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PubMed1988

Cholinergic neurons within the rat hippocampus: response to fimbria-fornix transection.

The distribution and morphologic characteristics of choline acetyltransferase (ChAT)-containing neurons were studied throughout the rostrocaudal extent of the rat hippocampus and in a midline area just dorsal to the dorsal hippocampus. Peroxidase reaction product was observed with the aid of immunohistochemical methods and a high-titer polyclonal antibody against ChAT, the acetylcholine biosynthetic enzyme. ChAT-positive cells in the hippocampus were characterized by small, round or oval perikarya with two or more proximal processes. They were located within the caudal and temporal hippocampal formation, predominantly within the subiculum, in the stratum lacunosum moleculare, at the border of the stratum lacunosum moleculare and the stratum radiatum, and in the molecular layer of the dentate gyrus. The cells resembled in morphology the small, bipolar and multipolar neocortical ChAT-immunoreactive cells. In addition to the hippocampus, ChAT-positive neurons were observed caudally in a region just above the dorsal hippocampal commissure and rostrally in the columns of the fornix. These cells were large with an oval perikarya and darkly labeled compared to neurons in the hippocampus. They more closely resembled the ChAT-positive neurons in the midline raphe of the medial septal nucleus. Examination of the rat hippocampus 2 and 8 weeks following unilateral lesioning of the fimbria-fornix and supracallosal striae revealed a sparse innervation of ChAT-positive fibers in the hippocampus ipsilateral to the lesion. ChAT-labeled neurons in the hippocampus did not appear to sprout in response to the lesion. In contrast, ChAT-positive cells in the midline did appear to sprout into the medial dorsal subiculum and dorsal medial hippocampus. We conclude that these two populations of cells are distinct with respect to their response to hippocampal denervation and, furthermore, that this distinction may be attributed to a differential response to nerve growth factor.

Animals↗
PubMed2003

Fetal hippocampal CA3 cell grafts enriched with fibroblast growth factor-2 exhibit enhanced neuronal integration into the lesioned aging rat hippocampus in a kainate model of temporal lobe epilepsy.

Aging impairs the conduciveness of the lesioned hippocampus for robust survival of neurons derived from homotopic fetal cell grafts (Zaman and Shetty, Neuroscience 109:537-553, 2002), suggesting a need for graft augmentation in fetal graft-mediated therapeutic strategies for the lesioned aging hippocampus. We hypothesize that pretreatment and grafting of donor hippocampal CA3 cells with fibroblast growth factor-2 (FGF-2) considerably enhances graft neuronal integration into the lesioned CA3 region of the aging hippocampus. We employed the optical fractionator cell counting method and quantified the number of surviving cells and neurons derived from 5'-bromodoxyuridine-labeled embryonic day 19 CA3 cell grafts pre-treated and transplanted with FGF-2 into the lesioned CA3 region of the middle-aged and aged rat hippocampus at 4 days post-lesion. In both middle-aged and aged hippocampus, pre-treatment and transplantation of CA3 cell grafts with FGF-2 resulted in a robust yield of surviving cells (72-80% of injected cells) and neurons (62-69% of injected cells) from grafts. The overall yield was dramatically greater than the yield observed earlier from standard (untreated) fetal CA3 cell grafts into the lesioned aging hippocampus but was highly comparable to that observed for standard fetal CA3 cell grafts into the lesioned young hippocampus (Zaman and Shetty, Neuroscience 109:537-553, 2002). Thus, a robust neuronal integration from fetal CA3 cell grafts can be achieved into the lesioned CA3 region of the aging hippocampus with a simple pre-treatment and grafting of donor fetal CA3 cells with FGF-2. These results have implications toward the development of suitable cell grafting strategies for repair of the lesioned aging hippocampus in neurodegenerative diseases, particularly the temporal lobe epilepsy, stroke, and Alzheimer's disease.

Animals↗
PubMed2004

Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin.

