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PubMed2003

The differential expression of corticotropin releasing factor and its binding protein in the gerbil hippocampal complex following seizure.

Considerable attention has been focused on the role of corticotropin releasing factor (CRF) as well as CRF-binding protein (CRF-BP) in neuropsychiatric disorders and neurodegenerative diseases including epilepsy. Therefore, in the present study, we investigated the temporal and spatial alteration of CRF and CRF-BP in the gerbil hippocampal complex in order to characterize the possible changes and associations with different sequelae of spontaneous seizure in these animals. CRF immunoreactivity was shown in the interneurons of the hippocampal complex at 30 min following seizure. Additionally, alteration of CRF-BP immunoreactivity was restricted to the entorhinal cortex after seizure. These results indicate some factors for consideration. First, in the gerbil hippocampal complex, the delayed increase of CRF immunoreactivity, in spite of its excitatory function, may attenuate seizure activity, but may not do so in epileptogenesis. Second, in contrast to the hippocampal complex, the increase in CRF-BP immunoreactivity in the entorhinal cortex following seizure may participate in feedback inhibitory modulation.

Animals↗
PubMed1996

Sprouting of crossed entorhinodentate fibers after a unilateral entorhinal lesion: anterograde tracing of fiber reorganization with Phaseolus vulgaris-leucoagglutinin (PHAL).

Fibers from the contralateral entorhinal cortex (EC) to the dentate gyrus partially replace the input lost after an ipsilateral EC lesion. To study the morphology and course of single sprouted crossed entorhinodentate fibers, the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHAL) was used. Rats that survived for 4 to 8 weeks after a unilateral entorhinal lesion received PHAL deposits into the entorhinal cortex contralateral to the lesion. Control animals received a similar PHAL deposit. Single PHAL-labeled fibers in the molecular layer of the contralateral (EC lesion) fascia dentata were drawn with a camera lucida, and an axon-branching index (branch points/100 microns axon length) was calculated for these crossed entorhinodentate fibers in controls and operated animals. In animals with EC lesions, the density of PHAL-labeled crossed entorhinodentate fibers had increased remarkably. Single crossed entorhinodentate axons showed significantly more axon branch points in experimental than in control animals. In addition, some axon segments displayed high densities of small axonal extensions. Frequently, tanglelike structures were observed in the denervated outer molecular layer. These tangles consisted of one or more PHAL-labeled axons that intertwined and formed an axon tangle filled completely with branches, extensions, and boutons. Our data indicate that crossed EC fibers sprout by forming additional collaterals, axonal extensions, and tangles. Abnormal neurite formations are a characteristic feature of plaques in Alzheimer's disease. Future studies must be done to show whether or not there is a close relationship between axonal tangles and plaques in Alzheimer's disease, which, like the present lesion paradigm, severely affects entorhinal projection neurons.

Acetylcholinesterase↗
PubMed1997

Expression of synaptophysin in sprouting neurons after entorhinal lesion in the rat.

Expression of the synaptic vesicle protein synaptophysin was studied in lesion-induced sprouting neurons of the contralateral entorhinal cortex and in the contralateral dentate gyrus using immunocytochemistry at the light- and electron-microscopic level. Perikaryal immunoreactivity for synaptophysin was found between 8 and 10 days postlesion. Light microscopy revealed that synaptophysin immunostaining was present in almost all neurons of layers II and III of the contralateral medial entorhinal cortex. These neurons give rise to the sprouting, crossed temporodentate pathway. In addition, some hilar neurons of the contralateral dentate gyrus, which are the parent cells of sprouting commissural fibers, were immunostained for synaptophysin. Transient immunostaining for synaptophysin was observed within cell bodies and dendrites. Additionally, the cell bodies were outlined by immunoreactive puncta, identified by electron microscopy as nerve terminals. Our results revealed that sprouting neurons express the major synaptic vesicle protein synaptophysin during reactive synaptogenesis in a pattern that reflects biosynthesis and sorting of this protein as seen in developing neurons during synapse formation.

Animals↗
PubMed1976

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.

Animals↗
PubMed1987

Facilitation of kindling by prior induction of long-term potentiation in the perforant path.

