Gestational stress induces persistent depressive‐like behavior and structural modifications within the postpartum nucleus accumbens

Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Pregnancy stress enhances vulnerability to PPD and has also been shown to increase depressive‐like behavior in postpartum rats. Thus, gestational stress may be an important translational risk factor that can be used to investigate the neurobiological mechanisms underlying PPD. Here we examined the effects of gestational stress on depressive‐like behavior during the early/mid and late postpartum periods and evaluated whether this was accompanied by altered structural plasticity in the nucleus accumbens (NAc), a brain region that has been linked to PPD. We show that early/mid (postpartum day 8) postpartum female rats exhibited more depressive‐like behavior in the forced swim test as compared with late postpartum females (postpartum day 22). However, 2 weeks of restraint stress during pregnancy increased depressive‐like behavior regardless of postpartum timepoint. In addition, dendritic length, branching and spine density on medium spiny neurons in the NAc shell were diminished in postpartum rats that experienced gestational stress although stress‐induced reductions in spine density were evident only in early/mid postpartum females. In the NAc core, structural plasticity was not affected by gestational stress but late postpartum females exhibited lower spine density and reduced dendritic length. Overall, these data not only demonstrate structural changes in the NAc across the postpartum period, they also show that postpartum depressive‐like behavior following exposure to gestational stress is associated with compromised structural plasticity in the NAc and thus may provide insight into the neural changes that could contribute to PPD.     

Enduring increases in anxiety‐like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats

Social isolation (SI) rearing, a model of early life stress, results in profound behavioral alterations, including increased anxiety‐like behavior, impaired sensorimotor gating and increased self‐administration of addictive substances. These changes are accompanied by alterations in mesolimbic dopamine function, such as increased dopamine and metabolite tissue content, increased dopamine responses to cues and psychostimulants, and increased dopamine neuron burst firing. Using voltammetric techniques, we examined the effects of SI rearing on dopamine transporter activity, vesicular release and dopamine D2‐type autoreceptor activity in the nucleus accumbens core. Long–Evans rats were housed in group (GH; 4/cage) or SI (1/cage) conditions from weaning into early adulthood [postnatal day (PD) 28–77]. After this initial housing period, rats were assessed on the elevated plus‐maze for an anxiety‐like phenotype, and then slice voltammetry experiments were performed. To study the enduring effects of SI rearing on anxiety‐like behavior and dopamine terminal function, another cohort of similarly reared rats was isolated for an additional 4 months (until PD 174) and then tested. Our findings demonstrate that SI rearing results in lasting increases in anxiety‐like behavior, dopamine release and dopamine transporter activity, but not D2 activity. Interestingly, GH‐reared rats that were isolated as adults did not develop the anxiety‐like behavior or dopamine changes seen in SI‐reared rats. Together, our data suggest that early life stress results in an anxiety‐like phenotype, with lasting increases in dopamine terminal function.     

Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat

Evidence recently provided has suggested a specific involvement of the GABAergic system in modulating positive reinforcing properties of several drugs of abuse through an action on mesolimbic dopaminergic neurons. The GABA(B) receptor agonist baclofen has been proposed as a potential therapeutic agent for the clinical treatment of several forms of drug addiction. In the present study, using the in vivo microdialysis technique, we investigated the effect of baclofen on nicotine, cocaine, and morphine-induced increase in extracellular dopamine (DA) levels in the shell of the nucleus accumbens, a brain area supposedly involved in the modulation of the central effects of several drugs of abuse, of freely moving rats. As expected, nicotine (0.6 mg/kg s.c.), morphine (5 mg/kg s.c.), and cocaine (7.5 mg/kg i.p.) administration in rats induced a marked increase in extracellular DA concentrations in the nucleus accumbens, reaching a maximum value of +205 +/- 8.4%, +300 +/- 22.2%, and +370 +/- 30.7%, respectively. Pretreatment with baclofen (1.25 and 2.5 mg/kg i.p.) dose-dependently reduced the nicotine-, morphine-, and cocaine-evoked DA release in the shell of the nucleus accumbens. Furthermore, baclofen alone did not elicit changes in basal DA extracellular levels up to 180 min. Taken together, our data are in line with previous reports demonstrating the ability of baclofen to modulate the mesolimbic DAergic transmission and indicate baclofen as a putative candidate in the pharmacotherapy of polydrug abuse.     

