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Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events, including mass shootings, assault, or natural disasters, events that consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examined synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle-dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation offosexpression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory, and fluctuating physiological levels of sex hormones may contribute to this effect.SIGNIFICANCE STATEMENT:Effects of stress on brain functions, including memory, are profound and sex-dependent. Acute stressors occurring simultaneously result in spatial memory impairments in males, but effects on females are unknown. Here we identified estrous cycle-dependent effects of such stresses on memory in females. Surprisingly, females with higher physiological estradiol experienced stress-induced memory impairment and a loss of underlying synapses. Memory- and stress-responsive brain regions interconnected with hippocampus were differentially activated across high and low estradiol mice, and predicted memory impairment. Thus, at functional, network, and cellular levels, physiological estradiol influences the effects of stress on memory in females, providing insight into mechanisms of prominent sex differences in stress-related memory disorders, such as post-traumatic stress disorder.

The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin- and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues.SIGNIFICANCE STATEMENTThe role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long-term inhibition of GluT4 impaired long-term memory, short-term memory was enhanced. These data further our understanding of the molecular mechanisms of memory and have particular significance for type 2 diabetes (in which GluT4 activity in the periphery is impaired) and Alzheimer's disease (which is linked to impaired brain insulin signaling and for which type 2 diabetes is a key risk factor). Both diseases cause marked impairment of hippocampal memory linked to hippocampal hypometabolism, suggesting the possibility that brain GluT4 dysregulation may be one cause of cognitive impairment in these disease states.

Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal synapses are bathed in a mixture of stress-released molecules, yet it is unknown whether or how these interact to mediate the effects of stress on memory. Here, we demonstrate novel synergistic actions of corticosterone and corticotropin-releasing hormone (CRH) on synaptic physiology and dendritic spine structure that mediate the profound effects of acute concurrent stresses on memory. Spatial memory in mice was impaired enduringly after acute concurrent stresses resulting from loss of synaptic potentiation associated with disrupted structure of synapse-bearing dendritic spines. Combined application of the stress hormones corticosterone and CRH recapitulated the physiological and structural defects provoked by acute stresses. Mechanistically, corticosterone and CRH, via their cognate receptors, acted synergistically on the spine-actin regulator RhoA, promoting its deactivation and degradation, respectively, and destabilizing spines. Accordingly, blocking the receptors of both hormones, but not each alone, rescued memory. Therefore, the synergistic actions of corticosterone and CRH at hippocampal synapses underlie memory impairments after concurrent and perhaps also single, severe acute stresses, with potential implications to spatial memory dysfunction in, for example, posttraumatic stress disorder.SIGNIFICANCE STATEMENTStress influences memory, an adaptive process crucial for survival. During stress, adrenal corticosterone and hippocampal corticotropin-releasing hormone (CRH) permeate memory-forming hippocampal synapses, yet it is unknown whether (and how) these hormones interact to mediate effects of stress. Here, we demonstrate novel synergistic actions of corticosterone and CRH on hippocampal synaptic plasticity and spine structure that mediate the memory-disrupting effects of stress. Combined application of both hormones provoked synaptic function collapse and spine disruption. Mechanistically, corticosterone and CRH synergized at the spine-actin regulator RhoA, promoting its deactivation and degradation, respectively, and destabilizing spines. Notably, blocking both hormones, but not each alone, prevented the enduring memory problems after acute concurrent stresses. Therefore, synergistic actions of corticosterone and CRH underlie enduring memory impairments after concurrent acute stresses, which might be relevant to spatial memory deficits described in posttraumatic stress disorder.

