Differential role of NMDA receptors in hippocampal-dependent spatial memory and plasticity in juvenile male and female rats.

Early life, or juvenility, stands out as the most pivotal phase in neurodevelopment due to its profound impact over the long-term cognition. During this period, significant changes are made in the brain's connections both within and between different areas, particularly in tandem with the development of more intricate behaviors. The hippocampus is among the brain regions that undergo significant postnatal remodeling, including dendritic arborization, synaptogenesis, the formation of complex spines and neuron proliferation. Given the crucial role of the hippocampus in spatial memory processing, it has been observed that spatial memory abilities continue to develop as the hippocampus matures, particularly before puberty. The N-methyl-d-aspartate (NMDA) type of glutamate receptor channel is crucial for the induction of activity-dependent synaptic plasticity and spatial memory formation in both rodents and humans. Although extensive evidence shows the role of NMDA receptors (NMDAr) in spatial memory and synaptic plasticity, the studies addressing the role of NMDAr in spatial memory of juveniles are sparse and mostly limited to adult males. In the present study, we, therefore, aimed to investigate the effects of systemic NMDAr blockade by the MK-801 on spatial memory (novel object location memory, OLM) and hippocampal plasticity in the form of long-term potentiation (LTP) of both male and female juvenile rats. Our results show the sex-dimorphic role of NMDAr in spatial memory and plasticity during juvenility, as systemic NMDAr blockade impairs the OLM and LTP in juvenile males without an effect on juvenile females. Taken together, our results demonstrate that spatial memory and hippocampal plasticity are NMDAr-dependent in juvenile males and NMDAr-independent in juvenile females. These sex-specific differences in the mechanisms of spatial memory and plasticity may imply gender-specific treatment for spatial memory disorders even in children.

Hippocampal oxytocin is involved in spatial memory and synaptic plasticity deficits following acute high-fat diet intake in juvenile rats.

The hippocampus undergoes maturation during juvenility, a period of increased vulnerability to environmental challenges. We recently found that acute high-fat diet (HFD) impaired hippocampal long-term potentiation (LTP) and hippocampal-dependent spatial memory. We also recently reported that similar HFD exposure affected prefrontal plasticity and social memory through decreased oxytocin levels in the prefrontal cortex. In the present study, we therefore evaluated whether hippocampal oxytocin levels are also affected by juvenile HFD and could mediate deficits of hippocampal LTP and spatial memory. We found that postweaning HFD decreased oxytocin levels in the CA1 of the dorsal hippocampus. Interestingly, systemic injection of high, but not low, dose of oxytocin rescued HFD-induced LTP impairment in CA1. Moreover, deficits in long-term object location memory (OLM) were prevented by systemic injection of both high and low dose of oxytocin as well as by intra-CA1 infusion of oxytocin receptor agonist. Finally, we found that blocking oxytocin receptors in CA1 impaired long-term OLM in control-fed juvenile rats. These results suggest that acute HFD intake lowers oxytocin levels in the CA1 that lead to CA1 plasticity impairment and spatial memory deficits in juveniles. Further, these results provide the first evidence for the regulatory role of oxytocin in spatial memory.

Acute social isolation and regrouping cause short- and long-term molecular changes in the rat medial amygdala.

Social isolation poses a severe mental and physiological burden on humans. Most animal models that investigate this effect are based on prolonged isolation, which does not mimic the milder conditions experienced by people in the real world. We show that in adult male rats, acute social isolation causes social memory loss. This memory loss is accompanied by significant changes in the expression of specific mRNAs and proteins in the medial amygdala, a brain structure that is crucial for social memory. These changes particularly involve the neurotrophic signaling and axon guidance pathways that are associated with neuronal network remodeling. Upon regrouping, memory returns, and most molecular changes are reversed within hours. However, the expression of some genes, especially those associated with neurodegenerative diseases remain modified for at least a day longer. These results suggest that acute social isolation and rapid resocialization, as experienced by millions during the COVID-19 pandemic, are sufficient to induce significant changes to neuronal networks, some of which may be pathological.

Differential Recruitment of the Infralimbic Cortex in Recent and Remote Retrieval and Extinction of Aversive Memory in Post-Weanling Rats.

