Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams.

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin-brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.

The neural circuits and molecular mechanisms underlying fear dysregulation in posttraumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD.

Sleep characteristics before assisted reproductive technology treatment predict reproductive outcomes: a prospective cohort study of Chinese infertile women.

Sleep disorders affect mental and physical health. Infertile women undergoing assisted reproductive technology (ART) treatment are prone to sleep disorders. Sleep condition, its influencing factors, and the association between sleep condition and ART treatment outcomes before treatment have not been explored within a population with a large sample size. Therefore, we investigated the sleep characteristics of 1002 Chinese infertile women before ovulation induction and investigated the influencing factors (negative and positive psychological factors, demographics, and fertility characteristics). We also examined whether sleep conditions before treatment predicted reproductive outcomes. We found that 24.1% of participants reported poor sleep quality. Women with primary infertility reported poorer sleep than women with secondary infertility. Negative psychological factors, including depression, anxiety, and perceived stress were associated with poor sleep, whereas positive affect was linked with good sleep. Adverse sleep characteristics, including poor subjective sleep quality, sleep disturbances, and poor sleep efficiency, decreased the quantity and quality of oocytes retrieved, fertilization rates, and clinical pregnancy rates. This study indicates that before ART treatment, a large number of females with infertility suffer from sleep problems, which are affected by psychological factors and infertility type, and unhealthy sleep characteristics may impair treatment outcomes. Our findings highlight the importance of screening and treatment for sleep disorders before the enrollment of ART treatment in infertile women.

MicroRNA expression profiles of stress susceptibility and resilience in the prelimbic and infralimbic cortex of rats after single prolonged stress.

The experience of traumatic stress can engender lasting memories associated with the trauma, often resulting in post-traumatic stress disorder (PTSD). However, only a minority of individuals develop PTSD symptoms upon exposure. The neurobiological mechanisms underlying the pathology of PTSD are poorly understood. Utilizing a rat model of PTSD, the Single Prolonged Stress (SPS) paradigm, we were able to differentiate between resilient and susceptible individuals. Fourteen days after the SPS exposure, we conducted the behavioral analyses using Elevated Plus Maze (EPM) and Open Field (OF) tests to identify male rats as trauma resilient or susceptible. We focused on the microRNA (miRNA) profiles of the infralimbic (IL) and prelimbic (PL) cortical regions, known to be crucial in regulating the stress response. Our investigation of stressed rats exposed to the SPS procedure yielded divergent response, and differential expression microRNAs (DEmiRs) analysis indicated significant differences in the IL and PL transcriptional response. In the IL cortex, the GO analysis revealed enriched GO terms in the resilient versus control comparison, specifically related to mitogen-activated protein kinase and MAP kinase signaling pathways for their molecular functions as well as cytosol and nucleoplasm for the biological process. In the susceptible versus resilient comparison, the changes in molecular functions were only manifested in the functions of regulation of transcription involved in the G1/S transition of the mitotic cell cycle and skeletal muscle satellite cell activation. However, no enriched GO terms were found in the susceptible versus control comparison. In the PL cortex, results indicated that the DEmiRs were enriched exclusively in the cellular component level of the endoplasmic reticulum lumen in the comparison between resilient and control rats. Overall, our study utilized an animal model of PTSD to investigate the potential correlation between stress-induced behavioral dysfunction and variations in miRNA expression. The aforementioned discoveries have the potential to pave the way for novel therapeutic approaches for PTSD, which could involve the targeted regulation of transcriptome expression.

Differential regulation of hippocampal transcriptome by circulating estrogen.

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.

Hollow CoS2 anchored on hierarchically porous carbon derived from Pien Tze Huang for high-performance supercapacitors.