Previous studies have revealed that a form of synaptic potentiation resembling long-term potentiation (LTP) occurs at various sites as a result of stimulation that leads to kindling. The present study evaluates what role this synaptic potentiation plays in the development of kindling following periodic stimulation of the entorhinal cortex of the rat. LTP was repetitively induced in the pathway from the entorhinal cortex (EC) to the dentate gyrus (DG) by daily stimulation with high frequency trains that led to LTP, but did not evoke afterdischarge (AD). Subsequently, animals received stimulation designed to induce kindling (that led to AD), and this stimulation was delivered once per day until kindled seizures were induced. While repetitive induction of LTP was not sufficient to produce kindling, prior induction of LTP significantly increased the rate of subsequent kindling as evidenced by a decrease in the number of kindling stimulations required to induce the kindled state. As a group, animals that had received stimulation designed to induce LTP developed kindled seizures after an average of 10 AD's, whereas a control group that had received non-potentiating stimulation required 25 AD's. These results indicate that LTP at EC-DG synapses cannot represent the mechanism of kindling following EC stimulation. However, synaptic potentiation at this site can facilitate the development of epileptogenesis in response to subsequent activation of the perforant path.

Action Potentials↗
PubMed1976

Reinnervation of dentate gyrus by homologous afferents following entorhinal cortical lesions in adult rats.

Granule cells of the rat dentate gyrus which are denervated by unilateral destruction of the entorhinal cortex are reinnervated in part by proliferation of surviving pathways from the contralateral entorhinal cortex. The cells of origin of these lesion-induced projections were identified by retrograde labeling with horseradish peroxidase and were the same cell type which normally project to the ipsilateral dentate gyrus

Afferent Pathways↗
PubMed2005

Entorhinal projections terminate onto principal neurons and interneurons in the subiculum: a quantitative electron microscopical analysis in the rat.

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

Animals↗
PubMed2002

Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry.

Place cells in hippocampal area CA1 may receive positional information from the intrahippocampal associative network in area CA3 or directly from the entorhinal cortex. To determine whether direct entorhinal connections support spatial firing and spatial memory, we removed all input from areas CA3 to CA1, thus isolating the CA1 area. Pyramidal cells in the isolated CA1 area developed sharp and stable place fields. Rats with an isolated CA1 area showed normal acquisition of an associative hippocampal-dependent spatial recognition task. Spatial recall was impaired. These results suggest that the hippocampus contains two functionally separable memory circuits: The direct entorhinal-CA1 system is sufficient for recollection-based recognition memory, but recall depends on intact CA3-CA1 connectivity.

Action Potentials↗
PubMed1994

Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease.

We quantified by microdensitometry the immunoreactivity (IR) to monoclonal antibodies (SP6, SP12, SP15 and SP18) against various synaptic proteins in the molecular layers of the dentate gyrus, CA4, CA3, CA1, subiculum and entorhinal cortex in Alzheimer's disease (AD), Lewy body variant of AD (LBV) and diffuse Lewy body disease (DLBD). A significant decrease in SP6 IR was observed in almost all regions in AD (28.4-70.1%, mean 41.3%), LBV (19.0-42.5%, mean 26.8%) and DLBD (19.9-31.7%, mean 27.1%) compared to controls. In addition, SP6 IR in the outer molecular layer of the dentate gyrus was strongly correlated with tangle count in the entorhinal cortex (r = -0.70, P < 0.002), suggesting loss of perforant pathway projection. Although the decrease in SP12 and SP15 IR was less pronounced, the mean values were decreased in dementia. Furthermore, SP12 and SP15 labeled a large number of neuritic plaques, and SP15 occasionally stained cortical LBs. The present findings indicate (i) that in the hippocampal-entorhinal formation, the decrease of synapse protein IR in AD is more severe than that in LBV and DLBD, (ii) that synaptic markers detect a subset of dystrophic neurites in the plaques and (iii) that synapse proteins are involved in the formation of cortical LBs.

Aged↗
PubMed2003

Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease.