The effects of sEH inhibitor on depression‐like behavior and neurogenesis in male mice

Currently antidepressants take several weeks to be effective, which is one of the main reasons why patients with depression quit therapy. In the present study, we examine the acute and subacute effects of soluble epoxide hydolase (sEH) inhibitor (sEHI), a compound shown to have antidepressant effects, on mice. We found that acute administration of sEHI TPPU decreases immobility time in the forced swimming test and reduces latency to feed in the novelty suppressed‐feeding test in adult male mice. Intraperitoneal administration of TPPU for seven days also increased interaction time of socially defeated mice in the social defeat test. Hippocampal BDNF expression and cell proliferation in the dentate gyrus increased six and 24 hours after TPPU treatment, respectively. Improvement in antidepressant behavior and cell proliferation were inhibited by BDNF‐trkB antagonist K252a, which suggests that anti‐depressant effects of sEHI may be involved in BDNF signaling. Taken together, our findings suggest that sEHI may provide a rapid antidepressant effect through alterations to BDNF‐trkB signaling in the hippocampus and may provide an alternative to current slow‐acting antidepressants. © 2017 Wiley Periodicals, Inc.     

Voluntary exercise induces anxiety‐like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis

Several studies investigated the effect of physical exercise on emotional behaviors in rodents; resulting findings however remain controversial. Despite the accepted notion that voluntary exercise alters behavior in the same manners as antidepressant drugs, several studies reported opposite or no effects at all. In an attempt to evaluate the effect of physical exercise on emotional behaviors and brain plasticity, we individually housed C57BL/6J male mice in cages equipped with a running wheel. Three weeks after continuous voluntary running we assessed their anxiety‐ and depression‐like behaviors. Tests included openfield, dark‐light‐box, elevated O‐maze, learned helplessness, and forced swim test. We measured corticosterone metabolite levels in feces collected over a 24‐h period and brain‐derived neurotrophic factor (BDNF) in several brain regions. Furthermore, cell proliferation and adult hippocampal neurogenesis were assessed using Ki67 and Doublecortin. Voluntary wheel running induced increased anxiety in the openfield, elevated O‐maze, and dark‐light‐box and higher levels of excreted corticosterone metabolites. We did not observe any antidepressant effect of running despite a significant increase of hippocampal neurogenesis and BDNF. These data are thus far the first to indicate that the effect of physical exercise in mice may be ambiguous. On one hand, the running‐induced increase of neurogenesis and BDNF seems to be irrelevant in tests for depression‐like behavior, at least in the present model where running activity exceeded previous reports. On the other hand, exercising mice display a more anxious phenotype and are exposed to higher levels of stress hormones such as corticosterone. Intriguingly, numbers of differentiating neurons correlate significantly with anxiety parameters in the openfield and dark‐light‐box. We therefore conclude that adult hippocampal neurogenesis is a crucial player in the genesis of anxiety. © 2009 Wiley‐Liss, Inc.     

Gene transfer of GLT-1, a glutamate transporter, into the nucleus accumbens shell attenuates methamphetamine- and morphine-induced conditioned place preference in rats

