Entorhinal cortex

The rat entorhinal cortex (EC) makes up the ventrocaudal part of the rat cerebral hemisphere. The EC borders the parasubiculum (PaS), piriform cortex and the amygdaloid complex. Dorsolaterally it borders the rhinal fissure and rostrally it forms its fundus and dorsal bank.

Stratification

In this description of the stratification/lamination of the entorhinal cortex, the most superficial layer, close to the pial surface of the brain comes first, followed by the layers below. The EC consists of six layers, four cell layers (II, III, V and VI) and two plexiform layers (I, IV or lamina dissecans). Layers II and V are sometimes split into a superficial part 'a' and deep part 'b' (Haug, 1976 (p. 17)). The Swanson atlas (2018), plates 28 - 48, show the location of layers IIa / IIb, but does not divide layer V. There are approximately 675.000 principle neurons in the EC (Schmidt, 2012). Several accounts of the cell counts in the EC and its layers/divisions have been published (e.g. Mulders, 1997; Merrill, 2001; Rapp, 2002; Gatome, 2010). For computer modelers, a book dedicated to hippocampal microcircuits is available (see Witter, 2018). In the list below, each layer is briefly described (See: Cappaert, 2015 for more details).

  • I: Plexiform layer; sparsely populated by horizontal and multipolar neurons (Blackstad, 1956; Haug, 1976)

  • II: Cell layer; containing medium and big sized modified pyramidal and pyramidal-like cells generally organized in clusters (Lorente de Nó, 1933; Klink and Alonso, 1997, Insausti et al, 1997).

  • IIa: in lateral portions of the EC, an outer layer IIa and a deeper layer IIb can be seen, separated by a narrow cell-sparse layer Insausti et al, 1997. Depending on the parcellation scheme, layer II = Layer IIa. In that case, layer II is narrower and layer IIb is considered to be superficial layer III.

  • IIb: in lateral portions of the EC, an outer layer IIa and a deeper layer IIb can be seen, separated by a narrow cell-sparse layer Insausti et al, 1997. Depending on the parcellation scheme, superficial layer III = Layer IIb. If layer IIb is differentiated, then layer III is narrower.

  • III: Cell layer; contains predominantly pyramidal cells, but also other cells of various sizes and shapes (e.g. multipolar, fusiform, horizontal and bipolar cells).

  • IV: Plexiform layer; contains scattered cell bodies of various sizes and shapes (e.g. pyramidal, fusiform and bipolar cells) Lingenhohl and Finch, 1991). Here we use layer IV as a synonym for the 'lamina dissecans'. However, some authors describe the 'lamina dissecans' as a separate entity (See also: Haug, 1976 (p.11), Stephan, 1975 (pp. 206-211, 650-653, 661, 665, 694). In the nomenclature by Lorente de Nó, 1933, the 'lamina dissecans' is considered to be the deep part of layer III (see also layer Va).

  • V: Cell layer; contains pyramidal, horizontal and polymorphic neurons.

  • Va: a few cells wide in diameter; contains large pyramidal neurons that are unequally distributed along the extent of both MEC and LEC Insausti et al, 1997. In the nomenclature by Lorente de Nó, 1933, the current layer Va was termed layer IV.

  • Vb: a few rows of cells wide in diameter; contains smaller neurons compared to layer Va and are more densely packed. Insausti et al, 1997

  • VI: Cell layer; contains pyramidal(-like) and multipolar cells

Subdivisions

Several parcellation schemes exist for the entorhinal cortex. Brodmann (1909) was the first who parceled the EC into two fields: A lateral area 28a (or LEC) and a medial area 28b (or MEC). Subsequent descriptions were made by (a.o.) Stephan, 1975, Witter (2002, Insausti et al, 1997, Witter, 2017). Here we use the 2 subfield division, but several authors subdivided the EC into more than 2 subfields. These subdivisions delineate CE, ME, DIE, VIE, VLE and AE. AE was later found not to be part of the EC (see: Kemppainen et al., 2002; Majak and Pitkänen, 2003). We use the term LEC to include DLE, DIE, and VIE, whereas MEC includes CE and ME.

See the 6 subdivisions of the entorhinal cortex in the Hippocampus Atlas

Lateral and medial entorhinal cortex: differentiation

Some of the characteristic cytoarchitectonic differences between LEC and MEC are:

  • LEC Layer II* is clearly demarcated; its cells are very densely packed and tend to be clustered in islands. The cells in MEC layer II are somewhat larger and show less of a distinct clustering into islands when viewed with a neuronal stain. However, the distribution of different celltypes in MEC do show a marked clustering in several species, including rat (Naumann et al, 2015, 2018).
  • he border between layers II* and III in MEC is not as sharp as in the LEC, although in both entorhinal areas the overall difference in cell size between layers II and III facilitate the delineation of the two layers.
  • The lamina dissecans of the MEC is sharply delineated but is less clear in the LEC. The other cell layers, in particular layers IV–VI, can be better differentiated from each other in the MEC than in the LEC, and cells in the deep layers of the MEC generally show a more radial or columnar arrangement.

In addition to cytoarchitecture as a criterion to subdivide the EC, one can look at its connectivity to define the LEC/MEC subfields. In the rat, LEC and MEC can also be distinguished by looking at their differential connectivity 1) to the molecular layer of the Dentate Gyrus (DG) and 2) to the differential connectivity along the proximodistal axis of hippocampal subfield CA1. Specifically:

  • The LEC-> DG projection terminates in the outer one third (close to the pial surface) of the dentate molecular layer, whereas the MEC->DG projection terminates in the middle one-third of the dentate molecular layer (Hjorth-Simonsen and Jeune, 1972; Hjorth-Simonsen, 1972).
  • The MEC-> CA1 projection terminates in the proximal part of CA1 (closer to the DG), whereas the LEC-> CA1 projection terminates in the distal part of CA1 (see also: van Strien et al., 2009).

Suggested reading

Canto, C.B. & Witter, M.P. (2012). Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex. Hippocampus, 22(6), 1277-1299. Resolve DOI

Cappaert, N. L. M., Van Strien, N. M., & Witter, M. P. (2015). Chapter 20 - Hippocampal Formation. In G. Paxinos (Ed.), The Rat Nervous System (Fourth Edition) (pp. 511–573). San Diego: Academic Press. € Buy from Elsevier

Witter M.P., Doan T.P., Jacobsen B., Nilssen E.S. & Ohara S. (2017). Architecture of the Entorhinal Cortex A Review of Entorhinal Anatomy in Rodents with Some Comparative Notes Front Syst Neurosci., 25(7), 838–857. Resolve DOI

Witter M.P. (2018). Connectivity of the Hippocampus In: Cutsuridis, V., Graham, B.P., Cobb, S., Vida, I. (Eds.) Hippocampal Microcircuits (pp 5 - 28 ). Springer; 2nd ed. 2018 edition (21 Feb 2019) € Buy from Springer

References

Blackstad, T. W. (1956). Commissural connections of the hippocampal region in the rat, with special reference to their mode of termination. The Journal of Comparative Neurology, 105(3), 417–537. Resolve DOI

Cappaert, N. L. M., Van Strien, N. M., & Witter, M. P. (2015). Chapter 20 - Hippocampal Formation. In G. Paxinos (Ed.), The Rat Nervous System (Fourth Edition) (pp. 511–573). San Diego: Academic Press.

Gatome C.W., Slomianka L., Lipp H.P. & Amrein I. (2010). Number estimates of neuronal phenotypes in layer II of the medial entorhinal cortex of rat and mouse. Neuroscience, 170(1), 156-165. Resolve DOI

Hjorth-Simonsen A. (1972). Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata. J Comp Neurol., 146(2), 219-232. Resolve DOI

Hjorth-Simonsen A. & Jeune B. (1972). Origin and termination of the hippocampal perforant path in the rat studied by silver impregnation. J Comp Neurol., 144(2), 215-232. Resolve DOI

Insausti R., Herrero M.T. & Witter M.P. (1997). Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus, 7(2), 146-183. Resolve DOI

Kemppainen S., Jolkkonen E. & Pitkänen A. (2002). Projections from the posterior cortical nucleus of the amygdala to the hippocampal formation and parahippocampal region in rat. Hippocampus, 12(6), 735-755. Resolve DOI

Lingenhöhl K. & Finch D.M. (1991). Morphological characterization of rat entorhinal neurons in vivo: soma-dendritic structure and axonal domains. Exp Brain Res, 84(1), 57-74. Resolve DOI

Lorente de Nó, R. (1933). Studies on the structure of cerebral cortex. Journal für Psychologie und Neurologie., 45(6), 381-438. You may find a copy here

Merrill D.A., Chiba A.A. & Tuszynski M.H. (2001). Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J Comp Neurol., 438(4), 445-456. Resolve DOI

Mulders W.H., West M.J. & Slomianka L. (1997). Neuron numbers in the presubiculum, parasubiculum, and entorhinal area of the rat. J Comp Neurol., 385(1), 83-94. Resolve DOI

Rapp P.R., Deroche P.S., Mao Y. & Burwell RD. (2002). Neuron number in the parahippocampal region is preserved in aged rats with spatial learning deficits. Cereb Cortex., 12(11),1171-1179. Resolve DOI

Schmidt B., Marrone D.F. & Markus E.J. (2012). Disambiguating the similar: the dentate gyrus and pattern separation. Behav Brain Res., 226(1),56-65. Resolve DOI

Stephan, H (1975) Allocortex In W Bargmann (Ed.), Handbuch der mikroskopischen Anatomie des Menschen Berlin : Springer. € Buy as E-Book

Strien, van, N.M., Cappaert, N.LM. & Witter, M.P. (2009). The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci., 10(4), 272-282. Read here

Witter, M.P. (2002). The parahippocampal region: Past, present, and future. (pp. 3–20). In M.P. Witter, & F.G. Wouterlood (Eds.) The Parahippocampal Region: Organization and Role in Cognitive Functions, London: Oxford University Press. € Find a copy

Chapter 20 - Hippocampal Formation.

Abstract

The hippocampal formation and parahippocampal region are prominent components of the rat nervous system and play a crucial role in learning, memory, and spatial navigation. Many new details regarding the entorhinal cortex have been discovered since the previous edition, and the growing interest in the area of CA2 has been covered in this chapter. Emphasis is on a conceptual change: instead of perceiving the hippocampal circuit as the standard sequential processing network, current insights favor the concept that multiple parallel networks are present. Many new facts, combined with a thorough restructuring of information and inclusion of pointers to relevant (online) resources, make this chapter relevant to both the novice and senior readership.

Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex.

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.

Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents.

Abstract

The origins and terminations of entorhinal cortical projections in the rat were analyzed in detail with retrograde and anterograde tracing techniques. Retrograde fluorescent tracers were injected in different portions of olfactory, medial frontal (infralimbic and prelimbic areas), lateral frontal (motor area), temporal (auditory), parietal (somatosensory), occipital (visual), cingulate, retrosplenial, insular, and perirhinal cortices. Anterograde tracer injections were placed in various parts of the rat entorhinal cortex to demonstrate the laminar and topographical distribution of the cortical projections of the entorhinal cortex. The retrograde experiments showed that each cortical area explored receives projections from a specific set of entorhinal neurons, limited in number and distribution. By far the most extensive entorhinal projection was directed to the perirhinal cortex. This projection, which arises from all layers, originates throughout the entorhinal cortex, although its major origin is from the more lateral and caudal parts of the entorhinal cortex. Projections to the medial frontal cortex and olfactory structures originate largely in layers II and III of much of the intermediate and medial portions of the entorhinal cortex, although a modest component arises from neurons in layer V of the more caudal parts of the entorhinal cortex. Neurons in layer V of an extremely laterally located strip of entorhinal cortex, positioned along the rhinal fissure, give rise to the projections to lateral frontal (motor), parietal (somatosensory), temporal (auditory), occipital (visual), anterior insular, and cingulate cortices. Neurons in layer V of the most caudal part of the entorhinal cortex originate projections to the retrosplenial cortex. The anterograde experiments confirmed these findings and showed that in general, the terminal fields of the entorhinal-cortical projections were densest in layers I, II, and III, although particularly in the more densely innervated areas, labeling in layer V was also present. Comparably distributed, but much weaker projections reach the contralateral hemisphere. Our results show that in the rat, hippocampal output can reach widespread portions of the neocortex through a relay in a very restricted part of the entorhinal cortex. However, most of the hippocampal-cortical connections will be mediated by way of entorhinal-perirhinal-cortical connections. We conclude that, in contrast to previous notions, the overall organization of the hippocampal-cortical connectivity in the rat is largely comparable to that in the monkey.

Studies on the structure of cerebral cortex.

Abstract

No abstract available

Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata.

Abstract

The hippocampus and fascia dentata receive their major extrinsic input from the entorhinal area through the so‐called perforant path. This pathway is now shown to be composed of at least two distinct fiber systems: (1) A medial perforant path coming from the medial part of the entorhinal area and terminating in the middle of the dentate molecular layer and in the deep half of the stratum lacunosum‐moleculare of the hippocampal subfield CA3. (2) A lateral perforant path from the lateral part of the entorhinal area to a superficial zone in the dentate molecular layer and to the superfcial part of the stratum lacunosum‐moleculare of CA3. This paper deals specifically with the lateral perforant path. A third group of perforant fibers, bing intermediate to the others with regard to both origin and termination has been noticed in one animal.The fiber‐course of the lateral perforant path is found to be identical to that previously described for the medial path. The terminal field is present along the whole axial extent of the hippocampus and fascia dentata, i.e., from the temporal tip to the subsplenial portion. No sings of degeneration corresponding to the so‐called alvear path were observed following lesions of either the medial or the lateral part of the entorhinal cortex. Terminal degeneration appeared in the molecular layer of the subiculum and CA1 and in the anterior continuation of the hippocampal formation subsequent to lesions including the prepyriform cortex.