The development of electrode materials with a high specific capacitance, power density, and long-term stability is essential and remains a challenge for developing supercapacitors. Cobalt sulfides (CoS2) are considered one of the most promising and widely studied electrode materials for supercapacitors. Herein, CoS2 and hierarchical porous carbon derived from Pien Tze Huang waste are assembled into a cobalt sulfide/carbon (CoS2/PZH) matrix composite using a one-step hydrothermal method to resolve the challenges of supercapacitors. The resulting CoS2/PZH composite material exhibits a hierarchical porous structure with hollow CoS2 embedded in a PZH framework. The uniform dispersion of the hierarchical porous structure CoS2/PZH is achieved due to the PZH framework, while the uniform decoration of the porous PZH with the hollow CoS2 prevents the PZH from stacking easily. Moreover, the excellent synergistic effect of the hierarchical porous and hollow structure of CoS2/PZH can shorten the electron/ion diffusion channels, expose additional active sites, and provide stable structures for subsequent reactions. As a result, the CoS2/PZH composite material displays a high initial specific capacity of 447.5 F g-1 at 0.5 A g-1, a high energy density of 22.38 W h kg-1, and long-term cycling stability (a retention rate of 92.3% over 10 000 cycles at 5 A g-1).

The effect of a methadone-initiated memory reconsolidation updating procedure in opioid use disorder: A translational study.

BACKGROUND: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. METHODS: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. FINDINGS: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). INTERPRETATION: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. FUNDING: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800).

Facile fabrication of self-supporting porous CuMoO4@Co3O4 nanosheets as a bifunctional electrocatalyst for efficient overall water splitting.

Research shows that redox complementarity and synergism among the ingredients of heterogeneous catalysts can enhance the performance of the catalyst. In this research, a porous CuMoO4@Co3O4 nanosheet electrocatalyst is prepared, which is uniformly decorated on nickel foam (NF) by hydrothermal reactions and the impregnation method. The CuMoO4@Co3O4 is an efficient bifunctional catalyst with prominent electrocatalytic activity and durability. It requires overpotentials of only 54 and 251 mV to obtain current densities of 10 and 50 mA cm-2 for the cathodic hydrogen evolution reaction (HER) and the anodic oxygen evolution reaction (OER) in 1.0 mol L-1 KOH, corresponding to Tafel slope values of 98.8 and 87.4 mV dec-1, respectively. Furthermore, the CuMoO4@Co3O4 shows excellent stability of 120 h chronopotentiometry at a current density of 100 mA cm-2 for the HER/OER. Notably, an alkaline electrolyzer (with CuMoO4@Co3O4 as the HER and OER electrodes) can deliver a current density of 10 mA cm-2 at a low voltage of 1.51 V. The catalytic activity of CuMoO4@Co3O4 can be attributed to the structure of the porous nanosheets and the synergistic effect between CuMoO4 and Co3O4.

Fabrication of PEBA/HZIF-8 Pervaporation Membranes for High Efficiency Phenol Recovery.

Phenol and its chemical derivatives serve as essential chemical materials are indispensable for the synthesis of many kinds of polymers. However, they are highly toxic, carcinogenic, difficult to be degraded biologically, and often found in aqueous effluents. Recovery of hazardous phenol from wastewater remains a daunting challenge. Herein, we prepared a hybrid membrane containing polyether block amide (PEBA) matrix and HZIF-8 fillers. To improve the compatibility between ZIF-8 and PEBA, ZIF-8 was modified by using polystyrene (PS) as a template to prepare porous HZIF-8. ZIF-8, composed of zinc nodes linked by the imidazole ring skeleton, is a kind of inorganic material with high hydrothermal stability, ordered pores, and hydrophobic microporous surfaces, which has a wide range of applications in membrane separation. The separation performance of the PEBA/HZIF-8 based membranes for phenol/water is improved due to the presence of PS on the surface of HZIF-8 and the imidazole ring skeleton in ZIF-8, which enhance the π-π interaction between HZIF-8 and phenol molecules. The effects of HZIF-8 content, feed phenol concentration, and feed temperature on the pervaporation performance of PEBA/HZIF-8 membranes were further investigated. The results showed that the pervaporation performance of the PEBA/HZIF-8-10 membrane was promising with a separation factor of 80.89 and permeate flux of 247.70 g/m2·h under the feed phenol concentration of 0.2 wt % at 80 °C. In addition, the PEBA/HZIF-8-10 membrane presented excellent stability, which has great prospect for practical application in phenol recovery from waste water.