Several lines of evidence have suggested that the glutamatergic system in the nucleus accumbens (NAc) plays an important role in the conditioned rewarding effect of drugs of abuse. In addition, it is recognized that extracellular glutamate is rapidly removed from the synaptic cleft by Na+-dependent glutamate transporters in neurons and glial cells, thereby maintaining physiological levels of glutamate. We previously reported that activation of glutamate uptake by a glutamate transporter activator attenuated the acquisition of conditioned place preference induced by methamphetamine and morphine in mice. In the present study, we examined the effects of gene transfer of a glial glutamate transporter, GLT-1, into the NAc shell by recombinant adenoviruses on methamphetamine- and morphine-induced conditioned place preference in rats. Bilateral infusion of the recombinant adenoviruses into the NAc shell efficiently increased GLT-1 expression surrounding the infusion site, at least during the period 2-8 days after the infusion. In the conditioned place preference paradigm, animals were conditioned with repeated subcutaneous injections of methamphetamine (2 mg/kg) or morphine (3 mg/kg). Intra-NAc shell overexpression of GLT-1 before the conditioning significantly attenuated the conditioned place preference induced by methamphetamine or morphine, when compared with control. However, it had no effect on the somatic signs of naloxone-precipitated morphine withdrawal. These results suggest that GLT-1 within the NAc shell plays an inhibitory role in the conditioned rewarding effects of methamphetamine and morphine but not the physical dependence on morphine.     

Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria‐like behavior and impairs hypothalamic‐pituitary‐adrenocortical axis feedback inhibition

Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Because we previously showed that antidepressants used to treat depression and anxiety decrease DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic‐ and antidepressant‐like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic–pituitary–adrenal (HPA) axis. Adeno‐associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP (DRN‐GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 21 days of social defeat or control handling and were tested for anxiety‐like behavior (open‐field test, elevated‐plus maze), depression‐like behavior [sucrose preference, forced‐swim test (FST), tail‐suspension test (TST)], social interaction, and circadian and stress‐induced HPA activity. DRN GR deletion decreased anxiety‐like behavior in control but not in defeated mice. DRN GR deletion decreased FST and tended to decrease TST despair‐like behavior in both control and defeated mice, but did not affect sucrose preference. Exploration of social (a novel mouse) as well as neutral (an empty box) targets was increased in DRNGRKO mice, suggesting that DRN GR deletion also promotes active coping. DRN GR deletion increased stress‐induced HPA activity without strongly altering circadian HPA activity. We have shown a novel role for DRN GR to mediate anxiety‐ and despair‐like behavior and to regulate HPA negative feedback during acute stress.     

Suppression of attack behavior in cats by stimulation of ventral tegmental area and nucleus accumbens

Low frequency (6 pps) stimulation of ventral tegmental area (VTA) and nucleus accumbens (NA) produced EEG synchronization and suppressed attack behavior elicited by hypothalamic stimulation. Both quiet biting and affective attack with rage were suppressed. Autonomic and non-directed somatic motor components of the attack reaction were unaffected.High frequency (60 pps) stimulation of VTA failed to suppress any components of the attack reaction; high frequency stimulation of NA, however, did produce suppression of attack.Low frequency (6 pps) sensory stimulation, delivered by photic or lateral geniculate stimulation, produced EEG synchronization but failed to cause suppression of attack. These results indicate that low frequency stimulation per se does not cause suppression of ongoing behavior.This study demonstrates that VTA and NA, components of the mesolimbic dopamine system, are involved in the inhibition of emotional-type behaviors.     

Postnatal light alters hypothalamic‐pituitary‐adrenal axis function and induces a depressive‐like phenotype in adult mice

The postnatal light environment that a mouse experiences during the critical first three postnatal weeks has long‐term effects on both its circadian rhythm output and clock gene expression. Furthermore, data from our lab suggest that postnatal light may also impact the hypothalamic‐pituitary‐adrenal (HPA) axis, which is a key regulator of stress. To test the effect of postnatal light exposure on adult stress responses and circadian rhythmicity, we raised mice under either 24‐h light – dark cycles (LD), constant light (LL) or constant dark (DD) during the first three postnatal weeks. After weaning we then exposed all animals to LD cycles (basal conditions), followed by LL (stressed conditions) environments. We examined brain neuropeptide and glucocorticoid receptor (GR) expression, plasma corticosterone concentration rhythm and body temperature rhythm, together with depression‐ and anxiety‐related behaviour. Results showed that LL‐ and DD‐raised mice exhibited decreased GR expression in the hippocampus, increased plasma corticosterone concentration at the onset of the dark phase and a depressive phenotype when exposed to LD cycles later in life. Furthermore, LL‐raised mice showed increased corticotrophin‐releasing hormone mRNA expression in the paraventricular nucleus of the hypothalamus. When exposed to LL as adults, LL‐raised mice showed a significant circadian rhythm of plasma corticosterone concentration, together with a shorter period and stronger circadian rhythm of body temperature compared to DD‐raised mice. Taken together, these data suggest that altered postnatal light environments have long‐term effects on the HPA axis and the circadian system, which can lead to altered stress responses and a depressive phenotype in adulthood.     

Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region

Psychological stress‐induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0 °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non‐shivering thermogenesis in brown adipose tissue (BAT) and thermoregulatory constriction of skin blood vessels, and also in a small population of tryptophan hydroxylase‐positive serotonergic neurons. Intraperitoneal injection of diazepam, an anxiolytic agent, but not indomethacin, an antipyretic, significantly reduced both the stress‐induced hyperthermia and Fos expression in these medullary raphe neuronal populations. Systemic blockade of β₃‐adrenoreceptors, which are abundantly expressed in BAT, also attenuated the stress‐induced hyperthermia. These results suggest that psychological stress signals activate VGLUT3‐expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through β₃‐adrenoreceptors.     

Single housing‐induced effects on cognitive impairment and depression‐like behavior in male and female mice involve neuroplasticity‐related signaling

Single‐housed stress elicits a range of social isolation‐related behavioral and neurobiological abnormalities. To investigate single housing‐induced behavioral changes and sex differences on stress outcomes, we examined single‐housed stress‐induced learning and memory impairment, depression‐like behaviors, neuroplasticity abnormalities and underlying mechanism. The results showed that male and female mice socially isolated for 8 weeks had significantly decreased memory acquisition, as demonstrated in the learning curve of the Morris water maze task. Memory consolidation and retrieval were also decreased in both the single‐housed male and female mice. These findings were corroborated further by the two classical animal models, Y‐maze and novel object recognition tests, as demonstrated by reduced spontaneous alternation and recognition index in both sexes of single‐housed mice. Subsequent studies suggested that single‐housed male mice exhibited increased immobility time in both the forced swim and tail suspension tests, while the female mice only exhibited increased immobility time in the tail suspension test. Moreover, single‐housed stress significantly decreased the apical and basal branch points, dendritic length, and spine density in the CA1 of hippocampal neurons in both male and female mice. These effects were consistent with decreased neuroplasticity and neuroprotective‐related molecules such as synaptophysin, PSD95, PKA, pCREB and BDNF expression. These findings suggest that loss of neuronal remodeling and neuroprotective mechanisms due to single housing are involved in behavioral changes in both male and female mice. The results provide further evidence that neuroplasticity‐related signaling plays a crucial role in isolation‐induced effects on neuropsychiatric behavioral deficits in both sexes.     

Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus

Harmine is a β-carboline alkaloid that inhibits monoamine reuptake systems. Findings point to an antidepressant effect of the compounds that increases the levels of monoamines after monoamine oxidase inhibition. The present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of harmine and imipramine in rats. To this aim, rats were acutely treated with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavior was assessed in the forced swimming and open-field tests. Afterwards, hippocampal BDNF protein levels were assessed in imipramine- and harmine-treated rats by ELISA-sandwich assay. We observed that harmine at doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time, and increased both climbing and swimming time of rats compared to saline group, without affecting locomotor activity. Acute administration of harmine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. Finally, these findings further support the hypothesis that harmine could be a new pharmacological target for the treatment of mood disorders.     

