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PubMed2005

Topographic activation of the medial entorhinal cortex by presubicular commissural projections.

Previous investigations have shown that presubicular commissural fibers traveling in the caudal part of the dorsal hippocampal commissure (PSD) selectively activated the dorsalmost portion of the entorhinal cortex (EC), where they discharged perforant path neurons to the dorsal dentate gyrus. The dentate activation was followed by that of the dorsal hippocampus. The aim of the present study was to ascertain whether presubiculum commissural projections traveling in the PSD can also activate ventral levels of the EC and, if so, whether this activation is followed by that of the dentate gyrus-hippocampal system in the ventral hippocampus. The experiments were carried out in adult, anesthetized guinea pigs by field potential analysis. The results showed that presubicular fibers traveling at different PSD loci selectively activated specific EC portions, with caudal fibers activating only the dorsal EC and more rostral fibers activating ventral EC points. The region activated by PSD projections corresponded to the medial EC. Current source-density (CSD) analysis revealed that at both dorsal and ventral EC levels excitatory synaptic potentials followed by neuron discharge were generated in layer II, site of origin of the perforant path to the dentate gyrus. Activation of either dorsal or ventral levels of the EC was followed by activation of the dentate gyrus-hippocampal system in corresponding hippocampal segments. The results provide physiological evidence that the commissural presubicular projections activate the EC in a topographic manner. The massive activation of perforant path neurons at all EC levels suggests that presubicular signals may strongly influence the functions played by the EC-dentate-hippocampal system.

Action Potentials↗
PubMed2006

Plasticity of synaptopodin and the spine apparatus organelle in the rat fascia dentata following entorhinal cortex lesion.

Synaptopodin is an actin-associated molecule essential for the formation of a spine apparatus in telencephalic spines. To study whether synaptopodin and the spine apparatus organelle are regulated under conditions of lesion-induced plasticity, synaptopodin and the spine apparatus were analyzed in granule cells of the rat fascia dentata following entorhinal denervation. Confocal microscopy was employed to quantify layer-specific changes in synaptopodin-immunoreactive puncta densities. Electron microscopy was used to quantify layer-specific changes in spine apparatus organelles. Within the denervated middle and outer molecular layers, the layers of deafferentation-induced spine loss, synaptogenesis, and spinogenesis, the density of synaptopodin puncta and the number of spine apparatuses decreased by 4 days postlesion and slowly recovered in parallel with spinogenesis by 180 days postlesion. Within the nondenervated inner molecular layer, the zone without deafferentation-induced spine loss, a rapid loss of synaptopodin puncta and spine apparatuses was also observed. In this layer, spine apparatus densities recovered by 14 days postlesion, in parallel with plastic remodeling at the synaptic level and the postlesional recovery of granule cell activity. These data demonstrate layer-specific changes in the distribution of synaptopodin and the spine apparatus organelle following partial denervation of granule cells: in the layer of spine loss, spine apparatus densities follow spine densities; in the layer of spine maintenance, however, spine apparatus densities appear to be regulated by other signals.

Animals↗
PubMed2004

Early eyelid opening enhances spontaneous alternation and accelerates the development of perforant path synaptic strength in the hippocampus of juvenile rats.

Development of the hippocampus is not entirely preprogrammed; its structure and function are sensitive to postnatal experience. For instance, neonatal handling/exposure to novelty and peripubertal environmental enrichment enhance hippocampal function and related memory abilities. However, these complex environmental manipulations make it difficult to deduce the primary stimuli that drive more rapid hippocampal maturation, and few experiments have studied the neural mechanisms that support the behavioral modifications. To address these issues, I performed early eyelid opening in rat pups and examined developmental alterations in exploration of a Y-maze and in synaptic transmission measured in hippocampal slices. Early eyelid opening accelerated development of spontaneous alternation. Additionally, early eyelid opening promoted more rapid remodeling of afferent input to the dentate gyrus and area CA1 as well as earlier maturation of perforant path synaptic physiology. These findings implicate visual input as an extrinsic factor that drives hippocampal development and the emergence of hippocampal-dependent behavior.

Animals↗
PubMed2005

Involvement of interferon-gamma and its receptor in the activation of astrocytes in the mouse hippocampus following entorhinal deafferentation.

