Impaired Fear Memory Research Articles

Anodal tDCS applied to the left frontal cortex abrogates scopolamine-induced fear memory deficit via the dopaminergic system

Evidence suggests that transcranial direct current stimulation (tDCS) modulates conditioned fear memories and has effects on cognitive flexibility via the dopaminergic system. This study examines whether modulation of scopolamine‑induced fear memory deficit by anodal tDCS could be mediated by the dopaminergic system. The male NMRI mice received scopolamine, 30 min before fear conditioning, and showed impaired contextual memory retention. Mice subjected to left frontal anodal stimulation for 20 or 30 min, before fear conditioning, impaired fear memory retrieval. Anodal application for 20 min significantly decreased scopolamine response on fear retention, while the one applied for 30 min did not alter. Moreover, anodal stimulation for 30 min abolished scopolamine‑induced fear memory deficit. Dopaminergic antagonists SCH23390 and sulpiride, alone or in combination, prevented the abolishment effect of anodal stimulation on scopolamine‑induced fear memory deficit, whereas they did not alter the impairing effect of scopolamine at the dose of 2 mg/kg. Our data suggest that anodal stimulation for 30 min abrogates the impairing effect of scopolamine on fear memory retention. This influence could be prevented by dopaminergic antagonists, indicating the involvement of the dopaminergic system in the effect of anodal stimulation on scopolamine‑induced fear memory deficit.

Glycogen synthase kinase-3 inhibition rescues sex-dependent contextual fear memory deficit in human immunodeficiency virus-1 transgenic mice.

A significant number of HIV-1 patients on antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV-1-transgenic 26 (Tg26) mouse model. Contextual- and cue-dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT-PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. Cue-dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV-1 long terminal repeat mRNA expression, reduced hippocampal synapsin-1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione increased levels of synapsin-1, BDNF and phosphorylated-GluA1 proteins, restored hippocampal basal synaptic transmission and LTP, and improved contextual fear memory in male Tg26 mice. Sex-dependent impairments in contextual fear memory and synaptic plasticity in Tg26 mice are associated with increased GSK3 activity. This implicates GSK3 inhibition as a potential therapeutic strategy to improve cognition in HIV-1 patients.

Defective memory engram reactivation underlies impaired fear memory recall in Fragile X syndrome.

Fragile X syndrome (FXS) is an X chromosome-linked disease associated with severe intellectual disabilities. Previous studies using the Fmr1 knockout (KO) mouse, an FXS mouse model, have attributed behavioral deficits to synaptic dysfunctions. However, how functional deficits at neural network level lead to abnormal behavioral learning remains unexplored. Here, we show that the efficacy of hippocampal engram reactivation is reduced in Fmr1 KO mice performing contextual fear memory recall. Experiencing an enriched environment (EE) prior to learning improved the engram reactivation efficacy and rescued memory recall in the Fmr1 KO mice. In addition, chemogenetically inhibiting EE-engaged neurons in CA1 reverses the rescue effect of EE on memory recall. Thus, our results suggest that inappropriate engram reactivation underlies cognitive deficits in FXS, and enriched environment may rescue cognitive deficits by improving network activation accuracy.

Habenula kisspeptin retrieves morphine impaired fear memory in zebrafish

The habenula is an evolutionarily conserved brain structure, which has recently been implicated in fear memory. In the zebrafish, kisspeptin (Kiss1) is predominantly expressed in the habenula, which has been implicated as a modulator of fear response. Hence, in the present study, we questioned whether Kiss1 has a role in fear memory and morphine-induced fear memory impairment using an odorant cue (alarm substances, AS)-induced fear avoidance paradigm in adult zebrafish, whereby the fear-conditioned memory can be assessed by a change of basal place preference (= avoidance) of fish due to AS-induced fear experience. Subsequently, to examine the possible role of Kiss1 neurons-serotonergic pathway, kiss1 mRNA and serotonin levels were measured. AS exposure triggered fear episodes and fear-conditioned place avoidance. Morphine treatment followed by AS exposure, significantly impaired fear memory with increased time-spent in AS-paired compartment. However, fish administered with Kiss1 (10–21 mol/fish) after morphine treatment had significantly lower kiss1 mRNA levels but retained fear memory. In addition, the total brain serotonin levels were significantly increased in AS- and Kiss1-treated groups as compared to control and morphine treated group. These results suggest that habenular Kiss1 might be involved in consolidation or retrieval of fear memory through the serotonin system.