Gut microbiota modulates the inflammatory response and cognitive impairment induced by sleep deprivation.

Sleep deprivation (SD) is increasingly common in modern society, which can lead to the dysregulation of inflammatory responses and cognitive impairment, but the mechanisms remain unclear. Emerging evidence suggests that gut microbiota plays a critical role in the pathogenesis and development of inflammatory and psychiatric diseases, possibly via gut microbiota-brain interactions and neuroinflammation. The present study investigated the impact of SD on gut microbiota composition and explored whether alterations of the gut microbiota play a causal role in chronic inflammatory states and cognitive impairment that are induced by SD. We found that SD-induced gut dysbiosis, inflammatory responses, and cognitive impairment in humans. Moreover, the absence of the gut microbiota suppressed inflammatory response and cognitive impairment induced by SD in germ-free (GF) mice. Transplantation of the "SD microbiota" into GF mice activated the Toll-like receptor 4/nuclear factor-κB signaling pathway and impaired cognitive function in the recipient mice. Mice that harbored "SD microbiota" also exhibited increases in neuroinflammation and microglial activity in the hippocampus and medial prefrontal cortex. These findings indicate that gut dysbiosis contributes to both peripheral and central inflammatory processes and cognitive deficits that are induced by SD, which may open avenues for potential interventions that can relieve the detrimental consequences of sleep loss.

TMS-EEG: An emerging tool to study the neurophysiologic biomarkers of psychiatric disorders.

The etiology of psychiatric disorders remains largely unknown. The exploration of the neurobiological mechanisms of mental illness helps improve diagnostic efficacy and develop new therapies. This review focuses on the application of concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) in various mental diseases, including major depressive disorder, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, substance use disorder, and insomnia. First, we summarize the commonly used protocols and output measures of TMS-EEG; then, we review the literature exploring the alterations in neural patterns, particularly cortical excitability, plasticity, and connectivity alterations, and studies that predict treatment responses and clinical states in mental disorders using TMS-EEG. Finally, we discuss the potential mechanisms underlying TMS-EEG in establishing biomarkers for psychiatric disorders and future research directions. This article is part of the special Issue on 'Stress, Addiction and Plasticity'.

Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects.

Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)-MBP87-99[A91, A96], MBP87-99[A91], and MBP87-99[R91, A96]-in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87-99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87-99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87-99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87-99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87-99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune-neural interactions may impact central nervous system function and alter an individual's response to stress.

Basolateral amygdala is required for reconsolidation updating of heroin-associated memory after prolonged withdrawal.

Postretrieval extinction procedures are effective nonpharmacological interventions for disrupting drug-associated memories. Nonetheless, the conditioned stimulus (CS) memory retrieval-extinction procedure is ineffective in inhibiting drug craving and relapse after prolonged withdrawal, which significantly undermines its therapeutic potential. In the present study, we showed that, unlike the CS memory retrieval-extinction procedure, noncontingent heroin injections (unconditioned stimulus [UCS]) 1 hour before the extinction sessions decreased the heroin-priming-induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28 days of withdrawal (ie, remote heroin-associated memories) in rats. The UCS retrieval manipulation induced reactivation of the basolateral amygdala (BLA) after prolonged withdrawal, and this reactivation was absent with the CS retrieval manipulation. Chemogenetic inactivation of the BLA abolished the inhibitory effect of the UCS memory retrieval-extinction procedure on heroin-priming-induced reinstatement after prolonged withdrawal. Furthermore, the combination of chemogenetic reactivation of BLA and CS retrieval-extinction procedure resembled the inhibitory effect of UCS retrieval-extinction procedure on heroin seeking after prolonged withdrawal. We also observed that the inhibitory effect of the UCS retrieval-extinction procedure is mediated by regulation of AMPA receptor endocytosis in the BLA. Our results demonstrate critical engagement of the BLA in reconsolidation updating of heroin-associated memory after prolonged withdrawal, extending our knowledge of the boundary conditions of the reconsolidation of drug-associated memories.