Localization of the δ‐opioid receptor and dopamine transporter in the nucleus accumbens shell: Implications for opiate and psychostimulant cross‐sensitization

Opiate‐ and psychostimulant‐induced modulation of dopamine transmission in the nucleus accumbens shell (AcbSh) is thought to play a key role in their potent reinforcing and locomotor effects. To investigate the cellular basis for potential functional interactions involving opiates active at the δ‐opioid receptor (DOR) and psychostimulants that bind selectively to the dopamine transporter (DAT), we examined the electron microscopic localization of their respective antisera in rat AcbSh. DOR immunoperoxidase labeling was seen primarily, and DAT immunogold particles exclusively, in axon terminals. In these terminals, DOR immunoreactivity was prominently associated with discrete segments of the plasma membrane and the membranes of nearby small synaptic and large dense core vesicles. DAT immunogold particles were almost exclusively distributed along nonsynaptic axonal plasma membranes. Thirty‐nine percent DOR‐labeled profiles (221/566) either apposed DAT‐immunoreactive terminals or also contained DAT. Of these 221 DOR‐labeled profiles, 13% were axon terminals containing DAT and 15% were dendritic spines apposed to DAT‐immunoreactive terminals. In contrast, 70% were morphologically heterogeneous axon terminals and small axons apposed to DAT‐immunoreactive terminals. Our results indicate that DOR agonists in the AcbSh can directly modulate the release of dopamine, as well as postsynaptic responses in spiny neurons that receive dopaminergic input, but act principally to control the presynaptic secretion of other neurotransmitters whose release may influence or be influenced by extracellular dopamine. Thus, while opiates and psychostimulants mainly have differential sites of action, cross‐sensitization of their addictive properties may occur through common neuronal targets. Synapse 34:1–10, 1999. © 1999 Wiley‐Liss, Inc.     

Asymmetrical expression of BDNF and NTRK3 genes in frontoparietal cortex of stress‐resilient rats in an animal model of depression

The current study is based on the “approach–withdrawal” theory of emotional regulation and lateralization of brain function in rodents, which has little been studied. The aim was to indentify asymmetry in hemispheric genes expression during depression. Depressive‐like symptoms were induced in rats using chronic mild stress protocol. The sucrose consumption test was performed to identify the anhedonic and stress‐resilient rats. After decapitation, RNA was extracted from frontotemporal cortex of both hemispheres of anhedonic and stress‐resilient rats. The pattern of gene expression in these samples was compared with controls by real‐time polymerase chain reaction. A linear mixed model analysis of variance was fitted to the data to estimate the effect of rat line. From the total of 30 rats in the experimental group, five rats were identified to be anhedonic and five were stress‐resilient, according to the result of sucrose‐consumption test. BDNF and NTRK‐3 were expressed at significantly lower levels in the right hemisphere of anhedonic rats compared with stress‐resilient rats. No significant difference was found between left hemispheres. Hemispheric asymmetry in the level of gene expression was only observed for the BDNF gene in stress‐resilient rats, upregulated in right hemisphere compared with the left. Expression of NTRK3, HTR2A, COMT, and SERT was not lateralized. There was no significant asymmetry between hemispheres of anhedonic rats. This study supports the evidence for the role of genes responsible for neural plasticity in pathophysiology of depression, emphasizing probable hemispheric asymmetry at level of gene expression. Synapse, 2014. © 2014 Wiley Periodicals, Inc.     

mu/delta Cooperativity and opposing kappa-opioid effects in nucleus accumbens-mediated antinociception in the rat