The activation of glial cells has been thought to be a universal and important reaction to trauma and pathology in the mammalian central nervous system. The mechanism of glial activation is not completely clear to date, but numerous cytokines have been demonstrated to effectively influence the process in vitro and in vivo. Here we reported the axotomy-induced upregulation of interferon-gamma (IFN-gamma) receptor mRNA in the mouse hippocampus following transections of the entorhinal afferents. Northern blot analysis showed that the transcripts of IFN-gamma receptor were upregulated in a transient manner in the deafferented mouse hippocampus. In situ hybridization confirmed the temporal upregulation of IFN-gamma receptor mRNA specifically in the denervated areas of the mouse hippocampus, which showed that the expression of IFN-gamma receptor mRNA rose slightly at 2 days postlesion, increased remarkably at 3 days postlesion, nearly reached the maximum at 7 days postlesion, and almost returned to control levels at 15 days postlesion. Double labeling further proved that the upregulated IFN-gamma receptor mRNA was confined to reactive astrocytes. At 2 and 3 days postlesion, we also observed the expression of IFN-gamma mRNA by a small number of cells in the denervated areas. We noted that the upregulation of both IFN-gamma and its receptor expression coincided spatiotemporally with astroglial activation, suggesting the potential involvement of IFN-gamma and its receptor in the activation process of astrocytes in the hippocampus following entorhinal deafferentation.

Animals↗
PubMed2006

Tumor necrosis factor and its p55 and p75 receptors are not required for axonal lesion-induced microgliosis in mouse fascia dentata.

Tumor necrosis factor (TNF) is a potent pro-inflammatory and neuromodulatory cytokine. In the CNS it is produced primarily by microglia and considered to regulate microglial activation. On the basis of previous observations of increased microglial TNF mRNA synthesis in areas of anterograde axonal and terminal degeneration in mice, we studied the effect of TNF and its p55 and p75 receptors on axonal lesion-induced microglial activation in fascia dentata following transection of the perforant path (PP) projection. Unexpectedly, cell counting showed that the axonal lesion-induced microglial response in TNF and TNF-p55p75 receptor knock out mice and C57BL/6 mice was similar 5 days after the lesion. In addition, the microglial expression of the lysosomal-associated antigen CD68, and the clearance of MBP(+) myelin debris appeared similar in TNF and TNF-p55p75 receptor knock out mice compared to C57BL/6 mice. Quantitative PCR and in situ hybridization showed the expression of TNF mRNA to be maximally upregulated 6 h after the lesion, and confirmed that TNF mRNA was still upregulated 5 days after lesion when microglial numbers, CD11b mRNA level, and cellular TNF-p55 and -p75 receptor mRNA level reached maximum. However, in spite of the induction of TNF mRNA, TNF protein level remained at base-line in fascia dentata using immunohistochemistry and ELISA. In conclusion, the results showed a lower than expected lesion-induced increase in TNF protein, and that neither TNF nor its receptors were required for the axonal lesion-induced microglial morphological transformation and proliferation or for the initial clearance of degenerated myelin in the PP-deafferented fascia dentata.

Animals↗
PubMed2003

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

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

Animals↗
PubMed2003

Activation of perforant path neurons to field CA1 by hippocampal projections.

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

Algorithms↗
PubMed2004

Encoding versus retrieval of spatial memory: double dissociation between the dentate gyrus and the perforant path inputs into CA3 in the dorsal hippocampus.

The hippocampus is an essential neural structure for spatial memory. Computational models suggest that the CA3 subregion of the hippocampus plays an essential role in encoding and retrieval of spatial memory. The perforant path (PPCA3) and dentate gyrus (DG)-mediated mossy fibers (MFs) compose major afferent inputs into CA3. A possible functional dissociation between these afferent inputs was attempted using a simple navigation test (i.e., the modified Hebb-Williams maze). Behavioral testing was combined with electrolytic lesions of PPCA3 or neurotoxic lesions of the DG, to eliminate each afferent input into CA3. Lesions in either afferent input into CA3 affected learning of an effective navigational path on the maze. The contributions of the two CA3 afferent inputs, however, were different regarding encoding and retrieval of memory measured based on indices operationally defined for the behavioral paradigm (i.e., encoding, the number of errors reduced within a day; retrieval, the number of errors reduced between days). The DG-lesioned animals exhibited deficits regarding the encoding index, but not the retrieval index, whereas the PPCA3-lesioned rats displayed deficits regarding the retrieval index, but not the encoding index. The results suggest that the two major afferent inputs of CA3 may contribute differentially to encoding and retrieval of spatial memory.