Traumatic Stress Produces Delayed Alterations of Synaptic Plasticity in Basolateral Amygdala.

Acute traumatic event exposure is a direct cause of post-traumatic stress disorder (PTSD). Amygdala is suggested to be associated with the development of PTSD. In our previous findings, different activation patterns of GABAergic neurons and glutamatergic neurons in early or late stages after stress were found. However, the neural plastic mechanism underlying the role of basolateral amygdala (BLA) in post-traumatic stress disorder remains unclear. Therefore, this study mainly aimed at investigating time-dependent morphologic and electrophysiological changes in BLA during the development of PTSD. We used single prolonged stress (SPS) procedure to establish PTSD model of rats. The rats showed no alterations in anxiety behavior as well as in dendritic spine density or synaptic transmission in BLA 1 day after SPS. However, 10 days after SPS, rats showed enhancement of anxiety behavior, and spine density and frequency of miniature excitatory and inhibitory postsynaptic currents in BLA. Our results suggested that after traumatic stress, BLA displayed delayed increase in both spinogenesis and synaptic transmission, which seemed to facilitate the development of PTSD.

Post-retrieval Extinction Prevents Reconsolidation of Methamphetamine Memory Traces and Subsequent Reinstatement of Methamphetamine Seeking.

Methamphetamine abuse has become a serious public health problem. However, effective treatment for methamphetamine addiction remains elusive, especially considering its high rate of relapse after treatment. A conditioned stimulus (CS) memory retrieval-extinction procedure has been demonstrated to decrease reinstatement of cocaine, heroin, and alcohol seeking in rats, and to reduce cue-induced cravings in heroin and nicotine addicts. The goal of the present study is to explore the effect of the CS memory retrieval-extinction procedure on methamphetamine seeking in rats and the underlying mechanisms. We found that daily retrieval of methamphetamine-associated memories 1 h before extinction sessions decreased subsequent drug priming-induced reinstatement, spontaneous recovery, and renewal of methamphetamine seeking. We also found that retrieval of methamphetamine-associated memories induced neuronal activation in the basolateral amygdala (BLA), while presenting extinction within the time window of reconsolidation abolished the neuronal activation in BLA. These results indicate that the CS memory retrieval-extinction procedure could prevent reconsolidation of methamphetamine memory traces in BLA and subsequent methamphetamine craving and relapse.

Role of prefrontal cortex in the extinction of drug memories.

It has been recognized that drug addiction engages aberrant process of learning and memory, and substantial studies have focused on developing effective treatment to erase the enduring drug memories to reduce the propensity to relapse. Extinction, a behavioral intervention exposing the individuals to the drug-associated cues repeatedly, can weaken the craving and relapse induced by drug-associated cues, but its clinic efficacy is limited. A clear understanding of the neuronal circuitry and molecular mechanism underlying extinction of drug memory will facilitate the successful use of extinction therapy in clinic. As a key component of mesolimbic system, medial prefrontal cortex (mPFC) has received particular attention largely in that PFC stands at the core of neural circuits for memory extinction and manipulating mPFC influences extinction of drug memories and subsequent relapse. Here, we review the recent advances in both animal models of drug abuse and human addicted patients toward the understanding of the mechanistic link between mPFC and drug memory, with particular emphasis on how mPFC contributes to the extinction of drug memory at levels ranging from neuronal architecture, synaptic plasticity to molecular signaling and epigenetic regulation, and discuss the clinic relevance of manipulating the extinction process of drug memory to prevent craving and relapse through enhancing mPFC function.

