Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.
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Explicit memory may depend on the hippocampus, whereas the amygdala may be part of an emotional memory system. Priming stimulation of the basolateral group of the amygdala (BLA) resulted in an enhanced long-term potentiation (LTP) in the dentate gyrus (DG) to perforant path (PP) stimulation 30, 90, 150, and 180 min after high-frequency stimulation (HFS). Exposure of rats to a behavioral stress is reported to inhibit DG LTP. Because the amygdala is thought to mediate emotional responses, we examined the apparent discrepancy between the effects of behavioral stress induced 1 hr before HFS to the PP and of amygdala priming on hippocampal plasticity by stimulating the BLA 1 hr before HFS to the PP. The two delayed protocols inhibited the expression of LTP to PP stimulation, whereas priming the BLA immediately before HFS to the PP enhanced DG LTP. Moreover, exposure to the behavioral stress blocked the enhancing effects of BLA priming on LTP. We propose that the activation of the BLA (either by behavioral stress or by direct electrical stimulation) has a biphasic effect on hippocampal plasticity: an immediate excitatory effect and a longer-lasting inhibitory effect. (+info)
Dynamic filtering of recognition memory codes in the hippocampus.
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Principal cells of the dentate gyrus (DG), CA3, and CA1 subfields of the hippocampus were recorded in rat during performance of an odor-guided delayed nonmatch-to-sample task with distinct sample and test phases. The hippocampus was found to possess multiple encoding modes. In the sample phase, odor-selective activity was restricted primarily to CA1 and, to a lesser extent, CA3. Odor representations in half of these cells were predictive of subsequent performance (i. e., correct vs error) in the test phase. Cells in each hippocampal subfield maintained elevated or suppressed activity in the delay interval relative to pre-odor baseline, but were indiscriminate with regard to sample odor identity. In the test phase, the regional distribution of odor-selective activity was inverse to that for the sample: maximal in DG and minimal in CA1. The inverted distribution of odor selectivity was also observed for cells that discriminated match/nonmatch trial types. Most match/nonmatch cells exhibited greater activity on correct nonmatch than error match trials, indicating the presence of a hippocampal recognition memory signal on trials where recognition occurred and its absence on trials where recognition failed. These findings reveal the hippocampus as a highly dynamic encoding device, restricting perceptual stimulus information to different subfields (or none, in the delay phase) depending on memory task contingencies. Moreover, the reduction in cue-specificity of match/nonmatch comparison signals as they pass through the hippocampal trisynaptic circuit may contribute to a generalized recognition signal for use in guiding behavior. (+info)
Pretraining prevents spatial learning impairment after saturation of hippocampal long-term potentiation.
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Spatial learning is impaired by NMDA receptor antagonists at doses that block hippocampal long-term potentiation (LTP). The deficit is not observed in animals that have received spatial or nonspatial pretraining in a different water maze. To determine whether this conditional impairment reflects debilitating sensorimotor effects of NMDA receptor antagonists in na inverted question markve animals, we compared spatial learning in na inverted question markve and pretrained animals in which induction of LTP was blocked by a saturation procedure with no obvious effects on sensorimotor functions. Rats with unilateral hippocampal lesions were implanted with multiple bipolar stimulation electrodes in the angular bundle and a recording electrode in the dentate gyrus of the intact hemisphere. Half of the rats were pretrained to find a hidden platform in a water maze. A week later, pretrained and na inverted question markve rats received either high-frequency (HF) or low-frequency (LF) stimulation at 2 hr intervals, until no further LTP could be induced. The stimulation did not interefere with performance on a balance task or a visual platform task. After stimulation, all rats were trained in a second water maze. Whereas na inverted question markve HF animals were impaired, pretrained HF animals acquired the new task rapidly and searched as extensively around the platform as LF control animals. These results suggest that pretraining prevents disruption of spatial learning after saturation of LTP in the absence of sensorimotor impairment, that hippocampal LTP might not be crucial for spatial representation per se, and that LTP may be involved only when spatial and contextual or procedural learning take place simultaneously. (+info)