Animals↗
PubMed2001

Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling.

Seizures in adult rats result in long-term deficits in learning and memory, as well as an enhanced susceptibility to further seizures. In contrast, fewer lasting changes have been found following seizures in rats younger than 20 days old. This age-dependency could be due to differing amounts of hippocampal neuronal damage produced by seizures at different ages. To determine if there is an early developmental resistance to seizure-induced hippocampal damage, we compared the effects of kainic acid (KA)-induced status epilepticus and amygdala kindling on hippocampal dentate gyrus anatomy and electrophysiology, in immature (16 day old) and adult rats. In adult rats, KA status epilepticus resulted in numerous silver-stained degenerating dentate hilar neurons, pyramidal cells in fields CA1 and CA3, and marked numerical reductions in CA3c pyramidal neuron counts (-57%) in separate rats. Two weeks following the last kindled seizure, some, but significantly less, CA3c pyramidal cell loss was observed (-26%). Both KA status epilepticus and kindling in duced mossy-fiber sprouting, as evidenced by ectopic Timm staining in supragranular layers of the dentate gyrus. In hippocampal slices from adult rats, paired-pulse stimulation of perforant path axons revealed a persistent enhancement of dentate granule-cell inhibition following KA status epilepticus or kindling. While seizures induced by KA or kindling in 16-day-old rats were typically more severe than in adults, the immature hippocampus exhibited markedly less KA-induced cell loss (-22%), no kindling-induced loss, no detectable synaptic rearrangement, and no change in dentate inhibition. These results demonstrate that, in immature rats, neither severe KA-induced seizures nor repeated kindled seizures produce the kind of hippocampal damage and changes associated with even less severe seizures in adults. The lesser magnitude of seizure-induced hippocampal alterations in immature rats may explain their greater resistance to long-term effects of seizures on neuronal function, as well as future seizure susceptibility. Conversely, hippocampal neuron loss and altered synaptic physiology in adults may contribute to increased sensitivity to epileptogenic stimuli, spontaneous seizures, and behavioral deficits.

Aging↗
PubMed2004

Parallel activation of field CA2 and dentate gyrus by synaptically elicited perforant path volleys.

Previous studies showed that dorsal psalterium (PSD) volleys to the entorhinal cortex (ENT) activated in layer II perforant path neurons projecting to the dentate gyrus. The discharge of layer II neurons was followed by the sequential activation of the dentate gyrus (DG), field CA3, field CA1. The aim of the present study was to ascertain whether in this experimental model field, CA2, a largely ignored sector, is activated either directly by perforant path volleys and/or indirectly by recurrent hippocampal projections. Field potentials evoked by single-shock PSD stimulation were recorded in anesthetized guinea pigs from ENT, DG, fields CA2, CA1, and CA3. Current source-density (CSD) analysis was used to localize the input/s to field CA2. The results showed the presence in field CA2 of an early population spike superimposed on a slow wave (early response) and of a late and smaller population spike, superimposed on a slow wave (late response). CSD analysis during the early CA2 response showed a current sink in stratum lacunosum-moleculare, followed by a sink moving from stratum radiatum to stratum pyramidale, suggesting that this response represented the activation and discharge of CA2 pyramidal neurons, mediated by perforant path fibers to this field. CSD analysis during the late response showed a current sink in middle stratum radiatum of CA2 followed by a sink moving from inner stratum radiatum to stratum pyramidale, suggesting that this response was mediated by Schaffer collaterals from field CA3. No early population spike was evoked in CA3. However, an early current sink of small magnitude was evoked in stratum lacunosum-moleculare of CA3, suggesting the presence of synaptic currents mediated by perforant path fibers to this field. The results provide novel information about the perforant path system, by showing that dorsal psalterium volleys to the entorhinal cortex activate perforant path neurons that evoke the parallel discharge of granule cells and CA2 pyramidal neurons and depolarization, but no discharge of CA3 pyramidal neurons. Consequently, field CA2 may mediate the direct transfer of ENT signals to hippocampal and extrahippocampal structures in parallel with the DG-CA3-CA1 system and may provide a security factor in situations in which the latter is disrupted.

Action Potentials↗
PubMed2004

Transcription factor NF-kappaB activation after in vivo perforant path LTP in mouse hippocampus.

