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Persistent alterations in synaptic plasticity and neurotransmission are thought to underlie the heightened risk of adolescent-onset drinkers to develop alcohol use disorders in adulthood. The bed nucleus of the stria terminalis (BNST) is a compelling region to study the consequences of early alcohol, as it is innervated by cortical structures which undergo continued maturation during adolescence and is critically involved in stress and negative affect-associated relapse. In adult mice, chronic ethanol induces long-term changes in GluN2B-containing NMDA receptors (NMDARs) of the BNST. It remains unclear, however, whether the adolescent BNST is susceptible to such persistent alcohol-induced modifications and, if so, whether they are preserved into adulthood. We therefore examined the short- and long-term consequences of adolescent intermittent ethanol exposure (AIE) on NMDAR transmission and plasticity in the BNST of male and female mice. Whole-cell voltage clamp recordings revealed greater glutamatergic tone in the BNST of AIE-treated males and females relative to air-controls. This change, which corresponded to an increase in presynaptic glutamate release, resulted in altered postsynaptic NMDAR metaplasticity and enhanced GluN2B transmission in males but not females. Only AIE-treated males displayed upregulated GluN2B expression (determined by western blot analysis). While these changes did not persist into adulthood under basal conditions, exposing adult males (but not females) to acute restraint stress reinstated AIE-induced alterations in NMDAR metaplasticity and GluN2B function. These data demonstrate that adolescent alcohol exposure specifically modifies NMDARs in the male BNST, that the plastic changes to NMDARs are long-lasting, and that they can be engaged by stress.

Allosteric modulators of metabotropic glutamate 5 receptors (mGlu5 receptors) have been identified as a promising treatment to independently alleviate both negative affective states and ethanol-seeking and intake. However, these conditions are often comorbid and might precipitate one another. Acute and protracted ethanol withdrawal can lead to negative affective states. In turn, these states are primary drivers of alcohol relapse, particularly among women. The current review synthesizes preclinical studies that have observed the role of mGlu5 receptor modulation in negative affective states following ethanol exposure. The primary behavioral assays discussed are ethanol-seeking and intake, development and extinction of ethanol-associated cues and contexts, behavioral despair, and anxiety-like activity. The work done to-date supports mGlu5 receptor modulation as a promising target for mediating negative affective states to reduce ethanol intake or prevent relapse. Limitations in interpreting these data include the lack of models that use alcohol-dependent animals, limited use of adolescent and female subjects, and a lack of comprehensive evaluations of negative affective-like behavior.

Introduction Epigenetic stimuli induce beneficial or detrimental changes in gene expression, and consequently, phenotype. Some of these phenotypes can manifest across the lifespan—and even in subsequent generations. Here, we used a mouse model of vascular cognitive impairment and dementia (VCID) to determine whether epigenetically induced resilience to specific dementia‐related phenotypes is heritable by first‐generation progeny. Methods Our systemic epigenetic therapy consisted of 2 months of repetitive hypoxic “conditioning” (RHC) prior to chronic cerebral hypoperfusion in adult C57BL/6J mice. Resultant changes in object recognition memory and hippocampal long‐term potentiation (LTP) were assessed 3 and 4 months later, respectively. Results Hypoperfusion‐induced memory/plasticity deficits were abrogated by RHC. Moreover, similarly robust dementia resilience was documented in untreated cerebral hypoperfused animals derived from RHC‐treated parents. Conclusions Our results in experimental VCID underscore the efficacy of epigenetics‐based treatments to prevent memory loss, and demonstrate for the first time the heritability of an induced resilience to dementia.

Adolescent alcohol use is one of the strongest predictors for the development of an alcohol use disorder (AUD). Notably, this period of risk coincides with the development of affective disorders, which disproportionately impact and drive problematic drinking behavior in women. Stress is a particularly salient factor that drives relapse during periods of abstinence. Previous work in our lab has shown that adolescent intermittent ethanol vapor (AIE) produces sex-dependent changes in glutamatergic activity in the bed nucleus of the stria terminalis (BNST) and behavioral outcomes following acute restraint stress in adulthood. In females, AIE disrupts group 1 metabotropic glutamate (mGlu1/5) receptor activity and enhances anhedonia-like behavior. The current study site-specifically knocked down mGlu5 receptors in the BNST of male and female Grm5loxp mice, exposed them to AIE, and observed the interaction of AIE and stress on negative affect-like behaviors in adulthood. These negative affect-like behaviors included the novelty-induced hypophagia task following acute restraint stress, open field activity, and contextual fear conditioning. Overall, we replicated our previous findings that AIE enhanced anhedonia-like activity in the novelty-induced hypophagia task in females and fear acquisition in males. The primary effect of BNST-mGlu5 receptor knockdown was that it independently enhanced anhedonia-like activity in females. Correlation analyses revealed that behavior in these paradigms showed poor interdependence. These results indicate that preclinical models of negative affective-like states encompass distinct features that may have independent, clinically relevant mechanisms. Further, modulating mGlu5 receptors is a prospective treatment target for females experiencing anhedonic-like states that make them susceptible to alcohol relapse.

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