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.     

Afferents to the entorhinal cortex of the rat studied by the method of retrograde transport of horseradish peroxidase

The afferents to the parahippocampal area of the rat were studied with retrograde transport of horseradish peroxidase injected into the medial entorhinal cortex, lateral entorhinal cortex, parasubiculum, presubiculum, or a large injection which stained all these structures as well as the ventral hippocampus. Control rats were injected with horseradish peroxidase into the overlying visual cortex. Labeled neurons in brains with injections into the medial entorhinal cortex and the adjacent parasubicular region were found in the ipsilateral and contralateral presubicular region, the medial septal nucleus, the thalamic nucleus reuniens, the dorsal part of the lateral nucleus of thalamus, the anterior periventricular nucleus of the thalamus, and the dorsal raphe nucleus. Brains with injections into the lateral entorhinal cortex yielded labeled neurons in the medial septal nucleus, nucleus reuniens, dorsal raphe nucleus, and nucleus locus ceruleus. Injections into the presubiculum resulted, in addition, in labeling of neurons in the lateral nucleus of the thalamus. Control injections aimed at the sensory cortex overlying the parahippocampal area yielded labeled neurons in the medial septal nucleus, the dorsal lateral geniculate nucleus, and the nucleus locus ceruleus.     

The distribution of cholecystokinin-like immunoreactive neurons and nerve terminals in the retrohippocampal region in the rat and guinea pig

The distribution of cholecystokinin (CCK)-like (CCK-L) immunoreactive cells and nerve terminals was studied in the brains from rats and guinea pigs by using antibodies to the octapeptide cholecystokinin (CCK-8). Analysis of serial horizontal and sagittal sections through the retrohippocampal region in colcicine-pretreated rats revealed a relatively large number of CCK-L immunoreactive cells in the pre- and parasubiculum, subiculum, and the medial and lateral entorhinal area (EA) at all dorsal to ventral levels of the region. In the EA, the CCK-positive cells were scattered in all layers without any clear pattern. Analysis of CCK-positive cells in the retrohippocampal region showed that these cells form a morphologically heterogeneous group. The types of CCK-L immunoreactive cells ranged from small (approximately 10 micrometers) round, ovoid, or fusiform to large (approximately 30 micrometers) multipolar and pyramidal. CCK-L immunoreactive nerve fibers and preterminal processes were unevenly distributed in the retrohippocampal region. The densest innervation was found in the parasubiculum, subiculum, and the ventrolateral entorhinal area. Only a few scattered fibers were detected in the molecular layers of these structures and the outer layers of the presubiculum. Within the EA and CCK innervation indicated a heterogeneous laminar distribution that was densest in layers II and IV of the medial and lateral EA and diffuse in layers I and II. In layer II the immunoreactive nerve terminals encircled the pyramidal cell bodies, while in layers IV to VI and the most ventral part of lateral entorhinal area (LEA) and the transitional area between LEA and piriform cortex the CCK processes were distributed in a netlike fashion without clear relation to the cytoarchitectural characteristics of the area.     

Effects of enriched postoperative housing conditions on spatial memory deficits in rats with selective lesions of either the hippocampus,subiculum or entorhinal cortex

Long-Evans male, adult rats received selective and bilateral lesions of either the hippocampus, subiculum or lateral entorhinal cortex, and were then housed for 30 days in either enriched or standard conditions. Rats were then tested in the eight-arm radial maze to assess spatial working memory and the strategies that were employed (i.e. pattern of arms visited). Lesions of the hippocampus induced both a working-memory impairment and a loss in the use of allocentric strategies to perform the task. Rats with lesions of the subiculum were also impaired but less than hippocampectomized rats and showed a similar pattern of arm visits as control rats. In contrast with other lesioned rats, rats with lateral entorhinal cortex lesions performed the task like control rats. Postoperative enriched housing conditions (EHC) globally enhanced performance of rats, but did not affect the strategies selected by the rats to solve the task. The beneficial effect of EHC was particularly obvious in rats with lesions of the subiculum. In enriched rats with such lesions, performance was not significantly different from that of control rats housed in standard conditions. The present results indicate that 1) the structures within the hippocampal formation are not similarly involved in spatial learning and memory processes and in the management of navigational demands of the radial maze, and 2) enriched conditions may enhance the spared spatial abilities of some lesioned rats thus promoting functional recovery.     

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.     

