Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.

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.     

Activity and plasticity in the CA1, the dentate gyrus, and the amygdala following controllable vs. uncontrollable water stress

The level of controllability has been shown to modulate the effects of stress on physiology and behavior. In the present study, we investigated the effects of controllable vs. uncontrollable stressors on plasticity in hippocampal CA1, the dentate gyrus (DG), and basal amygdala nucleus (B) in the rat, using the electrophysiological procedure of long-term potentiation (LTP). A naive group was left undisturbed until the electrophysiological recording commenced. Rats of the two controllable stress groups were trained in the Morris water maze to locate an invisible underwater platform (the first group), or visible platform (the second group), thus escaping from the water, before the recording. The uncontrollable stress group underwent the same procedure (exposure time to water was adjusted to the averaged exposure time of the first controllable group) without the escape platform. We first assessed the effects of stress and controllability on LTP in CA1. Both controllable stressors and the uncontrollable stress impaired CA1 LTP, with a more robust effect induced by the uncontrollable stress. We further assessed the effects of the same procedures on LTP in DG and B. The uncontrollable stress enhanced LTP in DG and increased baseline responses (suggesting uncontrollable stress-induced plasticity) in the amygdala. All the stressors decreased amygdalar LTP. An assessment of plasma levels of corticosterone (CORT), following the behavioral procedures, revealed an enhancement in CORT release following the uncontrollable, but not controllable stress, indicating the uncontrollable condition as the most stressful. These findings provide insight into the differential effects of stress and stress controllability on different hippocampal subregions and the amygdala.     

Prenatal ethanol exposure enhances NMDAR-dependent long-term potentiation in the adolescent female dentate gyrus

The dentate gyrus (DG) is a region of the hippocampus intimately involved with learning and memory. Prenatal exposure to either stress or ethanol can reduce long-term potentiation (LTP) in the male hippocampus but there is little information on how these prenatal events affect LTP in the adolescent female hippocampus. Previous studies suggest that deleterious effects of PNEE can, in part, be mediated by corticosterone, suggesting that prenatal stress might further enhance any alterations to LTP induced PNEE. When animals were exposed to a combination of prenatal stress and PNEE distinct sex differences emerged. Exposure to ethanol throughout gestation significantly reduced DG LTP in adolescent males but enhanced LTP in adolescent females. Combined exposure to stress and ethanol in utero reduced the ethanol-induced enhancement of LTP in females. On the other hand, exposure to stress and ethanol in utero did not alter the ethanol-induced reduction of LTP in males. These results indicate that prenatal ethanol and prenatal stress produce sex-specific alterations in synaptic plasticity in the adolescent hippocampus.     

Fear learning induces persistent facilitation of amygdala synaptic transmission

In the maintenance phase of fear memory, synaptic transmission is potentiated and the stimulus requirements and signalling mechanisms are altered for long-term potentiation (LTP) in the cortico-lateral amygdala (LA) pathway. These findings link amygdala synaptic plasticity to the coding of fear memories. Behavioural experiments suggest that the amygdala serves to store long-term fear memories. Here we provide electrophysiological evidence showing that synaptic alterations in rats induced by fear conditioning are evident in vitro 10 days after fear conditioning. We show that synaptic transmission was facilitated and that high-frequency stimulation dependent LTP (HFS-LTP) of the cortico-lateral amygdala pathway remained attenuated 10 days following fear conditioning. Additionally, we found that the low-frequency stimulation dependent LTP (LFS-LTP) measured 24 h after fear conditioning was absent 10 days post-training. The persistent facilitation of synaptic transmission and occlusion of HFS-LTP suggests that, unlike hippocampal coding of contextual fear memory, the cortico-lateral amygdala synapse is involved in the storage of long-term fear memories. However, the absence of LFS-LTP 10 days following fear conditioning suggests that amygdala physiology 1 day following fear learning may reflect a dynamic state during memory stabilization that is inactive during the long-term storage of fear memory. Results from these experiments have significant implications regarding the locus of storage for maladaptive fear memories and the synaptic alterations induced by these memories.     

Stress reverses plasticity in the pathway projecting from the ventromedial prefrontal cortex to the basolateral amygdala

We have previously shown that high-frequency stimulation to the basolateral amygdala (BLA) induces long-term potentiation (LTP) in the ventromedial prefrontal cortex (vmPFC) and that prior exposure to inescapable stress inhibits the induction of LTP in this pathway [Maroun & Richter-Levin (2003)J. Neurosci., 23, 4406-4409]. Here, we show that the reciprocal pathway projecting from the vmPFC to the BLA is resistant to the induction of LTP. Conversely, long-term depression (LTD) is robustly induced in the BLA in response to low-frequency stimulation to the vmPFC. Furthermore, prior exposure to inescapable stress reverses plasticity in this pathway, resulting in the promotion of LTP and the inhibition of LTD. Our findings suggest that, under normal and safe conditions, the vmPFC is unable to exert excitatory synaptic plasticity over the BLA; rather, LTD, which encodes memory of safety in the BLA, is favoured. Following stressful experiences, LTP in the BLA is promoted to encode memory of fear.     