To lesion the cholinergic input to the hippocampus, rats received injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB). The lesions produced near-total loss of choline acetyltransferase (ChAT)-positive neurons in the MS/VDB. The loss was accompanied, however, by only partial decreases (to 40% of control levels) in acetylcholine (ACh) release in the hippocampus. Moreover, ACh release in the hippocampus increased when lesioned and control rats were tested on a spontaneous alternation task, indicating that there was significant residual cholinergic function in the hippocampus. The lesions were sufficient to impair spontaneous alternation scores. However, this impairment could be reversed by either systemic or intra-hippocampal injections of the indirect cholinergic agonist, physostigmine, providing additional evidence of residual and effective cholinergic functions in the hippocampus of lesioned rats. Moreover, systemic injections of physostigmine at doses that produced mild tremors in control rats led to more severe tremors in the lesioned rats, suggesting upregulation of cholinergic mechanisms after saporin lesions, likely in brain areas other than the hippocampus. Thus, these findings provide evidence for decreases in cholinergic input to the hippocampus accompanied by deficits on a spontaneous alternation tasks. The findings also provide evidence for considerable residual cholinergic input to the hippocampus after saporin lesions of the MS/VDB. Together, the results suggest that 192 IgG-saporin lesions of the MS/VDB, using methods often employed, do not fully remove septohippocampal cholinergic input to the hippocampus but are nonetheless sufficient to produce impairments on a task impaired by hippocampal lesions.

Acetylcholine↗
PubMed2001

Storage, recall, and novelty detection of sequences by the hippocampus: elaborating on the SOCRATIC model to account for normal and aberrant effects of dopamine.

In order to understand how the molecular or cellular defects that underlie a disease of the nervous system lead to the observable symptoms, it is necessary to develop a large-scale neural model. Such a model must specify how specific molecular processes contribute to neuronal function, how neurons contribute to network function, and how networks interact to produce behavior. This is a challenging undertaking, but some limited progress has been made in understanding the memory functions of the hippocampus with this degree of detail. There is increasing evidence that the hippocampus has a special role in the learning of sequences and the linkage of specific memories to context. In the first part of this paper, we review a model (the SOCRATIC model) that describes how the dentate and CA3 hippocampal regions could store and recall memory sequences in context. A major line of evidence for sequence recall is the "phase precession" of hippocampal place cells. In the second part of the paper, we review the evidence for theta-gamma phase coding. According to a framework that incorporates this form of coding, the phase precession is interpreted as cued recall of a discrete sequence of items from long-term memory. The third part of the paper deals with the issue of how the hippocampus could learn memory sequences. We show that if multiple items can be active within a theta cycle through the action of a short-term "buffer," NMDA-dependent plasticity can lead to the learning of sequences presented at realistic item separation intervals. The evidence for such a buffer function is reviewed. An important underlying issue is whether the hippocampal circuitry is configured differently for learning and recall. We argue that there are indeed separate states for learning and recall, but that both involve theta oscillations, albeit in possibly different forms. This raises the question of how neuromodulatory input might switch the hippocampus between learning and recall states and more generally how different neuromodulatory inputs reconfigure the hippocampus for different functions. In the fifth part of this paper we review our studies of dopamine and dopamine/NMDA interactions in the control of synaptic function. Our results show that dopamine dramatically reduces the direct cortical input to CA1 (the perforant path input), while having little effect on the input from CA3. In order to interpret the functional consequences of this pathway-specific modulation, it is necessary to understand the function of CA1 and the role of dopaminergic input from the ventral tegmental area (VTA). In the sixth part of this paper we consider several possibilities and address the issue of how dopamine hyperfunction or NMDA hypofunction, abnormalities that may underlie schizophrenia, might lead to the symptoms of the disease. Relevant to this issue is the demonstrated role of the hippocampus in novelty detection, a function that is likely to depend on sequence recall by the hippocampus. Novelty signals are generated when reality does not match the expectations generated by sequence recall. One possible site for computing mismatch is CA1, since it receives predictions from CA3 and sensory "reality" via the perforant path. Our data suggest that disruption of this comparison would be expected under conditions of dopamine hyperfunction or NMDA hypofunction. Also relevant is the fact that the VTA, which fires in response to novelty, may both depend on hippocampal-dependent novelty detection processes and, in turn, affect hippocampal function. Through large-scale modeling that considers both the processes performed by the hippocampus and the neuromodulatory loops in which the hippocampus is embedded, it is becoming possible to generate working hypotheses that relate synaptic function and malfunction to behavior.