CA1 pyramidal cells are the primary output neurons of the hippocampus, carrying information about the result of hippocampal network processing to the subiculum and entorhinal cortex (EC) and thence out to the rest of the brain. The primary excitatory drive to the CA1 pyramidal cells comes via the Schaffer collateral (SC) projection from area CA3. There is also a direct projection from EC to stratum lacunosum-moleculare (SLM) of CA1, an input well positioned to modulate information flow through the hippocampus. High-frequency stimulation in SLM evokes an inhibition sufficiently strong to prevent CA1 pyramidal cells from spiking in response to SC input, a phenomenon we refer to as spike-blocking. We characterized the spike-blocking efficacy of burst stimulation (10 stimuli at 100 Hz) in SLM and found that it is greatest at approximately 300-600 ms after the burst, consistent with the time course of the slow GABA(B) signaling pathway. Spike-blocking efficacy increases in potency with the number of SLM stimuli in a burst, but also decreases with repeated presentations of SLM bursts. Spike-blocking was eliminated in the presence of GABA(B) antagonists. We have identified a candidate population of interneurons in SLM and distal stratum radiatum (SR) that may mediate this spike-blocking effect. We conclude that the output of CA1 pyramidal cells, and hence the hippocampus, is modulated in an input pattern-dependent manner by activation of the direct pathway from EC. (+info)
Cesium induces spontaneous epileptiform activity without changing extracellular potassium regulation in rat hippocampus.
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Cesium has been widely used to study the roles of the hyperpolarization-activated (I(h)) and inwardly rectifying potassium (K(IR)) channels in many neuronal and nonneuronal cell types. Recently, extracellular application of cesium has been shown to produce epileptiform activity in brain slices, but the mechanisms for this are not known. It has been proposed that cesium blocks the K(IR) in glia, resulting in an abnormal accumulation of potassium in the extracellular space and inducing epileptiform activity. This hypothesis has been tested in hippocampal slices and cultured hippocampal neurons using potassium-sensitive microelectrodes. In the present study, application of cesium produced spontaneous epileptiform discharges at physiological extracellular potassium concentration ([K(+)](o)) in the CA1 and CA3 regions of hippocampal slices. This epileptiform activity was not mimicked by increasing the [K(+)](o). The epileptiform discharges induced by cesium were not blocked by the N-methyl-D- aspartate (NMDA) receptor antagonist AP-5, but were blocked by the non-NMDA receptor antagonist CNQX. In the dentate gyrus, cesium induced the appearance of spontaneous nonsynaptic field bursts in 0 added calcium and 3 mM potassium. Moreover, cesium increased the frequency of field bursts already present. In contrast, ZD-7288, a specific I(h) blocker, did not cause spontaneous epileptiform activity in CA1 and CA3, nor did it affect the field bursts in the dentate gyrus, suggesting that cesium induced epileptiform activity is not directly related to blockade of the I(h). When potassium-sensitive microelectrodes were used to measure [K(+)](o), there was no significant increase in [K(+)](o) in CA1 and CA3 after cesium application. In the dentate gyrus, cesium did not change the baseline level of [K(+)](o) or the rate of [K(+)](o) clearance after the field bursts. In cultured hippocampal neurons, which have a large and relatively unrestricted extracellular space, cesium also produced cellular burst activity without significantly changing the resting membrane potential, which might indicate an increase in [K(+)](o). Our results suggest that cesium causes epileptiform activity by a mechanism unrelated to an alteration in [K(+)](o) regulation. (+info)
Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy.
