Entorhinal cortex of the monkey: V. Projections to the dentate gyrus, hippocampus, and subicular complex.

The topographic and laminar organization of entorhinal projections to the dentate gyrus, hippocampus, and subicular complex was investigated in the Macaca fascicularis monkey. Injections of 3H-amino acids were placed at various positions within the entorhinal cortex and the distribution of anterogradely labeled fibers and terminals within the other fields of the hippocampal formation was determined. Injections of the retrograde tracers Fast blue, Diamidino yellow, and wheat germ agglutinin-horseradish peroxidase (WGA-HRP) were also placed into the dentate gyrus, hippocampus, and subicular complex, and the distribution of retrogradely labeled cells in the entorhinal cortex was plotted using a computer-aided digitizing system. The entorhinal cortex gave rise to projections that terminated in the subiculum, in the CA1, CA2, and CA3 fields of the hippocampus, and in the dentate gyrus. Projections to the dentate gyrus, and fields CA3 and CA2 of the hippocampus, originated preferentially in layers II and VI of the entorhinal cortex whereas projections to CA1 and to the subiculum originated mainly in layers III and V. Anterograde tracing experiments demonstrated that all regions of the entorhinal cortex project to the outer two-thirds of the molecular layer of the dentate gyrus and to much of the radial extent of the stratum lacunosum-moleculare of CA3 and CA2. While the terminal distributions of entorhinal projections to the dentate gyrus, CA3, and CA2 were not as clearly laminated as in the rat, projections from rostral levels of the entorhinal cortex preferentially innervated the outer portion of the molecular layer and stratum lacunosum-moleculare, whereas more caudal levels of the entorhinal cortex projected relatively more heavily to the deeper portions of the entorhinal terminal zones. The entorhinal projection to the CA1 field of the hippocampus and to the subiculum followed a transverse rather than radial gradient of distribution. Rostral levels of the entorhinal cortex terminated most heavily at the border of CA1 and the subiculum. More caudal levels of the entorhinal cortex projected to progressively more distal portions of the subiculum (towards the presubiculum) and more proximal portions of CA1 (towards CA2). Lateral portions of the entorhinal cortex projected to caudal levels of the recipient fields and more medial parts of the entorhinal cortex projected to progressively more rostral portions of the fields.     

The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation

The origin and the terminations of the projections from the entorhinal cortex to the hippocampal formation of the mouse (C57BL/6J strain) have been studied using anterogradely and retrogradely transported tracers. The entorhinal cortex is principally divided into two areas, the lateral entorhinal area (LEA) and the medial entorhinal area (MEA). LEA is the origin of the lateral perforant path that terminates in the outer one-third of the molecular layer of the dentate gyrus, and MEA is the origin of the medial perforant path that ends in the middle one-third of the molecular layer of the dentate gyrus. This projection is mostly to the ispsilateral dentate gyrus; only a few labeled axons and terminals are found in the contralateral dentate gyrus. The projection to the dentate gyrus originates predominantly from neurons in layer II of the entorhinal cortex. The entorhinal cortex also projects to CA3 and CA1 and to subiculum; in both CA3 and CA1, the terminals are present in stratum lacunosum-moleculare, whereas in the subiculum the terminals are in the outer part of the molecular layer. The projection from the entorhinal cortex to CA3, CA1, and subiculum is bilateral, and it originates predominantly from neurons in layer III, but a small number of neurons in the deeper layers of the entorhinal cortex contributes to this projection. The projection of entorhinal cortex to the hippocampus is topographically organized, neurons in the lateral part of both LEA and MEA project to the dorsal part (i.e., septal pole) of the hippocampus, whereas the projection to the ventral (i.e., temporal pole) hippocampus originates from neurons in medial parts of the entorhinal cortex.     

Postnatal development of the hippocampal formation: a stereological study in macaque monkeys

We performed a stereological analysis of neuron number, neuronal soma size, and volume of individual regions and layers of the macaque monkey hippocampal formation during early postnatal development. We found a protracted period of neuron addition in the dentate gyrus throughout the first postnatal year and a concomitant late maturation of the granule cell population and individual dentate gyrus layers that extended beyond the first year of life. Although the development of CA3 generally paralleled that of the dentate gyrus, the distal portion of CA3, which receives direct entorhinal cortex projections, matured earlier than the proximal portion of CA3. CA1 matured earlier than the dentate gyrus and CA3. Interestingly, CA1 stratum lacunosum-moleculare, in which direct entorhinal cortex projections terminate, matured earlier than CA1 strata oriens, pyramidale, and radiatum, in which the CA3 projections terminate. The subiculum developed earlier than the dentate gyrus, CA3, and CA1, but not CA2. However, similarly to CA1, the molecular layer of the subiculum, in which the entorhinal cortex projections terminate, was overall more mature in the first postnatal year compared with the stratum pyramidale in which most of the CA1 projections terminate. Unlike other hippocampal fields, volumetric measurements suggested regressive events in the structural maturation of presubicular neurons and circuits. Finally, areal and neuron soma size measurements revealed an early maturation of the parasubiculum. We discuss the functional implications of the differential development of distinct hippocampal circuits for the emergence and maturation of different types of "hippocampus-dependent" memory processes, including spatial and episodic memories.     

Regional and laminar organization of projections from the presubiculum and parasubiculum to the entorhinal cortex: An anterograde tracing study in the rat

The regional and laminar organization of the projections from the presubiculum and the parasubiculum to the entorhinal cortex was analyzed in the rat with the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). The projections from the presubiculum were bilateral and confined to layers III and I of the medial entorhinal area (MEA). Both the ipsi- and the contralateral projections showed similar distributions and were almost of equal density. Projections to layer III of the entorhinal cortex arose predominantly from superficial layers of the presubiculum, whereas the fibers that reach layer I of the entorhinal cortex appear to originate preferentially from the deep layers of the presubiculum. These fibers also appeared to innervate weakly layer II of MEA. The parasubiculum distributed projections not only to MEA but also to the lateral entorhinal area (LEA), innervating layer II selectively. The innervation of LEA was quite dense and extensive. Very weak projections from the parasubiculum to the contralateral entorhinal cortex were observed in this study. The position of the terminal plexus in the entorhinal cortex was determined by the point of origin along both the dorsoventral and transverse or proximodistal axes of the presubiculum and parasubiculum. Projections from the presubiculum and parasubiculum entered the entorhinal cortex at the level of the injection, or slightly ventral to it, and the main terminal field was always present ventrally to the injection site. The dorsoventral axis of origin thus corresponded to a similarly oriented axis of termination in the entorhinal cortex. The distribution in relation to the origin along the transverse axis was more complex, and differences between the presubiculum and parasubiculum were present. The proximal presubiculum, i.e., the part closest to the subiculum, projected to the most lateral part of MEA and the central part of the presubiculum sent fibers to the most medial part of MEA. The distal part of the presubiculum, i.e., the part that borders the parasubiculum, projected to the central part of MEA. Projections from the portion of the parasubiculum directly adjacent to the presubiculum, the so-called proximal parasubiculum, reached medial parts of MEA, and those originating in the central part distributed preferentially to lateral parts of MEA and adjacent medial parts of LEA. The distal part of the parasubiculum that borders the entorhinal cortex projected mainly to almost the full mediolateral extent of LEA. The regional and laminar organizations of the projections from the presubiculum and parasubiculum to the entorhinal cortex suggest that information is selectively conveyed not only to different cell layers but also to restricted dorsoventral and mediolateral parts of the entorhinal cortex. © 1993 Wiley-Liss, Inc.     

Activation of perforant path neurons to field CA1 by hippocampal projections

Previous evidence showed that single-shock stimulation of dorsal hippocampal commissure (PSD) fibers to the entorhinal cortex led to sequential activation of perforant path neurons to the dentate gyrus, dentate granule cells, pyramidal neurons of hippocampal fields CA3 and CA1, and, through reentrant hippocampal impulses, neurons of deep and superficial layers of the entorhinal cortex. The aim of the present study was to ascertain whether perforant path neurons to CA1 are activated by the PSD input and/or by the reentrant hippocampal impulses in this model. Field potentials evoked by single-shock (0.1-Hz) or repetitive (1-4 Hz) PSD stimulation were recorded in anesthetized guinea pigs from the entorhinal cortex, dentate gyrus, fields CA1 and CA3, and subiculum. A current source-density analysis of the evoked potentials was used to localize the input to field CA1 and dentate gyrus. After either single-shock or repetitive PSD stimulation, an early current sink was found in the molecular layer of the dentate gyrus, but no sink was present in CA1. With low-frequency PSD stimulation, a late (approximately 40-ms) surface positive wave occurred in field CA1 alone. During this wave, a current sink was found in the stratum lacunosum-moleculare of CA1, but no sink was present in the dentate gyrus. The late wave had threshold and magnitude related to the building up of the response evoked by reentrant hippocampal impulses in layer III of the entorhinal cortex and was abolished by selective interruption of the perforant path to CA1. The results show that the commissural input to the entorhinal cortex activates perforant path neurons to the dentate gyrus, but not those to field CA1 which are recruited by repetitive hippocampal impulses. These findings show different frequency-dependent patterns of loop operation that might be related to different behaviors.     

