Sex Differences In Stress Inoculation Of Addiction-Like Phenotypes

类阿片使用障碍正在增加，经济和人力成本惊人。目前还不清楚为什么只有 服用阿片类药物的一部分人会产生依赖性，这促使人们努力了解促进阿片类药物依赖的因素。 滥用阿片类药物的脆弱性。然而，确定促进对实质性问题的复原力的因素也至关重要 使用障碍（SUD）。生命早期的经历可以改变风险/恢复能力，以适应以后的疾病发展。为 例如，早期生活中的压力，不是压倒性的，可以有一个“负”的影响，促进 在成年期发展韧性。在这里，我们使用了一个早期生活逆境的大鼠模型，有限的床上用品， 嵌套（LBN）模型，以评估这种操纵如何影响成年后的成瘾样表型。在黎巴嫩， 母鼠和它们的幼崽在出生后的第一周暴露在低资源环境中， 会给幼崽带来压力我们发现，LBN接种男性对成瘾样行为， 暴露于LBN的成年雄性大鼠自我施用的吗啡较少， 在正常的、资源充足的筑巢环境中长大的成年雄性。冲动的选择，一个危险因素， SUD，也进行了评估，LBN减少男性的冲动选择。LBN对这些行为没有影响 在雌性大鼠中。这个提议将决定LBN如何进一步改变类似加法的行为，以及 神经核（NAc）的生理学和转录组，这是一个关键的药物介导区域， 摄入量和冲动目标1将检验LBN移动吗啡剂量-反应曲线的假设 男性向左自我给药。这一目标也将决定LBN是否会减少冲动选择， 男性的冲动行为与我们的初步数据一致，女性LBN后的行为变化 是不期望的。目的2将检验LBN减少NAc中的神经递质传递的假设， 男性，但不是女性，这将促进恢复吗啡的增强功效的效果。之前 研究表明，早期的生活经历可以通过表观遗传修饰来重新编程大脑， 导致基因表达和神经元信号传导的持续变化。因此，目标3将确定性别特异性 LBN引起的NAc基因表达和伴随的染色质重塑事件的变化。我们 初步数据显示LBN降低了雄性中几种谷氨酸信号基因的表达。 某些组蛋白脱乙酰酶（HDAC），从组蛋白尾部去除乙酰基的酶， 在这些基因变化中。我们将测试HDAC对LBN衍生基因表达的功能相关性， 成瘾相关行为的变化和改变。总的来说，这一建议将揭示机制， 哪种LBN可以使男性抵抗成瘾样表型。值得注意的是，我们的调查团队 独特的定位，以评估从行为到分子水平的LBN诱导的变化。而且 LBN效应的性别特异性将使我们能够通过比较性别，确定促进LBN效应的新靶点。 对SUD的适应力，这可能导致开发更好的治疗方法，以减少阿片类药物滥用。

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 to 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 left 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 functional relevance of HDACs on LBN-derived gene expression changes and alterations 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.