There is increasing evidence that transcription factors (TFs) play a critical role in maintaining later phases of hippocampal long-term potentiation (LTP). We have been led to study the role in synaptic plasticity of the powerful, yet generally unheralded, NF-kappaB TF because it may serve as both a signaling molecule after its activation at the synapse and then a transcription initiator upon reaching the nucleus. In the present study, we show that LTP activates NF-kappaB in the intact mouse hippocampus. Mice were sacrificed 15 min after one of three treatments: tetanization (high-frequency stimulation [HFS]), low-frequency stimulation (LFS), or no stimulated control animals (CT). In a first study, nuclear NF-kappaB activity from hippocampus was estimated by electrophoretic mobility shift assays (EMSAs). A higher level of hippocampal TF binding to the NF-kappaB recognition element was found in the HFS group compared with LFS or CT. In a second study, NF-kappaB activity was evaluated by immunohistochemistry with a specific antibody that recognizes the activated form of NF-kappaB. This antibody binds to the exposed nuclear location sequence on the p65 subunit of NF-kappaB consequent to its dissociation from the inhibitory IkappaB molecule. In the four subfields of hippocampus examined--granule cell layer, hilus of the dentate gyrus, CA3 and CA1 pyramidal fields of the hippocampal gyrus--the highest levels of activated NF-kappaB, statistically significant in all cases were found after HFS. In certain comparisons, LFS animals also showed significant elevation with respect to CT. These results support the role of NF-kappaB as part of the synaptic signaling and transcriptional regulation mechanism required in long-term plasticity, emphasizing the combinatorial nature of TF function.

Animals↗
PubMed2006

Bidirectional redistribution of AMPA but not NMDA receptors after perforant path simulation in the adult rat hippocampus in vivo.

Long-term potentiation (LTP) in vitro reveals dynamic regulation of synaptic glutamate receptors. AMPA receptors may be inserted into synapses to increase neurotransmission, whereas NMDA receptors may redistribute within the synapse to alter the probability of subsequent plasticity. To date, the only evidence for these receptor dynamics in the hippocampus is from the studies of dissociated neurons and hippocampal slices taken from young animals. Although synaptic plasticity is induced easily, the extent of AMPA and NMDA receptor mobility after LTP is unknown in the adult, intact hippocampus. To test whether AMPA or NMDAR subunits undergo activity-dependent modifications in adult hippocampal synapses, we induced LTP at perforant path-dentate gyrus (DG) synapses in anesthetized adult rats, using high frequency stimulation (HFS), verified layer-specific Arc induction, and analyzed the distribution of postsynaptic AMPA and NMDAR subunits, using immunogold electron microscopy. The number of synapses with AMPA receptor labeling increased with LTP-inducing HFS in the stimulated region of the dendrite relative to the nonstimulated regions. The opposite trend was noted with low frequency stimulation (LFS). Moreover, HFS increased and LFS decreased the ratio of synaptic to extrasynaptic AMPA receptor labeling in the postsynaptic membrane. In contrast, HFS did not significantly alter NMDAR labeling. Thus, LTP in the adult hippocampus in vivo selectively enhanced AMPA but not NMDAR labeling specifically in synapses undergoing activity-dependent plasticity relative to the remainder of the dendritic tree. The results suggest a mechanism by which rapid adjustments in synaptic strength can occur through localized AMPA receptor mobility and that this process may be competitive across the dendritic tree.

Analysis of Variance↗
PubMed2006

Difference in time course of modulation of synaptic transmission by group II versus group III metabotropic glutamate receptors in region CA1 of the hippocampus.

We investigated the time course of modulation of synaptic transmission by group II and group III metabotropic glutamate receptors in region CA1 of the hippocampus. In the presence of 50 microM picrotoxin, pressure pulse application of 1 mM glutamate resulted in a fast onset of suppression of synaptic transmission in stratum lacunosum moleculare and a slower onset of suppression in stratum radiatum, with both effects returning to baseline over the course of several minutes. Application of 50 microM of the group II agonist (2R,4R)-APDC in stratum lacunosum moleculare resulted in the same fast onset of suppression while having no effect in stratum radiatum. Pressure pulse application of 100 microM DL-AP4 in stratum lacunosum moleculare and stratum radiatum resulted in a much slower onset of suppression of synaptic transmission than (2R,4R)-APDC. Suppression by (2R,4R)-APDC was accompanied by a rapid enhancement of paired pulse facilitation, indicative of a presynaptic mechanism. This demonstrates that activation of group II mGluRs in the hippocampus causes a fast onset of suppression in stratum lacunosum moleculare, while activation of group III mGluRs causes a slower onset of suppression. The difference in time course for group II vs. group III mGluRs suggests a different functional role, with group II playing a potential role in making synapses act as low pass filters.

Animals↗
PubMed2004

Dynamics of oligodendrocyte responses to anterograde axonal (Wallerian) and terminal degeneration in normal and TNF-transgenic mice.

The inflammatory cytokine tumour necrosis factor (TNF) can both induce oligodendrocyte and myelin pathology and promote proliferation of oligodendrocyte progenitor cells and remyelination. We have compared the response of the oligodendrocyte lineage to anterograde axonal (Wallerian) and terminal degeneration and lesion-induced axonal sprouting in the hippocampal dentate gyrus in TNF-transgenic mice with the response in genetically normal mice. Transectioning of the entorhino-dentate perforant path axonal projection increased hippocampal TNF mRNA expression in both types of mice, but to significantly larger levels in the TNF-transgenics. At 5 days after axonal transection, numbers of oligodendrocytes and myelin basic protein (MBP) mRNA expression in the denervated dentate gyrus in TNF-transgenic mice had increased to the same extent as in nontransgenic littermates. At this time, transgenics showed a tendency towards a greater increase in the number of juxtaposed, potentially proliferating oligodendrocytes. Noteworthy, at day 5 we also observed upregulation of MBP mRNA expression in adjacent hippocampal subregions with lesion-induced axonal sprouting, which were devoid of axonal degeneration, raising the possibility that sprouting axons provide trophic stimuli to the oligodendrocyte lineage. Twenty-eight days after lesioning, oligodendrocyte numbers and MBP mRNA expression were reduced to near normal levels. However, oligodendrocyte densities in the TNF-transgenic mice were significantly lower than in nontransgenics. We conclude that the early response of the oligodendrocyte lineage to axonal lesioning and lesion-induced axonal sprouting appears unaffected by the supranormal TNF levels in the TNF-transgenic mice. TNF may, however, have long-term inhibitory effects on the oligodendrocyte response to axonal lesioning.

Animals↗
PubMed2001

Immunoelectron microscopic localization of the neural recognition molecules L1, NCAM, and its isoform NCAM180, the NCAM-associated polysialic acid, beta1 integrin and the extracellular matrix molecule tenascin-R in synapses of the adult rat hippocampus.

We have investigated the possibility that morphologically different excitatory glutamatergic synapses of the "trisynaptic circuit" in the adult rodent hippocampus, which display different types of long-term potentiation (LTP), may express the immunoglobulin superfamily recognition molecules L1 and NCAM, the extracellular matrix molecule tenascin-R, and the extracellular matrix receptor constituent beta1 integrin in a differential manner. The neural cell adhesion molecules L1, NCAM (all three major isoforms), NCAM180 (the largest major isoform with the longest cytoplasmic domain), beta1 integrin, polysialic acid (PSA) associated with NCAM, and tenascin-R were localized by pre-embedding immunostaining procedures in the CA3/CA4 region (mossy fiber synapses) and in the dentate gyrus (spine synapses) of the adult rat hippocampus. Synaptic membranes of mossy fiber synapses where LTP is expressed presynaptically did not show detectable levels of immunoreactivity for any of the molecules/epitopes studied. L1, NCAM, and PSA, but not NCAM180 or beta1 integrin, were detectable on axonal membranes of fasciculating mossy fibers. In contrast to mossy fiber synapses, spine synapses in the outer third of the molecular layer of the dentate gyrus, which display postsynaptic expression mechanisms of LTP, were both immunopositive and immunonegative for NCAM, NCAM180, beta1 integrin, and PSA. Those spine synapses postsynaptically immunoreactive for NCAM or PSA also showed immunoreactivity on their presynaptic membranes. NCAM180 was not detectable presynaptically in spine synapses. L1 could not be found in spine synapses either pre- or postsynaptically. Also, the extracellular matrix molecule tenascin-R was not detectable in synaptic clefts of all synapses tested, but was amply present between fasciculating axons, axon-astrocyte contact areas, and astrocytic gap junctions. Differences in expression of the membrane-bound adhesion molecules at both types of synapses may reflect the different mechanisms for induction and/or maintenance of synaptic plasticity.