Acetylcholine↗
PubMed2002

Survival of fetal hippocampal CA3 cell grafts in the middle-aged and aged hippocampus: effect of host age and deafferentation.

The potential application of neural transplantation to many neurodegenerative disorders at early stages of disease progression would involve middle-aged and aged persons. Hence, it is important to examine critically the extent of graft cell survival in both intact and partially deafferented middle-aged and aged brain. We investigated the degree of survival of 5'-bromodeoxyuridine (BrdU)-labeled fetal hippocampal CA3 cells after grafting into both intact hippocampus and partially deafferented hippocampus (i.e., hippocampus contralateral to intracerebroventricular administration of kainic acid) of middle-aged and aged Fischer 344 rats. Absolute cell survival within these grafts was rigorously analyzed using BrdU immunostaining of serial sections and the optical fractionator cell counting method. In the intact hippocampus, graft cell survival was 23% of injected cells for middle-aged rats and 18% for aged rats, which is consistent with the survival of fetal hippocampal cells in the intact young adult hippocampus reported earlier (Shetty and Turner [1995] Neuroscience 67:561-582). A partial deafferentation at the time of grafting significantly enhanced the degree of graft cell survival to 35% of injected cells in the middle-aged hippocampus and 27% in the aged hippocampus. However, the overall graft cell survival after deafferentation was significantly (30%) greater in the middle-aged hippocampus compared with the aged hippocampus. These results reveal that 1) the degree of survival of fetal neural cells in the intact mature brain remains constant with aging and 2) a partial deafferentation of the mature host brain at the time of grafting enhances survival of grafted fetal cells, regardless of the host age. However, the overall extent of graft cell survival after deafferentation depends on the age of the mature brain at the time of deafferentation.

Age Factors↗
PubMed2001

The ventral hippocampus and fear conditioning in rats. Different anterograde amnesias of fear after tetrodotoxin inactivation and infusion of the GABA(A) agonist muscimol.

Studies on the involvement of the rat hippocampus in classical fear conditioning have focused mainly on the dorsal hippocampus and conditioning to a context. However, the ventral hippocampus has intimate connections with the amygdala and the nucleus accumbens, which are involved in classical fear conditioning to explicit and contextual cues. Consistently, a few recent lesion studies have indicated a role for the ventral hippocampus in classical fear conditioning to explicit and contextual cues. The present study examined whether neuronal activity within the ventral hippocampus is important for the formation of fear memory to explicit and contextual cues by classical fear conditioning. Tetrodotoxin (TTX; 10 ng/side), which completely blocks neuronal activity, or muscimol (1 microg/side), which increases GABA(A) receptor-mediated inhibition, were bilaterally infused into the ventral hippocampus of Wistar rats before the conditioning session of a classical fear-conditioning experiment. Conditioning to a tone and the context were assessed using freezing as a measure of conditioned fear. TTX blocked fear conditioning to both tone and context. Muscimol only blocked fear conditioning to the context. The data of the present study indicate that activity of neurons in the ventral hippocampus is necessary for the formation of fear memory to both explicit and contextual cues and that neurons in the ventral hippocampus that bear the GABA(A) receptor are important for the formation of fear conditioning to a context. In addition, both bilateral muscimol (0.5 microg/side and 1 microg/side) and TTX (5 ng/side and 10 ng/side) infusion into the ventral hippocampus dose-dependently decreased locomotor activity in an open-field experiment.

Acoustic Stimulation↗
PubMed1975

Projections of the hippocampus to the septal area in the squirrel monkey.

An experiment was performed to determine the projections of the anterior, central, and posterior regions of hippocampus to the spetum in the squirrel monkey. Lesions were placed in each of these regions of hippocampus in 18 animals. Survival times varied from 5 to 7 days. Tissues were stained principally by the Fink-Heimer I method for identification of degenerating axons and their terminals. Following lesions which destroyed one or more fields of the anterior third of hippocampus degenerating axons were traced through the fimbria and fornix to the lateral septal area where dense quantities of terminal degeneration were observed. Smaller quantities of terminal degeneration were noted in the nucleus accumbens as well. After lesions of the middle third of hippocampus terminal degeneration was observed in an intermediolateral position within the septum. Following lesions of the posterior third of hippocampus degenerating terminals were observed in the area of the medial septum. All regions of hippocampus send fibers to the nucleus of the diagonal band and to the olfactory tubercle. These findings indicate that in the primate the projection to the septum from the hippocampus is topographically organized along its longitudinal axis in a manner that links the anterior hippocampus to the lateral septum and the posterior hippocampus to the medial septum.