Mapping parahippocampal systems for recognition and recency memory in the absence of the rat hippocampus

The present study examined immediate‐early gene expression in the perirhinal cortex of rats with hippocampal lesions. The goal was to test those models of recognition memory which assume that the perirhinal cortex can function independently of the hippocampus. The c‐fos gene was targeted, as its expression in the perirhinal cortex is strongly associated with recognition memory. Four groups of rats were examined. Rats with hippocampal lesions and their surgical controls were given either a recognition memory task (novel vs. familiar objects) or a relative recency task (objects with differing degrees of familiarity). Perirhinal Fos expression in the hippocampal‐lesioned groups correlated with both recognition and recency performance. The hippocampal lesions, however, had no apparent effect on overall levels of perirhinal or entorhinal cortex c‐fos expression in response to novel objects, with only restricted effects being seen in the recency condition. Network analyses showed that whereas the patterns of parahippocampal interactions were differentially affected by novel or familiar objects, these correlated networks were not altered by hippocampal lesions. Additional analyses in control rats revealed two modes of correlated medial temporal activation. Novel stimuli recruited the pathway from the lateral entorhinal cortex (cortical layer II or III) to hippocampal field CA3, and thence to CA1. Familiar stimuli recruited the direct pathway from the lateral entorhinal cortex (principally layer III) to CA1. The present findings not only reveal the independence from the hippocampus of some perirhinal systems associated with recognition memory, but also show how novel stimuli engage hippocampal subfields in qualitatively different ways from familiar stimuli.     

The role of the agranular insular cortex in working memory for food reward value and allocentric space in rats

The present experiment examined the effects of quinolinic acid (125 mM) lesions of the agranular insular area on working memory for food reward value and working memory for spatial locations. In both tasks a go/no-go procedure was used. Working memory for food reward value was assessed using a delayed conditional discrimination in which either a 20% or 45% sugar content cereal was associated with a reinforcement and the other cereal was not. In the spatial locations task, rats were allowed to enter 12 arms in a radial maze for a food reinforcement. Of the 12 arm presentations, three or four arms were presented for a second time in a session which did not contain a reinforcement. The number of trials between the 1st and 2nd presentation of an arm ranged from 0 to 6 (lags). Working memory was assessed by the latency to enter an arm during the 2nd presentation. In the food reward value task, agranular insular lesions produced memory deficits in a delay-dependent manner. In contrast, agranular insular lesions did not impair working memory for spatial locations. These results add to accumulating evidence suggesting that different types of working memory are distributed across separate prefrontal subregions.     

The connections of presubiculum and parasubiculum in the rat.

The present study describes the differences and similarities between the connections of the presubiculum and parasubiculum based on retrograde and anterograde tracing experiments. The results demonstrate that both areas have several similar afferent connections, particularly those from subcortical areas such as the claustrum, diagonal band of Broca, anterior thalamus, nucleus reuniens, locus coeruleus, and raphe nuclei. Both subicular areas also are innervated by axons originating in the ipsilateral and contralateral entorhinal cortex, presubiculum, and parasubiculum. In contrast to these similarities, most axons innervating the presubiculum originate in the lateral dorsal thalamic nucleus, the claustrum, and the contralateral presubiculum. Conversely, the parasubiculum is innervated primarily by axons that originate in area CA1 of the hippocampus, the basolateral nucleus of the amygdala, and the contralateral presubiculum and parasubiculum. The major efferent projection from the presubiculum and parasubiculum courses bilaterally to the medial entorhinal cortex; however, the results of the present study confirm previous suggestions that presubicular axons terminate almost exclusively in layers I and III, whereas parasubicular axons innervate layer II. The presubiculum also projects to the anteroventral and laterodorsal nuclei of the thalamus, and the lateral ventral portion of the medial mammillary nucleus, whereas the parasubiculum projects prominently to the anterodorsal nucleus of the thalamus, the contralateral presubiculum and parasubiculum, and the lateral dorsal segment of the medial mammillary nucleus. Thus despite some similarities, the major connections of presubiculum and parasubiculum are distinct from one another and distinct from the projections of the adjacent subiculum and postsubiculum. These results suggest that the subicular cortex is considerably more complex than previously envisioned and indicate that each segment may subserve a distinct role in the processing of information by the hippocampal formation.     

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.     

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)     

Entorhinal cortex of the mouse: cytoarchitectonical organization.