BACKGROUND: We previously showed that the infralimbic medial prefrontal cortex (IL-mPFC) plays an important role in recent and remote memory retrieval and extinction of conditioned odor aversion (COA) and contextual fear conditioning (CFC) in adult rats. Because the mPFC undergoes maturation during post-weaning, here, we aimed to explore (1) whether post-weanling rats can form recent and remote COA and CFC memory, and (2) the role of the IL-mPFC in mediating these processes. METHODS: To investigate the retrieval process, we transiently inactivated the IL-mPFC with lidocaine prior to the retrieval test at either recent or remote time points. To target the consolidation process, we applied the protein synthesis inhibitor after the retrieval at recent or remote time points. RESULTS: Our results show that the post-weanling animals were able to develop both recent and remote memory of both COA and CFC. IL-mPFC manipulations had no effect on retrieval or extinction of recent and remote COA memory, suggesting that the IL has no effect in COA at this developmental stage. In contrast, the IL-mPFC played a role in (1) the extinction of recent, but not remote, CFC memory, and (2) the retrieval of remote, but not recent, CFC memory. Moreover, remote, but not recent, CFC retrieval enhanced c-Fos protein expression in the IL-mPFC. CONCLUSIONS: Altogether, these results point to a differential role of the IL-mPFC in recent and remote CFC memory retrieval and extinction and further confirm the differences in the role of IL-mPFC in these processes in post-weanling and adult animals.

Bidirectional modulation of hippocampal and amygdala synaptic plasticity by post-weaning obesogenic diet intake in male rats: Influence of the duration of diet exposure.

Obesity is a chronic condition associated with adverse memory and emotional outcomes in humans and animal models. We have recently demonstrated that post-weaning (i.e., periadolescent) high-fat diet (HFD)-induced obesity has opposite effect on hippocampal and amygdala-dependent memory in rodents: while HFD consumption impairs spatial and relational memory, it enhances cue-dependent emotional memory. However, it is still not clear whether this bidirectional HFD effect on memory is related to bidirectional alterations of hippocampal and amygdala synaptic plasticity and if it is influenced by the duration of diet intake. In the current study, we compared in male rats the impact of 2-3 and 6-7 months of HFD intake starting at weaning, thus covering adolescence, on in vivo long-term potentiation (LTP) recorded simultaneously in the hippocampal area CA1 and the basolateral amygdala (BLA). As expected, 6-7 months of HFD intake abolished LTP in the CA1 and enhanced LTP in the BLA. However, 2-3 months of of HFD exposure enhanced LTP in both CA1 and BLA suggesting a transient compensatory mechanism in hippocampus. These results indicate that post-weaning HFD intake progressively leads to bidirectional modulation of hippocampal and amygdala synaptic plasticity, as we previously demonstrated for related memory processes, yet with a different temporal dynamic.

Prefrontal Oxytocin is Involved in Impairments in Prefrontal Plasticity and Social Memory Following Acute Exposure to High Fat Diet in Juvenile Animals.

Juvenility represents a critical developmental phase during which exposure to a high fat diet (HFD) can severely modify cognitive and emotional functioning. The purpose of this study was to address how short and acute exposure to a HFD during juvenility affects social memory recognition and prefrontal long-term potentiation (LTP). As LTP and social memory depend on the neuromodulator oxytocin (OXY) and due to its role in metabolism, we also examined the effects of OXY in mediating HFD-induced alterations in social memory and LTP. Our results show that short exposure to a HFD during juvenility impairs social preference memory and prefrontal LTP. Interestingly, whereas systemic injections of OXY reversed the impairments in HFD-fed animals and impaired LTP and memory in control animals; prefrontal injections of the OXY agonist TGOT reversed the effects in HFD animals without affecting control animals. Exposure to HFD was associated with a reduction in the levels of OXY in the prefrontal compared to control animals. Interestingly, the restoration of social memory by TGOT in HFD animals was also associated with normalization of OXY in the prefrontal. These results point to a role that prefrontal OXY has in mediating the effects of HFD on memory and plasticity.

Perturbation of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Induces Trans-regional Metaplasticity at the Medial Prefrontal Cortex.