Intrinsic projections of the retrohippocampal region in the rat brain. I. The subicular complex

The intrahippocampal projections of the subicular complex were studied in the rat with the aid of the anterogradely transported lectin Phaseolus vulgaris leucoagglutinin (PHA-L). After iontophoretic injections of the lectin into the subiculum proper, presubiculum, or the parasubiculum, axons and terminal processes immunoreactive for PHA-L were traced to their respective terminal fields within the hippocampal region. After subicular injections PHA-L-stained axons could be followed both in a caudal and a rostral direction. The caudally directed fibers course around or within the angular bundle to enter layers VI and V of the medial entorhinal area (MEA). Many fibers penetrate through these layers to terminate in layer IV of the medial and the lateral entorhinal area, which contains a major terminal field of this projection. At more ventral levels, all layers of the entorhinal area are innervated by cells located in the subiculum. Other retrohippocampal projections of the subiculum proper include the deep and the outer two layers of the presubiculum and the medial sector of the parasubiculum, in addition to a massive projection which terminates in the retrosplenial cortex. The rostrally directed projections from the subiculum form a dense innervation of strata lacunosum, radiatum, oriens, and of individual pyramidal cells in the regio superior of the Ammon's horn. All these projections of the subiculum are exclusively ipsilateral. After injections of PHA-L into layers II and III of the presubiculum, both ipsi- and contralateral projections were traced to the outer three layers of the medial entorhinal area; the lateral entorhinal area apparently receives no innervation from the presubiculum. The innervation of layer III is very dense while in layer II and deep layer I, restricted zones of innervation are found. The fibers reach these layers via the deep layers of the MEA and through the molecular layer after first coursing around the parasubiculum. In addition, a minor projection from the presubiculum to the pyramidal cell layer of the subiculum and to the molecular layer of the hippocampal formation was found. PHA-L injections into the parasubiculum labeled fibers that form a dense innervation of layer II in the MEA and the medial part of the lateral EA, and of the most medial sector of layer III in the MEA. Layer I and the superficial part of layer II of the contralateral MEA also contain a dense terminal network after PHA-L injections into the parasubiculum.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry in the hippocampal formation of the New World monkey (Saimiri sciureus)

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) containing fibers and neurons within the hippocampal formation and entorhinal cortex of the new world monkey were determined using a direct histochemical procedure. Occasional intensely stained bipolar NADPH-d positive neurons were seen in the polymorphic zone within the hilus of the dentate gyrus and molecular layer of the hippocampus. Although virtually no intensely stained cells were seen in the CA subfields, a few small oval lightly stained NADPH-d perikarya were found subjacent to CA2. An occasional intensely stained multipolar NADPH-d containing neuron was observed in the subiculum, presubiculum and parasubiculum. In the entorhinal cortex, NADPH-d cells were scattered in all layers with the greatest preponderance in layers 5-6 and underlying white matter. Dense bands of NADPH-d fibers occurred in the outer layer of the molecular layer of the dentate gyrus and the hippocampo-subicular border. NADPH-d fibers also were seen in pre- and parasubicular regions. NADPH-d fiber staining in entorhinal cortex varied mediolaterally with an increasing laminar distribution more caudally. The heaviest bands of NADPH-d fibers occurred in layers 1 and 4 and the white matter-layer 6 border. The distribution patterns of this select neuronal population may be relevant to the study of hippocampal and entorhinal areas in neurodegenerative diseases.     