Origin and termination of the hippocampal perforant path in the rat studied by silver impregnation.

Abstract

A detailed study of the origin and termination of the so‐called perforant path of the hippocampal region has been made in the rat. This tract connects the entorhinal area with the hippocampus and the fascia dentata. At all dorso‐basal levels of the hippocampus, the terminal field has been shown to occupy the middle part of the molecular layer of the fascia dentata and that level of the stratum lacunosum‐moleculare of the hippocampal subfield CA3 which is close to the stratum radiatum. The outer and inner parts of the dentate molecular layer, the stratum lacunosum‐moleculare of subfield CA1, and the superficial part of the latter layer in CA3 contained fibers en passage only. The origin of the perforant path has been found to be in the medial part of the entorhinal area, from the most dorsal to the most ventral levels. The fibers arise in part at least from cells in layers I—III. Lesions of the lateral part of the entorhinal area leave the perforant path unaffected. A topical organization has been demonstrated: Lesions dorsal in the entorhinal area evoke terminal degeneration in antero‐rostral (septal) parts of the hippocampus only. More ventral lesions produce degeneration in increasingly caudal (temporal) segments of the hippocampus. Earlier descriptions of the route traversed by the perforant path have been confirmed. In addition, the axons to the most rostral parts of the hippocampus and fascia dentata have been shown to course superficially in the dorsal and rostral parts of the subiculum and CA1 which form an exposed part of the medial aspect of the hemisphere.

A three-plane architectonic atlas of the rat hippocampal region.

Abstract

The hippocampal region, comprising the hippocampal formation and the parahippocampal region, has been one of the most intensively studied parts of the brain for decades. Better understanding of its functional diversity and complexity has led to an increased demand for specificity in experimental procedures and manipulations. In view of the complex 3D structure of the hippocampal region, precisely positioned experimental approaches require a fine-grained architectural description that is available and readable to experimentalists lacking detailed anatomical experience. In this paper, we provide the first cyto- and chemoarchitectural description of the hippocampal formation and parahippocampal region in the rat at high resolution and in the three standard sectional planes: coronal, horizontal and sagittal. The atlas uses a series of adjacent sections stained for neurons and for a number of chemical marker substances, particularly parvalbumin and calbindin. All the borders defined in one plane have been cross-checked against their counterparts in the other two planes. The entire dataset will be made available as a web-based interactive application through the Rodent Brain WorkBench (http://www.rbwb.org) which, together with this paper, provides a unique atlas resource.

Chapter 20 - Hippocampal Formation.

Abstract

The hippocampal formation and parahippocampal region are prominent components of the rat nervous system and play a crucial role in learning, memory, and spatial navigation. Many new details regarding the entorhinal cortex have been discovered since the previous edition, and the growing interest in the area of CA2 has been covered in this chapter. Emphasis is on a conceptual change: instead of perceiving the hippocampal circuit as the standard sequential processing network, current insights favor the concept that multiple parallel networks are present. Many new facts, combined with a thorough restructuring of information and inclusion of pointers to relevant (online) resources, make this chapter relevant to both the novice and senior readership.

Commissural connections of the hippocampal region in the rat, with special reference to their mode of termination.

Introduction

In recent years increasing interest has been devoted to the hippocampus. Cajal's ( 1901, 1903, 1911) demonstration of the fibers to the hippocampus from the entorhinal area was confirmed by Lorente de Nó ( 1933, 1934). Experimental demonstration was given by Allen ( 1948) in the dog, by Adey and Meyer ( 1952a) in the monkey, and by the present author ( 1956) in the rat. The possible role of the hippocampus in olfaction, emotions, sexual activities, general mental activation, and other functions has been discussed (Brodal, 1947a, b; Grünthal, 1947; Kaada, 1951; Kaada and Jasper, 1952; Kaada, Jansen and Andersen, 1953; Green and Shimamoto, 1953; Walker, Thomson and McQueen, 1953; Green, 1954; and others). So far, however, the essential nature of its function has not been disclosed. Some additional information on the connections of this and the neighboring fields should be of interest. For convenience, the areas dealt with are here collectively termed the hippocampal region or regio hippocampica. (For orientation, see figs. 1, 2, 3, 5, 7.) This study is concerned with decussating fibers within this region, primarily their general pattern of termination as revealed by their early degeneration.

Number estimates of neuronal phenotypes in layer II of the medial entorhinal cortex of rat and mouse.

