Early life stress is known to impact vulnerability to psychopathological disorders in adulthood, including anxiety and alcohol use disorder (AUD), but the mechanisms underlying susceptibility to these outcomes are not fully understood. In the current study, we used adolescent social isolation (ASI) to determine whether Heterogeneous Stock (HS) rats, an outbred model used for genetic fine-mapping, could be used to study the genetics contributing to ASI-induced anxiety- and AUD-like behavior. We isolated (ASI) or group-housed (adolescent group-housed; AGH) 64 male HS rats at 4 weeks of age. After 5 weeks in these housing conditions, multiple anxiety and coping/despair-like behaviors were measured. All rats were then individually housed and assessed for voluntary ethanol self-administration. At euthanasia, synaptoneurosomes were isolated from a subset of brains to examine the expression of two proteins associated with alcohol drinking-related behaviors, GluA1 and SK2, in the dorsal (dHC) and ventral hippocampus (vHC). We found that ASI increased hyperactivity in the open field test relative to AGH, with no changes in other anxiety-like behaviors. Surprisingly, ASI rats demonstrated decreased immobility and increased climbing in the forced swim test relative to AGH. In contrast to prior studies by us and others, we found no difference in self-administration of 20% ethanol, with decreased ethanol self-administration in ASI relative to AGH rats at higher ethanol concentrations. Furthermore, while ASI in Long-Evans rats resulted in decreased SK2 expression in vHC synaptosomes, no differences were seen in vHC synaptosomes for SK2 or GluA1 in HS rats. These results demonstrate that HS rats are protected against many of the negative effects previously seen in response to ASI, namely anxiety-like behavior and increased ethanol self-administration. The current work suggests that a lack of change in SK2 and GluA1 expression levels in the vHC may play a role in conferring this protection.

众所周知，早期生活压力会影响成年后精神病理疾病的脆弱性，包括焦虑和酒精使用障碍（AUD），但对这些结果易感性的潜在机制尚不完全清楚。在当前的研究中，我们使用青少年社会隔离（ASI）来确定异种种群（HS）大鼠（一种用于遗传精细图谱的远交模型）是否可以用于研究导致 ASI 诱发的焦虑和 AUD 的遗传学。喜欢的行为。我们分离（ASI）或群养（青少年群养；AGH）64 只 4 周龄的雄性 HS 大鼠。在这些住房条件下呆了 5 周后，测量了多种焦虑和应对/绝望行为。然后将所有大鼠单独饲养并评估其自愿的乙醇自我施用。在安乐死时，从一部分大脑中分离出突触神经体，以检查背侧海马 (dHC) 和腹侧海马 (vHC) 中两种与饮酒相关行为相关的蛋白质 (GluA1 和 SK2) 的表达。我们发现，与 AGH 相比，ASI 在旷场测试中增加了多动症，而其他焦虑样行为没有变化。令人惊讶的是，与 AGH 相比，ASI 大鼠在强迫游泳测试中表现出不动性降低和攀爬性增加。与我们和其他人之前的研究相比，我们发现 20% 乙醇的自我给药没有差异，在较高乙醇浓度下，ASI 大鼠的乙醇自我给药量相对于 AGH 大鼠有所减少。此外，虽然 Long-Evans 大鼠中的 ASI 导致 vHC 突触体中 SK2 表达降低，但 HS 大鼠中 vHC 突触体中 SK2 或 GluA1 的表达没有差异。 这些结果表明，HS 大鼠可以免受先前在 ASI 反应中看到的许多负面影响，即焦虑样行为和增加乙醇自我给药。目前的工作表明，vHC 中 SK2 和 GluA1 表达水平缺乏变化可能在赋予这种保护中发挥作用。