Projections from the lateral,basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat

The amygdaloid complex and hippocampal formation mediate functions involving emotion and memory. To investigate the connections that regulate the interactions between these regions, we injected the anterograde tracer Phaseolus vulgaris-leucoagglutinin into various divisions of the lateral, basal, and accessory basal nuclei of the rat amygdala. The heaviest projection to the entorhinal cortex originates in the medial division of the lateral nucleus which innervates layer III of the ventral intermediate and dorsal intermediate subfields. In the basal nucleus, the heaviest projection arises in the parvicellular division and terminates in layer III of the amygdalo-entorhinal transitional subfield. In the accessory basal nucleus, the parvicellular division heavily innervates layer V of the ventral intermediate subfield. The most substantial projection to the hippocampus originates in the basal nucleus. The caudomedial portion of the parvicellular division projects heavily to the stratum oriens and stratum radiatum of CA3 and CA1. The accessory basal nucleus projects to the stratum lacunosum-moleculare of CA1. The subiculum receives a substantial input from the caudomedial parvicellular division. The parasubiculum receives dense projections from the caudal portion of the medial division of the lateral nucleus, the caudomedial parvicellular division of the basal nucleus, and the parvicellular division of the accessory basal nucleus. Our data show that select nuclear divisions of the amygdala project to the entorhinal cortex, hippocampus, subiculum, and parasubiculum in segregated rather than overlapping terminal fields. These data suggest that the amygdaloid complex is in a position to modulate different stages of information processing within the hippocampal formation. J. Comp. Neurol. 403:229–260, 1999. © 1999 Wiley-Liss, Inc.     

Cholinergic innervation of the primate hippocampal formation: II. Effects of fimbria/fornix transection

The distribution of choline acetyltransferase (ChAT)-immunoreactive and acetylcholines-terase (AChE)-positive fibers and terminals was analyzed in the hippocampal formation of macaque monkeys subjected to transection of the fimbria/fornix. Cases with either unilateral or bilateral transections were prepared, with post transection survival times ranging from 2 weeks to 1.5 years. The fimbria/fornix transection resulted in a dramatic decrease in the number of cholinergic fibers in most regions of the hippocampal formation. Some hippocampal regions. however, showed relatively greater sparing of ChAT- or AChE-positive fibers. In practically all regions of the hippocampal formation, residual AChE-positive fibers were more abundant than ChAT-immunoreactive fibers. In animals with unilateral lesions, the distribution patterns and density of AChE and ChAT staining on the side contralateral to the lesion were generally similar to those of sections from unlesioned control brains. The largest decreases in the densities of positive fibers were observed in the dentate gyrus, CA3 and CA2 fields of the hippocampus, subiculum, parasubiculum, and medial and caudal parts of the entorhinal cortex. Fibers were relatively better preserved in the rostral or uncal portion of the hippocampus and dentate gyrus and in the rostral portion of the entorhinal cortex. The presubiculum demonstrated remarkable sparing that contrasted with the almost complete loss of fibers in the parasubiculum. Interestingly, animals killed approximately 1.5 years after the fornix transection showed essentially the same pattern of fiber loss as the cases with shorter survival periods. This indicates that the residual ChAT-immunoreactive fibers, many of which reach the hippocampal formation through a ventral cholinergic pathway, are not capable of reinnervating the denervated portions of the hippocampal formation. This appears to distinguish the monkey from the rat, for which substantial sprouting and reinnervation of cholinergic fibers have been reported after similar lesions. © 1996 Wiley-Liss, Inc.     

Species differences in the projections from the entorhinal cortex to the hippocampus

Both differences and similarities exist between mammalian species in the projections from entorhinal cortex to the hippocampal formation. In most species, layer II cells of the entorhinal cortex project to the dentate gyrus, and they terminate in the outer two-thirds of the molecular layer of the dentate gyrus. The axons from layer III cells project bilaterally to areas CA(1) and CA(3) of the hippocampus, terminating in the stratum lacunosum moleculare. We have analyzed these projections in mice, and in general, the entorhinal cortex-to-hippocampus projections are similar to those in rats. Axons from layer II neurons terminate in the outer and middle thirds of the molecular layer of the dentate gyrus, and axons from layer III neurons terminate bilaterally in the stratum lacunosum moleculare of areas CA(1) and CA(3), and in the molecular layer of the subiculum. However, in contrast to rat, mouse entorhinal cortex neurons do not appreciably project to the contralateral dentate gyrus. Most species, including mice, show a similar topographical organization of the entorhinal-hippocampal projections, with neurons in the lateral part of both the lateral and medial entorhinal cortex projecting to the dorsal part or septal pole of the hippocampus, whereas the projection to the ventral hippocampus originates primarily from neurons in medial parts of the entorhinal cortex.     