The present study describes the cytoarchitectonical and chemoarchitectonical organization of the entorhinal cortex of the mouse (C57BL/6J strain). The entorhinal cortex is medially bordered by the parasubiculum, and laterally by the perirhinal cortex; rostrally and medially it is bordered by the piriform cortex, whereas caudally and dorsally it is bordered by the postrhinal cortex. The entorhinal cortex is divided into two main areas, i.e., the lateral entorhinal area (LEA) and the medial entorhinal area (MEA). Both entorhinal areas are further divided into subfields, i.e., LEA is divided into DLE (dorsolateral entorhinal field), DIE (dorsal intermediate entorhinal field), and VIE (ventral intermediate entorhinal field), whereas MEA is divided into CE (caudal entorhinal field) and ME (medial entorhinal field). Cytoarchitectonically, the main difference between LEA and MEA is displayed by layer II neurons: while these are in a dense layer in LEA, they are more dispersed in MEA. Further, in LEA there is a relatively cell-free zone between layers II and III; this zone is not present in MEA. Histochemically, in acetylcholinesterase (AChE)-stained material, MEA is characterized by darker-stained bands in the superficial layer (i.e., layer I) and in the lamina dissecans, in contrast to LEA, which is more evenly stained for AChE. Further, both the border with the perirhinal cortex and the border with the parasubiculum are characterized by dark-stained bands of AChE. The border between the entorhinal cortex and perirhinal cortex is also easily distinguished in parvalbumin-stained material; while the entorhinal cortex is darkly stained, the perirhinal cortex is lightly stained. In contrast, in sections stained for calretinin, the entorhinal cortex is more lightly stained than the parasubiculum, which has a darkly stained superficial layer, and a densely stained group of neurons in layer III.     

Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats

To examine the effects of lesions of the entorhinal cortex on limbic dopamine (DA) metabolism, DA and its metabolites were assayed in five brain regions (the medial prefrontal cortex, anterior cingulate cortex, caudate-putamen, accumbens nucleus, and lateral amygdala), 14 and 28 days after quinolinic acid or sham lesions of the left entorhinal cortex in rats. Concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) on day 14 in the medial prefrontal cortex, accumbens nucleus, and lateral amygdala of the entorhinal cortex lesioned animals were significantly decreased compared with the controls, but they returned to control levels on day 28. The concentration of DA in the lateral amygdala and spontaneous locomotion to a novel environment were significantly increased on day 28 after the lesion. These results suggest that entorhinal cortex lesions alter mesolimbic dopamine metabolism, particularly in the amygdala.     

Entorhinal cortex of the rat: Organization of intrinsic connections

Two sets of experiments were carried out to examine the organization of associational connections within the rat entorhinal cortex. First, a comprehensive analysis of the areal and laminar distribution of intrinsic projections was performed by using the anterograde tracers Phaseolus vulgaris–leuocoagglutinin (PHA-L) and biotinylated dextran amine (BDA). Second, retrograde tracers were injected into the dentate gyrus and PHA-L and BDA were injected into the entorhinal cortex to determine the extent to which entorhinal neurons that project to different septotemporal levels of the dentate gyrus are linked by intrinsic connections. The regional distribution of intrinsic projections within the entorhinal cortex was related to the location of the cells of origin along the mediolateral axis of the entorhinal cortex. Cells located in the lateral regions of the entorhinal cortex gave rise to intrinsic connections that largely remained within the lateral reaches of the entorhinal cortex, i.e., within the rostrocaudally situated entorhinal band of cells that projected to septal levels of the dentate gyrus. Cells located in the medial regions of the entorhinal cortex gave rise to intrinsic projections confined to the medial portion of the entorhinal cortex. Injections made into mid-mediolateral regions of the entorhinal cortex mainly gave rise to projections to mid-mediolateral levels, although some fibers did enter either lateral or medial portions of the entorhinal cortex. These patterns were the same regardless of whether the projections originated from the superficial (II–III) or deep (V–VI) layers of the entorhinal cortex. This organizational scheme indicates, and our combined retrograde/anterograde labeling studies confirmed, that laterally situated entorhinal neurons that project to septal levels of the dentate gyrus are not in direct communication with neurons projecting to the temporal portions of the dentate gyrus. These results suggest that entorhinal intrinsic connections allow for both integration (within a band) and segregation (across bands) of entorhinal cortical information processing. J. Comp. Neurol. 398:49–82, 1998. © 1998 Wiley-Liss, Inc.     

