. Here, I have aimed to update already existing excellent reviews on the subject and to raise the issue whether or not the known architecture of the field supports the generally accepted notion that CA3 is particularly wired to function as an autoassociative network. The data reviewed strongly support this notion but in addition point to connectional heterogeneities that may point to functional specializations in CA3, on top of its role as an autoassociative network uniquely relevant to efficient encoding and recall of information. PMID: 18007015 [PubMed - indexed for MEDLINE]

  • Related Articles Convergence of entorhinal and CA3 inputs onto pyramidal neurons and interneurons in hippocampal area CA1--an anatomical study in the rat. Hippocampus. 2008;18(3):266-80 Authors: Kajiwara R, Wouterlood FG, Sah A, Boekel AJ, Baks-te Bulte LT, Witter MP Abstract The entorhinal cortex (EC) conveys information to hippocampal field CA1 either directly by way of projections from principal neurons in layer III, or indirectly by axons from layer II via the dentate gyrus, CA3, and Schaffer collaterals. These two pathways differentially influence activity in CA1, yet conclusive evidence is lacking whether and to what extent they converge onto single CA1 neurons. Presently we studied such convergence. Different neuroanatomical tracers injected into layer III of EC and into CA3, respectively, tagged simultaneously the direct entorhino-hippocampal fibers and the indirect innervation of CA1 neurons by Schaffer collaterals. In slices of fixed brains we intracellularly filled CA1 pyramidal cells and interneurons in stratum lacunosum-moleculare (LM) and stratum radiatum (SR). Sections of these slices were scanned in a confocal laser scanning microscope. 3D-reconstruction was used to determine whether boutons of the labeled input fibers were in contact with the intracellularly filled neurons. We analyzed 12 pyramidal neurons and 21 interneurons. Perforant path innervation to pyramidal neurons in our material was observed to be denser than that from CA3. All pyramidal neurons and 17 of the interneurons received contacts of both perforant pathway and Schaffer input on their dendrites and cell bodies. Four interneurons, which were completely embedded in LM, received only labeled perforant pathway input. Thus, we found convergence of both projection systems on single CA1 pyramidal and interneurons with dendrites that access the layers where perforant pathway fibers and Schaffer collaterals end. PMID: 18000818 [PubMed - indexed for MEDLINE]

  • Related Articles Coexpression of vesicular glutamate transporters 1 and 2, glutamic acid decarboxylase and calretinin in rat entorhinal cortex. Brain Struct Funct. 2007 Dec;212(3-4):303-19 Authors: Wouterlood FG, Canto CB, Aliane V, Boekel AJ, Grosche J, Härtig W, Beliën JA, Witter MP Abstract We studied the distribution and coexpression of vesicular glutamate transporters (VGluT1, VGluT2), glutamic acid decarboxylase (GAD) and calretinin (CR, calcium-binding protein) in rat entorhinal cortex, using immunofluorescence staining and multichannel confocal laser scanning microscopy. Images were computer processed and subjected to automated 3D object recognition, colocalization analysis and 3D reconstruction. Since the VGluTs (in contrast to CR and GAD) occurred in fibers and axon terminals only, we focused our attention on these neuronal processes. An intense, punctate VGluT1-staining occurred everywhere in the entorhinal cortex. Our computer program resolved these punctae as small 3D objects. Also VGluT2 showed a punctate immunostaining pattern, yet with half the number of 3D objects per tissue volume compared with VGluT1, and with statistically significantly larger 3D objects. Both VGluTs were distributed homogeneously across cortical layers, with in MEA VGluT1 slightly more densely distributed than in LEA. The distribution pattern and the size distribution of GAD 3D objects resembled that of VGluT2. CR-immunopositive fibers were abundant in all cortical layers. In double-stained sections we noted ample colocalization of CR and VGluT2, whereas coexpression of CR and VGluT1 was nearly absent. Also in triple-staining experiments (VGluT2, GAD and CR combined) we noted coexpression of VGluT2 and CR and, in addition, frequent coexpression of GAD and CR. Modest colocalization occurred of VGluT2 and GAD, and incidental colocalization of all three markers. We conclude that the CR-containing axon terminals in the entorhinal cortex belong to at least two subpopulations of CR-neurons: a glutamatergic excitatory and a GABAergic inhibitory. PMID: 17965879 [PubMed - indexed for MEDLINE]

  • Related Articles Nonlinear changes in brain activity during continuous word repetition: an event-related multiparametric functional MR imaging study. AJNR Am J Neuroradiol. 2007 Oct;28(9):1715-21 Authors: Hagenbeek RE, Rombouts SA, Veltman DJ, Van Strien JW, Witter MP, Scheltens P, Barkhof F Abstract BACKGROUND AND PURPOSE: Changes in brain activation as a function of continuous multiparametric word recognition have not been studied before by using functional MR imaging (fMRI), to our knowledge. Our aim was to identify linear changes in brain activation and, what is more interesting, nonlinear changes in brain activation as a function of extended word repetition. MATERIALS AND METHODS: Fifteen healthy young right-handed individuals participated in this study. An event-related extended continuous word-recognition task with 30 target words was used to study the parametric effect of word recognition on brain activation. Word-recognition-related brain activation was studied as a function of 9 word repetitions. fMRI data were analyzed with a general linear model with regressors for linearly changing signal intensity and nonlinearly changing signal intensity, according to group average reaction time (RT) and individual RTs. RESULTS: A network generally associated with episodic memory recognition showed either constant or linearly decreasing brain activation as a function of word repetition. Furthermore, both anterior and posterior cingulate cortices and the left middle frontal gyrus followed the nonlinear curve of the group RT, whereas the anterior cingulate cortex was also associated with individual RT. CONCLUSION: Linear alteration in brain activation as a function of word repetition explained most changes in blood oxygen level-dependent signal intensity. Using a hierarchically orthogonalized model, we found evidence for nonlinear activation associated with both group and individual RTs. PMID: 17885253 [PubMed - indexed for MEDLINE]

  • Related Articles Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol Exp Neurol. 2007 Sep;66(9):819-27 Authors: Geurts JJ, Bö L, Roosendaal SD, Hazes T, Daniëls R, Barkhof F, Witter MP, Huitinga I, van der Valk P Abstract Memory impairment is especially prominent within the spectrum of cognitive deficits in multiple sclerosis (MS), and a crucial role for hippocampal pathology may therefore be expected in this disease. This study is the first to systematically assess hippocampal demyelination in MS. Hippocampal tissue samples of 19 chronic MS cases and 7 controls with non-neurologic disease were stained immunohistochemically for myelin proteolipid protein. Subsequently, number, location, and size of demyelinated lesions were assessed. Furthermore, the specimens were stained for HLA-DR to investigate microglia/macrophage activity. An unexpectedly high number of lesions (n = 37) was found in 15 of the 19 MS cases. Mixed intrahippocampal-perihippocampal lesions, which were more often found in cases with cognitive decline, were large and did not respect anatomical borders. Moderate microglial activation was frequently observed at the edges of these mixed lesions. Isolated intrahippocampal lesions were also frequently found. These were smaller than the mixed lesions and had a specific anatomical predilection: the cornu ammonis 2 subregion and the hilus of the dentate gyrus were consistently spared. Microglial activation was rare in isolated intrahippocampal lesions. Our results indicate that hippocampal demyelination is frequent and extensive in MS and that anatomical localization, size, and inflammatory activity vary for different lesion types. PMID: 17805012 [PubMed - indexed for MEDLINE]

  • Related Articles The perforant path: projections from the entorhinal cortex to the dentate gyrus. Prog Brain Res. 2007;163:43-61 Authors: Witter MP Abstract This paper provides a comprehensive description of the organization of projections from the entorhinal cortex to the dentate gyrus, which together with projections to other subfields of the hippocampal formation form the so-called perforant pathway. To this end, data that are primarily from anatomical studies in the rat will be summarized, complimented with comparative data from other species. The analysis of the organization of any of the connections of the hippocampus, including that of the entorhinal cortex to the dentate gyrus, is severely hampered because of the complex three-dimensional shape of the hippocampus. In particular in rodents, but to a lesser extent also in primates, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis. To amend this, we will describe own unpublished tracing data obtained in the rat with the use of the so-called extended preparation. A number of issues will be addressed. First, data will be summarized which will clarify the laminar origin of the perforant pathway within the entorhinal cortex. Second, we will discuss whether or not a radial organization, along the proximo-distal dendritic axis of granule cells, characterizes the entorhinal-dentate projection. Third, we will discuss whether this projection is governed by any transverse organization, and fourth, we will focus on the organization along the longitudinal axis. Finally, the synaptic organization and the contralateral entorhinal-dentate projection will be described briefly. Taken together, the available data suggest that the projection from the entorhinal cortex to the dentate gyrus is a fairly well conserved connection, present in all species studied, exhibiting a grossly similar organization. PMID: 17765711 [PubMed - indexed for MEDLINE]