Suppression of DNA Double-Strand Break Formation by DNA Polymerase β in Active DNA Demethylation Is Required for Development of Hippocampal Pyramidal Neurons.

Genome stability is essential for brain development and function, as de novo mutations during neuronal development cause psychiatric disorders. However, the contribution of DNA repair to genome stability in neurons remains elusive. Here, we demonstrate that the base excision repair protein DNA polymerase β (Polβ) is involved in hippocampal pyramidal neuron differentiation via a TET-mediated active DNA demethylation during early postnatal stages using Nex-Cre/Polβ fl/fl mice of either sex, in which forebrain postmitotic excitatory neurons lack Polβ expression. Polβ deficiency induced extensive DNA double-strand breaks (DSBs) in hippocampal pyramidal neurons, but not dentate gyrus granule cells, and to a lesser extent in neocortical neurons, during a period in which decreased levels of 5-methylcytosine and 5-hydroxymethylcytosine were observed in genomic DNA. Inhibition of the hydroxylation of 5-methylcytosine by expression of microRNAs miR-29a/b-1 diminished DSB formation. Conversely, its induction by TET1 catalytic domain overexpression increased DSBs in neocortical neurons. Furthermore, the damaged hippocampal neurons exhibited aberrant neuronal gene expression profiles and dendrite formation, but not apoptosis. Comprehensive behavioral analyses revealed impaired spatial reference memory and contextual fear memory in adulthood. Thus, Polβ maintains genome stability in the active DNA demethylation that occurs during early postnatal neuronal development, thereby contributing to differentiation and subsequent learning and memory.SIGNIFICANCE STATEMENT Increasing evidence suggests that de novo mutations during neuronal development cause psychiatric disorders. However, strikingly little is known about how DNA repair is involved in neuronal differentiation. We found that Polβ, a component of base excision repair, is required for differentiation of hippocampal pyramidal neurons in mice. Polβ deficiency transiently led to increased DNA double-strand breaks, but not apoptosis, in early postnatal hippocampal pyramidal neurons. This aberrant double-strand break formation was attributed to active DNA demethylation as an epigenetic regulation. Furthermore, the damaged neurons exhibited aberrant gene expression profiles and dendrite formation, resulting in impaired learning and memory in adulthood. Thus, these findings provide new insight into the contribution of DNA repair to the neuronal genome in early brain development.

Propranolol-induced inhibition of unconditioned stimulus-reactivated fear memory prevents the return of fear in humans

Fear memories can be reactivated by a fear-associated conditioned stimulus (CS) or unconditioned stimulus (US) and then undergo reconsolidation. Propranolol administration during CS retrieval-induced reconsolidation can impair fear memory that is specific to the reactivated CS. However, from a practical perspective, the US is often associated with multiple CSs, and each CS can induce a fear response. The present study sought to develop and test a US-based memory retrieval interference procedure with propranolol to disrupt the original fear memory and eliminate all CS-associated fear responses in humans. We recruited 127 young healthy volunteers and conducted three experiments. All of the subjects acquired fear conditioning, after which they received the β-adrenergic receptor antagonist propranolol (40 mg) or placebo (vitamin C) and were exposed to the US or CS to reactivate the original fear memory. Fear responses were measured. Oral propranolol administration 1 h before US retrieval significantly decreased subsequent fear responses and disrupted associations between all CSs and the US. However, propranolol administration before CS retrieval only inhibited the fear memory that was related to the reactivated CS. Moreover, the propranolol-induced inhibition of fear memory reconsolidation that was retrieved by the US had a relatively long-lasting effect (at least 2 weeks) and was also effective for remote fear memory. These findings indicate that the US-based memory retrieval interference procedure with propranolol can permanently decrease the fear response and prevent the return of fear for all CSs in humans. This procedure may open new avenues for treating fear-related disorders.

Small ubiquitin-like modifier 2 (SUMO2) is critical for memory processes in mice.

Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a posttranslational modification, modulates almost all major cellular processes. Mounting evidence indicates that SUMOylation plays a crucial role in maintaining and regulating neural function, and importantly its dysfunction is implicated in cognitive impairment in humans. We have previously shown that simultaneously silencing SUMO1-3 expression in neurons negatively affects cognitive function. However, the roles of the individual SUMOs in modulating cognition and the mechanisms that link SUMOylation to cognitive processes remain unknown. To address these questions, in this study, we have focused on SUMO2 and generated a new conditional Sumo2 knockout mouse line. We found that conditional deletion of Sumo2 predominantly in forebrain neurons resulted in marked impairments in various cognitive tests, including episodic and fear memory. Our data further suggest that these abnormalities are attributable neither to constitutive changes in gene expression nor to alterations in neuronal morphology, but they involve impairment in dynamic SUMOylation processes associated with synaptic plasticity. Finally, we provide evidence that dysfunction on hippocampal-based cognitive tasks was associated with a significant deficit in the maintenance of hippocampal long-term potentiation in Sumo2 knockout mice. Collectively, these data demonstrate that protein conjugation by SUMO2 is critically involved in cognitive processes.

Chemogenetic activation of the mPFC alleviates impaired fear memory extinction in an animal model of PTSD

Background and aimAlthough impaired extinction of fear memory (EFM) is a hallmark symptom of posttraumatic stress disorder (PTSD), the mechanisms underlying the impairment are unknown. Activation of the infralimbic cortex (IL) in the medial prefrontal cortex (mPFC) has been reported to predict successful fear extinction, whereas functionally disrupting this region impairs extinction. We examined whether chemogenetic activation of the IL could alleviate impaired EFM in a single prolonged stress (SPS) rat model of PTSD. MethodsChemogenetic activation of IL and prelimbic (PL) excitatory neurons was undertaken to evaluate EFM using a contextual fear conditioning paradigm. Neuronal activity in the IL was recorded using a 32-multichannel silicon electrode. To examine histological changes in the mPFC, apoptosis was measured by TUNEL staining. ResultsChemogenetic activation of excitatory neurons in the IL, but not the PL, enhanced EFM in sham rats and resulted in alleviation of EFM impairment in SPS rats. The alleviation of impaired EFM in SPS rats was observed during the extinction test session. Neuronal activity in the IL of SPS rats was lower than that of sham rats after clozapine-n-oxide administration. Increased apoptosis was found in the IL of SPS rats. ConclusionsThese findings suggest that a decreased excitatory response in the IL due, at least in part, to an increase in apoptosis in SPS rats leads to impaired EFM, and that neuronal activation during extinction training could be useful for the treatment of impaired EFM in PTSD patients.

A critical role of hippocampus for formation of remote cued fear memory

A unique feature of fear memory is its persistence that is highly relevant to fear and anxiety-related mental disorders. Recurrent reactivation of neural representations acquired from a traumatic event is thought to contribute to the indelibility of fear memory. Given a well-established role of hippocampus for memory reactivation, hippocampus is likely involved in consolidation process of fear memory. However, evidence suggests that formation of fear memory to a discrete sensory cue is hippocampus-independent. Here, using a pharmacological reversible inactivation of dorsal hippocampus in auditory cued fear conditioning by local infusion of muscimol, we demonstrate in mice that hippocampus is critical for remote memory formation of learned fear to the discrete sensory cue. Muscimol infusion before conditioning did not affect formation of recent auditory fear memory as previously reported. Same muscimol infusion, however, impaired remote auditory fear memory. Muscimol infusion before remote test of auditory fear memory did not affect memory retrieval, indicating hippocampus is not a brain site for storage of remote cued fear memory. Moreover, memory reactivation enforced by re-exposure to the conditioned tone could compensate for hippocampal inactivation, as memory-reactivated mice showed normal remote auditory fear memory despite hippocampal inactivation. Our findings support that hippocampus may have a general role for consolidation of remote associative memory through reactivation of memory trace, giving an insight into how learned fear persists over time.

Social Fear Memory Requires Two Stages of Protein Synthesis in Mice.

It is well known that long-term consolidation of newly acquired information, including information related to social fear, require de novo protein synthesis. However, the temporal dynamics of protein synthesis during the consolidation of social fear memories is unclear. To address this question, mice received a single systemic injection with the protein synthesis inhibitor, anisomycin, at different time-points before or after social fear conditioning (SFC), and memory was assessed 24 h later. We showed that anisomycin impaired the consolidation of social fear memories in a time-point-dependent manner. Mice that received anisomycin 20 min before, immediately after, 6 h, or 8 h after SFC showed reduced expression of social fear, indicating impaired social fear memory, whereas anisomycin caused no effects when administered 4 h after SFC. These results suggest that consolidation of social fear memories requires two stages of protein synthesis: (1) an initial stage starting during or immediately after SFC, and (2) a second stage starting around 6 h after SFC and lasting for at least 5 h.

Inducible and Conditional Stimulation of Adult Hippocampal Neurogenesis Rescues Cadmium-Induced Impairments of Adult Hippocampal Neurogenesis and Hippocampus-Dependent Memory in Mice.

Cadmium (Cd) is a heavy metal and an environmental pollutant. However, the full spectrum of its neurotoxicity and the underlying mechanisms are not completely understood. Our previous studies demonstrated that Cd exposure impairs adult hippocampal neurogenesis and hippocampus-dependent memory in mice. This study aims to determine if these adverse effects of Cd exposure can be mitigated by genetically and conditionally enhancing adult neurogenesis. To address this issue, we utilized the transgenic constitutive active MEK5 (caMEK5) mouse strain we previously developed and characterized. This mouse strain enables us to genetically and conditionally activate adult neurogenesis by administering tamoxifen to induce expression of a caMEK5 in adult neural stem/progenitor cells, which stimulates adult neurogenesis through activation of the endogenous extracellular signal-regulated kinase 5 mitogen-activated protein kinase pathway. The caMEK5 mice were exposed to 0.6 mg/l Cd through drinking water for 38 weeks. Once impairment of memory was confirmed, tamoxifen was administered to induce caMEK5 expression and to activate adult neurogenesis. Behavior tests were conducted at various time points to monitor hippocampus-dependent memory. Upon completion of the behavior tests, brain tissues were collected for cellular studies of adult hippocampal neurogenesis. We report here that Cd impaired hippocampus-dependent spatial memory and contextual fear memory in mice. These deficits were rescued by the tamoxifen induction of caMEK5 expression. Furthermore, Cd inhibition of adult hippocampal neurogenesis was also reversed. This rescue experiment provides strong evidence for a direct link between Cd-induced impairments of adult hippocampal neurogenesis and hippocampus-dependent memory.

Anandamide Signaling Augmentation Rescues Amygdala Synaptic Function and Comorbid Emotional Alterations in a Model of Epilepsy.

Epilepsy is often associated with emotional disturbances and the endocannabinoid (eCB) system tunes synaptic transmission in brain regions regulating emotional behavior. Thus, persistent alteration of eCB signaling after repeated seizures may contribute to the development of epilepsy-related emotional disorders. Here we report that repeatedly eliciting seizures (kindling) in the amygdala caused a long-term increase in anxiety and impaired fear memory retention, which was paralleled by an imbalance in GABA/glutamate presynaptic activity and alteration of synaptic plasticity in the basolateral amygdala (BLA), in male rats. Anandamide (AEA) content was downregulated after repeated seizures, and pharmacological enhancement of AEA signaling rescued seizure-induced anxiety by restoring the tonic control of the eCB signaling over glutamatergic transmission. Moreover, AEA signaling augmentation also rescued the seizure-induced alterations of fear memory by restoring the phasic control of eCB signaling over GABAergic activity and plasticity in the BLA. These results indicate that modulation of AEA signaling represents a potential and promising target for the treatment of comorbid emotional dysfunction associated with epilepsy.SIGNIFICANCE STATEMENT Epilepsy is a heterogeneous neurologic disorder commonly associated with comorbid emotional alterations. However, the management of epilepsy is usually restricted to the control of seizures. The endocannabinoid (eCB) system, particularly anandamide (AEA) signaling, controls neuronal excitability and seizure expression and regulates emotional behavior. We found that repeated seizures cause an allostatic maladaptation of AEA signaling in the amygdala that drives emotional alterations. Boosting AEA signaling through inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH), restored both synaptic and behavioral alterations. FAAH inhibitors dampen seizure activity in animal models and are used in clinical studies to treat the negative consequences associated with stress. Thereby, they are accessible and can be clinically evaluated to treat both seizures and comorbid conditions associated with epilepsy.

Blockade of muscarinic receptors impairs reconsolidation of older fear memory by decreasing cholinergic neurotransmission: A study in rat model of PTSD

The age and strength of fear memory are two potential parameters that can be influenced by the impairing effects of pharmacological agents on reconsolidation of fear memory. In reconsolidation, stored information is rendered labile again after being reactivated. Pharmacological manipulations at this stage result in an inability to retrieve the fear memories, suggesting that they are erased or persistently inhibited. This fear memory impairment phenomenon can be valuable to treat post-traumatic stress disorders (PTSD). Previously β-adrenergic antagonist propranolol has been repeatedly reported to impair fear memory in the treatment of PTSD. Atropine has also shown to disrupt memory formation. The present study was therefore designed to compare the effects of atropine and propranolol on reconsolidation of older fear memory in rat model of PTSD using Pavlovian fear conditioning apparatus. For this purpose 18 rats were taken and divided into control, atropine and propranolol groups and subjected to Pavlovian fear conditioning trials in order to develop animal model of PTSD. To evaluate the reconsolidation impairment of fear memory by atropine and propranolol, short term and long term memory was tested after reactivation of fear memory in rats. The present findings demonstrate that atropine significantly decreases fear expression. These results suggest that atropine significantly reduces the strength of fear memories and may be effective in the treatment of psychiatric disorders especially in PTSD.

Upregulation of AMPK Ameliorates Alzheimer's Disease-Like Tau Pathology and Memory Impairment.

The studies have shown that 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is involved in Alzheimer's disease (AD) pathology, but the effects of AMPK on AD-like Tau abnormal phosphorylation and its underlying mechanism remains unclear. Herein, we found that the mRNA expression and activity of AMPK are significantly decreased in the brains of the aging C57 mice and 3 × Tg AD mice when compared with their respective control. Moreover, when downregulation of AMPK with AAV-siAMPK-eGFP in the hippocampus CA3 of 3-month-old C57 mice, the mice display AD-like Tau hyperphosphorylation, fear memory impairment, and glycogen synthase kinase-3β (GSK3β) activity increased. On the other hand, there are also AD-like Tau hyperphosphorylation, impairment of fear memory, and AMPK activity decreased in streptozotocin (STZ) mice. Interestingly, AMPK overexpression could efficiently rescue AD-like Tau phosphorylation and brain impairment in STZ mice. Moreover, the activity of GSK3β and the level of Tau phosphorylation (Ser396 and Thr231 sites) were significantly decreased in HEK293 Tau cells transfected by AMPK plasmid or treated with agonists salicylate (SS), but GSK3β agonists Wortmannin (Wort) could ablate AMPK-mediated Tau dephosphorylation. Taken together, the study indicated that AMPK reduces Tau phosphorylation and improves brain function and inhibits GSK3β in AD-like model. These findings proved that AMPK might be a new target for AD in the future.

The role of glucocorticoid receptors in the induction and prevention of hippocampal abnormalities in an animal model of posttraumatic stress disorder.

Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Numerous clinical studies have led to the hypothesis that elevated glucocorticoid levels in response to extreme stress might trigger a pathophysiological cascade which consequently leads to functional and morphological changes in the hippocampus. To elucidate the pathophysiology of PTSD, we examined the alteration of hippocampal gene expression through the glucocorticoid receptor (GR) in the single prolonged stress (SPS) paradigm, a rat model of PTSD. We measured nuclear GRs by western blot, and the binding of GR to the promoter of Bcl-2 and Bax genes by chromatin immunoprecipitation-qPCR as well as the expression of these 2 genes by RT-PCR in the hippocampus of SPS rats. In addition, we examined the preventive effects of a GR antagonist on SPS-induced molecular, morphological, and behavioral alterations (hippocampal gene expression of Bcl-2 and Bax, hippocampal apoptosis using TUNEL staining, impaired fear memory extinction (FME) using the contextual fear conditioning paradigm). Exposure to SPS increased nuclear GR expression and GR binding to Bcl-2 gene, and decreased Bcl-2 mRNA expression. Administration of GR antagonist immediately after SPS prevented activation of the glucocorticoid cascade, hippocampal apoptosis, and impairment FME in SPS rats. The activation of GRs in response to severe stress may trigger the pathophysiological cascade leading to impaired FME and hippocampal apoptosis. In contrast, administration of GR antagonist could be useful for preventing the development of PTSD.