Intrinsic connections of the retrohippocampal region in the rat brain: III. The lateral entorhinal area

This paper describes the retrohippocampal projections of individual layers of the lateral entorhinal area as studied by the method of anterograde transport of the lectin Phaseolus vulgaris leucoagglutinin (PHA-L) in the rat. As in the medial entorhinal area (EA), (K?hler, '86a) PHA-L injections restricted to individual layers of the lateral EA resulted in labeling of sparse projections to the subicular complex (e.g., subiculum, pre- and parasubiculum), whereas projections to the perirhinal area and piriform cortex were prominent. All PHA-L injections resulted in the labeling of axons projecting longitudinally within the entorhinal area, in both dorsal and ventral directions, albeit the ventral projections were the most prominent ones. PHA-L injections into layers 2a and 2b resulted in labeling of axons that could be followed into layers 2a, 2b, and layer 1 on both sides of the injection site. Whereas numerous axons appeared to terminate in layer 2, most fibers ascended into layer 1, where they ran in a medial direction, passing the medial EA, around the parasubiculum to the presubiculum. Numerous axons were found to take a lateral route running past the lateral aspect of the lateral EA to the piriform cortex. The axons running medial in layer 2 did not enter the medial EA. After PHA-L injections into layer 3, a large number of axons left the labeled cells on both sides of the injection site, in addition to massive projections that ascended into layers 2b, 2a and 1, just above the injection. Few axons entered layers 2-6 of the medial EA, but numerous axons innervated layer 1, where they were found to run in the outer half of this layer. The axons running in a medial direction reached layer 1 of the presubiculum, whereas the laterally oriented ones innervated the molecular layer of the piriform cortex. PHA-L injections into layer 4 resulted in massive labeling of projections to all superficially located layers. Layers 1, and 2b through 5 were innervated lateral to, and layer 4 medial to, the injection site. After a PHA-L injection into layer 5, ascending projections were found innervating layers 1 through 4. The terminal fields were found to be particularly dense in the deep parts of layer 3 and in layer 1. This projection expanded laterally, but few projections reached into the medial sector of the lateral EA or into the medial EA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli

Changes in the expression of immediate early gene c-fos by noxious mechanical stimulation to the mandibular incisor pulp of rats were immunohistochemically examined in the hippocampus (Ammon's horn and dentate gyrus) and the retrohippocampus (subiculum, presubiculum, parasubiculum and entorhinal cortex). The highest control levels were found in subiculum, CA1, dentate and deep medial entorhinal cortex. Lower, but substantial levels were present in the other areas. Whereas weak dentinal stimulation caused increases in c-fos expression in some regions which were not statistically significant, strong tooth pulp stimulation caused a bilateral decrease in c-fos expression in every region except contralateral subiculum. These decreases reached statistical significance in superficial layer parasubiculum bilaterally (p<0.01), bilateral CA1 and ipsilateral side of superficial layer of medial entorhinal cortex (p<0.05). We suggest that inhibitory circuitry in hippocampal formation regions may be activated by peripheral noxious somatosensory inputs and this change in activity is accompanied by a change in the expression of the immediate early gene, c-fos.     

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.     

The effects of NMDA-induced retrohippocampal lesions on performance of four spatial memory tasks known to be sensitive to hippocampal damage in the rat

Four separate cohorts of rats were employed to examine the effects of cytotoxic retrohippocampal lesions in four spatial memory tasks which are known to be sensitive to direct hippocampal damage and/or fornix-fimbria lesions in the rat. Selective retrohippocampal lesions were made by means of multiple intracerebral infusions of NMDA centred on the entorhinal cortex bilaterally. Cell damage typically extended from the lateral entorhinal area to the distal ventral subiculum. Experiment 1 demonstrated that retrohippocampal lesions spared the acquisition of a reference memory task in the Morris water maze, in which the animals learned to escape from the water by swimming to a submerged platform in a fixed location. In the subsequent transfer test, when the escape platform was removed, rats with retrohippocampal lesions tended to spend less time searching in the appropriate quadrant compared to controls. Experiment 2 demonstrated that the lesions also spared the acquisition of a working memory version of the water maze task in which the location of the escape platform was varied between days. In experiment 3, both reference and working memory were assessed using an eight-arm radial maze in which the same four arms were constantly baited between trials. In the initial acquisition, reference memory but not working memory was affected by the lesions. During subsequent reversal learning in which previously baited arms were now no longer baited and vice versa, lesioned animals made significantly more reference memory errors as well as working memory errors. In experiment 4, spatial working memory was assessed in a delayed matching-to-position task conducted in a two-lever operant chamber. There was no evidence for any impairment in rats with retrohippocampal lesions in this task. The present study demonstrated that unlike direct hippocampal damage, retrohippocampal cell loss did not lead to a general impairment in spatial learning, implying that the integrity of the retrohippocampus and/or its interconnection with the hippocampal formation is not critical for normal hippocampal-dependent spatial learning and memory. This outcome is surprising for a number of current hippocampal theories, and suggests that other cortical as well as subcortical inputs to the hippocampus might be of more importance, and further raises the question regarding the functional significance of the retrohippocampal region. Introduction     