Presubicular and parasubicular cortical neurons of the rat: Electrophysiological and morphological properties

Intracellular recordings and Neurobiotin-injection were used to examine the electrophysiology and morphology of presubicular and parasubicular cortical neurons in horizontal slices from rat brains. Evoked responses were obtained by stimulation of subicular and entorhinal cortices. Stellate cells were recorded in layers II and V of presubiculum and parasubiculum. Superficial layer cells had spiny dendrites that were found to reach layer I. Deep layer cells had sparsely spiny dendrites or dendrites without spines that did not reach past layer IV. Pyramidal cells were recorded in layers III and V of presubiculum and layers II and V of parasubiculum. Superficial layer cells had spiny dendrites that were found to reach layer I. Deep layer cells had sparsely spiny dendrites or dendrites without spines that could reach layer II. Electrophysiologically, stellate and pyramidal cells were similar to one another, regardless of cell layer, exhibiting repetitive single spiking in response to depolarizing current injection. No cells were found to burst in response to current injection. While there were subtle electrophysiological differences among the cell types, stellate cells were more similar to pyramidal cells from the same or adjacent layers than to other stellate cells from more distant layers. Similarly, pyramidal cells were electrophysiologically more similar to nearby stellate cells than to other distant pyramidal cells. Cells of all layers responded to subicular stimulation with a short latency (<9 ms), excitatory postsynaptic potential. Superficial layer cells responded at short (<9 ms), longer (10–20 ms) and very long latencies (>20 ms) to stimulation of superficial layers of medial entorhinal cortex. Deep layer cells responded at short latencies (<9 ms) to stimulation of deep layers of medial entorhinal cortex. Many cells responded to both subicular and entorhinal inputs. Both pyramidal and stellate cells in the deep layer of pre/parasubiculum could exhibit population bursting behavior in response to stimulation of subiculum or entorhinal cortex. The results define the cellular morphology and basic electrophysiology of presubicular and parasubicular neurons of the rat brain as a step toward understanding the physiology of the retrohippocampal cortices. Hippocampus 7:117–129, 1997. © 1997 Wiley-Liss, Inc.     

Distribution of GABAergic cells and fibers in the hippocampal formation of the macaque monkey: an immunohistochemical and in situ hybridization study.

The gamma-aminobutyric acid (GABAergic) system of the hippocampal formation of Macaca fascicularis monkeys was studied immunohistochemically with a monoclonal antibody to GABA and with nonisotopic in situ hybridization with cRNA probes for glutamic acid decarboxylase 65 (GAD65) and GAD67. The highest densities of labeled cells were observed in the presubiculum, parasubiculum, entorhinal cortex, and subiculum, whereas the CA3 field and the dentate gyrus had the lowest densities of positive neurons. Within the dentate gyrus, most of the GABAergic neurons were located in the polymorphic layer and in the deep portion of the granule cell layer. GABAergic terminals were densest in the outer two-thirds of the molecular layer. GABAergic neurons were seen throughout all layers of the hippocampus. Terminal labeling was highest in the stratum lacunosum-moleculare. A higher terminal labeling was observed in the subiculum than in CA1 and was particularly prominent in layer II of the presubiculum. A bundle of GABAergic fibers was visible deep to the cell layers of the presubiculum and subiculum. This bundle could be followed into the angular bundle ipsilaterally and was continuous with stained fibers in the dorsal hippocampal commissure. This pattern of labeling is reminiscent of the presubicular projections to the contralateral entorhinal cortex. GABAergic cells were observed in all layers of the entorhinal cortex although the density was higher in layers II and III than in layers V and VI. The in situ hybridization preparations largely confirmed the distribution of GABAergic neurons in all fields of the hippocampal formation.     

Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat.