Perirhinal cortex inactivation produces retrieval deficits in fear extinction to a discontinuous visual stimulus.

Several studies suggest that the perirhinal cortex (PER) may function to unitize stimulus components across time or modalities. While the PER has been shown to be critical for fear acquisition to discontinuous stimuli, the role of the PER in fear extinction memory has not been evaluated. The current study assessed the involvement of the PER during fear extinction training to a continuous or discontinuous conditioned stimulus (CS). Rats were randomly assigned to 1 of 4 groups based on 2 factors: the CS type (a continuous or discontinuous light) and a pretesting PER manipulation (muscimol inactivation or saline). Results showed that PER inactivation impaired fear memory to both CS types; however, PER inactivation had only impaired extinction memory to the discontinuous light. These results suggest the role of the PER in stimulus unitization extends to supporting the acquisition of fear extinction memory. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Hypobaric hypoxia induced fear and extinction memory impairment and effect of Ginkgo biloba in its amelioration: Behavioral, neurochemical and molecular correlates

Regulated fear and extinction memory is essential for balanced behavioral response. Limbic brain regions are susceptible to hypobaric hypoxia (HH) and are putative target for fear extinction deficit and dysregulation. The present study aimed to examine the effect of HH and Ginkgo biloba extract (GBE) on fear and extinction memory with the underlying mechanism. Adult male Sprague-Dawley rats were evaluated for fear extinction and anxious behavior following GBE administration during HH exposure. Blood and tissue (PFC, hippocampus and amygdala) samples were collected for biochemical, morphological and molecular studies.Results revealed deficit in contextual and cued fear extinction following 3 days of HH exposure. Increased corticosterone, glutamate with decreased GABA level was found with marked pyknosis, decrease in apical dendritic length and number of functional spines. Decline in mRNA expression level of synaptic plasticity genes and immunoreactivity of BDNF, synaptophysin, PSD95, spinophilin was observed following HH exposure. GBE administration during HH exposure improved fear and extinction memory along with decline in anxious behavior. It restored corticosterone, glutamate and GABA levels with an increase in apical dendritic length and number of functional spines with a reduction in pyknosis. It also improved mRNA expression level and immunoreactivity of neurotrophic and synaptic proteins.The present study is the first which demonstrates fear extinction deficit and anxious behavior following HH exposure. GBE administration ameliorated fear and extinction memory dysregulation by restoration of neurotransmitter levels, neuronal pyknosis and synaptic connections along with improved neurotrophic and synaptic protein expressions.

Fear memory is impaired in hypobaric hypoxia: Role of synaptic plasticity and neuro-modulators in limbic region

AimsEvidence suggests that hypobaric hypoxia (HH) exposure causes biochemical and molecular level perturbations in brain resulting in associated cognitive dysfunction. However, the possible effect of HH on amygdala and the associated limbic regions based functions remains elusive. Regulated fear expression is essential for quick adaptations and optimal behavioral response. Therefore, the present study aims to investigate the effect of HH on biochemical and molecular mechanisms in amygdala involved in fear memory regulation along with the hippocampus and prefrontal cortex based fear memory. Materials and methodsAdult male Sprague Dawley rats were subjected to cued and contextual fear memory assessment following simulated HH exposure (25,000 ft) for 3 and 7 days. Plasma and limbic tissue (Prefrontal cortex, hippocampus and amygdala) samples were collected for biochemical and molecular studies. Key findingsResults revealed a decrease in contextual and cued fear memory retrieval, indicating fear memory dysregulation under HH exposure. Increased level of norepinephrine, dopamine, corticosterone and glutamate along with a decline in serotonin and GABA level was observed in plasma and limbic tissue after 3 and 7 days of HH exposure. Dysregulation of neuromodulation, neuronal survival and synaptic homeostasis was also evident from observed decline in tryptophan hydroxylase, BDNF, synaptophysin, synapsin1, PSD95 and an increase in tyrosine hydroxylase immunoreactivity in limbic region under HH exposure. SignificanceDysregulation of limbic region signaling molecules associated with survival and maintenance of synaptic plasticity (Synaptophysin, synapsin1 and PSD95), neurotrophic factor (BDNF) and shift in monoamines, corticosterone, glutamate and GABA levels may contribute to the HH induced fear memory impairment.