We previously demonstrated that noxious peripheral stimulation (e.g. subdermal capsaicin injection in the hind paw) produces antinociception that is mediated by opioid receptors in nucleus accumbens. The current study used the trigeminal jaw-opening nociceptive reflex responses in the rat to assess the role of intra-accumbens mu-, delta- and kappa-opioid receptors in the antinociceptive effect of noxious stimulation and intra-accumbens opioid agonism. Whilst intra-accumbens injection of either the mu-receptor-selective antagonist Cys2,Tyr3,Orn5,Pen7amide (CTOP) or the delta-receptor-selective antagonist naltrindole blocked capsaicin-induced antinociception, neither the selective mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO; 150 or 300 ng) nor the selective delta-agonist D-Pen2,5-enkephalin (DPDPE; 150 or 300 ng) alone induced antinociception. Simultaneous injection of DAMGO and DPDPE (150 ng each), however, produced significant antinociception. Capsaicin-induced antinociception was not blocked by the selective kappa-receptor antagonist nor-binaltorphimine, but was blocked by the kappa-agonist U69,593. U69,593 also antagonized the antinociceptive effect of the DAMGO/DPDPE combination. Thus, in nucleus accumbens, mu- and delta- but not kappa-opioid receptors contributed to capsaicin-induced antinociception; selective activation of individual receptor subtypes was insufficient, but coactivation of mu- and delta-opioid receptors induced antinociception, and kappa-receptors appeared to play an antianalgesic role in nucleus accumbens.     

Stage‐dependent C‐reflex,pain‐like behavior and opioid analgesia during the induction of chronic arthritis in rats

Chronic arthritis (CA) is a common clinical entity associated with persistent pain and limited response to opioid analgesic therapy. However, it is unknown whether these features of CA change depending on its stage of evolution. To address this, in a well‐established animal model of CA we studied the time course of electromyographic responses to electrical stimulation of C fibers (C‐reflex), pain‐like behavior as a response to mechanical nociceptive stimulation, and the inhibition of both responses by a prototypic opioid analgesic, morphine. To induce CA, rats received a single injection of complete Freund's adjuvant into the ankle joint and the C‐reflex responses to electrical stimuli or the nociceptive response to paw pressure test were studied 2, 4 or 6 weeks later. The C‐reflexes evoked by threshold and supra‐threshold electrical stimulation exhibited progressive increases together with enhancement of the nociceptive behavior to mechanical stimulation during induction of monoarthritis. Notably, while systemic morphine produced antinociceptive effects upon both experimental approaches, the effects were markedly reduced during the early stages of CA but enhanced at later stages. These data indicate that C‐reflex and pain‐like responses evolve in parallel, and are inhibited by morphine in a stage‐dependent manner through the induction of CA. The present results may contribute to explain the enhanced pain response and variable analgesic efficacy of opioids that characterize arthritic pain in humans.     

Circadian genes Period 1 and Period 2 in the nucleus accumbens regulate anxiety‐related behavior

It has been suggested for some time that circadian rhythm abnormalities underlie the development of multiple psychiatric disorders. However, it is unclear how disruptions in individual circadian genes might regulate mood and anxiety. Here we found that mice lacking functional mPeriod 1 (mPer1) or mPeriod 2 (mPer2) individually did not have consistent behavioral abnormalities in measures of anxiety‐related behavior. However, mice deficient in both mPer1 and mPer2 had an increase in levels of anxiety‐like behavior in multiple measures. Moreover, we found that mPer1 and mPer2 expression was reduced in the nucleus accumbens (NAc) after exposure to chronic social defeat stress, a paradigm that led to increased anxiety‐related behavior. Following social defeat, chronic treatment with fluoxetine normalized Per gene expression towards wild‐type levels. Knockdown of both mPer1 and mPer2 expression via RNA interference specifically in the NAc led to a similar increase in anxiety‐like behavior as seen in the mutant animals. Taken together, these results implicate the Per genes in the NAc in response to stress and the development of anxiety.     

Chronic activation of fear engrams induces extinction‐like behavior in ethanol‐exposed mice

Alcohol withdrawal directly impacts the brain's stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol‐seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear‐related memory processes in rodents such as extinction learning; however, the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction retrieval impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear‐conditioned context was impaired in ethanol‐exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol‐exposed and control mice. Chronic activation of these cells resulted in a context‐specific, extinction‐like reduction in fear responses in both control and ethanol‐exposed mice. These findings suggest that while ethanol can impair the retrieval an extinction memory, optogenetic manipulation of a fear engram is sufficient to induce an extinction‐like reduction in fear responses.