Animals↗
PubMed1993

Compensatory changes of in vivo acetylcholine and noradrenaline release in the hippocampus after partial deafferentation, as monitored by microdialysis.

Lesions of the fimbria-fornix pathways are known to induce a partial cholinergic and noradrenergic denervation of the hippocampal formation, which is followed by a slow and protracted collateral sprouting by the spared afferents. Using the intracerebral microdialysis technique, compensatory changes in extracellular levels of acetylcholine (ACh) and noradrenaline (NA) have been monitored over time in the partially denervated hippocampus of awake unrestrained rats subjected to an unilateral fimbria-fornix (FF) transection. One week after the lesion, baseline ACh output was reduced by 90% and 80% in the dorsal and ventral hippocampus, respectively, and it remained depressed still by 6 months after lesion. KCl-evoked and atropine-stimulated ACh efflux were equally reduced by 1 week after lesion, remained depressed at 3 months, but showed a significant recovery by 6 months post-lesion. Tissue choline acetyltransferase (ChAT) activity levels, initially reduced by 92% and 86%, in the dorsal and ventral hippocampus, respectively, recovered significantly by 3 months and remained unchanged at 6 months. Baseline NA output was significantly reduced (-80%) in the dorsal hippocampus by 1 week after the lesion and showed a partial recovery over time (to 50% of normal), whereas the ventral part was not significantly affected by the FF lesion. The significant FF lesion-induced reduction in KCl- or desipramine (DMI)-stimulated NA release observed in the dorsal hippocampus at 1 week after the lesion remained unchanged during the subsequent months. By contrast, in the ventral hippocampus, the initial 65-70% reduction in KCl- and DMI-stimulated NA release significantly recovered to normal levels within 3 months post-lesion. The NA tissue levels were significantly reduced by 4 weeks after lesion, in the dorsal hippocampus and did not show any significant recovery over time. In the ventral hippocampus, these levels were significantly reduced only at 4 weeks. Transmitter turnover, expressed as the ratio between dialysate levels and tissue ChAT or NA content, showed a 3-fold increase in the dorsal hippocampus at 4 weeks after lesion, but not at later time points. This indicates that the spared noradrenergic and cholinergic afferents respond to the partial denervation by a transient increase in transmitter turnover, evident as early as 4 weeks post-lesion in the region of maximal denervation. This was followed by a long-term increase in evoked transmitter release which may result from a slowly progressing compensatory sprouting of the spared afferents.

Acetylcholine↗
PubMedDate not supplied

The topographic organization of hypothalamic and brain stem projections to the hippocampus.

Direct projections primarily ipsilateral to hippocampus from medial septal, diagonal band, supramammillary, submammillothalamic, locus coeruleus, and dorsal and medianus raphe nuclei were demonstrated. The locus coeruleus projects primarily through the cingulum and fornix superior to the dorsal posterior hippocampus, with its terminal fields in the stratum lacunosum moleculare of the subiculum and areas CA 1-CA 2 of the dorsal posterior hippocampus. LC projections to the granular layer of the dentate hilus were not found. Raphe nuclei project through the cingulum, fornix superior, and primarily the fimbria, to the dorsal and ventral posterior hippocampus, with their terminal fields in the stratum lacunosum moleculare of the dorsal posterior subicular region, stratum radiatum of CA 1-CA 3 in the dorsal hippocampus, and the stratum polymorph of the dentate gyrus, primarily in its superficial part. Raphe projections to the anterior hippocampal rudiment were found. However, no projection was found to the subiculum of the ventral posterior hippocampus, nor to stratum oriens. Hypothalamic nuclei project through the fornix superior and the fimbria, mainly to the dorsal posterior hippocampus with abundant terminal fibers in the depth of the dentate hilus. Smaller cells in these hypothalamic nuclei appear projecting to the ventral hippocampus. The number of neurons in the entorhinal area, the diagonal band, and the hypothalamic nuclei projecting to the hippocampus suggests these groups as the main sources of the extrinsic hippocampal afferents. In addition, they may also serve as relay stations for inputs from more caudal nuclei, and the topographic organization of their terminal fields as described herein may have important functional implications.