The mechanisms of the strong inhibitory modulation of long-term potentiation in the rat dentate gyrus

The hippocampus is essential for the formation of certain types of memory, and synaptic plasticity such as long-term potentiation (LTP) is widely accepted as a cellular basis of hippocampus-dependent memory. Although LTP in both perforant path-dentate gyrus (DG) granule cell and CA3-CA1 pyramidal cell synapses is similarly dependent on activation of postsynaptic N-methyl-D-aspartate receptors, several reports suggest that modulation of LTP by γ-aminobutyric acid (GABA) receptor-mediated inhibitory inputs is stronger in perforant path-DG granule cell synapses. However, little is known about how different the mechanism and physiological relevance of the GABAergic modulation of LTP induction are among different brain regions. We confirmed that the action of GABA(A) receptor antagonists on LTP was more prominent in the DG, and explored the mechanism introducing such difference by examining two types of GABA(A) receptor-mediated inhibition, i.e. synaptic and tonic inhibition. As synaptic inhibition, we compared inhibitory vs. excitatory monosynaptic responses and their summation during an LTP-inducing stimulus, and found that the balance of the summated postsynaptic currents was biased toward inhibition in the DG. As tonic inhibition, or sustained activation of extrasynaptic GABA(A) receptors by ambient GABA, we measured the change in holding currents of the postsynaptic cells induced by GABA(A) receptor antagonists, and found that the tonic inhibition was significantly stronger in the DG. Furthermore, we found that tonic inhibition was associated with LTP modulation. Our results suggest that both the larger tonic inhibition and the larger inhibitory/excitatory summation balance during conditioning are involved in the stronger inhibitory modulation of LTP in the DG.     

Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity

Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal‐dependent memory is compromised while amygdala‐dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long‐term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light‐dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long‐term potentiation (LTP) in the CA1, (iii) impaired hippocampal‐dependent short‐term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala‐dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55‐212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal‐ and amygdala‐dependent processes. Moreover, the effects of WIN55‐212,2 and URB597 on Ext and acoustic startle were prevented by co‐administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55‐212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala.     

Effects of chronic stress on hippocampal long-term potentiation

Chronic stress causes atrophy of the apical dendrites of CA3 pyramidal neurons and deficits in spatial memory. We investigated the effects of chronic stress on hippocampal physiology and long-term potentiation (LTP) in the CA3 and dentate gyrus (DG). Rats were subjected to chronic (21 days, 6 h/day) restraint stress and tested for LTP 48 h following the last stress episode. Control animals were briefly handled each day, similar to the experimental group but without restraint. To eliminate acute stress effects, a second control group of rats was subjected to a single acute (6 h) restraint stress and tested for LTP 48 h later. Field potential recordings were made, under chloropent anesthesia, from the stratum lucidum of CA3, with stimulation of either the mossy fiber or commissural/associational pathways, or in the DG granule-cell layer, with stimulation of the medial perforant pathway. Chronic stress produced a suppression of LTP at 48 h compared to controls in a site-specific manner, namely, significantly lower LTP in the medial perforant input to the DG and also in the commissural/associational input to the CA3, but not in the mossy fiber input to CA3. The animals subjected to acute stress and tested 48 h later did not show a suppression in LTP. High-frequency stimulation (HFS) of the commissural/associational and mossy fiber inputs to CA3 produced epileptic afterdischarges in 56% of acutely stressed animals and in 29% of chronically stressed animals, whereas HFS caused afterdischarges in only 9% of nonstressed controls. No afterdischarges were seen in the medial perforant path input to DG. In order to explore the basis for these changes, we performed paired-pulse inhibition/facilitation (PPI/F) and current-source-density (CSD) analysis in stressed and control animals. For PPI/F, acute stress caused an overall significant enhancement of excitation in the commissural/associational input to CA3 and medial perforant path input to DG. In contrast, chronic stress did not produce significant changes in PPI/F. The CSD analysis revealed significant chronic stress-induced shifts in the current sources and sinks in the apical dendrites and pyramidal cell layers of the CA3 field but not in the DG. These results are consistent with the morphological findings for stress effects upon dendrites of CA3 neurons. Furthermore, they suggest that chronic stress produces changes in the input-output relationship in the hippocampal trisynaptic circuit which could affect information flow through this structure.     