  • Related Articles Cingulate cortex projections to the parahippocampal region and hippocampal formation in the rat. Hippocampus. 2007;17(10):957-76 Authors: Jones BF, Witter MP Abstract In the present study we aimed to determine the topographical and laminar characteristics of cingulate projections to the parahippocampal region and hippocampal formation in the rat, using the anterograde tracers Phaseolus vulgaris-leucoagglutinin and biotinylated dextranamine. The results show that all areas of the cingulate cortex project extensively to the parahippocampal region but not to the hippocampal formation. Rostral cingulate areas (infralimbic-, prelimbic cortices, rostral 1/3 of the dorsal anterior cingulate cortex) primarily project to the perirhinal and lateral entorhinal cortices. Projections from the remaining cingulate areas preferentially target the postrhinal and medial entorhinal cortices as well as the presubiculum and parasubiculum. At a more detailed level the projections show differences in topographical specificities according to their site of origin within the cingulate cortex suggesting the functional contribution of cingulate areas may differ at an individual level. This organization of the cingulate-parahippocampal projections relates to the overall organization of postulated parallel parahippocampal-hippocampal processing streams mediated through the lateral and medial entorhinal cortex respectively. The mid-rostrocaudal part of the dorsal anterior cingulate cortex appears to be connected to both networks as well as to rostral and caudal parts of the cingulate cortex. This region may therefore responsible for integrating information across these specific networks. PMID: 17598159 [PubMed - indexed for MEDLINE]

  • Related Articles Spatiotemporal analyses of interactions between entorhinal and CA1 projections to the subiculum in rat brain slices. Hippocampus. 2007;17(10):909-21 Authors: Cappaert NL, Wadman WJ, Witter MP Abstract The subiculum and the entorhinal cortex (EC) are important structures in processing and transmitting information between the neocortex and the hippocampus. The subiculum potentially receives information from the EC through two routes. In addition to a direct projection from EC to the subiculum, there is an indirect polysynaptic connection. The latter uses a number of possible pathways, which all converge onto the final projection from the hippocampal field CA1 to the subiculum. In this series of experiments we investigated to what extent activity in both pathways influences population activity of subicular neurons. We used voltage sensitive dyes in combined hippocampal-EC slices of the rat to measure the spatio-temporal activity patterns. To activate the two inputs to the subiculum, stimulation electrodes were placed in the stratum oriens/alveus of CA1 and in layer III of the medial EC. The response patterns evoked in the subiculum after electrical stimulation of each of these input pathways separately were compared with the response patterns after simultaneous stimulation of both areas (medial EC + CA1). A comparison of the computed added responses of the two individual stimulations with the measured responses after simultaneous stimulation suggests that both inputs are linearly added in the subiculum with very little nonlinear interactions. This strongly suggests that in the subiculum interaction at a single cell level of the direct and the indirect pathways from the EC is an unlikely scenario. PMID: 17559098 [PubMed - indexed for MEDLINE]

  • Related Articles Hippocampal shape analysis in Alzheimer's disease: a population-based study. Neuroimage. 2007 May 15;36(1):8-18 Authors: Scher AI, Xu Y, Korf ES, White LR, Scheltens P, Toga AW, Thompson PM, Hartley SW, Witter MP, Valentino DJ, Launer LJ Abstract BACKGROUND: Hippocampal atrophy--particularly of the CA1 region--may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n=24: age=82.5+/-4.6) or were not demented (n=102: age=83.0+/-5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. RESULTS: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903+/-857 mm(3) vs. 5540+/-805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and non-demented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region. PMID: 17434756 [PubMed - indexed for MEDLINE]

  • Related Articles Schemas and memory consolidation. Science. 2007 Apr 6;316(5821):76-82 Authors: Tse D, Langston RF, Kakeyama M, Bethus I, Spooner PA, Wood ER, Witter MP, Morris RG Abstract Memory encoding occurs rapidly, but the consolidation of memory in the neocortex has long been held to be a more gradual process. We now report, however, that systems consolidation can occur extremely quickly if an associative "schema" into which new information is incorporated has previously been created. In experiments using a hippocampal-dependent paired-associate task for rats, the memory of flavor-place associations became persistent over time as a putative neocortical schema gradually developed. New traces, trained for only one trial, then became assimilated and rapidly hippocampal-independent. Schemas also played a causal role in the creation of lasting associative memory representations during one-trial learning. The concept of neocortical schemas may unite psychological accounts of knowledge structures with neurobiological theories of systems memory consolidation. PMID: 17412951 [PubMed - indexed for MEDLINE]

  • Related Articles Spatial representation and the architecture of the entorhinal cortex. Trends Neurosci. 2006 Dec;29(12):671-8 Authors: Witter MP, Moser EI Abstract It has recently been recognized that the entorhinal cortex has a crucial role in spatial representation and navigation. How the position of an animal is computed within the entorhinal circuitry remains to be determined, but the architectural organization of this brain area might provide some clues. Here, we review three organizational principles--recurrent connectivity, interlaminar connectivity and modular organization--and propose how each of them might contribute to the emergence and maintenance of positional representations in entorhinal neural networks. PMID: 17069897 [PubMed - indexed for MEDLINE]

  • Related Articles Connections of the subiculum of the rat: topography in relation to columnar and laminar organization. Behav Brain Res. 2006 Nov 11;174(2):251-64 Authors: Witter MP Abstract This paper summarizes published as well as yet unpublished data on the organization of the subiculum. Because of the complex three-dimensional structure of the hippocampus, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis; particular focus therefore is on data using the so-called extended preparation. On the basis of our yet fragmented insights in the intrinsic network, as well as the known organization of major efferents and afferents, we propose that the subiculum is organized as a matrix of columnar modules along the transverse axis showing partial laminar connectivity. Although many pieces of the large-scale puzzle on the subicular neuronal network as part of an input-output network for the hippocampus are still missing, it appears that subicular organization is different from that known for CA1. This indicates that major functional differences between CA1 and the subiculum are to be expected. PMID: 16876886 [PubMed - indexed for MEDLINE]

  • Related Articles Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science. 2006 May 5;312(5774):758-62 Authors: Sargolini F, Fyhn M, Hafting T, McNaughton BL, Witter MP, Moser MB, Moser EI Abstract Grid cells in the medial entorhinal cortex (MEC) are part of an environment-independent spatial coordinate system. To determine how information about location, direction, and distance is integrated in the grid-cell network, we recorded from each principal cell layer of MEC in rats that explored two-dimensional environments. Whereas layer II was predominated by grid cells, grid cells colocalized with head-direction cells and conjunctive grid x head-direction cells in the deeper layers. All cell types were modulated by running speed. The conjunction of positional, directional, and translational information in a single MEC cell type may enable grid coordinates to be updated during self-motion-based navigation. PMID: 16675704 [PubMed - indexed for MEDLINE]

  • Related Articles Differential regional atrophy of the cingulate gyrus in Alzheimer disease: a volumetric MRI study. Cereb Cortex. 2006 Dec;16(12):1701-8 Authors: Jones BF, Barnes J, Uylings HB, Fox NC, Frost C, Witter MP, Scheltens P Abstract Magnetic resonance imaging-based volumetric measurements provide a useful technique for quantifying in vivo regional cerebral atrophy in Alzheimer disease (AD). Histopathological studies have shown the cingulate cortex, a cytoarchitectonically heterogeneous region, to be severely affected in AD. In this study, we developed and validated a manual segmentation protocol, based on macroscopic characteristics such as gyri and sulci patterns, in order to assess volumetric changes in 4 cingulate regions of interest. Cingulate cortical volumes of 10 familial AD patients were compared with 10 age- and sex-matched controls. Inter- and intrarater reliability coefficients were high for all cingulate regions (91.9-99.4%). All 4 cingulate regions were significantly smaller (P < 0.05) in AD cases compared with controls: rostral anterior cingulate gyrus (22.5% smaller), caudal anterior cingulate gyrus (20.7% smaller), posterior cingulate gyrus (44.1% smaller), and retrosplenial cortex (21.5% smaller). The atrophy in the posterior cingulate region was significantly greater than that in other cingulate regions (P < 0.001), suggesting a higher vulnerability for this region in familial AD. Considering the functional and connectional differences of these 4 cingulate regions, detection and monitoring of their atrophy may provide insights into the natural history of AD and may help in the search for diagnostic markers for early AD. PMID: 16400164 [PubMed - indexed for MEDLINE]

  • Related Articles Entorhinal projections terminate onto principal neurons and interneurons in the subiculum: a quantitative electron microscopical analysis in the rat. Neuroscience. 2005;136(3):729-39 Authors: Baks-Te Bulte L, Wouterlood FG, Vinkenoog M, Witter MP Abstract The synaptic organization of projections to the subiculum from superficial layers of the lateral and medial entorhinal cortex was analyzed in the rat, using anterograde neuroanatomical tracing followed by electron microscopical quantification. Our aim was to assess the synaptic organization and whether the two projection components (lateral, medial) within the perforant pathway are qualitatively and quantitatively similar with respect to the types of synapses formed and with respect to the postsynaptic targets of these entorhinal projections. The tracer biotinylated dextran amine (BDA) was injected into the lateral and medial entorhinal cortex, respectively, and resulting anterograde labeling in the subiculum was studied. For each of the two projection components, we analyzed in four animals (2 x 2) a total of 100 synapses/animal with respect to features of the synapse type, i.e. asymmetrical or symmetrical, as well as regarding their postsynaptic target, i.e. dendritic shaft or spine. No clear differences were observed between the two pathways. The majority of the synapses were of the asymmetrical type, making contact with spines (78%) or with dendritic shafts (14%). A low percentage of symmetrical synapses targeted dendritic shafts (4.2%) or spines (1.3%). About 2.5% of the synapses remained undetermined. The findings indicate that the majority of entorhinal fibers reaching the subiculum exert an excitatory influence primarily onto principal neurons, with a much smaller feed forward inhibitory component. Only a small percentage of entorhinal fibers in the subiculum appears to be inhibitory, largely influencing interneurons. PMID: 16344147 [PubMed - indexed for MEDLINE]