A disconnection analysis of hippocampal function

A disconnection analysis determined the extent to which the fornix, hippocampus and entorhinal cortex are components of the same functional system in tasks that require working memory. Preoperatively, rats were trained to perform accurately on a radial arm maze. Then various combinations of unilateral and bilateral lesions were placed in the fornix and entorhinal cortex, either with or without a transection of the hippocampal commissures. When the lesions left intact at least one pathway through the hippocampus interconnecting the fornix and entorhinal cortex, rats performed normally. Either an uncrossed pathway (following a unilateral lesion of the fornix, transection of the hippocampal commissures, and an ipsilateral lesion of the entorhinal cortex) or a crossed pathway (following a unilateral lesion of the fornix and a contralateral lesion of the entorhinal cortex, leaving the hippocampal commissures intact) was sufficient. When the lesions produced a complete bilateral disconnection of the fornix and entorhinal cortex, rats performed poorly. The results indicate that the hippocampal system provides a functional connection between the subcortical structures associated with the fornix and the neocortical structures associated with the entorhinal cortex, and that without this connection normal processing of working memory can not occur.     

Connections between the retrosplenial cortex and the hippocampal formation in the rat: a review.

The retrosplenial cortex is situated at the crossroads between the hippocampal formation and many areas of the neocortex, but few studies have examined the connections between the hippocampal formation and the retrosplenial cortex in detail. Each subdivision of the retrosplenial cortex projects to a discrete terminal field in the hippocampal formation. The retrosplenial dysgranular cortex (Rdg) projects to the postsubiculum, caudal parts of parasubiculum, caudal and lateral parts of the entorhinal cortex, and the perirhinal cortex. The retrosplenial granular b cortex (Rgb) projects only to the postsubiculum, but the retrosplenial granular a cortex (Rga) projects to the postsubiculu, rostral presubiculum, parasubiculum, and caudal medial entorhinal cortex. Reciprocating projections from the hippocampal formation to Rdg originate in septal parts of CA1, postsubiculum, and caudal parts of the entorhinal cortex, but these are only sparse projections. In contrast, Rgb and Rga receive dense projections from the hippocampal formation. The hippocampal projection to Rgb originates in area CA1, dorsal (septal) subiculum, and post-subiculum. Conversely, Rga is innervated by ventral (temporal) subiculum and postsubiculum. Further, the connections between the retrosplenial cortex and the hippocampal formation are topographically organized. Rostral retrosplenial cortex is connected primarily to the septal (rostrodorsal) hippocampal formation, while caudal parts of the retrosplenial cortex are connected with temporal (caudoventral) areas of the hippocampal formation. Together, the elaborate connections between the retrosplenial cortex and the hippocampal formation suggest that this projection provides an important pathway by which the hippocampus affects learning, memory, and emotional behavior.     

Functional differentiation within the medial temporal lobe in the rat

The structures that comprise the medial temporal lobe (MTL) have been implicated in learning and memory. The question of primary concern in the present research was whether the group of anatomically related structures (hippocampus, subiculum, presubiculum/parasubiculum, entorhinal cortex, perirhinal/postrhinal cortex) are involved in mediating a similar memory process or whether the individual structures are differentially involved in memory processes and/or in handling various types of information. A series of five experiments were carried out that involved selectively lesioning the main MTL structures and testing each animal on radial-maze tasks and procedures that provided measures of two different memory processes (reference memory, working memory) and the utilization of two kinds of information (spatial, nonspatial). The structures were found to differ functionally, with the hippocampus and the presubiculum/parasubiculum being especially involved in processing spatial information, and the perirhinal/postrhinal cortex having a specific role in remembering information over a brief time period (working memory). Lesions of the entorhinal cortex failed to affect consistently either memory process or type of information handled, but they did result in impairments in learning the complex spatial discrimination requiring reference memory and in working memory involving nonspatial information. The pattern of behavioral impairments resulting from damage to these discrete MTL structures suggests that several of the structures make unique contributions to learning and memory.