Calpain-GRIP Signaling in Nucleus Accumbens Core Mediates the Reconsolidation of Drug Reward Memory.

Exposure to drug-paired cues causes drug memories to be in a destabilized state and interfering with memory reconsolidation can inhibit relapse. Calpain, a calcium-dependent neutral cysteine protease, is involved in synaptic plasticity and the formation of long-term fear memory. However, the role of calpain in the reconsolidation of drug reward memory is still unknown. In the present study, using a conditioned place preference (CPP) model, we found that exposure to drug-paired contextual stimuli induced the activation of calpain and decreased the expression of glutamate receptor interacting protein 1 (GRIP1) in the nucleus accumbens (NAc) core, but not shell, of male rats. Infusions of calpain inhibitors in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory and blocked retrieval-induced calpain activation and GRIP1 degradation. The suppressive effect of calpain inhibitors on the expression of drug-induced CPP lasted for at least 14 d. The inhibition of calpain without retrieval 6 h after retrieval or after exposure to an unpaired context had no effects on the expression of reward memory. Calpain inhibition after retrieval also decreased cocaine seeking in a self-administration model and this effect did not recover spontaneously after 28 d. Moreover, the knock-down of GRIP1 expression in the NAc core by lentivirus-mediated short-hairpin RNA blocked disruption of the reconsolidation of drug cue memories that was induced by calpain inhibitor treatment. These results suggest that calpain activity in the NAc core is crucial for the reconsolidation of drug reward memory via the regulation of GRIP1 expression.SIGNIFICANCE STATEMENT Calpain plays an important role in synaptic plasticity and long-term memory consolidation, however, its role in the reconsolidation of drug cue memory remains unknown. Using conditioned place preference and self-administration procedures, we found that exposure to drug-paired cues induced the activation of calpain and decreased glutamate receptor interacting protein 1 (GRIP1) expression in the nucleus accumbens (NAc) core. The inhibition of calpain activity in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory that was blocked by prior GRIP1 knock-down. Our findings indicate that calpain-GRIP signaling is essential for the restabilization process that is associated with drug cue memory and the inhibition of calpain activity may be a novel strategy for the prevention of drug relapse.

Predictable Chronic Mild Stress during Adolescence Promotes Fear Memory Extinction in Adulthood.

Early-life stress in adolescence has a long-lasting influence on brain function in adulthood, and it is mostly recognized as a predisposing factor for mental illnesses, such as anxiety and posttraumatic stress disorder. Previous studies also indicated that adolescent predictable chronic mild stress (PCMS) in early life promotes resilience to depression- and anxiety-like behaviors in adulthood. However, the role of PCMS in associated memory process is still unclear. In the present study, we found that adolescent PCMS facilitated extinction and inhibited fear response in reinstatement and spontaneous recovery tests in adult rats, and this effect was still present 1 week later. PCMS in adolescence increased the activity of brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in infralimbic cortex (IL) but not prelimbic cortex in adulthood. Intra-IL infusion of BDNF antibody and the ERK1/2 inhibitor U0126 reversed PCMS-induced enhancement of fear extinction. Moreover, we found that PCMS decreased DNA methylation of the Bdnf gene at exons IV and VI and elevated the mRNA levels of Bdnf in the IL. Our findings indicate that adolescent PCMS exposure promotes fear memory extinction in adulthood, which reevaluates the traditional notion of adolescent stress.

Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse.

BACKGROUND: Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms. METHODS: In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used tyramide-amplified immunohistochemistry-fluorescence in situ hybridization to examine neural ensembles in the basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus- or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles. RESULTS: Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited subsequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More important, within BLA, distinct neuronal ensembles encoded pavlovian CPP and operant self-administration reward memories and nicotine (the UCS) injections in the home cage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles inhibited both nicotine CPP and relapse to nicotine seeking. CONCLUSIONS: Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse.