Piriform cortex efferents to the entorhinal cortex in vivo: kindling-induced potentiation and the enhancement of long-term potentiation by low-frequency piriform cortex or medial septal stimulation

The entorhinal cortex receives input from many cortical areas and mediates the flow of information between these sites and the hippocampal formation. Long-term synaptic plasticity in cortical efferents to the entorhinal cortex may contribute to the transmission of neural activity to the hippocampus, as well as the storage of information, but little is known about plasticity in these pathways. We describe here the use of evoked field potential recordings from chronically implanted electrodes in the rat entorhinal cortex to investigate synaptic plasticity in the large piriform (olfactory) cortex projection to the superficial layers of the entorhinal cortex. Both kindling-induced potentiation and long-term potentiation (LTP) were tested. In addition, we attempted to modulate LTP induction by the co-induction of frequency potentiation and by the co-activation of the medial septum. Epileptogenic kindling stimulations of the piriform cortex (1-s, 60-Hz trains 3 times/day for 5 days) were found to result in a reliable potentiation of field responses evoked by piriform cortex test pulses. Non-epileptogenic tetanization of the piriform cortex with 400-Hz 16-pulse trains reliably resulted in LTP effects. These effects could be augmented by embedding brief LTP induction stimuli within 11-pulse, 15-Hz trains that alone produce only frequency potentiation. Co-activating the medial septum with 10-Hz trains, just prior to tetanization of the piriform cortex, augmented LTP of piriform cortex inputs to the entorhinal cortex in an input-specific manner. All potentiation effects were found to last for periods of weeks. These findings demonstrate that both epileptogenic and non-epileptogenic piriform cortex stimulation induces lasting potentiation of population field responses in the entorhinal cortex of the awake rat. The LTP effects were inducible in a graded manner and were sensitive to the temporal context of stimulation. The finding that low-frequency activation of the septum can enhance plasticity in the entorhinal cortex adds to a body of data indicating a role for the medial septum in contributing to theta activity and plasticity in both the entorhinal cortex and hippocampal formation. Hippocampus 7:257–270, 1997. © 1997 Wiley-Liss, Inc.     

Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats

Stress impairs hippocampal long-term potentiation (LTP), a model of synaptic plasticity that is assumed to underlie memory formation. In the amygdala, little is known about the effects of stress on LTP, or about its longevity. Here we assessed the ability of entorhinal cortex (EC) stimulation to induce LTP simultaneously in the basal amygdaloid nucleus (B) and in the dentate gyrus (DG) of freely behaving Wistar rats. We also tested whether LTP persists over days. Once established, we investigated the effects of acute vs. repeated inescapable stressful experiences on LTP in both structures. Results show that B, like DG, sustained LTP for 7 days. Furthermore, a single exposure to moderate stress facilitated LTP in B but did not affect DG LTP. Stress re-exposure inhibited LTP in DG but only long-lasting LTP (>3 days) in B. Behaviourally, animals exhibited a higher immobility when re-exposed to the stressor than with a single/first exposure. These data support a role for B in memory storage. Furthermore, they support a differential involvement of the amygdala and hippocampus in memory formation and storage depending on the emotional characteristics of the experience.     

The connections of the hippocampal region. New observations on efferent connections in the guinea pig, and their functional implications

This article deals with the efferent connections of the hippocampal region, and considers the functional implications of these projections. The hippocampus receives indirect sensory information from many structures in the brain. Most of these afferents terminate in the superficial layers (I-III) of the entorhinal area. From cells in layers II and III of entorhinal area projections arise which terminate in hippocampus and fascia dentata, the perforant paths. Internal hippocampal projections constitute a unidirectional system of connections which project back to the deep layers (IV-VI) of the entorhinal area. The efferents from these layers may be divided into cortically terminating efferents, which originate from layer IV, and subcortically terminating efferents, which originate from layers V and VI. The cortically terminating projections end in regions of association cortex, and in limbic cortex. The subcortical projections terminate in the caudate, the putamen, and the accumbens nucleus. A hippocampal influence on these subcortical structures may seem surprising, but is logical when one takes into consideration reports on the functional associations between the striatum and the hippocampus. The findings suggest that the role of the hippocampus may be to gather input from all sensory modalities, to assign priorities continuously between these inputs, and as a result, to modify behavior via its influence on subcortical motor centres.     