  • Related Articles Verapamil prevents, in a dose-dependent way, the loss of ChAT-immunoreactive neurons in the cerebral cortex following lesions of the rat nucleus basalis magnocellularis. Exp Brain Res. 2006 Apr;170(3):368-75 Authors: Popović M, Caballero-Bleda M, Popović N, Puelles L, van Groen T, Witter MP Abstract In the present study we analysed the neuroprotective effect of the L-type voltage-dependent calcium channel antagonist verapamil on cholineacetyltransferase (ChAT)-immunoreactive neurons in the cerebral cortex of rats with bilateral electrolytic lesions of the nucleus basalis magnocellularis (NBM). Treatment with verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg/12 h i.p.) started 24 h after NBM lesions and lasted 8 days. Animals were sacrificed on day 21 after NBM-lesions. The bilateral NBM-lesions produced significant loss of ChAT-immunoreactive neurons in frontal, parietal and temporal cortex. Although the number of ChAT-positive neurons was significantly higher in NBM-lesioned animals treated with verapamil at a dose of 2.5, 5.0 and 10.0 mg/kg than in saline treated ones, the most significant effect was obtained at a dose of 5 mg/kg. This is, to our knowledge, the first report showing an inverted U-shape mode of neuroprotective action of the calcium antagonist verapamil, at morphological level in this particular model of brain damage. The demonstrated beneficial effect of verapamil treatment suggests that the regulation of calcium homeostasis during the early period after NBM lesions might be a possible treatment to prevent neurodegenerative processes in the rat cerebral cortex. PMID: 16328269 [PubMed - indexed for MEDLINE]

  • Related Articles Presubiculum stimulation in vivo evokes distinct oscillations in superficial and deep entorhinal cortex layers in chronic epileptic rats. J Neurosci. 2005 Sep 21;25(38):8755-65 Authors: Tolner EA, Kloosterman F, van Vliet EA, Witter MP, Silva FH, Gorter JA Abstract The characteristic cell loss in layer III of the medial entorhinal area (MEA-III) in human mesial temporal lobe epilepsy is reproduced in the rat kainate model of the disease. To understand how this cell loss affects the functional properties of the MEA, we investigated whether projections from the presubiculum (prS), providing a main input to the MEA-III, are altered in this epileptic rat model. Injections of an anterograde tracer in the prS revealed bilateral projection fibers mainly to the MEA-III in both control and chronic epileptic rats. We further examined the prS-MEA circuitry using a 16-channel electrode probe covering the MEA in anesthetized control and chronic epileptic rats. With a second 16-channel probe, we recorded signals in the hippocampus. Current source density analysis indicated that, after prS double-pulse stimulation, afterdischarges in the form of oscillations (20-45 Hz) occurred that were confined to the superficial layers of the MEA in all epileptic rats displaying MEA-III neuronal loss. Slower oscillations (theta range) were occasionally observed in the deep MEA layers and the dentate gyrus. This kind of oscillation was never observed in control rats. We conclude that dynamical changes occur in an extensive network within the temporal lobe in epileptic rats, manifested as different kinds of oscillations, the characteristics of which depend on local properties of particular subareas. These findings emphasize the significance of the entorhinal cortex in temporal lobe epilepsy and suggest that the superficial cell layers could play an important role in distributing oscillatory activity. PMID: 16177045 [PubMed - indexed for MEDLINE]

  • Related Articles Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch Gen Psychiatry. 2005 Aug;62(8):922-33 Authors: van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, van Balkom AJ, van Oppen P, van Dyck R Abstract CONTEXT: Attentional bias to disease-relevant emotional cues is considered to be pathogenetically relevant in anxiety disorders. OBJECTIVE: To investigate functional neural correlates and disease specificity of attentional bias across different anxiety disorders. DESIGN: A cognitive and emotional Stroop task, consisting of congruent and incongruent color words, obsessive-compulsive disorder (OCD)-related and panic-related negative words, and neutral words, was used in 3 patient groups and a control group during functional magnetic resonance imaging. SETTING: Academic outpatient department for anxiety disorders. PATIENTS AND PARTICIPANTS: Medication-free patients with OCD (n = 16), panic disorder (PD) (n = 15), and hypochondriasis (n = 13) and 19 controls. MAIN OUTCOME MEASURE: Voxel-wise analyses of cerebral blood flow changes for contrasts of interest (incongruent vs congruent color words, OCD-related vs neutral words, and panic-related vs neutral words) within and between groups. RESULTS: During incongruent vs congruent color naming, all patient groups recruited additional posterior brain regions relative to controls, but performance was impaired only in OCD. In OCD, color naming OCD-related, but not PD-related, words correlated with increased activation of frontal-striatal and temporal regions, although performance was unimpaired. In contrast, in PD, increased frontal-striatal involvement was found during color naming both OCD-related and panic-related words. In PD, color naming panic-related words was slowed and correlated with increased activation of the right amygdala and hippocampus. Patients with hypochondriasis showed a similar activation pattern to patients with PD. CONCLUSIONS: Our results support the hypothesis of increased distractibility for irrelevant information in patients with OCD, PD, and hypochondriasis associated with frontal-striatal and limbic involvement compared with controls. Although patients with OCD did not display an attentional bias in behavior relative to controls, there was a clear, specific neural response during color naming OCD-related words, involving mainly ventral brain regions. In contrast, generalized emotional interference effects were found in PD and hypochondriasis, involving ventral and widespread dorsal brain regions, reflecting not only unconscious emotional stimulus processing but also increased cognitive elaboration. PMID: 16061770 [PubMed - indexed for MEDLINE]

  • Related Articles Intrinsic connections of the cingulate cortex in the rat suggest the existence of multiple functionally segregated networks. Neuroscience. 2005;133(1):193-207 Authors: Jones BF, Groenewegen HJ, Witter MP Abstract The cingulate cortex is a functionally and morphologically heterogeneous cortical area comprising a number of interconnected subregions. To date, the exact anatomy of intracingulate connections has not been studied in detail. In the present study we aimed to determine the topographical and laminar characteristics of intrinsic cingulate connections in the rat, using the anterograde tracers Phaseolus vulgaris-leucoagglutinin and biotinylated dextran amine. For assessment of these data we further refined and compared the existing cytoarchitectonic descriptions of the two major cingulate constituents, the anterior cingulate and retrosplenial cortices. The results of this study demonstrate that rostral areas, i.e. the infralimbic and prelimbic cortices and the rostral one third of the dorsal anterior cingulate cortex are primarily interconnected with each other and not with other cingulate areas. The caudal two thirds of the dorsal anterior cingulate cortex project to the caudal part of the ventral anterior cingulate cortex, whereas the entire ventral anterior cingulate cortex projects to only the mid-rostro-caudal part of the dorsal anterior cingulate cortex. Dense reciprocal connections exist between the remaining, i.e. the supracallosal parts of the anterior cingulate and retrosplenial cortices with a general rostro-caudal topography, in the sense that the rostral part of the anterior cingulate cortex and caudal part of the retrosplenial cortex are interconnected and the same holds true for the caudal part of the anterior cingulate cortex and rostral part of the retrosplenial cortex. This topographical pattern of intracingulate connections relates to the results of several functional studies, suggesting that specific cingulate functions depend on a number of interconnected cingulate subregions. Through their intricate associational connections, these subregions form functionally segregated networks. PMID: 15893643 [PubMed - indexed for MEDLINE]

  • Related Articles Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography. Psychiatry Res. 2004 Dec 30;132(3):225-37 Authors: van den Heuvel OA, Veltman DJ, Groenewegen HJ, Dolan RJ, Cath DC, Boellaard R, Mesina CT, van Balkom AJ, van Oppen P, Witter MP, Lammertsma AA, van Dyck R Abstract Previous imaging studies of obsessive-compulsive symptom states have implicated frontal-striatal and limbic regions in the pathophysiology of obsessive-compulsive disorder (OCD). Functional imaging studies, however, have yielded inconsistent results, presumably due to methodological differences (patient inclusion criteria, stimulus paradigm, imaging technique, and absence of control groups). In the present study, randomized presentation of contamination-related and neutral visual stimuli was used to investigate the neurophysiological correlates of contamination fear in a group of medication-free OCD patients with washing behaviors and healthy controls. A total of 21 subjects (11 OCD patients and 10 healthy controls) were scanned using H(2)(15)O positron emission tomography (PET). Subjects were presented with pictures of clean and dirty surroundings and were requested to make indoor/outdoor decisions to control for attention differences. State anxiety and obsessionality were rated after each scan using visual analogue scales. Main effects of stimulus type (contamination vs. neutral) were found in bilateral occipital cortex in both groups. A significant group interaction effect was observed in the left amygdala reflecting enhanced activity in response to contamination stimuli in OCD patients. Sensitization effects were observed in the right amygdala in the OCD group; these paralleled an increase in levels of distress and obsessionality as well as a decrease in dorsolateral prefrontal activity. The findings of the present study are consistent with the hypothesis of decreased frontal-striatal control of limbic structures, specifically the amygdala, resulting in an inadequate fear response in OCD patients with contamination fear. PMID: 15664794 [PubMed - indexed for MEDLINE]