The present study re-examines, with autoradiographic methods, the pattern of termination of fibers originating from various medio-lateral divisions of the entorhinal cortex on dentate granule cells and on hippocampal pyramidal cells of the rat. Entorhinal fibers were found to distribute in a proximo-distal gradient along the dendrites of dentate granule cells, with afferents from the medial entorhinal area terminating in the innermost portion of the entorhinal synaptic field, afferents from the lateral entorhinal area terminating in the most superficial portions of the entorhinal synaptic field, and intermediate medio-lateral locations in the entorhinal area terminating in intermediate locations in the entorhinal synaptic zone. A similar graded pattern of termination of medial and lateral entorhinal fibers was apparent in the very slight crossed projection of the entorhinal area to the contralateral dentate gyrus. In addition, a comparable gradient in the pattern of termination of entorhinal fibers was evident in the entorhinal projection field in the distal regions of the pyramidal cells of regio inferior of the hippocampus proper. Entorhinal projections to regio superior were, however, organized in quite a different fashion. In this zone, there was no evidence of a proximo-distal gradient in the patterns of termination of medial and lateral entorhinal areas along the dendrites of regio superior pyramidal cells. Rather, the medio-lateral organization was in a longitudinal dimension, with medial entorhinal afferents terminating in the portions of regio superior near the CA1-CA2 transition, and lateral entorhinal afferents terminating furthest from the CA1-CA2 transition, immediately adjacent to the CA1-subicular transition, and in the molecular layer of the subiculum proper. A comparable longitudinal organization of entorhinal projections to regio superior was also evident in the zones of termination of the crossed temporo-ammonic tract, contralateral to the injection. These results demonstrate a heretofore unrecognized complexity in the patterns of projection of the entorhinal area to the hippocampal formation, and illustrate that the entorhinal cortex cannot be divided into only two discrete divisions on the basis of the pattern of projection.     

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

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.     

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

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.     

An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat.

The efferent connections of the hippocampal formation of the rat have been re-examined autoradiographically following the injection of small quantities of 3H-amino acids (usually 3H-proline) into different parts of Ammon's horn and the adjoining structures. The findings indicate quite clearly that each component of the hippocampal formation has a distinctive pattern of efferent connections and that each component of the fornix system arises from a specific subdivision of the hippocampus or the adjoining cortical fields. Thus, the precommissural fornix has been found to originate solely in fields CA1-3 of the hippocampus proper and from the subiculum; the projection to the anterior nuclear complex of the thalamus arises more posteriorly in the pre- and/or parasubiculum and the postsubicular area; the projection to the mammillary complex which comprises a major part of the descending columns of the fornix has its origin in the dorsal subiculum and the pre- and/or parasubiculum; and finally, the medial cortico-hypothalamic tract arises from the ventral subiculum. The lateral septal nuclei (and the adjoining parts of the posterior septal complex) constitute the only subcortical projection field of the pyramidal cells in fields CA1-3 of Ammon's horn. There is a rostral extension of the pre-commissural fornix to the bed nucleus of the stria terminalis, the nucleus accumbens, the medial and posterior parts of the anterior olfactory nucleus, the taenia tecta, and the infralimbic area, which appears to arise from the temporal part of field CA1 or the adjacent part of the ventral subiculum. The projection of Ammon's horn upon the lateral septal complex shows a high degree of topographic organization (such that different parts of fields CA1 and CA3 project in an ordered manner to different zones within the lateral septal nucleus). The septal projection of "CA2" and field CA3 is bilateral, while that of field CA1 is strictly unilateral. In addition to its subcortical projections, the hippocampus has been found to give rise to a surprisingly extensive series of intracortical association connections. For example, all parts of fields CA1, CA2 and CA3 project to the subiculum, and at least some parts of these fields send fibers to the pre- and parasubiculum, and to the entorhinal perirhinal, retrosplenial and cingulate areas. From the region of the pre- and parasubiculum there is a projection to the entorhinal cortex and the parasubiculum of both sides. That part of the postsubiculum (= dorsal part of the presubiculum) which we have examined has been found to project to the cingulate and retrosplenial areas ipsilaterally, and to the entorhinal cortex and parasubiculum bilaterally.     

