Departments of Psychiatry.
Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
J Neurosci. 2023 Oct 18;43(42):7056-7068. doi: 10.1523/JNEUROSCI.0717-23.2023. Epub 2023 Sep 1.
The central nucleus of the amygdala (CeA) is implicated in alcohol use disorder (AUD) and AUD-associated plasticity. The CeA is a primarily GABAergic nucleus that is subdivided into lateral and medial compartments with genetically diverse subpopulations. GABA receptors are heteromeric pentamers with subunits conferring distinct physiological characteristics. GABA receptor signaling in the CeA has been implicated in ethanol-associated plasticity; however, population-specific changes in inhibitory signaling and subunit expression remain unclear. Here, we combined electrophysiology with single-cell gene expression analysis of population markers and GABA receptor subunits to examine population-specific changes in inhibitory control in male and female rats following chronic ethanol exposure. We found that chronic ethanol exposure and withdrawal produced global changes in GABA receptor subunit expression at the transcript and protein levels, increased excitability in female CeA neurons, and increased inhibitory synaptic transmission in male CeA neurons. When we examined CeA neurons at the single-cell level we found heterogenous populations, as previously reported. We observed ethanol-induced increases in excitability only in somatostatin neurons in the CeA of females, decreases in excitability only in the protein kinase C delta (PKCd) population in males, and ethanol-induced increases in inhibitory transmission in male PKCd and calbindin 2-expressing CeA neurons. There were no population-specific differences in GABA receptor (Gabr) subunits in males but reduced GabrA5 expression in female somatostatin neurons. Collectively, these findings suggest that defined CeA populations display differential ethanol sensitivity in males and females, which may play a role in sex differences in vulnerability to AUD or expression of AUD pathology. The CeA is involved in the effects of ethanol in the brain; however, the population-specific changes in CeA activity remain unclear. We used recordings of CeA neuronal activity and single-cell gene expression to examine population-specific changes in inhibitory control in male and female rats following chronic ethanol exposure and found sex- and population-specific effects of chronic ethanol exposure and withdrawal. Specifically, female CeA neurons displayed increased excitability in the somatostatin CeA population, whereas male CeA neurons displayed increased inhibitory control in both PKCd and calbindin populations and decreased excitability in the PKCd population. These findings identify CeA populations that display differential sensitivity to ethanol exposure, which may contribute to sex differences in vulnerability to alcohol use disorder.
杏仁中央核（CeA）与酒精使用障碍（AUD）和 AUD 相关的可塑性有关。CeA 是一个主要的 GABA 能核，分为外侧和内侧隔室，具有遗传上不同的亚群。GABA 受体是异源五聚体，亚基赋予不同的生理特征。CeA 中的 GABA 受体信号与乙醇相关的可塑性有关；然而，抑制性信号和亚基表达的群体特异性变化仍不清楚。在这里，我们结合电生理学和群体标记物的单细胞基因表达分析，研究了慢性乙醇暴露后雄性和雌性大鼠 CeA 中抑制性控制的群体特异性变化。我们发现，慢性乙醇暴露和戒断会导致 GABA 受体亚基表达在转录和蛋白水平上的全局变化，增加雌性 CeA 神经元的兴奋性，并增加雄性 CeA 神经元的抑制性突触传递。当我们在单细胞水平检查 CeA 神经元时，我们发现了像以前报道的那样，存在异质群体。我们发现，乙醇仅在雌性 CeA 的生长抑素神经元中诱导兴奋性增加，仅在雄性的蛋白激酶 C 德尔塔（PKCd）群体中诱导兴奋性降低，并且在雄性的 PKCd 和钙结合蛋白 2 表达的 CeA 神经元中诱导抑制性传递增加。在雄性中，没有发现 GABA 受体（Gabr）亚基的群体特异性差异，但在雌性生长抑素神经元中 GabrA5 的表达减少。总的来说，这些发现表明，特定的 CeA 群体在雄性和雌性中表现出对乙醇的不同敏感性，这可能在 AUD 的易感性或 AUD 病理表现的性别差异中发挥作用。CeA 参与了乙醇在大脑中的作用；然而，CeA 活性的群体特异性变化仍不清楚。我们使用 CeA 神经元活动的记录和单细胞基因表达来研究慢性乙醇暴露后雄性和雌性大鼠抑制性控制的群体特异性变化，并发现慢性乙醇暴露和戒断的性别和群体特异性影响。具体来说，雌性 CeA 神经元在生长抑素 CeA 群体中表现出兴奋性增加，而雄性 CeA 神经元在 PKCd 和钙结合蛋白 2 群体中表现出抑制性控制增加，在 PKCd 群体中表现出兴奋性降低。这些发现确定了对乙醇暴露表现出不同敏感性的 CeA 群体，这可能有助于酒精使用障碍的易感性的性别差异。