  • Related Articles Neurophysiological correlates of habituation during exposure in spider phobia. Psychiatry Res. 2004 Dec 15;132(2):149-58 Authors: Veltman DJ, Tuinebreijer WE, Winkelman D, Lammertsma AA, Witter MP, Dolan RJ, Emmelkamp PM Abstract Imaging studies using symptom-provocation paradigms in specific phobia have yielded contradictory results, possibly reflecting a failure to account for habituation processes. Given that a single session of exposure in vivo can result in significant improvement in specific phobia, we used prolonged exposure to phobic stimuli to identify CNS regions showing habituation. Eighteen subjects (12 with spider phobia, 6 healthy controls) underwent H(2)(15)O-positron emission tomography while being continuously presented with pictures of spiders or butterflies. Results showed main effects (spiders>butterflies) in the phobia group in the left fusiform gyrus (FG) and the right parahippocampal gyrus (PHG), with bilateral perirhinal cortex and right limbic areas approaching significance. Group x condition effects were found in the right amygdala and PHG. During spider scans, large habituation effects were observed in the anterior medial temporal lobe (MTL) bilaterally. Regression analyses demonstrated that state anxiety was correlated with activity in left amygdala, bilateral perirhinal cortex, right FG, and periaquaductal grey; by contrast, phobic fear was only associated with right-sided hippocampal activity. We conclude that prolonged exposure to phobic stimuli is associated with a significant decrease in bilateral anterior MTL regional cerebral blood flow. Right anterior MTL, identified when comparing phobic vs. neutral stimuli and habituation to phobic vs. neutral stimuli in the phobia group, implicates this region in phobic fear. Analyses of covariance suggest a further functional segregation with state anxiety being linked to enhanced activity in amygdala, perirhinal cortex, and tegmentum, and phobic fear with enhanced right hippocampal activity, suggesting a neuroanatomical differentiation between emotional-vegetative and cognitive aspects of (phobic) fear. PMID: 15598549 [PubMed - indexed for MEDLINE]

  • Related Articles Spatial representation in the entorhinal cortex. Science. 2004 Aug 27;305(5688):1258-64 Authors: Fyhn M, Molden S, Witter MP, Moser EI, Moser MB Abstract As the interface between hippocampus and neocortex, the entorhinal cortex is likely to play a pivotal role in memory. To determine how information is represented in this area, we measured spatial modulation of neural activity in layers of medial entorhinal cortex projecting to the hippocampus. Close to the postrhinal-entorhinal border, entorhinal neurons had stable and discrete multipeaked place fields, predicting the rat's location as accurately as place cells in the hippocampus. Precise positional modulation was not observed more ventromedially in the entorhinal cortex or upstream in the postrhinal cortex, suggesting that sensory input is transformed into durable allocentric spatial representations internally in the dorsocaudal medial entorhinal cortex. PMID: 15333832 [PubMed - indexed for MEDLINE]

  • Related Articles Input from the presubiculum to dendrites of layer-V neurons of the medial entorhinal cortex of the rat. Brain Res. 2004 Jul 2;1013(1):1-12 Authors: Wouterlood FG, Van Haeften T, Eijkhoudt M, Baks-Te-Bulte L, Goede PH, Witter MP Abstract The entorhinal cortex (EC) and the hippocampus are reciprocally connected. Neurons in the superficial layers of EC project to the hippocampus, whereas deep entorhinal layers receive return connections. In the deep layers of EC, pyramidal neurons in layer V possess apical dendrites that ascend towards the cortical surface through layers IIII and II. These dendrites ramify in layer I. By way of their apical dendrites, such layer-V pyramidal cells may be exposed to input destined for the superficial entorhinal neurons. A specific and dense fiber projection that typically ends in superficial entorhinal layers of the medial EC originates in the presubiculum. To investigate whether apical dendrites of deep entorhinal pyramidal neurons indeed receive input from this projection, we injected the anterograde tracer PHA-L in the presubiculum or we lesioned the presubiculum, and we applied in the same experiments the tracer Neurobiotin trade mark pericellularly in layer V of the medial EC of 17 rats. PHA-L labeled presubiculum axons in the superficial layers apposing apical segments of Neurobiotin labeled layer-V cell dendrites were studied with a confocal fluorescence laserscanning microscope. Axons and dendrites were 3D reconstructed from series of confocal images. In cases in which the presubiculum had been lesioned, material was investigated in the electron microscope. At the confocal fluorescence microscope level we found numerous close contacts, i.e. appositions of boutons on labeled presubiculum fibers with identified dendrites of layer-V neurons. In the electron microscope we observed synapses between degenerating axon terminals and spines on dendrites belonging to layer-V neurons. Hence we conclude that layer-V neurons receive synaptic contacts from presubiculum neurons. These findings indicate that entorhinal layer-V neurons have access to information destined for the superficial layers and eventually the hippocampal formation. At the same time, they have access to the hippocampally processed version of that information. PMID: 15196963 [PubMed - indexed for MEDLINE]

  • Related Articles Cytoarchitectonic characterization of the parahippocampal region of the guinea pig. J Comp Neurol. 2004 Jun 21;474(2):289-303 Authors: Uva L, Grüschke S, Biella G, De Curtis M, Witter MP Abstract The cytoarchitectonic features of the parahippocampal region (PHR) in the guinea pig are described, based on coronal, horizontal, and sagittal 50-microm sections stained for Nissl substance, zinc, parvalbumin, or calbindin. We differentiate between perirhinal (PRC), postrhinal (POR), and entorhinal (ERC) cortices. PRC is divided into areas 35 and 36 occupying the fundus and the dorsal bank of the rhinal fissure, respectively. POR is located caudal to the PRC. POR and area 36 show a dense, clustered cellular layer II and a thinner layer III in comparison to the adjacent neocortex, and they differ from each other with respect to the orientation of the somata of layer VI neurons. Area 35 is characterized by a thin layer II that is not very different from layer III. Layer IV is (dys)granular in area 36 and POR, and is absent in area 35 and ERC. ERC, located ventromedial to the PRC and POR, is subdivided in six fields, of which field 5 is adjacent to area 35. In both area 35 and field 5, no clear differentiation between layers II and III is present. Field 5 shows a darker cellular stain and exhibits a cell-free zone or lamina dissecans between layers III and V. Medial to field 5, an area characterized by large cell clusters in layer II is designated field 4. The latter field is replaced by field 3 rostromedially, which also typically shows clustering of layer II neurons. These cell clusters in field 3, however, are much more constant in size in spacing compared to those in field 4. The caudomedial portion of ERC is subdivided into fields 1, 1', and 2. The latter, characterized by a homogeneous distribution of neurons in all layers with large darkly stained neurons in layer V is positioned rostral to field 1 and caudomedial to fields 4 and 5. In field 1, layers V and VI are thinner, and layer II neurons are smaller then in field 1' and field 2. We conclude that the architectonic features of the guinea pig PHR are comparable to those described in other mammals, particularly the rat. PMID: 15164428 [PubMed - indexed for MEDLINE]

  • Related Articles Common pathway in the medial temporal lobe for storage and recovery of words as revealed by event-related functional MRI. Hippocampus. 2004;14(2):163-9 Authors: Daselaar SM, Veltman DJ, Witter MP Abstract Lesion studies have provided compelling evidence that episodic memory is dependent on the integrity of the medial temporal lobe (MTL). This role of the MTL in episodic memory has been supported by several neuroimaging studies during both episodic encoding and retrieval. After two meta-analyses of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, we investigated a possible dissociation within the MTL memory system in relation to encoding and retrieval processes. Based on previous reports that specifically related the function of the MTL in episodic memory to successful encoding and actual recovery of information, we applied event-related fMRI to compare successful encoding of words (ES) directly with successful recognition of those same words (RS). Our results did not indicate a clear dissociation between encoding and retrieval activations in the MTL. Instead, a region in the left MTL, covering the parahippocampal cortex and hippocampal formation, which was activated during ES almost completely overlapped with the area that was activated during RS. An additional region in the left anterior MTL, including the entorhinal cortex, was found to be activated exclusively during ES. Research has indicated that a large percentage of cells in this region are particularly sensitive to the relative novelty of stimuli. Our results, therefore, suggest that the parahippocampal/hippocampal region is involved in the formation and subsequent reactivation of memory traces, whereas the activity observed in the entorhinal cortex may reflect elementary memory processes related to novelty detection. PMID: 15098722 [PubMed - indexed for MEDLINE]

  • Related Articles Morphological and numerical analysis of synaptic interactions between neurons in deep and superficial layers of the entorhinal cortex of the rat. Hippocampus. 2003;13(8):943-52 Authors: van Haeften T, Baks-te-Bulte L, Goede PH, Wouterlood FG, Witter MP Abstract Neurons providing connections between the deep and superficial layers of the entorhinal cortex (EC) constitute a pivotal link in the network underlying reverberation and gating of neuronal activity in the entorhinal-hippocampal system. To learn more of these deep-to-superficial neurons and their targets, we applied the tracer Neurobiotin pericellularly in layer V of the medial EC of 12 rats. Labeled axons in the superficial layers were studied with light and electron microscopy, and their synaptic organization recorded. Neurobiotin-labeled layer V neurons displayed "Golgi-like" staining. Two major cell types were distinguished among these neurons: (1) pyramidal neurons with apical spiny dendrites traversing all layers and ramifying in layer I, and (2) horizontal neurons with dendrites confined to the deep layers. Labeled axons ramified profusely in layer III, superficially in layer II and deep in layer I. Analysis of labeled axon terminals in layers I-II and III showed that most synapses (95%) were asymmetrical. Of these synapses, 56% occurred with spines (presumably belonging to principal neurons) and 44% with dendritic shafts (presumably interneurons). A small fraction of the synapses (5%) was of the symmetrical type. Such synapses were mainly seen on dendritic shafts. We found in two sections a symmetrical synapse on a spine. These findings suggest that the deep to superficial projection is mainly excitatory in nature, and that these fibers subserve both excitation and feed-forward inhibition. There is an additional, much weaker, inhibitory component in this projection, which may have a disinhibitory effect on the entorhinal network in the superficial layers. PMID: 14750656 [PubMed - indexed for MEDLINE]