Cortical projections of the non-entorhinal hippocampal formation in the cynomolgus monkey (Macaca fascicularis)

Episodic memory consolidation requires the integrity of the anatomical pathways between the cerebral cortex and the hippocampal formation. Whilst the largest cortical output of the hippocampal formation originates in the entorhinal cortex, direct projections from CA1, subiculum and presubiculum to the cortex have been reported. The aim of this study is the assessment of the extent, topography and relative strength of those projections, as a parallel/alternate route of memory processing. A total of 45 injections in 28 Macaca fascicularis monkeys were used. Cortical deposits of fluorescent tracers (20 cases, 3% Fast Blue, 2% Diamidino Yellow) or 1% WGA-HRP (eight cases) were made in different cortical areas of the frontal, temporal and parietal lobes, as well as cingulate cortex by direct exposure of the cortical surface. After appropriate survival, animals were perfused and the brains serially sectioned at 50 microm and the retrograde labelling charted with an X-Y digitizing system. Retrograde neuronal labelling was observed in CA1, subiculum, presubiculum and parasubiculum; it was absent in the dentate gyrus, CA3 and CA2. Compared to other portions of the hippocampal formation, the CA1-subiculum border had the highest number of labelled neurons (especially after deposits in the rostral perirhinal cortex), followed by medial frontal cortex, temporal pole, orbitofrontal, anterior and posterior cingulate cortices, parietal and inferotemporal cortices, and no labelling after posterior inferotemporal and lateral frontal cortices. Our results indicate that CA1, subiculum, presubiculum and parasubiculum send direct output to cortical areas. This nonentorhinal, hippocampal formation cortical output may be relevant in memory processing.     

Two reentrant pathways in the hippocampal-entorhinal system

The entorhinal cortex has long been recognized as an important interface between the hippocampal formation and the neocortex. The notion of bidirectional connections between the entorhinal cortex and the hippocampal formation have led to the suggestion that hippocampal output originating in CA1 and subiculum may reenter hippocampal subfields via the entorhinal cortex. To investigate this, we used simultaneous multi-site field potential recordings and current source density analysis in the entorhinal cortex and hippocampal formation of the rat in vivo. Under ketamine/xylazine anesthesia, we found that repetitive stimulation of subiculum or Schaffer collaterals facilitated entorhinal responses, such that a population spike appeared in layer III. In addition, a current sink in stratum lacunosum-moleculare of area CA1 was found, that followed responses in the entorhinal cortex, indicating reentrance into this area. Responses indicating reentrance in the dentate gyrus were not found under ketamine/xylazine anesthesia, but were readily evoked under urethane anesthesia. Reentrance into CA1 was also encountered under urethane anesthesia. These results suggest that parallel, but possibly functionally distinct, connections are present between the output of the hippocampal formation and cells in layers III and II of the entorhinal cortex that project to area CA1 and the dentate gyrus, respectively.     

Long-term deficits in water maze spatial conditional alternation performance following retrohippocampal lesions in rats

The effects of large bilateral retrohippocampal lesions on long-term performance of conditional spatial alternation, incorporating a strong working memory component, were examined using a T-maze task motivated by swim-escape. The lesions, which included entorhinal cortex, subiculum, pre- and parasubiculum and invaded the molecular layer of the dentate gyrus, completely eliminated the previously acquired conditional alternation learning, and performance failed to recover with 40 days of testing. These findings support the contention that retrohippocampal structures are an important and necessary component of the neural circuitry mediating working memory.     

Prostanoids in the preoptic hypothalamus mediate systemic lipopolysaccharide-induced hyperalgesia in rats

The hippocampal trisynaptic pathway is comprised of superficial entorhinal afferents (part of the perforant path) to dentate granule cells, dentate mossy fiber inputs to CA3 pyramidal neurons, and CA3 cell projections to CA1 pyramidal neurons. This CA1 output is among others to the subiculum, and both CA1 and subiculum project to the entorhinal cortex to close the loop. Smaller circuits involving fewer hippocampal and parahippocampal regions have also been described. We present morphological and electrophysiological evidence from rat brain slices for a projection from subiculum back into area CA1. Axons of neurobiotin-labeled subicular pyramidal neurons were visualized in the apical dendritic region of CA1. Spontaneous activity in isolated subiculum--CA1 slices was produced by bathing slices in reduced magnesium media. Events in CA1 always followed events in proximal subiculum. Disruption of this subiculum--CA1 circuit with a radially oriented knife cut in the apical dendritic region between subiculum and CA1 eliminated afterdischarges in subicular and CA1 events, but did not de-synchronize the two regions. Full transections between CA1 and subiculum were necessary to functionally isolate the two regions. Only subiculum remained spontaneously active. We conclude that a subiculum--CA1 circuit supports afterdischarges in both regions and synchronizes their activity. This circuit may serve to maintain a level of depolarization in subicular and CA1 pyramidal neurons well beyond the duration of excitatory synaptic potentials resulting from activation of the trisynaptic circuitry.