Animals↗
PubMed2002

Reduced field response to perforant path stimulation after adrenalectomy: effect of nimodipine treatment.

Adrenalectomy enhances apoptosis in the rat dentate gyrus and concurrently decreases the field response of dentate cells to perforant path stimulation. Recent data showed that calcium current amplitude is increased 1 day prior to the appearance of apoptotic cells, pointing to calcium as a risk factor for the onset of apoptosis. We here tested if in vivo administration of nimodipine-thus presumably reducing dentate calcium influx through L type calcium channels-prevents the appearance of apoptotic cells and the change in field responses after adrenalectomy. It was found that nimodipine does not largely alter the number of animals with apoptosis nor the average number of apoptotic cells in the tip of the suprapyramidal blade of the dentate gyrus. After nimodipine treatment, field responses in the dentate gyrus of adrenalectomized rats were comparable to responses in adrenally intact rats. However, this was due to a reduction of the field response in slices from adrenally intact rats, rather than a prevention of synaptic impairment in adrenalectomized rats. The data clearly indicates that in vivo nimodipine treatment is insufficient to prevent apoptosis and synaptic impairment after adrenalectomy.

Animals↗
PubMed2004

Aging impairs the late phase of long-term potentiation at the medial perforant path-CA3 synapse in awake rats.

The effects of aging on long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 are well documented, but LTP at the medial perforant path (MPP)-CA3 synapse of aged animals has remained unexplored. Because the MPP-DG and Schaffer-collateral-CA1 synapses account for only about 20% of total hippocampal synapses, global understanding of how aging affects hippocampal plasticity has remained limited. Much is known about LTP induction in the hippocampal formation, whereas the mechanisms that regulate LTP maintenance are less understood, especially during aging. We investigated the effects of aging on MPP-CA3 LTP induction and maintenance in awake rats. As is the case in the DG and CA1, high-frequency stimulation-induced LTP at the MPP-CA3 synapse is normal in aged rats. These data indicate that N-methyl-D-aspartate (NMDA) receptor-mediated processes are intact at the MPP-CA3 synapse in aged rats. In contrast, aging impaired the magnitude and duration of MPP-CA3 LTP over a period of days. Also, these data are consistent with reports that area CA3 is especially susceptible to age-related changes. Our data suggest that aging impairs mechanisms that regulate the late phase of MPP-CA3 LTP and contribute to a more global understanding of how aging affects hippocampal plasticity.

Aging↗
PubMed1989

New theory of hippocampal function: associated rehearsal of multiplexed coded symbols.

A new theory of the role of the hippocampus in the selective storage of information in long-term memory is presented. This theory is based on the very recent discovery that neurons in the mammalian cerebral cortex transmit extremely precise copies of patterns of discharge in time when specific sensory inputs are presented, patterns that are interpreted to code for or symbolize specific items of information. The theory incorporates and provides an explanation for both the complex and unique internal structure of the hippocampal formation (the hippocampus and associated dentate gyrus) and the roles of many of the direct and indirect connections that structure makes with other brain structures. It also explains the deficits in learning that result from damage to the hippocampus and/or tracts that provide inputs to (or outputs from) this body as well as the role of the hippocampal formation in mapping the relationship of an individual to objects in its environment. The proposed enplanation is as follows. The hippocampal formation functions as a coordinated structure that, specifically, generates multiple copies of two different kinds of symbols (i.e., specific patterns of trains of nerve discharges in time). These two kinds of patterns are respectively provided by the entorhinal cortex through the perforant-alvear pathways and by the septal region, through the fornix, one of the two inputs to and the only output from the hippocampal formation. These two separate and different kinds of patterns are used to make multiplexed patterns that are ultimately transmitted to the cingulate gyrus and from there to other cortical memory storage locations. This transmission of amplified representations of different symbols occurs through the fornix. From there they are either transmitted to the mammilary bodies in the hypothalamus and from there to the anterior thalamic nuclei or, alternatively, directly to the anterior thalamic nuclei, bypassing the mammilary bodies. These thalamic nuclei in turn project the information to the cingulate gyrus of the cortex. The effect of the transmission of these mixtures of symbols is to cause the coordinated rehearsal and selective storage of relationships between separate inputs (specifically, patterns of discharge that symbolize different aspects of input) that are of probable significance to the survival of the system. The repeated presentation of such specific combinations of representations (symbols) then causes rehearsal-consolidation of these symbol associations as more permanent memories.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