  • Related Articles Electrophysiological characterization of interlaminar entorhinal connections: an essential link for re-entrance in the hippocampal-entorhinal system. Eur J Neurosci. 2003 Dec;18(11):3037-52 Authors: Kloosterman F, Van Haeften T, Witter MP, Lopes Da Silva FH Abstract The hippocampal formation communicates with the neocortex mainly through the adjacent entorhinal cortex. Neurons projecting to the hippocampal formation are found in the superficial layers of the entorhinal cortex and are largely segregated from the neurons receiving hippocampal output, which are located in deep entorhinal layers. We studied the communication between deep and superficial entorhinal layers in the anaesthetized rat using field potential recordings, current source density analysis and single unit measurements. We found that subiculum stimulation was able to excite entorhinal neurons in deep layers. This response was followed by current sinks in superficial layers. Both responses were subject to frequency dependent facilitation, but not depression. Selective blockade of deep layer responses also abolished subsequent superficial layer responses. This clearly demonstrates a functional deep-to-superficial layer communication in the entorhinal cortex, which can be triggered by hippocampal output. This pathway may provide a means by which processed hippocampal output is integrated or compared with new incoming information in superficial entorhinal layers, and it constitutes an important link in the process of re-entrance of activity in the hippocampal-entorhinal network, which may be important for consolidation of memories or retaining information for short periods. PMID: 14656299 [PubMed - indexed for MEDLINE]

  • Related Articles Contributions of thalamic nuclei to declarative memory functioning. Cortex. 2003 Sep-Dec;39(4-5):1047-62 Authors: Van der Werf YD, Jolles J, Witter MP, Uylings HB Abstract In spite of the acknowledged role that the thalamus plays in declarative memory, details about the precise memory processes it is involved in and which are the structures of the thalamus that contribute to these processes remain unknown. An overview is presented of human clinical and animal experimental findings showing the involvement of the thalamus, at the level of white matter tracts and separate nuclei, in aspects of memory functioning. The region in the thalamus that contributes to declarative memory is the anterior and medial division, containing the anterior nuclei, the medial dorsal nucleus and the intralaminar and midline nuclei. A lesion to the anterior nuclei or their afferent white matter tract, the mammillothalamic tract, results in deficits of encoding of new stimuli. Lesions to the medial dorsal nucleus affect executive processes pertaining to declarative memory, such as the use of memory strategies for retrieval; damage to the intralaminar and midline nuclei results in decreased arousal and thus affects the declarative memory process. Based on anatomical and functional data, a theory is proposed of how the thalamus might play a role at different levels of declarative memory functioning. Firstly, the anterior and mediodorsal nucleus are involved in processing the contents of the stimuli for storage and recall. The anterior nuclei influence the selection of material to be stored and remembered, whereas the mediodorsal nucleus is involved in the coordination and selection of the strategies used to retrieve material. Secondly, the intralaminar and midline nuclei and specifically the lateral and ventral components, maintain a necessary state of the cortical regions involved in the ongoing memory processes. The two types of function subserved by these groups of thalamic nuclei, focussing on contents vs. state, need to work in parallel to mediate and allow memory functioning, respectively. PMID: 14584566 [PubMed - indexed for MEDLINE]

  • Related Articles A cytoarchitectonic study of the hippocampal formation of the tree shrew (Tupaia belangeri). J Chem Neuroanat. 2003 Aug;26(1):1-15 Authors: Keuker JI, Rochford CD, Witter MP, Fuchs E Abstract Tree shrews constitute an interesting animal model to study the impact of stress or aging on the hippocampal formation, a brain structure known to be affected under such environmental or internal influences. To perform detailed investigations of the hippocampal formation, adequate knowledge of its anatomy should be present. Until now, the hippocampal formation of the tree shrew has not yet been studied extensively. The main objective of this study, therefore, was to describe the subfield boundaries in various levels of the dorsoventral hippocampal axis of the tree shrew (Tupaia belangeri) in detail. The secondary aim was to clarify whether a separate CA2 field can actually be distinguished in the tree shrew hippocampus, a fact that was denied in former reports. In addition, we aimed at investigating whether or not a CA4 subfield can be identified in the tree shrew's hippocampus. The immunocytochemical distribution of microtubule-associated protein 2 and the calcium-binding proteins, parvalbumin and calbindin, and the characteristics of Nissl staining in adjacent sections were compared. Because of the rather dorsoventral orientation of the long hippocampal axis in tree shrews, staining patterns were analyzed mainly in horizontal sections. The subiculum and the hippocampal CA1 and CA3 areas were easily identified. Moreover, we were able to demonstrate the existence of a distinct CA2 subfield in the tree shrew's Ammon's horn, contrary to previous reports. However, our results indicate that a CA4 field in the tree shrew hippocampal formation cannot be identified with the methods that we used. Therefore, supposed CA4 pyramidal neurons should be included into the CA3 field. PMID: 12954527 [PubMed - indexed for MEDLINE]

  • Related Articles Synaptic contacts between identified neurons visualized in the confocal laser scanning microscope. Neuroanatomical tracing combined with immunofluorescence detection of post-synaptic density proteins and target neuron-markers. J Neurosci Methods. 2003 Sep 30;128(1-2):129-42 Authors: Wouterlood FG, Böckers T, Witter MP Abstract The axons of neurons in the CNS with their delicate ramification patterns and terminal boutons can be visualized with conventional neuroanatomical techniques with a high degree of accuracy. Whether identified terminal boutons form synaptic contacts with target neurons identified by a second and different marker needs resolution beyond that offered by conventional light microscopy. The morphological elements associated with synaptic connectivity consist of specialized pre- and post-synaptic junctional complexes known as the pre- and post-synaptic densities. Electron microscopy of these junctional complexes consumes much time and resources. In an attempt to increase the speed with which we can analyze networks of neurons we developed a high-resolution triple-fluorescence approach including neuroanatomical tracing, immunofluorescence, confocal laserscanning and 3D-computer reconstruction to pinpoint at the light microscopic level the three elements involved in synaptic connectivity: afferent fibers and their terminal boutons, close apposition with neurons identified by the presence of a fluorescent marker, and sandwiched in between a post-synaptic density marker. We used morphological criteria for the detection of axon terminals (swellings on fibers). Antibodies against ProSAP2/Shank3, a post-synaptic density-associated scaffolding protein, were used to pinpoint the location of the synaptic junctions. The results show the existence of sandwich-like configurations: pre-synaptic fiber, ProSAP2/Shank3, post-synaptic neuron. Thus we feel that we can minimize (and perhaps completely eliminate) the need for electron microscopy and hence dramatically increase the overall efficiency of neuroanatomical tracing and network analysis. PMID: 12948556 [PubMed - indexed for MEDLINE]

  • Related Articles GAP-43 mRNA and protein expression in the hippocampal and parahippocampal region during the course of epileptogenesis in rats. Eur J Neurosci. 2003 Jun;17(11):2369-80 Authors: Tolner EA, van Vliet EA, Holtmaat AJ, Aronica E, Witter MP, da Silva FH, Gorter JA Abstract In order to reveal axonal rewiring in the hippocampal and parahippocampal regions after status epilepticus, we investigated the temporal evolution of growth-associated protein-43 (GAP-43) mRNA and protein expression in two rat models of mesial temporal lobe epilepsy (MTLE). Status epilepticus (SE) was induced by electrical stimulation of the angular bundle or by intraperitoneal kainic acid (KA) injections. Despite increased GAP-43 mRNA expression in dentate granule cells at 24 h after SE, GAP-43 protein expression in the inner molecular layer (IML) of the dentate gyrus decreased progressively after 24 h after SE in both models. Nevertheless robust mossy fiber sprouting (MFS) was evident in the IML of chronic epileptic rats. Remaining GAP-43 protein expression in the IML in chronic epileptic rats did not correlate with the extent of MFS, but with the number of surviving hilar neurons. In the parahippocampal region, GAP-43 mRNA expression was decreased in layer III of the medial entorhinal area (MEAIII) in parallel with extensive neuronal loss in this layer. There was a tendency of GAP-43 mRNA up-regulation in the presubiculum, a region that projects to MEAIII. With regard to this parahippocampal region, however, changes in GAP-43 mRNA expression were not followed by protein changes. The presence of the presynaptic protein GAP-43 in a neurodegenerated MEAIII indicates that fibers still project to this layer. Whether reorganization of fibers has occurred in this region after SE needs to be investigated with tools other than GAP-43. PMID: 12814368 [PubMed - indexed for MEDLINE]

  • Related Articles Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia. 2003;41(10):1330-44 Authors: Van der Werf YD, Scheltens P, Lindeboom J, Witter MP, Uylings HB, Jolles J Abstract The thalamus plays a crucial role in memory, executive functioning and attention. It remains, however, unclear whether thalamic structures have specific roles in each of these functions. We tested 22 cases of thalamic infarction, proven with MR imaging, using experimental and established neuropsychological tests. We performed a lesion-overlap study in standardised stereotactic space of patients sharing a certain deficit, corrected for the lesion distribution of patients without such deficits and determined the regions of interest using an atlas of the human thalamus. We checked for additional, non-thalamic, damage and for deficient comprehension and perception that would preclude interpretation of the results. Non-thalamic damage such as white matter lesions, hippocampal atrophy, sulcal widening and infarctions occur significantly more often in patients aged over 60. The patients with additional damage overlapped to a major degree with those who showed loss of orientation, or lack of comprehension of the test requirements. In the 10 patients judged 'clean', we observed a deficit of episodic long-term memory with relative sparing of intellectual capacities and short-term memory when the mammillo-thalamic tract was damaged. Lesions including the medial dorsal nucleus, midline nuclei and/or intralaminar nuclei accompany executive dysfunctioning. Reduced simple processing speed and attention are associated with age, but not with a particular structure in the thalamus. Complex attention deficits follow damage to the intralaminar nuclei.We conclude that the analysis of structure-function relationships must take into account extra-structure damage which may explain cognitive deficits. Separate thalamic structures are involved in memory, executive functioning and attention. PMID: 12757906 [PubMed - indexed for MEDLINE]

  • Related Articles Amygdala input promotes spread of excitatory neural activity from perirhinal cortex to the entorhinal-hippocampal circuit. J Neurophysiol. 2003 Apr;89(4):2176-84 Authors: Kajiwara R, Takashima I, Mimura Y, Witter MP, Iijima T Abstract A number of sensory modalities most likely converge in the rat perirhinal cortex. The perirhinal cortex also interconnects with the amygdala, which plays an important role in various motivational and emotional behaviors. The neural pathway from the perirhinal cortex to the entorhinal cortex is considered one of the main paths into the entorhinal-hippocampal network, which has a crucial role in memory processes. To investigate the potential associative function of the perirhinal cortex with respect to sensory and motivational stimuli and the influence of the association on the perirhinal-entorhinal-hippocampal neurocircuit, we prepared rat brain slices including the perirhinal cortex, entorhinal cortex, hippocampal formation, and amygdala. We used an optical imaging technique with a voltage-sensitive dye to analyze 1) the spatial and functional distribution of inputs from the lateral nucleus of the amygdala to the perirhinal cortex; 2) the spread of neural activity in the perirhinal cortex after layers II/III stimulation, which mimics sensory input to the perirhinal cortex; and 3) the effect of associative inputs to the perirhinal cortex from both the lateral amygdaloid nucleus and layers II/III of the perirhinal cortex on the perirhinal-entorhinal-hippocampal neurocircuit. Following stimulation in the superficial layers of the perirhinal cortex, electrical activity only propagated into the entorhinal cortex when sufficient activation occurred in the deep layers of perirhinal area 35. We observed that single stimulation of either the perirhinal cortex or amygdala did not result in sufficient neural activation of the deep layers of areas 35 to provoke activity propagation into the entorhinal cortex. However, the deep layers of area 35 were depolarized much more strongly when the two stimuli were applied simultaneously, resulting in spreading activation in the entorhinal cortex. Our observations suggest that a functional neural basis for the association of higher-order sensory inputs and emotion-related inputs exists in the perirhinal cortex and that transfer of sensory information to the entorhinal-hippocampal circuitry might be affected by the association of that information with incoming information from the amygdala. PMID: 12611981 [PubMed - indexed for MEDLINE]

  • Related Articles Topographical and laminar organization of subicular projections to the parahippocampal region of the rat. J Comp Neurol. 2003 Jan 6;455(2):156-71 Authors: Kloosterman F, Witter MP, Van Haeften T Abstract In this study, we analyzed in detail the topographic organization of the subiculoparahippocampal projection in the rat. The anterograde tracers Phaseolus vulgaris leucoagglutinin-L and biotinylated dextran amine were injected into the subiculum at different septotemporal and transverse levels. Deep layers of the ento-, peri-, and postrhinal cortices are the main recipients of subicular projections, but in all cases we noted that a small fraction of the projections also terminates in the superficial layers II and III. Analysis of the fiber patterns in the parahippocampal region revealed a topographic organization, depending on the location of the cells of origin along both the transverse and the septotemporal axes of the subiculum. Projections originating from subicular cells close to CA1, i.e., proximal part of subiculum, terminate exclusively in the lateral entorhinal cortex and in the perirhinal cortex. In contrast, projections from cells closer to the subiculum-presubiculum border, i.e., distal part of subiculum, terminate in the medial entorhinal cortex and in the postrhinal cortex. In addition, cells in septal portions of the subiculum project to a lateral band of entorhinal cortex parallel to the rhinal sulcus and to peri- or postrhinal cortices, whereas cells in more temporal portions project to more medial parts of the entorhinal cortex. These results indicate that subicular projections to the parahippocampal region precisely reciprocate the known inputs from this region to the hippocampal formation. We thus suggest that the reciprocal connectivity between the subiculum and the parahippocampal region is organized as parallel pathways that serve to segregate information flow and thus maintain the identity of processed information. Although this parallel organization is comparable to that of the CA1-parahippocampal projections, differences exist with respect to the degree of collateralization. PMID: 12454982 [PubMed - indexed for MEDLINE]

  • Related Articles The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness. Brain Res Brain Res Rev. 2002 Sep;39(2-3):107-40 Authors: Van der Werf YD, Witter MP, Groenewegen HJ Abstract The thalamic midline and intralaminar nuclei, long thought to be a non-specific arousing system in the brain, have been shown to be involved in separate and specific brain functions, such as specific cognitive, sensory and motor functions. Fundamental to the participation of the midline and intralaminar nuclei in such diverse functions seems to be a role in awareness. It is unknown whether the midline and intralaminar nuclei, together often referred to as the 'non-specific' nuclei of the thalamus, act together or whether each nucleus is involved idiosyncratically in separate circuits underlying cortical processes. Detailed knowledge of the connectivity of each of these nuclei is needed to judge the nature of their contribution to cortical functioning. The present account provides an overview of the results of neuroanatomical tracing studies on the connections of the individual intralaminar and midline thalamic nuclei in the rat, that have been performed over the past decade in our laboratory. The results are discussed together with those reported by other laboratories, and with those obtained in other species. On the basis of the patterns of the afferent and efferent projections, we conclude that the midline and intralaminar thalamic nuclei can be clustered into four groups. Each of the groups can be shown to have its own set of target and input structures, both cortically and subcortically. These anatomical relationships, in combination with functional studies in animals and in humans, lead us to propose that the midline and intralaminar nuclei as a whole play a role in awareness, with each of the groups subserving a role in a different aspect of awareness. The following groups can be discerned: (1) a dorsal group, consisting of the paraventricular, parataenial and intermediodorsal nuclei, involved in viscero-limbic functions; (2) a lateral group, comprising the central lateral and paracentral nuclei and the anterior part of the central medial nucleus, involved in cognitive functions; (3) a ventral group, made up of the reuniens and rhomboid nucleus and the posterior part of the central medial nucleus, involved in multimodal sensory processing; (4) a posterior group, consisting of the centre médian and parafascicular nuclei, involved in limbic motor functions. PMID: 12423763 [PubMed - indexed for MEDLINE]

  • Related Articles Memory impairment in temporal lobe epilepsy: the role of entorhinal lesions. Epilepsy Res. 2002 Jun;50(1-2):161-77 Authors: Schwarcz R, Witter MP Abstract Temporal lobe epilepsy (TLE) patients are frequently afflicted with deficits in spatial and other forms of declarative memory. This impairment is likely associated with the medial temporal lobe, which suffers widespread damage in the disease. Physiological and lesion studies, as well as examinations of the complex connectivity of the medial temporal lobe in animals and humans, have identified the entorhinal cortex (EC) as a key structure in the function and dysfunction of this brain region. Lesions in EC layer III, which normally provides monosynaptic input to area CA1 of the hippocampus, frequently occur in TLE and may be causally related to the memory impairments seen in the disease. Lesions that are initially largely restricted to EC layer III can be produced in rats by focal intra-entorhinal injections of 'indirect excitotoxins' such as aminooxyacetic acid or gamma-acetylenic GABA. These animals eventually show more extensive neurodegeneration in temporal lobe structures and, after a latent period, exhibit spontaneously recurring seizure activity. These progressive features, which may mimic events that occur in TLE, provide new opportunities to explore the role of the EC in memory deficits associated with TLE. These animals will also be useful for evaluating new treatment strategies that focus on the prevention of pathological events in the EC. PMID: 12151126 [PubMed - indexed for MEDLINE]

  • Related Articles Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry. Science. 2002 Jun 21;296(5576):2243-6 Authors: Brun VH, Otnass MK, Molden S, Steffenach HA, Witter MP, Moser MB, Moser EI Abstract Place cells in hippocampal area CA1 may receive positional information from the intrahippocampal associative network in area CA3 or directly from the entorhinal cortex. To determine whether direct entorhinal connections support spatial firing and spatial memory, we removed all input from areas CA3 to CA1, thus isolating the CA1 area. Pyramidal cells in the isolated CA1 area developed sharp and stable place fields. Rats with an isolated CA1 area showed normal acquisition of an associative hippocampal-dependent spatial recognition task. Spatial recall was impaired. These results suggest that the hippocampus contains two functionally separable memory circuits: The direct entorhinal-CA1 system is sufficient for recollection-based recognition memory, but recall depends on intact CA3-CA1 connectivity. PMID: 12077421 [PubMed - indexed for MEDLINE]