Animals↗
PubMed2006

Unexpected expression of orexin-B in basal conditions and increased levels in the adult rat hippocampus during pilocarpine-induced epileptogenesis.

Orexin-A (OX-A) and -B (OX-B) peptides present in the hippocampus are considered to be exclusively contained in fibers arising from hypothalamus neurons, which were established as the only source of orexins (OXs). Because OX-A is known to exert excitatory actions in the hippocampus, we hypothesized that the level of OXs targeted toward the hippocampus may be increased following status-epilepticus (SE)-induced epileptogenesis in the rat pilocarpine model of temporal lobe epilepsy. We found that tissue concentration of prepro-OX mRNA, which encodes for both peptides, rapidly decreased in the hypothalamus of rats having experienced pilocarpine-induced SE (Pilo-SE) followed by a reduced density of OX-A and OX-B immunopositive fibers arising from these neurons. By contrast, it was unexpected to detect within the hippocampus the presence of prepro-OX mRNA in basal conditions and to evidence its up-regulation during the 1- to 3-day period following Pilo-SE. The number of prepro-OX mRNA copies determined by real-time RT-PCR was approximately 50-fold lower in the hippocampus than that in the hypothalamus, precluding the use of in situ hybridization to localize the cells which synthesize the transcript within the hippocampus. The increase in prepro-OX mRNA level within the hippocampus was accompanied by the detection of OX-B-like immunoreactivity 2-3 days post-SE, not only in pyramidal neurons, granule cells and cell bodies resembling interneurons, but also in some astrocytes scattered throughout the hippocampus. The present data suggest that the gene encoding OXs can be activated in the hippocampus, which may play a role in the pathogenesis of epilepsy.

Analysis of Variance↗
PubMed2005

Propagation of amygdala-kindled seizures to the hippocampus in the rat: electroencephalographic features and behavioural correlates.

BACKGROUND: The propagation of amygdala-kindled seizures to the dorsal and ventral hippocampus was examined, in rats. The relation of contralateral seizure propagation to the onset of generalized convulsions was also studied. METHODS: In all subjects, electrodes were implanted in the amygdala. Two additional electrodes were implanted (bilaterally) in the dorsal (n = 6) or ventral (n = 8) hippocampus. Kindling stimulations were delivered twice daily (interval 4 h). RESULTS: Initially, triggered after-discharges (ADs) were recorded only in the amygdala. With repeated stimulation, the AD propagated to the hippocampus. Rates of propagation were as follows (mean # of stimulations +/- SEM): ipsilateral ventral hippocampus, 4.0 +/- 0.9; ipsilateral dorsal hippocampus, 6.2 +/- 1.4; contralateral dorsal hippocampus, 7.5 +/- 1.4; contralateral ventral hippocampus, 8.5 +/- 1.0. AD propagation to contralateral sites was significantly slower than to ipsilateral sites. Ipsilateral hippocampal recruitment occurred between stages 1 and 2 (partial seizures), whereas contralateral hippocampal recruitment occurred between stages 2 and 3 (transition to generalized seizures). SUMMARY: These results indicate that during amygdala-kindling, it takes several stimulations before discharge propagates to the hippocampus. The close link between contralateral hippocampus involvement and seizure generalization warrants further study, and may lead to a better understanding of the pathways involved in seizure spread.

Amygdala↗
PubMed2004

Bcl-2 immunoreactive neurons are differentially distributed in subregions of the amygdala and hippocampus of the adult macaque.