GABAergic synapses in the basolateral amygdala (BLA) play an important role in fear memory generation. We have previously reported that reduction in GABAergic synapses innervating specifically at the axon initial segment (AIS) of principal neurons of BLA, by neurofascin (NF) knockdown, impairs fear extinction. BLA is bidirectionally connected with the medial prefrontal cortex (mPFC), which is a key region involved in extinction of acquired fear memory. Here, we showed that reducing AIS GABAergic synapses within the BLA leads to impairment of synaptic plasticity in the BLA-mPFC pathway, as well as in the ventral subiculum (vSub)-mPFC pathway, which is independent of BLA involvement. The results suggest that the alteration within the BLA subsequently resulted in a form of trans-regional metaplasticity in the mPFC. In support of that notion, we observed that NF knockdown induced a severe deficit in behavioral flexibility as measured by reversal learning. Interestingly, reversal learning similar to extinction learning is an mPFC-dependent behavior. In agreement with that, measurement of the immediate-early gene, c-Fos immunoreactivity after reversal learning was reduced in the mPFC and BLA, supporting further the notion that the BLA GABAergic manipulation resulted in trans-regional metaplastic alterations within the mPFC.

Different mechanisms underlie stress-induced changes in plasticity and metaplasticity in the prefrontal cortex of juvenile and adult animals: Emotional-induced metaplasticity in the prefrontal cortex.

Metaplasticity is the dynamic regulation of the ability to induce activity-dependent synaptic plasticity and is governed by the prior history of the synapses. Previous reports by others and us have shown that behavioral stress induces a form of emotional metaplasticity that affects the ability to induce LTP in the subiculum-medial prefrontal cortex pathway, which depends on NMDA receptors (NMDAr). However, studies addressing the effects of stress on LTP and metaplasticity have mainly focused on the adult animal. Here we compared the effects of exposure to stress on the induction of LTP in adult and juvenile animals and examined whether a low dose of NMDAr antagonist (MK801) that does not affect LTP per se would differentially affect stress-induced metaplasticity in adult and juvenile animals. Our findings show that exposure to the elevated platform differentially affects the induction of LTP in adult and juvenile animals. Specifically, whereas exposure to stress resulted in impaired LTP in adult animals, it resulted in enhanced LTP in juvenile animals. Similarly, while MK801 failed to inhibit the induction of LTP in both age groups, it resulted in inhibition of stress-induced enhanced LTP in juvenile animals, but did not affect stress-induced impaired LTP in adult animals. Taken together, these findings demonstrate that emotional metaplasticity is differently dependent on NMDAr in adult and juvenile animals that may stem from developmental differences in the NMDA receptor representation. These results further confirm that the mechanisms of plasticity following stress are distinctive in the two groups of age.

Oxytocin in the amygdala and not the prefrontal cortex enhances fear and impairs extinction in the juvenile rat.

A growing body of evidence suggests that the hypothalamic neuropeptide oxytocin (OT), aside from its central role in the regulation of social behavior, reduces fear and anxiety. The functional and opposing interactions of the medial prefrontal cortex (mPFC) and the amygdala in regulation of fear provide a unique experimental setting to examine the effects of OT on fear and extinction. Recent evidence suggests that in the adult animal OT can play a dual role in the regulation of fear leading to contrasting effects on fear depending on the manipulated brain region and the time of manipulations. The OT system is one of the systems that undergoes major changes throughout development, however, its role in regulating fear in young animals has not been widely explored. We recently showed that the mechanisms of extinction, and specifically engagement of the mPFC in extinction, are not identical in adult and juvenile animals. Thus, the purpose of this study was to elucidate the effects of OT on fear and extinction in juvenile animals. To that end, we determine extinction, by measuring freezing at different time points, following microinjection of the OT agonist, TGOT, into the mPFC, the basolateral and the central nuclei of the amygdala (BLA and CeA, respectively). The results show that whereas TGOT microinjections into the IL-mPFC did not affect extinction, microinjections into the amygdala were mainly associated with enhanced fear and impaired extinction. These results further emphasize the differences between adult and juvenile brains.

PI3-kinase cascade has a differential role in acquisition and extinction of conditioned fear memory in juvenile and adult rats.

The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in phosphorylation of Akt in the BLA and mPFC after fear conditioning and extinction in juvenile and adult rats and (2) the effect of BLA and mPFC localized inhibition of the PI3K following acquisition and extinction of contextual fear memory. Our results show that Akt phosphorylation is increased following acquisition of contextual fear learning in the BLA but not in the mPFC in adult and juvenile rats. Extinction learning was not associated with changes in Akt phosphorylation. Although there were no differences in the pattern of phosphorylation of Akt either in adult or juvenile rats, microinjection of the PI3K inhibitor, LY294002, into the BLA or mPFC elicited differential effects on fear memory acquisition and extinction, depending on the site and timing of the microinjection, as well as on the age of the animal. These results suggest that PI3K/Akt has a differential role in formation, retrieval, and extinction of contextual fear memory in juvenile and adult animals, and point to developmental differences between adult and juvenile rats in mechanisms of extinction.