  • Related Articles Projections from the parahippocampal region to the prefrontal cortex in the rat: evidence of multiple pathways. Eur J Neurosci. 2002 Apr;15(8):1400-7 Authors: Delatour B, Witter MP Abstract The purpose of the present study was to investigate, by means of anterograde tracing methods, the detailed organization of the parahippocampal-prefrontal projections in the rat brain. Efferents from the perirhinal cortex were found to terminate principally in both the ventromedial (prelimbic and infralimbic cortices) and lateral (agranular insular cortex) regions of the prefrontal cortex. Terminal fields were observed mainly in the superficial layers of the prefrontal cortex. Projections arising from the dorsolateral entorhinal cortex, which borders the perirhinal cortex along its ventral extent, were similarly directed to the ventromedial and lateral prefrontal cortices but also encompassed other frontal areas (dorsomedial and orbital prefrontal regions). Terminal fields of entorhinal projections were also found in the superficial layers of the prefrontal cortex. A third pathway, taking its source in the post-rhinal cortex, presented striking topographical differences with the two other output systems. Hence, post-rhinal efferences terminated only in the ventrolateral orbital area. The results indicate that two main routes originate from the parahippocampal region to reach the prefrontal cortex. One pathway involves the rostral and lateral portions of the parahippocampal region (perirhinal and dorsolateral entorhinal cortices), and the other relies on its most caudal region, the post-rhinal cortex. The presence of such different multiple parahippocampal-prefrontal pathways may have functional relevance for learning and memory processes. PMID: 11994135 [PubMed - indexed for MEDLINE]

  • Related Articles Anterior medial temporal lobe activation during attempted retrieval of encoded visuospatial scenes: an event-related fMRI study. Neuroimage. 2001 Jul;14(1 Pt 1):67-76 Authors: Rombouts SA, Barkhof F, Witter MP, Machielsen WC, Scheltens P Abstract Various studies have shown that the medial temporal lobe (MTL), which consists of the hippocampus and parahippocampal gyrus, is important for episodic memory. Earlier fMRI studies substantiated this role by showing activation upon encoding of visuospatial scenes. In this study we used event-related fMRI to study whether the cognitive process of retrieval of visuospatial scenes, tested with the use of a recognition paradigm, also activates the MTL. Nine subjects (mean age 24 years) were presented previously studied color pictures (old) and pictures they had never seen before (new) in a mixed trial design. Data analysis allowed calculation of the fMRI response of correct judgments on new pictures, old pictures, and false judgments. Since we used previously encoded color pictures as old stimuli, we also included an encoding paradigm in the current set of experiments. This allowed us to compare encoding and recognition activation in the MTL of exactly the same pictures in the same subjects. Correct judgments on new pictures showed an increased activation in the anterior parahippocampus bilaterally and the right anterior hippocampus compared to judgments on old pictures in the recognition experiment. The former judgments took significantly longer, indicating that retrieval of successfully stored information is less demanding than the effort to retrieve nonencoded information. A comparison of the two experimental data sets showed evidence for a functional segregation of encoding and retrieving color pictures. We conclude that the left posterior parahippocampal gyrus responds during encoding, while on the other hand the left anterior parahippocampal gyrus and the right anterior hippocampus were more strongly involved in retrieval. PMID: 11525338 [PubMed - indexed for MEDLINE]

  • Related Articles Intrinsic connectivity of the rat subiculum: I. Dendritic morphology and patterns of axonal arborization by pyramidal neurons. J Comp Neurol. 2001 Jul 9;435(4):490-505 Authors: Harris E, Witter MP, Weinstein G, Stewart M Abstract The dendritic and axonal morphology of rat subicular neurons was studied in single cells labeled with Neurobiotin. Electrophysiological classification of cells as intrinsic burst firing or regular spiking neurons was correlated with morphologic patterns and cell locations. Every cell had dendritic branches that reached the outer molecular layer, with most cells having branches that reached the hippocampal fissure. All but two pyramidal cells had axon collaterals that entered the deep white matter (alveus). Branching patterns of apical dendrites varied as a function of the cell's soma location along the fissure-alveus axis of the cell layer. The first major dendritic branch point for most cells occurred at the superficial edge of the cell layer giving deep cells long primary apical dendrites and superficial cells short or absent primary apical dendrites. In contrast, basal dendritic arbors were similar across cells regardless of cell position. Apical and basal dendrites of all cells had numerous spines. Superficial and deep cells also differed in axonal collateralization. Deep cells (mostly intrinsically bursting [IB] class) had one or more ascending axon collaterals that typically remained within the region circumscribed by their apical dendrites. Superficial cells (mostly regular spiking [RS] class) tended to have axon collaterals that reached longer distances in the cell layer. Numerous varicosities and axonal extensions were present on axon collaterals in the cell layer and in the apical dendritic region, suggesting intrinsic connectivity. Axonal varicosities and extensions were found on axons that entered presubiculum, entorhinal cortex or CA1, supporting the notion that these were projection cells. Local collaterals were distinctly thinner than collaterals that would leave the subiculum, suggesting little or no myelin on local collaterals and some myelin on efferent fibers. We conclude that both IB and RS classes of subicular principal cells make synaptic contacts in and apical to the cell layer. Based on the patterns of axonal arborization, we suggest that subiculum has at least a crude columnar and laminar architecture, with ascending collaterals of deep cells forming columns and broader axonal arbors of superficial cells serving to distribute activity across multiple columns. PMID: 11406828 [PubMed - indexed for MEDLINE]

  • Related Articles Reciprocal connections between the entorhinal cortex and hippocampal fields CA1 and the subiculum are in register with the projections from CA1 to the subiculum. Hippocampus. 2001;11(2):99-104 Authors: Naber PA, Lopes da Silva FH, Witter MP Abstract The topology of the connections between the entorhinal cortex (EC), area CA1, and the subiculum is characterized by selective and restricted origin and termination along the transverse or proximodistal axis of CA1 and the subiculum. In the present study, we analyzed whether neurons in CA1 and the subiculum that receive EC projections are interconnected and give rise to return projections to EC, such that they terminate deep in the area of origin of the EC-to-CA1/subiculum projections. Both for the lateral and medial subdivision of EC, the projections to CA1/subiculum, as well as the projections from CA1 to the subiculum and back to EC, are rather divergent. Interestingly, we only rarely observed evidence for the presence of "reentry loops," i.e., cells in layer III of EC giving rise to projections to interconnected neurons in CA1 and the subiculum, while the targeted CA1 neurons also projected back to the deep layers of the area of origin of the pathway in EC. We conclude that although fibers originating from a restricted part of EC distribute extensively in a divergent way along the longitudinal axis of CA1 and the subiculum, only restricted portions of the latter two areas, receiving inputs from the same entorhinal area, are interconnected. Moreover, only a small percentage of the CA1 neurons that project to the correspondingly innervated subicular neurons give rise to projections that return to the deep layers of the originating part of EC. The present findings are taken to indicate that the EC-hippocampal circuitry functionally comprises many parallel-organized specific "reentry loops." PMID: 11345131 [PubMed - indexed for MEDLINE]

  • Related Articles Evidence for a direct projection from the postrhinal cortex to the subiculum in the rat. Hippocampus. 2001;11(2):105-17 Authors: Naber PA, Witter MP, Lopes da Silva FH Abstract Behavioral data indicate that three of the areas which form the parahippocampal region in the rat, i.e., the entorhinal, perirhinal, and postrhinal cortices, have different, although related functions that also differ from those of the hippocampal formation. These functional differences might be related to differences in connectivity, on the one hand with parts of the association cortex, and on the other with the hippocampal formation. In a previous study, we showed the existence of both a direct and an indirect projection from the perirhinal cortex to areas CA1 and subiculum of the hippocampus. Here we present the result of a second study, demonstrating a similarly organized projection from the postrhinal cortex to the subiculum, comprising both a direct and an indirect route. Electrical stimulation of the postrhinal cortex in vivo evoked field potentials throughout the subiculum and the dentate gyrus. Current source density analysis in both the subiculum and dentate gyrus revealed the presence of sink-source pairs, indicative of a synaptic termination. Based on comparison with the sink-source pairs found after stimulation of the medial entorhinal cortex, we conclude that the connection between the postrhinal cortex and the dentate gyrus most likely is formed by a polysynaptic pathway mediated via the medial entorhinal cortex, while the pathway from the postrhinal cortex to the subiculum is likely monosynaptic. In order to substantiate these findings, we carried out several tracer experiments. Anterograde tracer injections in the postrhinal cortex resulted in labeled fibers in limited parts of the subiculum, but no anatomical evidence for a projection of the postrhinal cortex to the dentate gyrus was found. Additional retrograde tracer injections in the subiculum also showed evidence for a direct postrhinal-to-subiculum projection with a strong topological organization. Based on these combined anatomical and electrophysiological data, we conclude that the postrhinal cortex indeed can reach the subiculum via both a direct and an indirect pathway. PMID: 11345118 [PubMed - indexed for MEDLINE]