Introduction

Modelling entorhinal function or evaluating the consequences of neuronal losses which accompany neurodegenerative disorders requires detailed information on the quantitative cellular composition of the normal entorhinal cortex. Using design-based stereological methods, we estimated the numbers, proportions, densities and sectional areas of layer II cells in the medial entorhinal area (MEA), and its constituent caudal entorhinal (CE) and medial entorhinal (ME) fields, in the rat and mouse. We estimated layer II of the MEA to contain ∼58,000 neurons in the rat and ∼24,000 neurons in the mouse. Field CE accounted for more than three-quarters of the total neuron population in both species. In the rat, layer II of the MEA is comprised of 38% ovoid stellate cells, 29% polygonal stellate cells and 17% pyramidal cells. The remainder is comprised of much smaller populations of horizontal bipolar, tripolar, oblique pyramidal and small round cells. In the mouse, MEA layer II is comprised of 52% ovoid stellate cells, 22% polygonal stellate cells and 14% pyramidal cells. Significant species differences in the proportions of ovoid and polygonal stellate cells suggest differences in physiological and functional properties. The majority of MEA layer II cells contribute to the entorhinal-hippocampal pathways. The degree of divergence from MEA layer II cells to the dentate granule cells was similar in the rat and mouse. In both rat and mouse, the only dorsoventral difference we observed is a gradient in polygonal stellate cell sectional area, which may relate to the dorsoventral increase in the size and spacing of individual neuronal firing fields. In summary, we found species-specific cellular compositions of MEA layer II, while, within a species, quantitative parameters other than cell size are stable along the dorsoventral and mediolateral axis of the MEA.

Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents.

Abstract

The origins and terminations of entorhinal cortical projections in the rat were analyzed in detail with retrograde and anterograde tracing techniques. Retrograde fluorescent tracers were injected in different portions of olfactory, medial frontal (infralimbic and prelimbic areas), lateral frontal (motor area), temporal (auditory), parietal (somatosensory), occipital (visual), cingulate, retrosplenial, insular, and perirhinal cortices. Anterograde tracer injections were placed in various parts of the rat entorhinal cortex to demonstrate the laminar and topographical distribution of the cortical projections of the entorhinal cortex. The retrograde experiments showed that each cortical area explored receives projections from a specific set of entorhinal neurons, limited in number and distribution. By far the most extensive entorhinal projection was directed to the perirhinal cortex. This projection, which arises from all layers, originates throughout the entorhinal cortex, although its major origin is from the more lateral and caudal parts of the entorhinal cortex. Projections to the medial frontal cortex and olfactory structures originate largely in layers II and III of much of the intermediate and medial portions of the entorhinal cortex, although a modest component arises from neurons in layer V of the more caudal parts of the entorhinal cortex. Neurons in layer V of an extremely laterally located strip of entorhinal cortex, positioned along the rhinal fissure, give rise to the projections to lateral frontal (motor), parietal (somatosensory), temporal (auditory), occipital (visual), anterior insular, and cingulate cortices. Neurons in layer V of the most caudal part of the entorhinal cortex originate projections to the retrosplenial cortex. The anterograde experiments confirmed these findings and showed that in general, the terminal fields of the entorhinal-cortical projections were densest in layers I, II, and III, although particularly in the more densely innervated areas, labeling in layer V was also present. Comparably distributed, but much weaker projections reach the contralateral hemisphere. Our results show that in the rat, hippocampal output can reach widespread portions of the neocortex through a relay in a very restricted part of the entorhinal cortex. However, most of the hippocampal-cortical connections will be mediated by way of entorhinal-perirhinal-cortical connections. We conclude that, in contrast to previous notions, the overall organization of the hippocampal-cortical connectivity in the rat is largely comparable to that in the monkey.

Projections from the posterior cortical nucleus of the amygdala to the hippocampal formation and parahippocampal region in rat.