The amygdala and hippocampus are key limbic structures of the temporal lobe, and are implicated in the pathology of mood disorders. Bcl-2, an intracellular protein, has recently been identified in the primate amygdala and hippocampus, and is now recognized as an intracellular target of mood stabilizing drugs. However, there are few data on the cellular phenotypes of bcl-2-expressing cells, or their distribution in specific subregions of the amygdala and hippocampus. We used a number of histochemical markers to define specific subregions of the primate amygdala and hippocampus, and examined phenotype-specific distributions of bcl-2 immunoreactive cells within each subregion. Immature-appearing bcl-2 labeled neurons, which co-contain class III beta-tubulin immunoreactivity, are found in distinct subregions in each structure. In the amygdala, bcl-2 positive neurons with an immature morphology are densely distributed in the paralaminar nucleus and intercalated cell islands, the parvicellular basal nucleus, and the ventral periamygdaloid cortex and amygdalohippocampal area. In the hippocampus, immature-appearing bcl-2-labeled cells are confined to the polymorph layer (subgranular zone), and base of the granule cell layer in the dentate gyrus. Well-differentiated neurons also express bcl-2. In the amygdala, labeled cells with mature phenotypes are concentrated in the parvicellular basal nucleus, the accessory basal nucleus, and the periamygdaloid cortex. The medial nucleus and central extended amygdala also contain many well-differentiated bcl-2 positive cells. In the hippocampus, the dentate gyrus and Ammon's horn contain many bcl-2 immunoreactive nonpyramidal cells. These are preferentially distributed in the rostral hippocampus. CA3 and CA2 contain relatively higher concentrations of bcl-2-labeled cells than CA1 and the subiculum. Bcl-2 is thus important in intrinsic circuitry of the hippocampus, and in amygdaloid subregions modulated by the hippocampus. In addition, the extended amygdala, a key amygdaloid output, is richly endowed with bcl-2 positive cells. This distribution suggests a role for bcl-2 in circuits mediating emotional learning and memory which may be targets of mood stabilizing drugs.

Amygdala↗
PubMed2001

Oxytocinergic neurotransmission at the hippocampus in the central neural regulation of penile erection in the rat.

OBJECTIVES: To investigate whether there is an oxytocinergic neurotransmission at the hippocampus involved in the central regulation of penile erection in the rat. METHODS: Male adult Sprague-Dawley (n = 27) rats anesthetized with pentobarbital were used. A 26-gauge needle was inserted into the corpus cavernosum to measure the intracavernous pressure (ICP) and the systemic and mean arterial pressure and heart rate simultaneously. The following studies were performed: stereotaxic delivery of oxytocin acetate (3 pmol/100 nL) into the hippocampus; microinjection of a mixture of [d(CH(2))(5)-Tyr(Me)(2)-Orn(8)]-vasotocin (3 pmol/100 nL) and oxytocin (3 pmol/100 nL) into the hippocampus; injection of saline into the hippocampus; and intracavernous injection of oxytocin (3 pmol/100 microL). The ICP and hemodynamic parameters were monitored after each administration of the experimental agents. RESULTS: After administration of oxytocin into the hippocampus, a significant increase in the ICP occurred from resting (8.8 +/- 1.7 mm Hg) to a peak at 49.6 +/- 12.5 mm Hg and persisted for 18.6 +/- 9.4 minutes after an onset latency of 500.0 +/- 389.7 seconds. However, no change in the ICP occurred after administration of [d(CH(2))(5)-Tyr(Me)(2)-Orn(8)]-vasotocin plus oxytocin into the hippocampus. In addition, no elevation of ICP occurred after administration of saline to the hippocampus or after intracavernous injection of oxytocin. CONCLUSIONS: The results demonstrate that administration of oxytocin into the hippocampus induces penile erection in the rat. However, concomitant administration of oxytocin and its antagonist was ineffective in eliciting penile erection. These observations suggest that oxytocinergic neurotransmission at the hippocampus may be involved in the central neural regulation of the penile erection in the rat.

Animals↗
PubMed2002

Combined neurotrophic supplementation and caspase inhibition enhances survival of fetal hippocampal CA3 cell grafts in lesioned CA3 region of the aging hippocampus.

