Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA.
Neuropsychopharmacology. 2023 Jul;48(8):1133-1143. doi: 10.1038/s41386-022-01442-x. Epub 2022 Sep 9.
α-adrenergic receptor (α-AR) agonists are candidate substance use disorder therapeutics due to their ability to recruit noradrenergic autoreceptors to dampen stress system engagement. However, we recently found that postsynaptic α-ARs are required for stress-induced reinstatement of cocaine-conditioned behavior. Understanding the ensembles recruited by these postsynaptic receptors (heteroceptors) is necessary to understand noradrenergic circuit control. We utilized a variety of approaches in FosTRAP (Targeted Recombination in Active Populations) mice to define an ensemble of cells activated by the α-AR partial agonist guanfacine ("Guansembles") in the bed nucleus of the stria terminalis (BST/BNST), a region key to stress-induced reinstatement of drug seeking. We define BNST "Guansembles" and show they differ from restraint stress-activated cells. Guanfacine produced inhibition of cAMP-dependent signaling in Guansembles, while chronic restraint stress increased cAMP-dependent signaling. Guanfacine both excited and inhibited aspects of Guansemble neuronal activity. Further, while some stressors produced overall reductions in Guansemble activity, active coping events during restraint stress and exposure to unexpected shocks were both associated with Guansemble recruitment. Using viral tracing, we define a BNST Guansemble afferent network that includes regions involved in the interplay of stress and homeostatic functions. Finally, we show that activation of Guansembles produces alterations in behavior on the elevated plus maze consistent with task-specific anxiety-like behavior. Overall, we define a population of BNST neurons recruited by α-AR signaling that opposes the behavioral action of canonical autoreceptor α-AR populations and which are differentially recruited by distinct stressors. Moreover, we demonstrate stressor-specific physiological responses in a specific neuronal population.
α-肾上腺素能受体 (α-AR) 激动剂是候选的物质使用障碍治疗药物，因为它们能够招募去甲肾上腺素能自身受体以抑制应激系统的参与。然而，我们最近发现，突触后 α-AR 对于应激诱导的可卡因条件行为的复吸是必需的。了解这些突触后受体（异源受体）募集的集合对于理解去甲肾上腺素能回路控制是必要的。我们利用 FosTRAP（活跃群体中的靶向重组）小鼠中的多种方法来定义一个集合，该集合由床核终纹床核（BST/BNST）中的 α-AR 部分激动剂胍法辛（“胍集合”）激活，该区域对于应激诱导的药物寻求复吸至关重要。我们定义了 BNST“胍集合”，并表明它们与束缚应激激活的细胞不同。胍法辛在胍集合中产生抑制 cAMP 依赖性信号转导，而慢性束缚应激增加了 cAMP 依赖性信号转导。胍法辛兴奋和抑制了胍集合神经元活动的各个方面。此外，虽然一些应激源总体上减少了胍集合的活动，但在束缚应激期间的积极应对事件以及暴露于意外冲击都与胍集合的募集有关。使用病毒追踪，我们定义了 BNST 胍集合传入网络，该网络包括涉及应激和稳态功能相互作用的区域。最后，我们表明激活胍集合会导致在高架十字迷宫上的行为改变，与特定任务的焦虑样行为一致。总体而言，我们定义了一个由 α-AR 信号募集的 BNST 神经元群体，该群体与经典自身受体 α-AR 群体的行为作用相反，并且由不同的应激源募集。此外，我们证明了特定神经元群体中的应激特异性生理反应。