Abstract

The posterior cortical nucleus of the amygdala is involved in the processing of pheromonal information and presumably participates in ingestive, defensive, and reproductive behaviors as a part of the vomeronasal amygdala. Recent studies suggest that the posterior cortical nucleus might also modulate memory processing via its connections to the medial temporal lobe memory system. To investigate the projections from the posterior cortical nucleus to the hippocampal formation and the parahippocampal region, as well as the intra-amygdaloid connectivity in detail, we injected the anterograde tracer phaseolus vulgaris-leucoagglutinin into different rostrocaudal levels of the posterior cortical nucleus. Within the hippocampal formation, the stratum lacunosum-moleculare of the temporal CA1 subfield and the adjacent molecular layer of the proximal temporal subiculum received a moderate projection. Within the parahippocampal region, the ventral intermediate, dorsal intermediate, and medial subfields of the entorhinal cortex received light to moderate projections. Most of the labeled terminals were in layers I, II, and III. In the ventral intermediate subfield, layers V and VI were also moderately innervated. Layers I and II of the parasubiculum received a light projection. There were no projections to the presubiculum or to the perirhinal and postrhinal cortices. The heaviest intranuclear projection was directed to the deep part of layer I and to layer II of the posterior cortical nucleus. There were moderate-to-heavy intra-amygdaloid projections terminating in the bed nucleus of the accessory olfactory tract, the central division of the medial nucleus, and the sulcal division of the periamygdaloid cortex. Our data suggest that via these topographically organized projections, pheromonal information processed within the posterior cortical nucleus can influence memory formation in the hippocampal and parahippocampal areas. Also, these pathways provide routes through which seizure activity can spread from the epileptic amygdala to the surrounding region of the temporal lobe.

Morphological characteristics of layer II projection neurons in the rat medial entorhinal cortex.

Abstract

The entorhinal cortex receives inputs from a variety of neocortical regions. Neurons in layer II of the entorhinal cortex originate one component of the perforant path which conveys this information to the dentate gyrus and hippocampus. The current study extends our previous work on the electro-responsive properties of layer II neurons of the medial entorhinal cortex in which we distinguished two categories of layer II neurons based on their electrophysiological attributes (Alonso and Klink [1993] J Neurophysiol 70: 128-143). Here we report on the morphological features of layer II projection neurons, as revealed by in vitro intracellular injection of biocytin. We now report that the two electrophysiologically distinct types of neurons correspond to morphologically distinct types of cells. All neurons (65% of the total cells recorded) that developed sustained, subthreshold, sinusoidal membrane potential oscillations were found to have a stellate appearance. Neurons that did not exhibit oscillatory behavior had either a pyramidal-like (32%) or a horizontal cell morphology (3%). Stellate cells had multiple, thick, primary dendrites. Their widely diverging upper dendritic domain expanded mediolaterally over a distance of around 500 microns close to the pial surface. This mediolateral extent was more than double that of the pyramidal-like cells. Dendrites of stellate cells demonstrated long dendritic appendages, and their dendritic spines had a more complex morphology than those of nonstellates. The stellate cell axons emerged from a primary dendrite and were more than double the thickness (approximately 1.4 microns) of the axons of nonstellate cells. Recurrent axonal collaterization appeared more extensive in axons arising from stellate cells than from pyramidal-like cells.

Morphological characterization of rat entorhinal neurons in vivo: soma-dendritic structure and axonal domains

Summary

We used in vivo intracellular labeling with horseradish peroxidase in order to study the somadendritic morphology and axonal projections of rat entorhinal neurons. The cells responded to hippocampal stimulation with inhibitory postsynaptic potentials, and thus likely received direct or indirect hippocampal input. All cells (n = 24) showed extensive dendritic domains that extended in some cases for more than 1 mm. The dendrites of layer II neurons were largely restricted to layers I and II or layers I–III, while the dendrites of deeper cells could extend through all cortical layers. Computed 3D rotations showed that the basilar dendrites of deep pyramids extended roughly parallel to the cortical layering, and that they were mostly confined to the layer containing the soma and layers immediately adjacent. Total dendritic lengths averaged 9.8 mm ± 3.8 (SD), and ranged from 5 mm to more than 18 mm. Axonal processes could be visualized in 21 cells. Most of these showed axonal branching within the entorhinal cortex, sometimes extensive. Efferent axonal domains were reconstructed in detail in 3 layer II stellate cells. All 3 projected axons across the subicular complex to the dentate gyrus. One of these cells showed an extensive net-like axonal domain that also projected to several other structures, including the hippocampus proper, subicular complex, and the amygdalo-piriform transition area. The axons of layer III and IV cells projected to the angular bundle, where they continued in a rostral direction. In contrast to the layer II, III and IV cells, no efferent axonal branches leaving the entorhinal cortex could be visualized in 5 layer V neurons. The data indicate that entorhinal neurons can integrate input from a considerable volume of entorhinal cortex by virtue of their extensive dendritic domains, and provide a further basis for specifying the layers in which cells receive synaptic input. The extensive axonal branching pattern seen in most of the cells would support divergent propagation of their activity.

Studies on the structure of cerebral cortex.

Abstract

No abstract available

Projections from the periamygdaloid cortex to the amygdaloid complex, the hippocampal formation, and the parahippocampal region: a PHA-L study in the rat.