Stress: metaplastic effects in the hippocampus

Memory impairments, which occur regularly across species as a result of aging, disease and psychological insults (for example, stress), constitute a useful area for investigation into the neurobiological basis of learning and memory. Memory researchers have identified the hippocampus as a crucial brain structure involved in key aspects of memory formation. The most widely accepted putative mechanisms of memory storage in this structure are LTP and LTD. The hippocampus is enriched with receptors for corticosterone (a glucocorticoid hormone released in response to stress) and it plays a role in glucocorticoid negative feedback and, therefore, some hippocampal functioning might be particularly susceptible to stress. In support of this view, stress-induced modifications in learning, synaptic plasticity and endangerment of neurons have been seen in the hippocampus. Stress and glucocorticoids appear to exert a metaplastic effect through the modulation of Ca²⁺ levels. We propose a synaptic model that provides a conceptual scaffold to structure our understanding of the manifold actions of stress on the hippocampus. Accordingly, we suggest that stress-induced metaplasticity could disrupt Ca²⁺ homeostasis and thus endanger hippocampal neurons.     

The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus

The dentate gyrus (DG) of the hippocampus plays a crucial role in learning and memory. This subregion is unique in its ability to generate new neurons throughout life and integrate these new neurons into the hippocampal circuitry. Neurogenesis has further been implicated in hippocampal plasticity and depression. Exposure to chronic stress affects DG function and morphology and suppresses neurogenesis and long-term potentiation (LTP) with consequences for cognition. Previous studies demonstrated that glucocorticoid receptor (GR) blockade by a brief treatment with the GR antagonist mifepristone (RU486) rapidly reverses the stress and glucocorticoid effects on neurogenesis. The molecular pathways underlying both the stress-induced effects and the RU486 effects on the DG are, however, largely unknown. The aim of this study was therefore (1) to investigate by microarray analysis which genes and pathways in the DG are sensitive to chronic stress and (2) to investigate to what extent blockade of GR can normalize these stress-induced effects on DG gene expression. Chronic stress exposure affected the expression of 90 genes in the DG (P < 0.01), with an overrepresentation of genes involved in brain development and morphogenesis and synaptic transmission. RU486 treatment of stressed animals affected expression of 107 genes; however, mostly different genes than those responding to stress. Interestingly, we found CREBBP to be normalized by RU486 treatment to levels observed in control animals, suggesting that CREB-signaling may play a central role in mediating the chronic stress effects on neurogenesis, LTP and calcium currents. The identified genetic pathways provide insight into the stress-induced adaptive plasticity of the hippocampal DG that is so central in learning and memory and will direct future studies on the functional outcome and modulation of these stress effects.     

Complex modulation by stress of the effect of seizures on long term potentiation in mouse hippocampal slices

Stress has a profound effect on ability to express neuronal plasticity, learning, and memory. Likewise, epileptic seizures lead to massive changes in brain connectivity, and in ability to undergo long term changes in reactivity to afferent stimulation. In this study, we analyzed possible long lasting interactions between a stressful experience and reactivity to pilocarpine, on the ability to produce long term potentiation (LTP) in a mouse hippocampus. Pilocarpine lowers paired pulse potentiation as well as LTP in CA1 region of the mouse hippocampal slice. When stress experience precedes exposure to pilocarpine, it protects the brain from the lasting effect of pilocarpine. When stress follows pilocarpine, it exacerbates the effect of the drug, to produce a long lasting reduction in LTP. These changes are accompanied by a parallel change in blood corticosterone level. A single exposure to selective mineralo‐ or gluco‐corticosterone (MR and GR, respectively) agonists and antagonists can mimic the stress effects, indicating that GR's underlie the lasting detrimental effects of stress whereas MRs are instrumental in counteracting the effects of stress. These studies open a new avenue of understanding of the interactive effects of stress and epileptic seizures on brain plasticity.     

Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats

We have recently found that synaptic pathway from the basolateral amygdala (BLA) to the dentate gyrus (DG) displays N-methyl-D-aspartate (NMDA) receptor-independent form of long-term potentiation (LTP), which should be a valuable model for elucidating neural mechanisms linking emotion and memory. To explore its cellular mechanisms, we investigated the effects of L-type Ca(2+) channel blockers on LTP in this pathway of anesthetized rats. Intraperitoneal administration of verapamil (3-30 mg/kg) or diltiazem (6-20 mg/kg) significantly impaired the induction of LTP following high-frequency stimulation. When verapamil was administered after high-frequency stimulation, it did not affect the pre-established LTP. These results suggest that activation of L-type Ca(2+) channels is necessary for the induction of LTP in the BLA-DG pathway.     