Stress is known to impair working memory performance. This disruptive effect of stress on working memory has been linked to a decrease in the activity of the dorsolateral prefrontal cortex (dlPFC). In the present experiment, we tested whether transcranial direct current stimulation (tDCS) of the dlPFC can prevent stress-induced working memory impairments. We tested 120 healthy participants in a 2 d, sham-controlled, double-blind between-subjects design. Participants completed a test of their individual baseline working memory capacity on day 1. On day 2, participants were exposed to either a stressor or a control manipulation before they performed a visuospatial and a verbal working memory task. While participants completed the tasks, anodal, cathodal, or sham tDCS was applied over the right dlPFC. Stress impaired working memory performance in both tasks, albeit to a lesser extent in the verbal compared with the visuospatial working memory task. This stress-induced working memory impairment was prevented by anodal, but not sham or cathodal, stimulation of the dlPFC. Compared with sham or cathodal stimulation, anodal tDCS led to significantly better working memory performance in both tasks after stress. Our findings indicate a causal role of the dlPFC in working memory impairments after acute stress and point to anodal tDCS as a promising tool to reduce cognitive deficits related to working memory in stress-related mental disorders, such as depression, schizophrenia, or post-traumatic stress disorder.SIGNIFICANCE STATEMENTWorking memory deficits are prominent in stress-related mental disorders, such as depression, schizophrenia, or post-traumatic stress disorder. Similar working memory impairments have been observed in healthy individuals exposed to acute stress. So far, attempts to prevent such stress-induced working memory deficits focused mainly on pharmacological interventions. Here, we tested the idea that transcranial direct current stimulation of the dorsolateral prefrontal cortex (dlPFC), a critical neural substrate of working memory, may prevent working memory impairments after stress. Our results indicate that anodal stimulation of the dlPFC may indeed preserve working memory performance under stress, suggesting that the dlPFC plays a causal role in stress-induced working memory deficits and pointing to a potential new avenue to prevent stress-induced cognitive impairments.

Stress constitutes an organism's essential physiological response to the environment, and it exerts variable influences on memory depending on the context, type, and duration of the stressor ([Vogel and Schwabe, 2016][1]). Generally, acute stressors are thought to boost memory formation, possibly as

Contains fulltext : 150747.pdf (Publisher’s version ) (Open Access) Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19 degrees C and 25 degrees C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 mug/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. SIGNIFICANCE STATEMENT: Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.

Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown ofBaf53bbefore training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity.SIGNIFICANCE STATEMENTRecent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for memory consolidation during long-term memory formation. Our results thus provide an idea about how nucleosome remodeling can be regulated during long-term memory formation and contributes to the permanent storage of associative fear memory in the lateral amygdala, which is relevant to fear and anxiety-related mental disorders.

The cellular and molecular effects of stress on the amygdala are strikingly different compared with those in the hippocampus. Previous findings on stress-induced plasticity were based primarily on postmortem analysis within individual areas. However, little is known about how stress affects dynamic changes and interactions in neuronal activity between the two areas. Hence, we simultaneously monitoredin vivoactivity of neuronal populations located in hippocampal areas CA1 and CA3 and the lateral amygdala (LA) in rats during and after chronic immobilization stress. The amplitude of auditory-evoked potentials (AEPs) in the hippocampus increased transiently only after a single 2 h stress but not when it was repeated for 10 d. In contrast, both acute and chronic stress caused a persistent increase in AEPs in the LA. Chronic stress also elicited a sustained increase in the LA but a decrease in the hippocampus in the evoked power of gamma and beta frequencies. Moreover, beta and gamma synchrony was reduced between areas CA1 and CA3 but enhanced between the LA and hippocampus after chronic stress. Granger causality spectra revealed a strong directional influence from the LA to area CA1 that persisted throughout and even 10 d after chronic stress. However, directional coupling from hippocampal area CA3 to CA1 became weaker at the end of chronic stress. Thus, our findings suggest that the growing dominance of amygdalar activity over the hippocampus during and even after chronic stress may contribute to the enhanced emotional symptoms, alongside impaired cognitive function, seen in stress-related psychiatric disorders.

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF1) located on pyramidal cell dendrites. Additionally, chronic CRF1occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF1receptors. Central or peripheral administration of a CRF1blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH–CRF1interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF1occupancypost hocnormalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.