Abstract

The periamygdaloid cortex, an amygdaloid region that processes olfactory information, projects to the hippocampal formation and parahippocampal region. To elucidate the topographic details of these projections, pathways were anterogradely traced using Phaseolus vulgaris leukoagglutinin (PHA-L) in 14 rats. First, we investigated the intradivisional, interdivisional, and intra-amygdaloid connections of various subfields [periamygdaloid subfield (PAC), medial subfield (PACm), sulcal subfield (PACs)] of the periamygdaloid cortex. Thereafter, we focused on projections to the hippocampal formation (dentate gyrus, hippocampus proper, subiculum) and to the parahippocampal region (presubiculum, parasubiculum, entorhinal, and perirhinal and postrhinal cortices). The PACm had the heaviest intradivisional projections and it also originated light interdivisional projections to other periamygdaloid subfields. Projections from the other subfields converged in the PACs. All subfields provided substantial intra-amygdaloid projections to the medial and posterior cortical nuclei. In addition, the PAC subfield projected to the ventrolateral and medial divisions of the lateral nucleus. The heaviest periamygdalohippocampal projections originated in the PACm and PACs, which projected moderately to the temporal end of the stratum lacunosum moleculare of the CA1 subfield and to the molecular layer of the ventral subiculum. The PACm also projected moderately to the temporal CA3 subfield. The heaviest projections to the entorhinal cortex originated in the PACs and terminated in the amygdalo-entorhinal, ventral intermediate, and medial subfields. Area 35 of the perirhinal cortex was lightly innervated by the PAC subfield. Thus, these connections might allow for olfactory information entering the amygdala to become associated with signals from other sensory modalities that enter the amygdala via other nuclei. Further, the periamygdalohippocampal pathways might form one route by which the amygdala modulates memory formation and retrieval in the medial temporal lobe memory system. These pathways can also facilitate the spread of seizure activity from the amygdala to the hippocampal and parahippocampal regions in temporal lobe epilepsy.

Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats.

Abstract

Despite abundant evidence of behavioral and electrophysiological dysfunction of the rodent hippocampal formation with aging, the structural basis of age-related cognitive decline remains unclear. Recently, unbiased stereological studies of the mammalian hippocampus have found little evidence to support the dogma that cellular loss accompanies hippocampal aging, thereby supporting an alternative hypothesis that aging is marked by widespread conservation of neuronal number. However, to date, the effects of aging have not been reported in another key component of memory systems in the rodent brain, the entorhinal cortex. In the present study, we stereologically estimated total neuronal number and size (cross-sectional area and cell volume) in the subdivisions and cellular layers of the rat entorhinal cortex, using the optical fractionator and nucleator, respectively. Comparisons were made among Fischer 344 rats that were young, aged-impaired, and aged-unimpaired (based on functional analysis in the Morris water maze). No significant differences in cell number or size were observed in any of the entorhinal subdivisions or laminae examined in each group. Thus, aging is associated with widespread conservation of neuronal number, despite varying degrees of cognitive decline, in all memory-related systems examined to date. These data suggest that mechanisms of age-related cognitive decline are to be found in parameters other than neuronal number or size in the cortex of the mammalian brain.

Neuron numbers in the presubiculum, parasubiculum, and entorhinal area of the rat.

Abstract

Estimates of neuron numbers have been useful in studies of neurodegenerative disorders, and in their animal models, and in the computational modeling of hippocampal function. Although the retrohippocampal region (presubiculum, parasubiculum, and entorhinal area) is an integral part of the hippocampal circuitry and is affected selectively in a number of disorders, estimates of neuron numbers in the rat retrohippocampal region have yet to be published. Such data are necessary ingredients for computational models of the function of this region and will also facilitate a comparison of this region in rats and primates, which will help to determine how well we may expect rat models to predict function and dysfunction in primate brains. In the present study, we used the optical fractionator to estimate the number of neurons in the rat retrohippocampal region. The following estimates were obtained: 3.3 x 10(5) in presubicular layers II and III, 1.5 x 10(5) in parasubicular layers II and III, 2.2 x 10(5) in the combined pre- and parasubicular layers V and VI, 6.6 x 10(4) in medial entorhinal area (MEA) layer II, 1.3 x 10(5) in MEA layer III, 1.9 x 10(5) in MEA layers V and VI, 4.6 x 10(4) in lateral entorhinal area (LEA) layer II, 1.2 x 10(5) in LEA layer III, and 1.4 x 10(5) in LEA layers V and VI. A surprising finding was the large numbers of neurons in the pre- and parasubiculum, which indicate an important role of these areas in the control of the entorhino-hippocampal projection. A comparison of the numbers of neurons in the hippocampus and entorhinal areas in rats with similar estimates in humans revealed that gross input-output relations are largely conserved. Differences between rats and humans may be accounted for by more prominent entorhino-neocortical projections in primates and consequent increases in the number of neurons in the hippocampus and retrohippocampal region, which are dedicated to these projections.