Cell cycle events play a major role in the loss of neurons in advanced Alzheimer's disease (AD). It is currently unknown, however, whether the same is true for the neuronal losses in early disease stages. To explore this issue we analyzed brain autopsy material from individuals clinically categorized with mild cognitive impairment (MCI), many if not most of whom will progress to AD. Immunocytochemistry for three cell cycle-related proteins, proliferating cell nuclear antigen, cyclin D, and cyclin B, was performed on sections from hippocampus, basal nucleus of Meynert, and entorhinal cortex. The results obtained from MCI cases were compared with material from individuals diagnosed with AD and those without cognitive impairment. In both hippocampus and basal nucleus, there was a significant percentage of cell cycle immunopositive neurons in the MCI cases. These percentages were similar to those found in the AD cases but significantly higher than non-cognitively impaired controls. In entorhinal cortex, the density of cell cycle-positive neurons was greater in MCI than in AD. However, we observed large variations in the percentages of immunopositive neurons from individual to individual. These findings lend support to the hypothesis that both the mechanism of cell loss (a cell cycle-induced death) and the rate of cell loss (a slow atrophy over several months) are identical at all stages of the AD disease process. The implication of the findings for human clinical trials is discussed.

Aged↗
PubMed2000

The pathological substrate of limbic epilepsy: neuronal loss in the medial dorsal thalamic nucleus as the consistent change.

PURPOSE: The focus of research in limbic epilepsy has been the hippocampus because of its well-known pathology of hippocampal atrophy and sclerosis as well as the strong propensity for this structure to seize under a variety of circumstances. There is ample evidence, however, for pathological alterations in other regions of the limbic system in limbic/mesial temporal lobe epilepsy, including the amygdala, the entorhinal cortex, and, in some cases, the thalamus. In this preliminary evaluation of the pathological substrate for limbic epilepsy, we wished to determine if there was consistent anatomic change at extrahippocampal sites. METHODS: We compared paraffin sections of brains from rats with chronic spontaneous limbic epilepsy and age-matched controls to determine the consistency of the pathology at five sites: the hippocampus, amygdala, entorhinal cortex, piriform cortex, and medial dorsal thalamus. RESULTS: In a qualitative evaluation of these sections taken from standardized positions, we found that the medial dorsal thalamic nucleus in the epileptic animals was the site that was consistently involved with neuronal loss. With all other sites, at least several animals had qualitatively normal tissue. CONCLUSIONS: This finding suggests that neuronal loss in the medial dorsal thalamus may be the consistent pathology in limbic epilepsy, at least in an animal model of the disorder. The presence of a structurally abnormal subcortical region with broad connections to the limbic sites involved with chronic epilepsy may have implications for our understanding of the pathophysiology of this disorder.

Animals↗
PubMed1994

Selective activation of deep layer (V-VI) retrohippocampal cortical neurons during hippocampal sharp waves in the behaving rat.

The coordinated activity of hippocampal neurons is reflected by macroscopic patterns, theta and sharp waves (SPW), evident in extracellular field recordings. The importance of these patterns is underscored by the ordered relation of specific neuronal populations to each pattern as well as the relation of each pattern to distinct behavioral states. During awake immobility, consummatory behavior, and slow wave sleep, CA3 and CA1 neurons participate in organized population bursts during SPW. In contrast, during theta-associated exploratory activity, the majority of principle cells are silent. Considerably less is known about the discharge properties of retrohippocampal neurons during theta, and particularly during SPW. These retrohippocampal neurons (entorhinal cortical, parasubicular, presubicular, and subicular) process and transmit information between the neocortex and the hippocampus. The present study examined the activity of these neurons in freely behaving rats during SPW (awake immobility) as well as theta (locomotion and REM sleep). A qualitative distinction between the activity of deep (V-VI) and superficial (II-III) layer retrohippocampal neurons was observed in relation to SPW as compared to theta. Deep layer retrohippocampal neurons exhibited a concurrent increase in activity during hippocampal SPW. In contrast, deep layer neurons were not modulated by the prominent theta oscillations observed throughout the hippocampus and entorhinal cortex. On the other hand, superficial layer retrohippocampal neurons were often phase-related to theta oscillations, but were surprisingly indifferent to the SPW-associated population bursting occurring within the deep layers. These findings indicate a concerted discharge of the hippocampal and retrohippocampal cortices during SPW that includes neurons within CA3, CA1, and subiculum as well as neurons in layers V-VI of the presubiculum, parasubiculum, and entorhinal cortex. Further, they suggest a temporal discontinuity in the input/output relations between the hippocampus and retrohippocampal structures. We suggest that SPW-associated population bursts in hippocampal and retrohippocampal cortices exert a powerful depolarizing effect on their postsynaptic neocortical targets and may represent a physiological mechanism for memory trace transfer from the hippocampus to the neocortex.