Fetal hippocampal CA3 cells show excellent survival when homotopically grafted into the kainic acid-lesioned CA3 region of the young adult hippocampus, a model of temporal lobe epilepsy. However, survival of these cells in the kainic acid-lesioned CA3 region of the aging hippocampus is unknown. We hypothesize that fetal CA3 grafts into the lesioned CA3 region of the middle-aged and aged hippocampus exhibit significantly diminished cell survival compared with similar grafts in the lesioned young adult hippocampus unless pre-treated and transplanted with factors that augment graft cell survival. We analyzed cell survival of 5'-bromodeoxyuridine-labeled embryonic day 19 CA3 grafts following their transplantation into the lesioned CA3 region of the middle-aged and aged rat hippocampus. Grafts were placed 4 days after an i.c.v. administration of kainic acid, and absolute cell survival of grafts was quantified 1 month after grafting using 5'-bromodeoxyuridine immunostaining of serial sections and the optical fractionator counting method. Grafts into both middle-aged and aged hippocampus exhibited analogous but significantly diminished cell survival (30% of injected cells) compared with similar grafts into the young adult hippocampus (72% cell survival). However, the extent of cell survival of CA3 grafts pre-treated and transplanted with a combination of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 and the caspase inhibitor acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone was significantly enhanced in both middle-aged and aged hippocampus (51-63% cell survival). These results underscore that aging impairs the conduciveness of the CA3 region for robust survival of homotopic fetal CA3 grafts after lesion. However, a combined neurotrophic supplementation and caspase inhibition significantly enhances survival of fetal CA3 cells in the lesioned aging hippocampus. Thus, pre-treatment and grafting of donor cells with a combination of factors that support growth of specific donor cells may considerably enhance survival and integration of fetal grafts into the lesioned aging CNS in clinical trials.

Aging↗
PubMed1997

Relations between acetylcholine release and electrophysiological characteristics of theta rhythm: a microdialysis study in the urethane-anesthetized rat hippocampus.

In urethane-anesthetized rats, recording electrodes were implanted in the left dorsal hippocampus and a dialysis probe was placed in the contralateral dorsal or ventral hippocampus. Samples of extracellular acetylcholine (ACh) levels were assessed at 10-min intervals over a period of 30 min using microdialysis with high-performance liquid chromatography with electrochemical detection. EEG was recorded during the same period and amplitude, frequency, and duration of theta rhythm were calculated for each of the three 10-min intervals. Data were analyzed using the two-tailed Spearman rank-order correlation test. A positive and high rank correlation coefficient (rho = 0.90, p < 0.01, n = 8) was seen between the average ACh outflow in the dorsal hippocampus and the average theta amplitude, both being calculated for the entire collection period. A lower but statistically significant positive correlation (rho = 0.59, p < 0.01) between dorsal hippocampus ACh output and theta amplitude was also found when the couples of values collected for the 30-min period were pooled (n = 20). In contrast, frequency and duration of theta were not significantly correlated with dorsal hippocampus ACh release. Also, no statistically significant correlation (p > 0.05) was found between ACh output in the ventral hippocampus and theta parameters. Because changes in hippocampal ACh outflow are believed to be the reflection of changes in number and/or level of activity of cholinergic afferents to the dorsal hippocampus, our present findings support the view that, at least in the dorsal hippocampus of the urethane-anesthetized rat, the septohippocampal cholinergic projection regulates the theta amplitude but not frequency. Finally, the possibility that ACh outflow increase and tonic release in the hippocampus is not a sufficient condition to induce and maintain theta in the urethane-anesthetized rat is discussed.

Acetylcholine↗
PubMed2001

Adenovirus-mediated transfer and expression of beta-gal in injured hippocampus after traumatic brain injury in mice.