Neuron number in the parahippocampal region is preserved in aged rats with spatial learning deficits.

Abstract

The entorhinal, perirhinal and parahippocampal cortices are anatomically positioned to mediate the bi-directional flow of information between the hippocampus and neocortex. Consistent with this organization, damage involving the parahippocampal region causes significant learning and memory impairment in young subjects. Although recent evidence indicates that neuron death in the hippocampus is not required to account for the effects of normal aging on learning and memory, other findings suggest that changes in parahippocampal interactions with the hippocampus may play a significant role. Prompted by this background, we tested the possibility that age-related deficits in hippocampal learning are coupled with neuron death in the parahippocampal region. The experiments took advantage of a well-characterized rat model of cognitive aging in combination with stereological methods for quantifying neuron number. The results demonstrate that total neuron number in the entorhinal, perirhinal and postrhinal cortices is largely preserved during normal aging. Furthermore, individual variability in hippocampal learning among the aged rats failed to correlate with neuron number in any region examined and there was no indication of selective or disproportionate loss among the aged animals with the most pronounced cognitive impairment. Taken together with earlier findings from the same study population, the results demonstrate that age-related cognitive decline can occur in the absence of significant neuron death in any major, cytoarchitectonically defined component of the hippocampal system. These findings provide an essential framework for identifying the basis of cognitive aging, suggesting that alterations in connectivity and other changes are more likely causative factors.

Disambiguating the similar: the dentate gyrus and pattern separation.

Abstract

The human hippocampus supports the formation of episodic memory without confusing new memories with old ones. To accomplish this, the brain must disambiguate memories (i.e., accentuate the differences between experiences). There is convergent evidence linking pattern separation to the dentate gyrus. Damage to the dentate gyrus reduces an organism's ability to differentiate between similar objects. The dentate gyrus has tenfold more principle cells than its cortical input, allowing for a divergence in information flow. Dentate gyrus granule neurons also show a very different pattern of representing the environment than "classic" place cells in CA1 and CA3, or grid cells in the entorhinal cortex. More recently immediate early genes have been used to "timestamp" activity of individual cells throughout the dentate gyrus. These data indicate that the dentate gyrus robustly differentiates similar situations. The degree of differentiation is non-linear, with even small changes in input inducing a near maximal response in the dentate. Furthermore this differentiation occurs throughout the dentate gyrus longitudinal (dorsal-ventral) axis. Conversely, the data point to a divergence in information processing between the dentate gyrus suprapyramidal and infrapyramidal blades possibly related to differences in organization within these regions. The accumulated evidence from different approaches converges to support a role for the dentate gyrus in pattern separation. There are however inconsistencies that may require incorporation of neurogenesis and hippocampal microcircuits into the currents models. They also suggest different roles for the dentate gyrus suprapyramidal and infrapyramidal blades, and the responsiveness of CA3 to dentate input.

Brain maps 4.0-Structure of the rat brain: An open access atlas with global nervous system nomenclature ontology and flatmaps.

Abstract

The fourth edition (following editions in 1992, 1998, 2004) of Brain maps: structure of the rat brain is presented here as an open access internet resource for the neuroscience community. One new feature is a set of 10 hierarchical nomenclature tables that define and describe all parts of the rat nervous system within the framework of a strictly topographic system devised previously for the human nervous system. These tables constitute a global ontology for knowledge management systems dealing with neural circuitry. A second new feature is an aligned atlas of bilateral flatmaps illustrating rat nervous system development from the neural plate stage to the adult stage, where most gray matter regions, white matter tracts, ganglia, and nerves listed in the nomenclature tables are illustrated schematically. These flatmaps are convenient for future development of online applications analogous to "Google Maps" for systems neuroscience. The third new feature is a completely revised Atlas of the rat brain in spatially aligned transverse sections that can serve as a framework for 3-D modeling. Atlas parcellation is little changed from the preceding edition, but the nomenclature for rat is now aligned with an emerging panmammalian neuroanatomical nomenclature. All figures are presented in Adobe Illustrator vector graphics format that can be manipulated, modified, and resized as desired, and freely used with a Creative Commons license.

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© Copyright 2007 - 2022 N.L.M. Cappaert & N.M. van Strien. All rights reserved. Content is available under Attribution-Noncommercial-No Derivative Works 3.0 Unported. Currently this work is financially supported by the Dutch Research Council. Project DOI: 10.21942/uva.19786213.v1