Animals↗
PubMed2000

The involvement of recurrent connections in area CA3 in establishing the properties of place fields: a model.

Strong constraints on the neural mechanisms underlying the formation of place fields in the rodent hippocampus come from the systematic changes in spatial activity patterns that are consequent on systematic environmental manipulations. We describe an attractor network model of area CA3 in which local, recurrent, excitatory, and inhibitory interactions generate appropriate place cell representations from location- and direction-specific activity in the entorhinal cortex. In the model, familiarity with the environment, as reflected by activity in neuromodulatory systems, influences the efficacy and plasticity of the recurrent and feedforward inputs to CA3. In unfamiliar, novel, environments, mossy fiber inputs impose activity patterns on CA3, and the recurrent collaterals and the perforant path inputs are subject to graded Hebbian plasticity. This sculpts CA3 attractors and associates them with activity patterns in the entorhinal cortex. In familiar environments, place fields are controlled by the way that perforant path inputs select among the attractors. Depending on the training experience provided, the model generates place fields that are either directional or nondirectional and whose changes when the environment undergoes simple geometric transformations are in accordance with experimental data. Representations of multiple environments can be stored and recalled with little interference, and these have the appropriate degrees of similarity in visually similar environments.

Animals↗
PubMed1997

Parallel input to the hippocampal memory system through peri- and postrhinal cortices.

In the rat, the rhinal cortices consist of the perirhinal, postrhinal and entorhinal cortices. The perirhinal and postrhinal cortices, which serve as major input sources to the entorhinal cortex, receive functionally different types of information. In this study we looked at the projections from the perirhinal and postrhinal cortices to the different parts of the entorhinal cortices using an anterograde tracing technique. Our results show that the perirhinal cortex preferentially projects to the lateral entorhinal cortex, whereas the postrhinal cortex mainly sends fibers to the medial entorhinal cortex. Since the lateral and medial entorhinal cortices are differentially connected with the hippocampus, we suggest that functionally different types of information are processed in parallel in the hippocampal memory system.

Animals↗
PubMed2000

Regionally selective changes in brain lysosomes occur in the transition from young adulthood to middle age in rats.

The possibility that brain aging in rats exhibits regional variations of the type found in humans was studied using lysosomal chemistry as a marker. Age-related (two vs 12months; male Sprague-Dawley) differences in cathepsin D immunostaining were pronounced in the superficial layers of entorhinal cortex and in hippocampal field CA1, but not in neocortex and field CA3. Three changes were recorded: an increase in the intraneuronal area occupied by labeled lysosomes; clumping of immunopositive material within neurons; more intense cytoplasmic staining. Western blot analyses indicated that the increases involved the active forms of cathepsin D rather than their proenzyme. Shrinkage of cathepsin-D-positive neuronal cell bodies was observed in entorhinal cortex but not in neocortical sampling zones. Age-related lysosomal changes as seen with cathepsin B immunocytochemistry were considerably more subtle than those obtained with cathepsin D antibodies. In contrast, a set of glial and/or vascular elements located in a distal dendritic field of the middle-aged hippocampus was much more immunoreactive for cathepsin B than cathepsin D. The areas exhibiting sizeable changes in the present study are reported to be particularly vulnerable to aging in humans. The results thus suggest that aspects of brain aging common to mammals help shape neurosenescence patterns in humans.

Aging↗
PubMed2000

The lesional and epileptogenic consequences of lithium-pilocarpine-induced status epilepticus are affected by previous exposure to isolated seizures: effects of amygdala kindling and maximal electroshocks.