Juvenile obesity enhances emotional memory and amygdala plasticity through glucocorticoids.

In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic-pituitary-adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor-malaise and tone-shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD-induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function.

Learning-induced bidirectional plasticity of intrinsic neuronal excitability reflects the valence of the outcome.

Long-term memory is supported not only by modulation of synaptic strength, but also by modifications in intrinsic neuronal properties. Learning-induced enhancement of neuronal excitability has been shown in the hippocampus and the piriform cortex, where it lasts for days and is involved in maintaining the learned skills. The basolateral amygdala (BLA) is suggested to encode positive and negative significance of information, thus forming a unique experimental setting to monitor bidirectional changes as a function of the valence change. In rodents, olfaction is a major modality that guides goal-directed behavior. Here, we show that intrinsic neuronal excitability in BLA pyramidal neurons is differentially modified by positive and negative olfactory learning and explore the cellular mechanisms of such bidirectional intrinsic neuronal plasticity. Learning of complex olfactory-discrimination task, in which success was rewarded with drinking water, resulted with enhanced intrinsic excitability. Such enhancement is mediated by reduction in the slow potassium current. In contrast, olfactory fear conditioning, in which the animal learned to associate the odor with an electric shock, resulted in decreased intrinsic excitability, mediated by activation of the µ-opioid-sensitive potassium current. We suggest that positive and negative changes in BLA excitability contribute to the encoding of opposite odor-value behaviors.

Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons.

Stress-sensitive psychopathologies such as post-traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex-to-BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non-conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress-related disorders.

Inhibition of the PI3 kinase cascade in corticolimbic circuit: temporal and differential effects on contextual fear and extinction.

We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders.

Epigenetic (re)programming of gene expression changes of CB1R and FAAH in the medial prefrontal cortex in response to early life and adolescence stress exposure.

Environmental factors, including stress, that are experienced during early life (ELS) or adolescence are potential risk factors for the development of behavioral and mental disorders later in life. The endocannabinoid system plays a major role in the regulation of stress responses and emotional behavior, thereby acting as a mediator of stress vulnerability and resilience. Among the critical factors, which determine the magnitude and direction of long-term consequences of stress exposure is age, i.e., the maturity of brain circuits during stress exposure. Thus, the present study addressed the hypotheses that ELS and adolescent stress differentially affect the expression of regulatory elements of the endocannabinoid system, cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) in the medial prefrontal cortex (mPFC) of adult female rats. We also tested the hypothesis that the proposed gene expression changes are epigenetically modulated via altered DNA-methylation. The specific aims were to investigate if (i) ELS and adolescent stress as single stressors induce changes in CB1R and FAAH expression (ii) ELS exposure influences the effect of adolescent stress on CB1R and FAAH expression, and (iii) if the proposed gene expression changes are paralleled by changes of DNA methylation. The following experimental groups were investigated: (1) non-stressed controls (CON), (2) ELS exposure (ELS), (3) adolescent stress exposure (forced swimming; FS), (4) ELS + FS exposure. We found an up-regulation of CB1R expression in both single-stressor groups and a reduction back to control levels in the ELS + FS group. An up-regulation of FAAH expression was found only in the FS group. The data indicate that ELS, i.e., stress during a very immature stage of brain development, exerts a buffering programming effect on gene expression changes induced by adolescent stress. The detected gene expression changes were accompanied by altered DNA methylation patterns in the promoter region of these genes, specifically, a negative correlation of mean CB1R DNA methylation with gene expression was found. Our results also indicate that ELS induces a long-term "(re)programming" effect, characterized by CpG-site specific changes within the promoter regions of the two genes that influence gene expression changes in response to FS at adolescence.

Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning.