Activation of brain-derived neurotrophic factor signaling in the basal forebrain reverses acute sleep deprivation-induced fear memory impairments.

IntroductionThe mechanisms underlying sleep deprivation‐induced memory impairments and relevant compensatory signaling pathways remain elusive. We tested the hypothesis that increased brain‐derived neurotrophic factor (BDNF) expression in the basal forebrain following acute sleep deprivation was a compensatory mechanism to maintain fear memory performance.MethodsAdult male Wistar rats were deprived of 6‐hr total sleep from the beginning of the light cycle. The effects of sleep deprivation on BDNF protein expression and activation of downstream tropomyosin receptor kinase B (TrkB)/phospholipase C‐γ1 (PLCγ1) signaling in the basal forebrain and fear memory consolidation were examined. BDNF or selective downstream TrkB receptor antagonist ANA‐12 was further injected into the basal forebrain bilaterally to observe the changes in fear memory consolidation in response to modulation of the BDNF/TrkB signaling.ResultsSix hours of sleep deprivation‐induced both short‐ and long‐term fear memory impairments. Increased BDNF protein expression and TrkB and PLCγ1 phosphorylation in the basal forebrain were observed after sleep deprivation. Microinjection of BDNF into the basal forebrain partly reversed fear memory deficits caused by sleep deprivation, which were accompanied by increased BDNF protein levels and TrkB/PLCγ1 activation. After ANA‐12 microinjection, sleep deprivation‐induced activation of the BDNF/TrkB pathway was inhibited and impairments of fear memory consolidation were further aggravated.ConclusionsAcute sleep deprivation induces compensatory increase of BDNF expression in the basal forebrain. Microinjection of BDNF into the basal forebrain mitigates the fear memory impairments caused by sleep deprivation by activating TrkB/PLCγ1 signaling.

IQGAP1/ERK regulates fear memory formation via histone posttranslational modifications induced by HDAC2.

Epigenetic mechanisms of learning and memory are particularly interesting topics in neuroscience that have recently been investigated. As shown in our previous study, IQGAP1, a scaffolding protein of MAPK, is involved in fear memory through interactions with GluN2A-containing NMDA receptors and the ERK1/2 cascade. However, researchers have not determined whether histone posttranslational modifications are regulated by the IQGAP1/ERK signaling pathway. We performed in vivo studies using IQGAP1-/- and IQGAP1+/+ mice to provide insights into the specific functions of IQGAP1 in memory processes and the precise mechanisms underlying its regulatory effects. IQGAP1-/- mice exhibited impaired fear memory, decreased levels of phosphorylated ERK1/2 and histone H3S10, decreased acetylation of H3K14, and decreased c-Fos expression in the hippocampus compared to IQGAP1+/+ mice after fear conditioning. HDAC2 was significantly enriched at the c-fos gene promoter in IQGAP1-/- mice. Correspondingly, the disruption of the epigenetic regulation induced by ERK1/2 signaling through an intra-hippocampal injection of the MEK antagonist U0126 or GluN2A-selective pharmacological antagonist NVP-AAM077 blocked context-dependent memory formation, while no changes were observed after treatment with the GluN2B-selective antagonist Ro25-6981. The administration of SAHA, a non-specific HDAC inhibitor, or knock-down of HDAC2 with shHDAC2-AAV in the dorsal hippocampus significantly rescued the impaired fear memory formation, H3S10 phosphorylation, H3K14 acetylation, and c-Fos expression in IQGAP1-/- mice. Thus, we postulated that the IQGAP1/ERK-dependent mechanism regulating histone posttranslational modifications via HDAC2 potentially underlies memory formation.