Contains fulltext : 81492.pdf (Publisher’s version ) (Open Access) Stressful, aversive events are extremely well remembered. Such a declarative memory enhancement is evidently beneficial for survival, but the same mechanism may become maladaptive and culminate in mental diseases such as posttraumatic stress disorder (PTSD). Stress hormones are known to enhance postlearning consolidation of aversive memories but are also thought to have immediate effects on attentional, sensory, and mnemonic processes at memory formation. Despite their significance for our understanding of the etiology of stress-related mental disorders, effects of acute stress at memory formation, and their brain correlates at the system scale, remain elusive. Using an integrated experimental approach, we probed the neural correlates of memory formation while participants underwent a controlled stress induction procedure in a crossover design. Physiological (cortisol level, heart rate, and pupil dilation) and subjective measures confirmed acute stress. Remarkably, reduced hippocampal activation during encoding predicted stress-enhanced memory performance, both within and between participants. Stress, moreover, amplified early visual and inferior temporal responses, suggesting that hypervigilant processing goes along with enhanced inferior temporal information reduction to relay a higher proportion of task-relevant information to the hippocampus. Thus, acute stress affects neural correlates of memory formation in an unexpected manner, the understanding of which may elucidate mechanisms underlying psychological trauma etiology.

A coordinated activation of multiple interlinked signaling pathways involving cAMP-dependent protein kinase (PKA) and mitogen-activated extracellular signal-regulated kinases (Mek-1/2) regulates gene expression and neuronal changes underlying memory consolidation. In the present study we investigated whether these molecular cascades might mediate the effects of stress on memory formation. We also investigated the role of hippocampal corticotropin-releasing factor receptor 2 (CRF2) in stress-enhanced learning and molecular signaling mediated by PKA, Mek-1/2, and their downstream targets extracellularly regulated kinases 1 and 2 (Erk-1/2) and p90-ribosomal-s-kinase-1 (p90Rsk-1).Acute 1 hr immobilization was used as a stressful stimulus, and one-trial context-dependent fear conditioning was used as a model for associative learning. Training of BALB/c mice 3 hr after the end of immobilization resulted in an enhancement of conditioned fear, as indicated by significantly increased freezing behavior of stressed when compared with nonstressed mice. Interestingly, Erk-1/2 phosphorylation after conditioning of nonstressed and stressed mice depended on PKA and Mek-1/2, respectively. Intrahippocampal injection of the selective Mek-1/2 inhibitor U0126 or CRF2antagonist antisauvagine-30 (aSvg-30) prevented stress-enhanced fear conditioning and Mek-1/2-dependent activation of Erk-1/2 and p90Rsk-1. aSvg-30 did not affect the phosphorylation of the PKA regulatory subunit II of stressed mice. The molecular and behavioral effects of CRF2coincided with stress-induced upregulation ofCRF2mRNA.These results suggest that modulation of Mek-1/2-dependent signaling by hippocampal CRF2can be selectively involved in the delayed effects of stress on memory consolidation.

A memory trace in its active state is susceptible to interference by amnesic agents, such as hypothermia and electroconvulsive shock, and by NMDA receptor antagonists, suggesting that a time-dependent consolidation process occurs each time a memory is reactivated. The role of β noradrenergic receptors in reconsolidation in rats was examined in both a positively reinforced radial maze task and a footshock-reinforced conditioned emotional response task. For the former, rats were trained over several days in a spatial reference memory task and received a single reactivation trial followed by propranolol. A temporally graded impairment was observed when propranolol treatment occurred after the memory reactivation trial. In the emotional task, memory impairing effects of propranolol were greater when the drug was administered after a reactivation trial than when administered immediately after the initial training. These results suggest that reactivation of memory triggers a β receptor-dependent cascade of intracellular events, recapitulating that which occurs during initial postacquisition consolidation, thus permitting reorganization of the existing memory as a function of new information in the retrieval environment. This remarkable lability of an active memory trace provides a new basis for pharmacotherapeutic intervention in such syndromes as Posttraumatic Stress Disorder. β adrenoreceptor antagonists may be promising pharmacological agents for attenuating debilitating memories at the time of their controlled reactivation.