Aquaporin-4 deficiency impairs synaptic plasticity and associative fear memory in the lateral amygdala: involvement of downregulation of glutamate transporter-1 expression

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression.     

Brief novelty exposure facilitates dentate gyrus LTP in aged rats

Aging is associated with a decreased capacity for dentate gyrus (DG) granule cell depolarization as well as reduced perforant path activation. Although it is well established that the maintenance of DG long-term potentiation (LTP) over days is impaired in aged, as compared to young animals, the threshold for inducing this LTP has never been investigated in aged, awake animals. In addition, although exposure to novelty prior to theta-burst stimulation (TBS) increases both the induction and longevity of DG LTP in adult rats, the effects of exposure to novelty on LTP in aged rats have never been investigated. Here, we report that although TBS delivered in the home cage induces robust and long-lasting DG LTP in young rats, TBS fails to induce DG LTP in aged rats. Interestingly, delivery of TBS to aged rats exploring novel environments induces robust and long-lasting LTP, with the induction, but not the longevity, of this LTP being similar in magnitude to that observed in young rats delivered TBS in the home cage. These results indicate that although TBS-induced DG LTP is impaired in aged, as compared to young rats, TBS during exploration of novel environments is sufficient to rescue age-related deficits in DG LTP. We discuss these observations in the context of previous findings suggesting that the facilitation of LTP by exposure to novel environments results as a consequence of reduced network inhibition in the DG and we suggest that, in spite of age-related changes in the DG, this capacity persists in aged rats and represents a nondietary and nonpharmacological way to facilitate DG LTP during aging.     

Long-term potentiation in the reciprocal corticohippocampal and corticocortical pathways in the chronically implanted, freely moving rat

The hippocampus and adjacent cortical structures, including the entorhinal, perirhinal, and parahippocampal cortices, appear to serve as an integrated memory system. This extended hippocampal system is believed to influence memory and consolidation through an extensive set of reciprocal connections with widespread areas of the neocortex. Long-term potentiation (LTP) has been well-examined in the intrinsic connections of the hippocampus and neocortex. However, LTP in the pathways and structures thought to convey information between the hippocampus and neocortex has received little attention. If these pathways and structures are involved in information storage, and if LTP reflects a general synaptic encoding mechanism, then these systems are also likely to support LTP. In this paper we discuss a series of experiments aimed at investigating LTP in the efferents between the hippocampus and neocortex in chronically implanted animals. In the first experiment, the efferents of the perirhinal cortex were stimulated. LTP in the dentate gyrus (DG) reached asymptote more slowly than is typically seen following perforant path stimulation, whereas the frontal area (M1) reached asymptote more quickly than reported following corticocortical stimulation. The DG and M1 LTP was long-lasting, but entorhinal cortex LTP had decayed to baseline levels after a week. In the second experiment, the hippocampal efferents were stimulated. The perirhinal, entorhinal, and frontal cortex showed a similar slow potentiation, with only the perirhinal cortex levels returning to baseline after a week. In the third experiment, the projections from M1 were tested. The perirhinal cortex and hippocampus showed a long-lasting LTP. Although LTP was found in all pathways examined, there were differences in the induction and decay rate, and these properties may correspond to differences in learning rate and longevity of information storage.     

Brain-derived neurotrophic factor in amygdala-dependent learning.

The neurotrophin brain-derived neurotrophic factor (BDNF) has recently emerged as a possible molecular mediator of activity-dependent synaptic plasticity underlying learning and memory. Long-term potentiation (LTP) within the hippocampus and hippocampally dependent behaviors has been the primary model for examining the role of BDNF in learning and memory. However, these studies are limited by an incomplete understanding of the complex behavioral function of hippocampal circuitry, making it difficult to unravel the molecular machinery responsible for the formation and storage of these memories. In contrast, the amygdala and its role in Pavlovian fear conditioning promise to provide us with new insights into the mechanisms of BDNF-mediated synaptic plasticity during the learning and memory process. This article reviews the different levels of research on BDNF in learning and memory. The focus is primarily on the use of Pavlovian fear conditioning as a learning model that allows for the examination of the role of BDNF in the amygdala, following a single learning session and within a well-understood neural circuit.     

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11–18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22–31) performed one two‐trial Y‐maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not long‐term potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine‐exposed juvenile offspring. The morphine group also showed poorer performance for the Y‐maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP‐spike potentiation. Then a loss of GABA‐containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offspring's dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy. © 2008 Wiley‐Liss, Inc.     