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Hippocampal sclerosis (HS) is a common derangement in many patients with temporal lobe epilepsy. As a result of neuronal cell loss in the hilar region of the hippocampus, it is proposed that mossy fibres sprout and re-innervate new regions of the dentate gyrus. This sprouting may cause recurrent excitation that may lead to the generation of seizures. Here, we determined neuronal density, and synaptophysin and glial fibrillary acidic protein (GFAP) immunoreactivity in hippocampal specimens from patients with pharmaco-resistant temporal lobe epilepsy. Patients were classified into two groups: those with severe and those with no HS. Non-epileptic autopsy tissue served as controls. Mossy fibre sprouting was investigated in these two groups of epilepsy patients using Timm's staining and an immunohistochemical staining of the presynaptic growth-associated protein B-50 (also known as GAP-43, neuromodulin, F1). B-50 immunoreactivity in the different sub-areas of the hippocampus was quantified by image analysis. Our results show the following: (i) in both groups of temporal lobe epilepsy patients, there was a significant loss in cell number in all major hippocampal sub-areas compared with autopsy control tissue; (ii) in HS patients, when compared with non-HS patients, there was a further decline in the number of principal cells in all hippocampal sub-areas analysed, which was associated with an increase in GFAP immunoreactivity; (iii) the decline in cell density was accompanied by a reduced number of synaptic terminals; (iv) in the HS group, there were sprouted mossy fibres in the supragranular layer (SGL) of the dentate gyrus; (v) there was an increase in synaptophysin immunostaining in the SGL indicating that functionally active nerve terminals were formed; and (vi) B-50 immunoreactivity was also increased in the SGL in the HS group compared with the non-HS and control groups. These data showed that all temporal lobe epilepsy hippocampi investigated had severe neuronal cell loss which was most dramatic in the HS group, where it was accompanied by a severe loss of synapses. In the HS group, mossy fibre sprouting into the SGL was found. The increase in B-50 immunoreactivity in the SGL indicated that there was still active sprouting. This sprouting was accompanied by an increased density of synapses, indicating that mossy fibre terminals are not only anatomically present, but probably also functional. Thus, functional glutamatergic mossy fibre terminals are in the right position to synapse on to the dendrites of granule cells and thus may contribute to the onset of seizures. (+info)
Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1.
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Lef1 and other genes of the LEF1/TCF family of transcription factors are nuclear mediators of Wnt signaling. Here we examine the expression pattern and functional importance of Lef1 in the developing forebrain of the mouse. Lef1 is expressed in the developing hippocampus, and LEF1-deficient embryos lack dentate gyrus granule cells but contain glial cells and interneurons in the region of the dentate gyrus. In mouse embryos homozygous for a Lef1-lacZ fusion gene, which encodes a protein that is not only deficient in DNA binding but also interferes with (beta)-catenin-mediated transcriptional activation by other LEF1/TCF proteins, the entire hippocampus including the CA fields is missing. Thus, LEF1 regulates the generation of dentate gyrus granule cells, and together with other LEF1/TCF proteins, the development of the hippocampus. (+info)
Corticotropin-releasing factor produces a protein synthesis--dependent long-lasting potentiation in dentate gyrus neurons.
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Corticotropin-releasing factor (CRF) was shown to produce a long-lasting potentiation of synaptic efficacy in dentate gyrus neurons of the rat hippocampus in vivo. This potentiation was shown to share some similarities with tetanization-induced long-term potentiation (LTP). In the present study, we further examined the mechanism underlying CRF-induced long-lasting potentiation in rat hippocampus in vivo. Results indicated that the RNA synthesis inhibitor actinomycin-D, at a concentration that did not change basal synaptic transmission alone (5 microgram), significantly decreased CRF-induced potentiation. Similarly, the protein synthesis inhibitor emetine, at a concentration that did not affect hippocampal synaptic transmission alone (5 microgram), also markedly inhibited CRF-induced potentiation. These results suggest that like the late phase of LTP, CRF-induced long-lasting potentiation also critically depend on protein synthesis. Further, prior maximum excitation of dentate gyrus neurons with tetanization occluded further potentiation of these neurons produced by CRF and vise versa. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed that CRF mRNA level in the dentate gyrus was significantly increased 1 h after LTP recording. Together with our previous findings that CRF antagonist dose-dependently diminishes tetanization-induced LTP, these results suggest that both CRF-induced long-lasting potentiation and tetanization-induced LTP require protein synthesis and that CRF neurons are possibly involved in the neural circuits underlying LTP. (+info)