Hippocampal-neocortical interaction: a hierarchy of associativity

The structures forming the medial temporal lobe appear to be necessary for the establishment of long-term declarative memory. In particular, they may be involved in the "consolidation" of information in higher-order associational cortices, perhaps through feedback projections. This review highlights the fact that the medial temporal lobe is organized as a hierarchy of associational networks. Indeed, associational connections within the perirhinal, parahippocampal, and entorhinal cortices enables a significant amount of integration of unimodal and polymodal inputs, so that only highly integrated information reaches the remainder of the hippocampal formation. The feedback efferent projections from the perirhinal and parahippocampal cortices to the neocortex largely reciprocate the afferent projections from the neocortex to these areas. There are, however, noticeable differences in the degree of reciprocity of connections between the perirhinal and parahippocampal cortices and certain areas of the neocortex, in particular in the frontal and temporal lobes. These observations are particularly important for models of hippocampal-neocortical interaction and long-term storage of information in the neocortex. Furthermore, recent functional studies suggest that the perirhinal and parahippocampal cortices are more than interfaces for communication between the neocortex and the hippocampal formation. These structures participate actively in memory processes, but the precise role they play in the service of memory or other cognitive functions is currently unclear.     

The effects of tetanic stimulation on plasticity of remote synapses in the hippocampus-perirhinal cortex-amygdala network

In the temporal lobe, multiple synaptic pathways reciprocally link different structures. These multiple pathways play an important role in the integrity of the function of the temporal lobe and malfunction in this network has been suggested to underlie some neurological disorders such as epilepsy. To test whether the induction of long‐term potentiation (LTP) in one temporal lobe structure would modulate functional synaptic plasticity in other structures of this network, tetanic stimulation was applied to the white matter of the perirhinal cortex, Schaffer collaterals of the hippocampus, or the external capsule in combined rat amygdala–hippocampus–cortex slices. This tetanic stimulation was accompanied by enhancement of the evoked field potential slope in the third layer of perirhinal cortex, hippocampal CA1 area, and the lateral amygdala. Induction of LTP in each of these structures was concomitant with increased evoked field potentials in the neighboring structures. Surgical disconnection of anatomical pathways between these structures inhibited this concomitant enhancement of theevoked field potential slope. Both NMDA and AMPA glutamate sub‐receptors were involved in changes of synaptic plasticity elicited by induction of LTP in the neighboring structures. The present data indicate a reciprocal control among the perirhinal cortex, the amygdala, and the hippocampus plasticity. This could be important for the formation and retention of the medial temporal lobe‐dependent memory and may play a role in the involvement of all different regions of the temporal lobe in pathological conditions such as epilepsy that affect this brain structure. Synapse 66:965–974, 2012. © 2012 Wiley Periodicals, Inc.     

Direct connection between perirhinal cortex and hippocampus is a major constituent of the lateral perforant path

Single-pulse stimulation of the perirhinal cortex (PRC) evoked field responses in the dorsal hippocampal CA1 region in urethane-anesthetized rats. In depth profiles conducted by moving the PRC stimulating electrode, the largest amplitude hippocampal potential was generated when the stimulating electrode was located within the perirhinal region. More dorsal (temporal cortex) or more ventral (lateral entorhinal cortex) stimulating sites elicited minimal hippocampal potentials. The hippocampal response was maintained during 100 Hz stimulation of the PRC, suggesting that it was monosynaptic, and high-frequency stimulation (400 Hz) of the PRC produced a significant potentiation of hippocampal CA1 field potentials (46.73 ± 4.14%). When the PRC and the lateral perforant path (LPP) were stimulated separately, the depth/amplitude profiles obtained from a roving recording electrode located within the dorsal hippocampus were similar. In order to determine if fibers from PRC project to the hippocampus via the LPP, the PRC-CA1 and LPP-CA1 potentials were recorded prior to and during procaine (20%, 0.5 μl) blockade of the LPP. A simultaneous loss of both potentials was observed immediately following procaine infusion, while a commissural control potential was unaffected. Both LPP and PRC potentials returned approximately 30–40 min later. Electrolytic lesions of PRC produced a significant decrease in the amplitude of LPP-hippocampal potentials when testing was conducted 4–5 days postlesion. Lesions of lateral entorhinal cortex or temporal cortex did not produce such effects. These data suggest that a direct pathway from perirhinal cortex to the dorsal hippocampal CA1 field can undergo long-term potentiation (LTP) and that this pathway makes a major contribution to the lateral perforant path. © 1996 Wiley-Liss, Inc.     

The subiculum to entorhinal cortex projection is capable of sustaining both short- and long-term plastic changes

The hippocampus communicates with the neocortex via the entorhinal cortex. These areas are thought to be critically involved in the consolidation of memories. The hippocampus is considered to be the site of association of sensory information, which is then laid down for long-term storage in the neocortex. We examined the projection from the subiculum to the entorhinal cortex to determine whether it could function to transfer this hippocampally-processed information to the neocortex. Following stimulation in the subiculum we demonstrate a negative-going deflection followed by a positive-going deflection in the entorhinal cortex. This projection is capable of short-term plastic changes in the form of PPF. FIn addition, we demonstrate that long-term synaptic changes in the form of LTP and LTD could be sustained for at least 30min on this pathway. Finally we show that PPF changes after LTP and LTD, suggesting that a presynaptic mechanism may be involved in both of these pathways.     

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.     

Identifying cortical inputs to the rat hippocampus that subserve allocentric spatial processes: a simple problem with a complex answer

A consideration of the cortical projections to the hippocampus provides a number of candidate regions that might provide distal sensory information needed for allocentric processing. Prominent among the input regions are the entorhinal cortex, the perirhinal cortex, the postrhinal cortex, and the retrosplenial cortex. A review of these sites reveals the surprising fact that in spite of their anatomical connections, removal of the perirhinal and postrhinal cortices has little or no effect on spatial tasks and hence does not functionally disconnect the hippocampus. Extensive retrosplenial lesions have only mild effects, and even lesions of the entorhinal cortex only partially mimic the effects of hippocampal lesions upon tests of spatial memory. In contrast, studies using c-fos imaging support the involvement of the entorhinal, postrhinal, and retrosplenial cortices, but not the perirhinal cortex. It is argued that there exist multiple aspects of spatial memory, and this is reflected in the multiple routes by which cortical information can reach the hippocampus. One consequence is that lesions in a single site often have surprisingly mild effects on standard spatial tests.     

Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. I. Temporal lobe afferents.

In this investigation the efferent projections from ventral temporal neocortical and limbic cortical areas to the entorhinal and perirhinal cortices have been investigated in the rhesus monkey using silver impregnation methods. It was observed that virtually all ventral temporal neocortical areas contribute some afferents to the transitional zones of periallocortex (perirhinal and prorhinal cortices) forming the walls of the rhinal sulcus. These areas in turn project medially to the entorhinal cortex and hippocampus. Additional direct sources of afferent input to the entorhinal cortex were found to originate in Brodmann's areas 51, 49 and 27, and Bonin and Bailey's areas TF and TH. These connections have been characterized as final relays in multisynaptic cortico-cortical pathways linking the entorhinal cortex and, ultimately, hippocampus to the association areas of the frontal, parietal, temporal, and occipital lobes.     

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

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. Hippocampus 7:146–183, 1997. © 1997 Wiley-Liss, Inc.     

An experimental study of the ventral striatum of the golden hamster. I. Neuronal connections of the nucleus accumbens

As part of an experimental study of the ventral striatum, the horseradish peroxidase (HRP) method was used to examine the afferent and efferent neuronal connections of the nucleus accumbens. Following iontophoretic applications or hydraulic injections of HRP in nucleus accumbens, cells labeled by retrograde transport of HRP were observed in the ipsilateral telencephalon in the posterior agranular insular, perirhinal, entorhinal, and primary olfactory cortices, in the subiculum and hippocampal field CA1, and in the anterior and posterior divisions of the basolateral amygdaloid nucleus. In the diencephalon, labeled neurons were present ipsilaterally in the central medial, paracentral and parafascicular intralaminar nuclei, and in the midline nuclei parataenialis, paraventricularis, and reuniens. Retrograde labeling was observed in the ipsilateral brainstem in cells of the ventral tegmental area and dorsal raphe. Many of these projections to nucleus accumbens were found to be topographically organized. Anterograde transport of HRP from nucleus accumbens demonstrated ipsilateral terminal fields in the ventral pallidum and substantia nigra, pars reticulata. The afferent projections to nucleus accumbens from the posterior insular and perirhinal neocortices, intralaminar thalamus, and the dopamine-containing ventral tegmental area are analogous to the connections of the caudatoputamen, as are the efferents from nucleus accumbens to the substantia nigra and ventral globus pallidus. These connections substantiate the classification of nucleus accumbens as a striatal structure and provide support for the recently proposed concept of the ventral striatum. Furthermore, the demonstration that a number of limbic system structures, including the amygdala, hippocampal formation, entorhinal cortex, and olfactory cortex are important sources of afferents to the nucleus accumbens, suggests that the ventral striatum may serve to integrate limbic information into the striatal system.     

Connections of the parahippocampal cortex. I. Cortical afferents

In the present study in the cat the parahippocampal cortex denotes the caudoventral part of the limbic lobe and is composed of the entorhinal and perirhinal cortices. The cytoarchitecture of these areas and their borders with adjacent cortical areas are briefly discussed. The organization of the cortical afferents of the parahippocampal cortex was studied with the aid of retrograde and anterograde tracing techniques. In order to identify the source of cortical afferents, injections of retrograde tracers such as wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP), or the fluorescent substances fast blue or nuclear yellow, were placed in different parts of the parahippocampal cortex. In an attempt to further disclose the topographical and laminar organization of the afferent pathways, injections of tritiated amino acids were placed in cortical areas that were found to project to the parahippocampal cortex. The results of these experiments indicate that fibers from olfactory-related areas, the hippocampus, and other parts of the limbic cortex project only to the entorhinal cortex. The afferents from olfactory structures terminate predominantly superficially, whereas hippocampal and limbic cortical afferents are directed mainly to layers deep to the lamina dissecans. Paralimbic areas, including the anterior cingulate and the prelimbic cortices on the medial aspect, and the orbitofrontal and granular and agranular insular cortices on the lateral aspect of the hemisphere, project to the entorhinal cortex and medial parts of area 35 of the perirhinal cortex. These mostly mesocortical afferents terminate in both the superficial and deep layers of the entorhinal and perirhinal cortices. Parasensory association areas, which form part of the neocortex, do not project farther medially in the parahippocampal cortex than the perirhinal areas 35 and 36. These afferents mainly stem from a rather wide rim of neocortex that lies directly adjacent to area 36 and extends from the posterior sylvian gyrus via the posterior ectosylvian gyrus into the posterior suprasylvian gyrus. There is a rostrocaudal topographical arrangement in these projections such that rostral cortical areas distribute more rostrally and caudal parts project to more caudal parts of the perirhinal cortex. The cortex of the posterior suprasylvian gyrus contains the paravisual areas 20 and 21. The posterior sylvian gyrus most probably represents a para-auditory association area, whereas the most ventral part of the posterior ectosylvian gyrus may constitute a convergence area for visual and auditory inputs.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Functional connections and epileptic spread between hippocampus, entorhinal cortex and amygdala in a modified horizontal slice preparation of the rat brain

The hippocampus, the entorhinal cortex and the amygdala are interconnected structures of the limbic system that are implicated in memory and emotional behaviour. They demonstrate synaptic plasticity and are susceptible to development of temporal lobe epilepsy, which may lead to emotional and psychological disturbances. Their relative anatomical disposition has limited the study of neurotransmission and epileptic spread between these three regions in previous in vitro preparations. Here we describe a novel, modified-horizontal slice preparation that includes in the same plane the hippocampus, entorhinal cortex and amygdala. We found that, following application of bicuculline, each region in our preparation could generate spontaneous bursts that resembled epileptic interictal spikes. This spontaneous activity initiated in the hippocampal CA3/2 region, from where it propagated and controlled the activity in the entorhinal cortex and the amygdala. We found that this spontaneous bursting activity could spread via two different pathways. The first pathway comprises the well-known subiculum-entorhinal cortex-perirhinal cortex-amygdala route. The second pathway consists of a direct connection between the CA1 region and perirhinal cortex, through which the hippocampal bursting activity can spread to the amygdala while bypassing the entorhinal cortex. Thus, our experiments provide a new in vitro model of initiation and spread of epileptic-like activity in the ventral part of the limbic system, which includes a novel, fast and functional connection between the CA1 region and perirhinal cortex.     

Hippocampal conjunctive encoding,storage, and recall: Avoiding a trade-off

The hippocampus and related structures are thought to be capable of (1) representing cortical activity in a way that minimizes overlap of the representations assigned to different cortical patterns (pattern separation); and (2) modifying synaptic connections so that these representations can later be reinstated from partial or noisy versions of the cortical activity pattern that was present at the time of storage (pattern completion). We point out that there is a trade-off between pattern separation and completion and propose that the unique anatomical and physiological properties of the hippocampus might serve to minimize this trade-off. We use analytical methods to determine quantitative estimates of both separation and completion for specified parameterized models of the hippocampus. These estimates are then used to evaluate the role of various properties and of the hippocampus, such as the activity levels seen in different hippocampal regions, synaptic potentiation and depression, the multi-layer connectivity of the system, and the relatively focused and strong mossy fiber projections. This analysis is focused on the feedforward pathways from the entorhinal cortex (EC) to the dentate gyrus (DG) and region CA3. Among our results are the following: (1) Hebbian synaptic modification (LTP) facilitates completion but reduces separation, unless the strengths of synapses from inactive presynaptic units to active postsynaptic units are reduced (LTD). (2) Multiple layers, as in EC to DG to CA3, allow the compounding of pattern separation, but not pattern completion. (3) The variance of the input signal carried by the mossy fibers is important for separation, not the raw strength, which may explain why the mossy fiber inputs are few and relatively strong, rather than many and relatively weak like the other hippocampal pathways. (4) The EC projects to CA3 both directly and indirectly via the DG, which suggests that the two-stage pathway may dominate during pattern separation and the one-stage pathway may dominate during completion; methods the hippocampus may use to enhance this effect are discussed. © 1994 Wiley-Liss, Inc.     

Connections of the parahippocampal cortex in the cat. V. Intrinsic connections; comments on input/output connections with the hippocampus

The present report is the last in a series of papers on the connectivity of the parahippocampal cortex in the cat, which in this species is considered to be composed of the entorhinal and perirhinal cortices. Injections of anterogradely transported tritiated amino acids and the retrograde tracers HRP, WGA-HRP, fast blue, or nuclear yellow were placed within the limits of the parahippocampal cortex. An analysis was made of the resulting pattern of anterograde labeling and of the distribution of retrogradely labeled neurons within the parahippocampal cortex. It appears that within the parahippocampal cortex of the cat a framework exists, which is composed of longitudinal and transverse connections, organized according to three principles: Medially directed projections originate mostly in superficial layers, whereas laterally directed fibers come from deep layers. The longitudinal connections span the entire rostrocaudal extent of the parahippocampal cortex, whereas the mediolateral extent of the transverse connections is in general more restricted. Based on the organization of these longitudinal and transverse connections four longitudinal zones are recognized. The lateral entorhinal cortex (LEA) projects both within the entorhinal cortex and to the perirhinal cortex, whereas the intrinsic projections of the medial entorhinal cortex (MEA) are confined to the entorhinal cortex. These results are discussed in conjunction with the main organizational features of the afferent and efferent connections of the parahippocampal cortex of the cat. The premise is made that the cytoarchitectonically defined subdivisions of the cortex can be grouped into four areas, each with its own set of fiber connections and subserving different functional roles. A lateral area, constituted by the perirhinal areas 35 and 36, and the caudally adjacent postsplenial cortex, serves as a peripheral area through which the rest of the parahippocampal cortex--i.e., LEA and MEA, and ultimately the hippocampal formation--reciprocally communicates with extensive neocortical, subcortical, and thalamic regions associated with higher-order behavior. The medial part of LEA, constituted by the ventrolateral (VLEA) and ventromedial (VMEA) divisions, has reciprocal connections with the hippocampal formation and with the cortex, partly via the perirhinal cortex, and is connected with a number of subcortical structures such as the amygdala and the striatum.(ABSTRACT TRUNCATED AT 400 WORDS)     

Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy

OBJECTIVE: The objective of this study was to assess the volumes of medial temporal lobe structures using high resolution magnetic resonance images from patients with chronic refractory medial temporal lobe epilepsy (MTLE). METHODS: We studied 30 healthy subjects, and 25 patients with drug refractory MTLE and unilateral hippocampal atrophy (HA). We used T1 magnetic resonance images with 1 mm isotropic voxels, and applied a field non-homogeneity correction and a linear stereotaxic transformation into a standard space. The structures of interest are the entorhinal cortex, perirhinal cortex, parahippocampal cortex, temporopolar cortex, hippocampus, and amygdala. Structures were identified by visual examination of the coronal, sagittal, and axial planes. The threshold of statistical significance was set to p<0.05. RESULTS: Patients with right and left MTLE showed a reduction in volume of the entorhinal (p<0.001) and perirhinal (p<0.01) cortices ipsilateral to the HA, compared with normal controls. Patients with right MTLE exhibited a significant asymmetry of all studied structures; the right hemisphere structures had smaller volume than their left side counterparts. We did not observe linear correlations between the volumes of different structures of the medial temporal lobe in patients with MTLE. CONCLUSION: Patients with refractory MTLE have damage in the temporal lobe that extends beyond the hippocampus, and affects the regions with close anatomical and functional connections to the hippocampus.     

Reciprocal entorhinal-hippocampal connections established by human fetal midgestation

Little is known about the timing or sequence of genesis of connections between different areas of the developing human cerebral cortex. It has been shown that connections between areas V1 and V2 of the visual isocortex are established at about 37 weeks of gestation (Burkhalter [1993] Cerebr. Cortex 3:476–487), suggesting that cortico-cortical connections appear late in the 40-week human gestational period. However, there are indications from other studies that connections between subdivisions of the hippocampal formation may be established much earlier, by about 20 weeks of human gestation. To investigate this possibility, the lipophilic bidirectional tracer 1,1′ dioctadecyl-3,3,3′,3-tetramethylindocarbocyanine perchlorate (DiI) was used to study connections between the entorhinal cortex, hippocampus, and temporal lobe neocortex in paraformaldehyde-fixed postmortem fetal tissue. The DiI transport revealed robust reciprocal connections between the entorhinal cortex, hippocampus, and subiculum, which were consistently present at 19 weeks of gestation (the earliest age studied), and which were anatomically similar to those in adult primates. Specifically, projections to the hippocampus and subiculum originated from neurons in the entorhinal cortex (EC) layers 2 and 3, whereas reciprocal projections to the EC originated from pyramidal neurons in the cornu ammonis region CA1 and the subiculum. In contrast, the perforant pathway projection from EC to the dentate gyrus, and all connections with the neocortex, reached only rudimentary stages of development by 22 weeks of gestation (the latest age studied). These findings suggest that hippocampal pathways develop prior to isocortical pathways, and that reciprocal entorhinal-hippocampal projections may be among the first cortico-cortical connections to be established in the human brain. © 1996 Wiley-Liss, Inc.