Extinction learning is associated with a decline of the conditioned fear response (CR). However, re-exposure to the unconditioned stimulus (US, shock) is associated with the return of the fear response. This study aimed to study the role of protein synthesis and actin rearrangement in the CA1 hippocampal subregion and the basolateral amygdala (BLA) in acquisition and reacquisition of contextual fear conditioning. To that end, we trained rats on contextual fear conditioning and extinction, and on the last extinction training session we reconditioned the animals by re-exposure to the US. Immediately after, rats were microinfused with the protein synthesis inhibitor anisomycin or the actin rearrangement inhibitor cytochalasin D into either the BLA or the CA1. The results of this study show differential involvement of anisomycin and cytochalasin D in the acquisition and reacquisition of contextual fear conditioning. Specifically, while the microinfusion of anisomycin into the BLA or the CA1 immediately after reconditioning of fear did not inhibit the return of fear, the microinfusion of cytochalsin D into either the BLA or the CA1 attenuated fear responses. Interestingly, the initial acquisition of contextual fear memory is dependent on intra-BLA and CA1 protein synthesis and cytoskeletal rearrangement, since the microinfusion of these drugs blocked the formation of long-term fear memory. The results suggest that the two processes of acquisition and reacquisition of fear are not identical and they engage different mechanisms.

Olfactory learning-induced enhancement of the predisposition for LTP induction.

Learning of a particularly difficult olfactory-discrimination (OD) task results in acquisition of rule learning. This enhancement in learning capability is accompanied by the long-term enhancement of synaptic connectivity between piriform cortex pyramidal neurons. In this study we examined whether olfactory rule learning would modify the predisposition to induce long-term potentiation (LTP) in the pathway projecting from the piriform cortex to the olfactory bulb. We report that OD learning was associated with enhancement in the predisposition to induce LTP. This learning-related effect may be affected by process generation of new granule cells located in the olfactory bulb.

Differential Age-dependent Mechanisms of High-frequency Stimulation-induced Potentiation in the Prefrontal Cortex-Basolateral Amygdala Pathway Following Fear Extinction.

Post-weaning is a critical period for brain maturation in the rat and is comparable to childhood and adolescences in humans. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) are two brain regions that continue to mature during post-weaning and establish a critical circuit regulating the acquisition and extinction of conditioned fear. We previously demonstrated that exposure to stress leads to significant differences between adults and PWs in the kinetics of extinction behavior as well as differential effects on long-term potentiation. In the current experiments, we aimed to investigate whether prior fear or extinction learning would elicit differences in the ability to induce electrical LTP in the mPFC-BLA pathway in the adult and PW animals. To that end, we subjected adult and PW rats to auditory fear conditioning and extinction, followed by high-frequency stimulation (HFS) to induce LTP. The results indicate that when the conditioning protocol is adjusted to produce comparable extinction kinetics in both age groups, no LTP can be induced after fear conditioning in the mPFC-BLA pathway. Importantly, after extinction, LTP was successfully induced, and a significant difference was observed in the levels of potentiation between adults and PW rats. Further, freezing levels during extinction positively correlated with the magnitude of LTP only in adult animals. These results suggest that the changes occurring at the synaptic level following fear extinction are dissimilar in adult and PW animals. Our results further strengthen the assertion that PW and adult fear extinction learning may rely on different mechanisms.

Stress and amygdala suppression of metaplasticity in the medial prefrontal cortex.

The term "metaplasticity" refers to the modulation of the ability to induce synaptic plasticity of the form of long-term potentiation (LTP) or long-term depression (LTD) following prior activation of the synapses. While often electrophysiological manipulations are used to demonstrate this phenomenon, prior behavioral manipulations such as exposure to stress were also found to affect the ability to induce LTP and LTD. Interestingly, amygdala stimulation was found to have effects on subsequent LTP induction that resemble those of stress. Here, we report that exposure to stress or basolateral amygdala (BLA) stimulation induces a form of metaplasticity, which prevents the ability of a second episode of stress or BLA activation to suppress LTP in the ventral hippocampus-medial prefrontal cortex (mPFC) pathway. This form of metaplasticity is N-methyl-D-aspartic acid (NMDA)-dependent since the injection of the NMDA partial agonist D-cycloserine prevented the inhibition of LTP induced by prior exposure of stress or BLA activation. Furthermore, blocking NMDA receptors by MK801 before the exposure to stress prevented the ability of the emotional manipulation to inhibit the subsequent modulation of plasticity, resulting in impaired LTP in the mPFC. Taken together, these findings demonstrate a new form of NMDA-dependent emotional metaplasticity in the ventral hippocampus-mPFC pathway.