In models of focal cerebral ischemia, adenoviral gene transfer is often attenuated or delayed versus naive. After controlled cortical impact (CCI)-induced traumatic brain injury in mice, CA1 and CA3 hippocampus exhibit delayed neuronal death by 3 days, with subsequent near complete loss of hippocampus by 21 days. We hypothesized that adenoviral-mediated expression of the reporter gene beta-Galactosidase (beta-Gal) in hippocampus would be attenuated after CCI in mice. C57BL6 mice (n = 16) were subjected to either CCI to left parietal cortex or sham (burr hole). Adenovirus carrying the beta-Gal gene (AdlacZ; 1 x 10(9) plaque-forming units [pfu]/mL) was then injected into left dorsal hippocampus. At 24 or 72 h, beta-Gal expression was quantified (mU/mg protein). Separate mice (n = 10) were used to study beta-Gal spatial distribution in brain sections. Beta-Gal expression in left hippocampus was similar in shams at 24 h (48.4 +/- 4.1) versus 72 h (68.8 +/- 8.8, not significant). CCI did not reduce beta-Gal expression in left hippocampus (68.8 +/- 8.8 versus 88.1 +/- 7.0 at 72 h, sham versus CCI, not significant). In contrast, CCI reduced beta-Gal expression in right (contralateral) hippocampus versus sham (p < 0.05 at both 24 and 72 h). Beta-Gal was seen in many cell types in ipsilateral hippocampus, including CA3 neurons. Despite eventual loss of ipsilateral hippocampus, adenovirus-mediated gene transfer was surprisingly robust early after CCI providing an opportunity to test novel genes targeting delayed hippocampal neuronal death.

Adenoviridae↗
PubMedDate not supplied

Acetylcholine release in the hippocampus and striatum during place and response training.

These experiments examined the release of acetylcholine in the hippocampus and striatum when rats were trained, within single sessions, on place or response versions of food-rewarded mazes. Microdialysis samples of extra-cellular fluid were collected from the hippocampus and striatum at 5-min increments before, during, and after training. These samples were later analyzed for ACh content using HPLC methods. In Experiment 1, ACh release in both the hippocampus and striatum increased during training on both the place and response tasks. The magnitude of increase of training-related ACh release in the striatum was greater in rats trained on the response task than in rats trained on the place task, while the magnitude of ACh release in the hippocampus was comparable in the two tasks. Experiment 2 tested the possibility that the hippocampus was engaged and participated in learning the response task, as well as the place task, because of the availability of extra-maze cues. Rats were trained on a response version of a maze under either cue-rich or cue-poor conditions. The findings indicate that ACh release in the hippocampus increased similarly under both cue conditions, but declined during training on the cue-poor condition, when spatial processing by the hippocampus would not be suitable for solving the maze. In addition, high baseline levels of ACh release in the hippocampus predicted rapid learning in the cue-rich condition and slow learning in the cue-poor condition. These findings suggest that ACh release in the hippocampus augments response learning when extra-maze cues can be used to solve the maze but impairs response learning when extra-maze cues are not available for use in solving the maze.

Acetylcholine↗
PubMed2005

Increased seizure susceptibility of the hippocampus compared with the neocortex of the immature mouse brain in vitro.

PURPOSE: The temporal lobe seems particularly susceptible to seizure activity. Mesial temporal lobe structures, including the hippocampus, have the lowest seizure thresholds in the brain. Conversely, thresholds in the frontal neocortex are significantly higher. The development of intact, isolated preparations of hippocampus and neocortex in vitro allows for study into mechanisms governing seizure threshold. METHODS: Epileptiform discharges in isolated mouse neocortical blocks were compared with the contralateral intact hippocampus, isolated from the same brain, by using the low-Mg2+, 4 aminopyridine (4-AP), and low-Ca2+ in vitro seizure models. The pharmacology of low Mg(2+)-induced ictal-like events (ILEs) generated in the hippocampus and neocortex was then compared by using glutamatergic antagonists DL-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the Ca2+ channel antagonist, nifedipine. RESULTS: Neocortical blocks generated both recurrent, spontaneous ILEs and interictal-like events under low-Mg2+ artificial CSF (aCSF) perfusion, distinct from those generated in the hippocampus. ILEs from the hippocampus displayed lower thresholds and longer durations as compared with isolated neocortical blocks. Similar results were obtained during 4-AP perfusion. Perfusion with low-Ca2+ ACSF did not produce stereotypical ILEs in the neocortical block, producing instead recurrent, slow depolarizations. Both ILEs and recurrent, slow depolarizations were produced in the hippocampus. Application of APV and nifedipine exacerbated low Mg(2+)-induced ILEs in the hippocampus but not the neocortex, indicating a distinct pharmacology for partial seizures of different brain regions. CONCLUSIONS: The developing mouse hippocampus demonstrates increased ictogenesis compared with the developing neocortex in vitro, consistent with clinical observations and in vivo experimental models.

2-Amino-5-phosphonovalerate↗