Basolateral amygdala D1- and D2-dopaminergic system promotes the formation of long-term potentiation in the dentate gyrus of anesthetized rats

We have previously found that the induction of hippocampal long-term potentiation (LTP) is modulated by neuron activities in the basolateral amygdala (BLA). However, little is known about what neurotransmitter system in the BLA contributes to modulation of hippocampal LTP. In the present study, we investigated possible involvement of BLA dopaminergic system in the induction of LTP at the perforant path (PP)–dentate gyrus (DG) granule cell synapses of anesthetized rats. The induction of PP–DG LTP was significantly attenuated by intra-BLA injection of the D₁ receptor antagonist SCH23390 (2 or 6 nmol) or the D₂ receptor antagonists, chlorpromazine (30 or 100 nmol) or haloperidol (4.4 or 13.3 nmol). The effects of SCH23390 and haloperidol were abolished by concomitant intra-BLA injection of the D₁ receptor agonist SKF38393 (17 nmol) and the D₂ receptor agonist quinpirole (3 nmol), respectively. Furthermore, lesioning with 6-hydroxydopamine of the ventral tegmental area, the origin of the dopaminergic system projecting to the BLA, resulted in attenuated PP–DG LTP, which was restored by intra-BLA injection of SKF38393 or quipirole. These results suggest that the induction of PP–DG LTP is promoted by the BLA dopaminergic system via both D₁ and D₂ receptors.     

Cocaine decreases the expression of PSA-NCAM protein and attenuates long-term potentiation via glucocorticoid receptors in the rat dentate gyrus

The present study investigated a potential role for glucocorticoid (GR) and mineralocorticoid (MR) receptors in the detrimental effects of single cocaine (COC) administration on both the number of polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neurons and the induction of long-term potentiation (LTP) in the rat dentate gyrus (DG). The effects of COC (15 mg/kg i.p.) on the number of PSA-NCAM-positive neurons and the induction of LTP observed 2 days after COC administration were abolished either by depleting circulating corticosterone after administration of metyrapone (100 mg/kg s.c. given 3 h before COC) or by pharmacologically blocking GRs using mifepristone (RU 38486, 10 mg/kg s.c. given 1 h before COC). Administration of the MR blocker spironolactone (50 mg/kg s.c. given 1 h before COC) did not alter the effects of COC on the number of PSA-NCAM-positive neurons or LTP induction. Results have also shown that COC does not change the rate of cell proliferation, as measured by the presence of Ki-67 and the incorporation of bromodeoxyuridine (100 mg/kg i.p. given 2 h after COC) into the newly born cells in the DG 2 days after COC administration. Finally, we observed that GRs colocalized with some, but not all, PSA-NCAM-positive neurons, whereas MRs showed no colocalization with neurons positive for PSA-NCAM in the DG. These data indicate that a single dose of COC may arrest hippocampal susceptibility to plastic changes and lead to functional impairments through the alteration of hippocampal structure and the formation of memory traces.     

The Basomedial and Basolateral Amygdaloid Nuclei Contribute to the Induction of Long-term Potentiation in the Dentate Gyrus In Vivo

Recent behavioural studies have provided evidence that the amygdala modulates hippocampal-dependent memory. To test the possibility that the amygdala modulates hippocampal synaptic plasticity, we investigated the effects of surgical lesions of the amygdaloid nuclei on the induction of long-term potentiation (LTP) in the dentate gyrus of anaesthetized rats. Previously we reported that LTP in the dentate gyrus was attenuated by lesion of the basolateral amygdala, but was not affected by lesion of the central amygdala. In the present study, dentate gyrus LTP was significantly attenuated by basomedial amygdala lesion but not by medial amygdala lesion. These results suggest that, among the amygdaloid nuclei, the basomedial and basolateral nuclei are involved in the modulation of hippocampal plasticity. The roles of the basomedial and basolateral amygdala were further supported by experiments examining the effects of electrical stimulation of these nuclei. High-frequency stimulation of the basomedial amygdala alone did not induce dentate gyrus LTP, but when applied at the same time as tetanic stimulation of the perforant path increased the magnitude of the dentate gyrus LTP. Similarly, high-frequency stimulation of the basolateral amygdala enhanced LTP induced by tetanic stimulation of the perforant path. Furthermore, facilitation of dentate gyrus LTP by basomedial or basolateral amygdala stimulation was observed even in rats lesioned in either amygdala, suggesting that neurons in the basomedial and basolateral amygdala can modulate dentate gyrus LTP independently. Activity-dependent facilitation of hippocampal plasticity by the basomedial and basolateral amygdala may underlie memory processing associated with emotion.