Sex differences in stress inoculation of addiction-like phenotypes

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Opioid use disorder is on the rise and the economic and human cost is staggering. It remains unclear why only a subset of people who take opioids develop dependence, prompting efforts to understand factors that promote vulnerability to opioid misuse. However, it is also critical to identify factors that promote resilience to substance use disorder (SUD). Experiences early in life can alter risk/resilience for the later development of disorders. For example, early life stress that is not overwhelming can have an “inoculating” effect that promotes the development of resilience in adulthood. Here we use a rat model of early life adversity, the limited bedding and nesting (LBN) model, to assess how this manipulation affects addiction-like phenotypes in adulthood. In LBN, dams and their pups are exposed to a low resource environment during the pups first week of life, which induces stress in the pups. We found that LBN inoculates males against addiction-like behaviors, such that adult male rats exposed to LBN self-administer less morphine and are less motivated to take morphine than adult males raised in a normal, adequately resourced, nesting environment. Impulsive choice, a risk factor for SUD, was also assessed, and LBN reduced impulsive choice in males. LBN had no effect on these behaviors in female rats. This proposal will determine how LBN further alters addition-like behaviors, as well as changes the physiology and the transcriptome of the nucleus accumbens (NAc), a region that critically mediates drug intake and impulsivity. Aim 1 will test the hypothesis that LBN shifts the dose-response curve for morphine self- administration to the right in males. This aim will also determine if LBN reduces both impulsive choice and impulsive action in males. Consistent with our preliminary data, behavioral changes following LBN in females are not expected. Aim 2 will test the hypothesis that LBN reduces glutamatergic transmission in the NAc of males, but not females, an effect that would promote resilience to the reinforcing efficacy of morphine. Prior work has demonstrated that early life experience can reprogram the brain through epigenetic modifications that lead to persistent changes in gene expression and neuronal signaling. Thus, Aim 3 will identify sex-specific changes in gene expression and accompanying chromatin remodeling events in the NAc elicited by LBN. Our preliminary data reveal that LBN reduces the expression of several glutamate signaling genes in males. Certain histone deacetylases (HDACs), enzymes that remove acetyl groups from histone tails, are implicated in these gene changes. We will test the behavioral relevance of these HDACs by manipulating their function within the NAc and determining whether they mediate resilience to addiction-related behavior. Collectively, this proposal will reveal mechanisms by which LBN can inoculate males against addiction-like phenotypes. Notably, our team of investigators is uniquely positioned to assess LBN-induced changes from the behavioral to the molecular level. Moreover, the sex-specificity of the LBN effects will allow us to, by comparing the sexes, identify novel targets that promote resilience to SUD, which may lead to the development of better therapies to reduce opioid misuse.