In temporal lobe epilepsy, the occurrence of seizures seems to correlate with the presence of lesions underlying the establishment of a hyperexcitable circuit. However, in the lithium-pilocarpine model of epilepsy, neuronal damage occurs both in the structures belonging to the circuit of initiation and maintenance of the seizures (forebrain limbic system) as in the propagation areas (cortex and thalamus) and in the circuit of remote control of seizures (substantia nigra pars reticulata). To determine whether or not we could protect the brain from lesions and epileptogenesis induced by status epilepticus and identify cerebral structures involved in the genesis of epilepsy, we studied the effects of the chronic exposure to non-deleterious seizures, either focalized with secondary generalization (amygdala kindling, kindled-pilocarpine rats), or primary generalized (ear-clip electroshocks, electroshock-pilocarpine rats) on neuronal damage and epileptogenesis induced by lithium-pilocarpine status epilepticus. These animals were compared to rats subjected to status epilepticus but not pretreated with seizures (sham-kindled-pilocarpine or sham-electroshock-pilocarpine rats). Compared to sham-pilocarpine rats, neuronal damage was prevented in the limbic system of the kindled-pilocarpine rats, except in the hilus of the dentate gyrus and the entorhinal cortex, while it was enhanced in rats pretreated with electroshocks, mainly in the entorhinal and perirhinal cortices. Most sham-kindled- and sham-electroshock-pilocarpine rats (92-100%) developed recurrent seizures after a silent period of 40-54days. Likewise, all kindled-pilocarpine rats developed spontaneous seizures after the same latency as their sham controls, while only two of 10 electroshock-pilocarpine rats became epileptic after a delay of 106-151days. The present data show that the apparent antiepileptic properties of electroshocks correlate with extensive damage in midbrain cortical regions, which may prevent the propagation of seizures from the hippocampus and inhibit their motor expression. Conversely, the extensive neuroprotection of the limbic system but not the hilus and entorhinal cortex provided by amygdala kindling does not prevent epileptogenesis. Thus, the hilus, the entorhinal and/or perirhinal cortex may be key structure(s) for the establishment of epilepsy.

Amygdala↗
PubMed1997

Immediate early gene expression and delayed cell death in limbic areas of the rat brain after kainic acid treatment and recovery in the cold.

Systemic injection of kainic acid (KA) results in characteristic behaviors and programmed cell death in some regions of the rat brain. We used KA followed by recovery at 4 degrees C to restrict damage to limbic structures and compared patterns of immediate early gene (IEG) expression and associated DNA binding activity in these damaged areas with that in spared brain regions. Male Wistar rats were injected with KA (12 mg/kg, i.p.) and kept at 4 degrees C for 5 h. This treatment reduced the severity of behaviors and restricted damage (observed by Nissl staining) to the CA1 and CA3 regions of the hippocampus and an area including the entorhinal cortex. DNA laddering, characteristic of apoptosis, was first evident in the hippocampus and the entorhinal cortex 18 and 22 h after KA, respectively. The pattern of IEG mRNA induction fell into three classes: IEGs that were induced in both damaged and spared areas (c-fos, fos B, jun B, and egr-1), IEGs that were induced specifically in the damaged areas (fra-2 and c-jun), and an IEG that was significantly induced by saline injection and/or the cold treatment (jun D). The pattern of immunoreactivity closely followed that of mRNA expression. Binding to the AP-1 and EGR DNA consensus sequences increased in all three regions studied. This study describes a unique modification of the animal model of KA-induced neurotoxicity which may prove a useful tool for dissecting the molecular cascade that ultimately results in programmed cell death.

Animals↗
PubMed1996

Development and application of a modified monoclonal hybridoma technique for isolating monoclonal antibodies to human brain regions.

We developed a modified monoclonal hybridoma technique that combines two conventional methods: a conventional immunosuppression method with cyclophosphamide treatment and an in vitro immunization method. This technique is advantageous over conventional methodologies because it requires a shorter period for immunization of mice and a smaller quantity of antigen, and gives rise to antibody-secreting hybridomas with higher efficiency. One monoclonal hybridoma line, designated as BG5, was established by this technique after activation of lymphocytes with muramyl dipeptide and with the immunogen obtained from human entorhinal cortex. Western blot analysis showed a relatively high expression of BG5 antigen in human entorhinal cortex. Our results suggest that this hybridoma technique may rapidly facilitate the acquisition of brain region-specific antibodies. We call this technique 'suppression immunization followed by in vitro stimulation procedure' (SOFISTIC).

Antibodies, Monoclonal↗