Based largely on dissociations of the effects of different lesions on learning and memory, memories for different attributes appear to be organized in independent neural systems. Results obtained with direct injections of drugs into one brain region at a time support a similar conclusion. The present experiments investigated the effects of simultaneous pharmacological manipulation of two neural systems, the amygdala and the septohippocampal system, to examine possible interactions of memory modulation across systems. Morphine injected into the medial septum impaired memory both for avoidance training and during spontaneous alternation. When glucose was concomitantly administered to the amygdala, glucose reversed the morphine-induced deficits in memory during alternation but not for avoidance training. These results suggest that the amygdala is involved in modulation of spatial memory processes and that direct injections of memory-modulating drugs into the amygdala do not always modulate memory for aversive events. These findings are contrary to predictions from the findings of lesion studies and of studies using direct injections of drugs into single brain areas. Thus, the independence of neural systems responsible for processing different classes of memory is less clear than implied by studies using lesions or injections of drugs into single brain areas.

Learning and memory are supported by anatomically and functionally distinct systems. Recent research suggests that stress may alter the contributions of multiple memory systems to learning, yet the underlying mechanism in the human brain remains completely unknown. Using event-related functional magnetic resonance imaging, we asked in the present experiment whether stress may modulate the engagement of hippocampus-based “declarative” and striatum-based “procedural” memory systems during classification learning in humans and what brain mechanisms are involved in this effect. We found that stress reduced declarative knowledge about the learning task and changed the used learning strategy from a single-cue-based declarative strategy to a multicue-based procedural strategy, whereas learning performance per se remained unaffected by stress. Neuroimaging revealed that hippocampal activity correlated positively with task performance in the control condition, whereas striatal activity correlated with performance in the stress condition. After stress, hippocampal activity was reduced and even negatively correlated with learning performance. These findings show for the first time that stress alters the engagement of multiple memory systems in the human brain. Stress impaired the hippocampus-dependent system and allowed the striatum to control behavior. The shift toward “procedural” learning after stress appears to rescue task performance, whereas attempts to engage the “declarative” system disrupt performance.

Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal-PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal-PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction. These findings evidence a fundamental role of the PFC in maladaptive responses to stress and identify this area as a target for intervention in stress-related disorders., This work was supported in part by an Acções Integradas Luso-Alemãs grant from the German Academic Exchange Service and the Portuguese Rectors’ Conference, and Mobility Grant 183/2006 from the Institut National de la Santé et de la RechercheMédicale andthe Cabinetfor International Relations ofthe PortugueseMinistry of Science and Higher Education.

Although corticosterone (a stress hormone) is known to influence social behavior and memory processes, little has been explored concerning its modulatory role in social recognition. In rats, social recognition memory for conspecifics typically lasts

Stress is a biologically significant factor shown to influence synaptic plasticity and memory functioning in the hippocampus. This study examined the role of the amygdala, a brain structure implicated in coordinating stress behaviors and modulating memory consolidation, in mediating stress effects on hippocampal long-term potentiation (LTP) and memory in rats. Electrolytic lesions of the amygdala effectively blocked the adverse physiological and behavioral effects of restraint and tailshock stress, without impeding the increase in corticosterone secretion to stress. Physiologically, hippocampal slices from stressed animals exhibited impaired LTP relative to slices from unstressed control animals, whereas hippocampal slices from stressed animals with amygdalar lesions exhibited normal LTP. Behaviorally, stressed animals were impaired in retention of a hippocampal-dependent hidden platform version of the Morris water maze task, and this impairment was blocked by amygdalar lesions. In a fixed location–visible platform water maze task that can be acquired by independent hippocampal and nonhippocampal memory systems, stress enhanced the use of nonhippocampal-based memory to acquire the task. These results indicate that an intact amygdala is necessary for the expression of the modulatory effects of stress on hippocampal LTP and memory.