  • Related Articles Functional MR imaging in Alzheimer's disease during memory encoding. AJNR Am J Neuroradiol. 2000 Nov-Dec;21(10):1869-75 Authors: Rombouts SA, Barkhof F, Veltman DJ, Machielsen WC, Witter MP, Bierlaagh MA, Lazeron RH, Valk J, Scheltens P Abstract BACKGROUND AND PURPOSE: We applied functional MR imaging with a learning task in healthy elderly volunteers and in patients with Alzheimer's disease to study brain activation during memory performance. The purpose was to determine the feasibility of functional MR imaging during a learning task in healthy elderly volunteers and in patients with Alzheimer's disease and to test our hypothesis that brain activation is decreased in the medial temporal lobe (MTL) memory system in patients with Alzheimer's disease compared with control volunteers. METHODS: In 12 patients with mild to moderate forms of Alzheimer's disease and 10 elderly control volunteers, activation of the MTL memory system was studied. We used two learning tasks that required the encoding of new information into memory. After the functional MR imaging experiment, participants were tested for recognition of the encoded objects. RESULTS: In the elderly control volunteers, activation during memory encoding was observed in medial and lateral temporal lobe structures (fusiform, parietal and occipital parts, and hippocampal formation) and in the frontal cortex, as reported previously in studies of young control volunteers. Focusing on the MTL, we observed that activation was significantly decreased in patients with Alzheimer's disease compared with control volunteers in the left hippocampus and parahippocampal gyrus bilaterally during the first encoding task but not during the second (P < .05, uncorrected). CONCLUSION: Functional MR imaging with a learning task seems feasible in elderly volunteers and in patients with Alzheimer's disease. The measured functional signal decrease in MTL areas warrants further exploration of the (early) diagnostic usefulness of functional MR imaging in cases of Alzheimer's disease and other dementias. PMID: 11110539 [PubMed - indexed for MEDLINE]

  • Related Articles Visualizing brain activation during planning: the tower of London test adapted for functional MR imaging. AJNR Am J Neuroradiol. 2000 Sep;21(8):1407-14 Authors: Lazeron RH, Rombouts SA, Machielsen WC, Scheltens P, Witter MP, Uylings HB, Barkhof F Abstract BACKGROUND AND PURPOSE: Recent positron emission tomography and single-photon emission CT studies using the Tower of London test have shown that brain activation during planning activities primarily resides in the prefrontal cortex. In this study, we adapted the Tower of London test for functional MR imaging. METHODS: For use with functional MR imaging, a block design of the test was created, in which planning stages were contrasted with counting of colored balls. For nine healthy participants, multisection echo-planar functional MR imaging was performed to assess brain activation based on changes in blood oxygen level. Activation maps for individual participants and a group average map were created. RESULTS: In the group average map, activation in the dorsolateral prefrontal cortex, the anterior part of the cingulate cortex, the cuneus and precuneus, the supramarginal and angular gyrus in the parietal lobe, and the frontal opercular area of the insula was seen. These findings are in agreement with grouped data of previous positron emission tomography results. Functional MR imaging enabled us to investigate brain activation during planning activities with high spatial (and temporal) resolution in individual patients, showing that the dorsolateral prefrontal cortex was activated in all participants studied. CONCLUSION: Presented is a working functional MR imaging version of the planning task. The high sensitivity of functional MR imaging may allow the use of this test for patients with possible (pre)frontal disorders. PMID: 11003272 [PubMed - indexed for MEDLINE]

  • Related Articles Differential distribution of barrel or visual cortex. Evoked responses along the rostro-caudal axis of the peri- and postrhinal cortices. Brain Res. 2000 Sep 22;877(2):298-305 Authors: Naber PA, Witter MP, Lopes da Silva FH Abstract The functional connections between the barrel cortex and visual cortex on the one hand and the perirhinal (PER) and postrhinal (POR) cortices on the other hand were investigated in the rat. Stimulation of the barrel cortex evoked field potentials throughout the longitudinal extent of both PER and POR. In contrast, visual cortex stimulation evoked responses only in the caudal portion of PER as well as in POR. Therefore, the information from the visual cortex on the way to the hippocampus is transferred preferentially by a relay in POR, whereas somatosensory information is transferred via both PER and POR. Moreover, stimulation of both cortical regions elicited firing of multiple units; however, unit activity was more commonly found in POR than in PER. We conclude that the transfer of somatosensory and visual information to the hippocampal formation is preferentially mediated by parallel channels through PER and POR respectively. Although the information transfer through these channels does overlap to some extent, each channel appears to have specific properties. PMID: 10986344 [PubMed - indexed for MEDLINE]

  • Related Articles Cortico-hippocampal communication by way of parallel parahippocampal-subicular pathways. Hippocampus. 2000;10(4):398-410 Authors: Witter MP, Naber PA, van Haeften T, Machielsen WC, Rombouts SA, Barkhof F, Scheltens P, Lopes da Silva FH Abstract The hippocampal memory system, consisting of the hippocampal formation and the adjacent parahippocampal region, is known to play an important role in learning and memory processes. In recent years, evidence from a variety of experimental approaches indicates that each of the constituting fields of the hippocampal memory system may serve functionally different, yet complementary roles. Understanding the anatomical organization of cortico-parahippocampal-hippocampal connectivity may lead to a further understanding of these potential functional differences. In the present paper we present the two main conclusions of experiments in which we studied the anatomical organization of the hippocampal memory system of the rat in detail, with a focus on the pivotal position of the entorhinal cortex. We first conclude that the simple traditional view of the entorhinal cortex as simply the input and output structure of the hippocampal formation needs to be modified. Second, our data indicate the existence of two parallel pathways through the hippocampal memory system, arising from the perirhinal and postrhinal cortex. These two parallel pathways may be involved in separately processing functionally different types of sensory information. This second proposition will be subsequently evaluated on the basis of series of electrophysiological studies we carried out in rats and some preliminary functional brain imaging studies in humans. PMID: 10985279 [PubMed - indexed for MEDLINE]

  • Related Articles Calretinin in the entorhinal cortex of the rat: distribution, morphology, ultrastructure of neurons, and co-localization with gamma-aminobutyric acid and parvalbumin. J Comp Neurol. 2000 Sep 18;425(2):177-92 Authors: Wouterlood FG, van Denderen JC, van Haeften T, Witter MP Abstract Calretinin is a marker that differentially labels neurons in the central nervous system. We used this marker to distinguish subtypes of neurons within the general population of neurons in the entorhinal cortex of the rat. The distribution, morphology, and ultrastructure of calretinin-immunopositive neurons in this cortical area were documented. We further analyzed the co-localization of the marker with gamma-aminobutyric acid (GABA) and studied whether calretinin-positive neurons project to the hippocampal formation. Methods used included single-label immunocytochemistry at the light and electron microscopic level, retrograde tracing combined with immunocytochemistry, and double-label confocal laser scanning microscopy (CLSM). The entorhinal cortex contained calretinin-positive cells in a scattered fashion, in all layers except layer IV (lamina dissecans). Bipolar and multipolar dendritic configurations were present, displaying smooth dendrites. Bipolar cells had a uniform morphology whereas the multipolar calretinin cell population consisted of large neurons, cells with long ascending dendrites, horizontally oriented neurons, and small spherical cells. Retrograde tracing combined with immunocytochemistry showed that calretinin is not present in cells projecting to the hippocampus. Few synapic contacts between calretinin-positive axon terminals and immunopositive cell bodies and dendrites were seen. Most axon terminals of calretinin fibers formed asymmetrical synapses, and immunopositive axons were always unmyelinated. Results obtained in the CLSM indicate that calretinin co-exists in only 18-20% of the GABAergic cell population (mostly small spherical and bipolar cells). Thus, the entorhinal cortex contains two classes of calretinin interneurons: GABA positive and GABA negative. The first class is presumably a classical, GABAergic inhibitory interneuron. The finding of calretinin-immunoreactive axon terminals with asymmetrical synapses suggests that the second class of calretinin neuron is a novel type of a (presumably excitatory) interneuron. PMID: 10954838 [PubMed - indexed for MEDLINE]

  • Related Articles Presubicular input to the dendrites of layer-V entorhinal neurons in the rat. Ann N Y Acad Sci. 2000 Jun;911:471-3 Authors: van Haeften T, Wouterlood FG, Witter MP PMID: 10911896 [PubMed - indexed for MEDLINE]

  • Related Articles Networks of the hippocampal memory system of the rat. The pivotal role of the subiculum. Ann N Y Acad Sci. 2000 Jun;911:392-403 Authors: Naber PA, Witter MP, Lopes Silva FH Abstract The hippocampal system, consisting of the hippocampus, subiculum, and adjacent parahippocampal region, is known to play an important role in learning and memory processes. It is also known that the originally proposed trisynaptic circuit is a simplified representation of the organization of this system. In this paper, we present evidence, both anatomically and electrophysiologically, for the existence of direct and indirect parallel pathways through the hippocampal memory system arising from the perirhinal and postrhinal cortex. These pathways form nested loops. The subiculum occupies a central position within these loops. In the subiculum, both "raw" and highly processed information will converge. Therefore, we propose that the subiculum occupies a pivotal position in the hippocampal memory system, both as recipient and comparator of signals and as a distributor of processed information. PMID: 10911887 [PubMed - indexed for MEDLINE]

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