Synaptic and Behavioral Correlates of Early Life Stress in the BLA

描述(由申请人提供)：本申请为Ruth L.Kirschstein NRSA个人博士前奖学金，由Mary Jane Skelly提交，寻求在Jeffrey L.Weiner博士、博士、维克森林大学医学院生理学和药理学系教授的指导下进行研究培训的资金。韦纳博士的实验室致力于阐明焦虑和酒精滥用障碍之间的关系，并确定这些障碍典型的适应不良行为的突触关联。本文中包含的实验将通过首次调查青少年社交隔离形式的慢性发展应激对杏仁基底外侧核(BLA)抑制性肾上腺素受体(AR)信号的影响来扩展这项研究。我们发现，青春期的社交隔离导致成年雄性Long-Evans大鼠焦虑样行为的表达增加和酒精自我管理，并阻断了条件性恐惧的消退。此外，来自我们实验室和许多其他实验室的证据表明，AR信号中断与这些截然不同但相关的行为的病因学有关，我们假设BLA是表达这种中断的重要神经位点。具体地说，我们认为，社会隔离改变了去甲肾上腺素对BLA受体的兴奋和抑制平衡效应，导致BLA兴奋输出增加，这反过来又加剧了焦虑和饮酒。简而言之，目标1将研究社会隔离对BA抑制输入(局部反馈中间神经元和前馈外侧囊旁细胞(LPCS))信号的影响，并确定这些输入的GABA能信号的AR易化是否在社会隔离后发生改变。众所周知，局部抑制神经元间的活性在恐惧条件作用下降低，在灭绝后增加~由于我们的数据表明，社会隔离阻止了灭绝学习，我们假设局部和LPC突触的GABA能信号中断可能是原因。因此，这一目标还将调查BLA抑制突触是否在社交隔离后通过恐惧条件反射和消退训练相对于群体居住的对照组发生差异改变，以及改变的AR抑制是否对观察到的任何差异起到作用。重要的是，Aim 2将使用渗透性微泵来确定，增强AR介导的LPC GABA能信号，单独或同时阻断BLA受体的兴奋效应，是否逆转了社交隔离症状的应激相关行为。拟议的实验将极大地促进我们对这些常见并存疾病的理解，并可能为治疗焦虑症、酒精中毒和创伤后应激障碍的症状指明新的药理靶点。

DESCRIPTION (provided by applicant): This application for a Ruth L. Kirschstein NRSA for Individual Predoctoral Fellowship is submitted by Mary Jane Skelly, seeking funding for research training under the tutelage of Jeffrey L. Weiner, Ph.D., Professor in the Department of Physiology and Pharmacology at Wake Forest University School of Medicine. Dr. Weiner's lab is devoted to elucidating the relationship between anxiety and ethanol abuse disorders, and identifying the synaptic correlates of the maladaptive behaviors typical of these disorders. The experiments contained herein will extend this research by investigating, for the first time, the effects of chronic developmental stress in the form of adolescent social isolation on inhibitory adrenoreceptor (AR) signaling in the basolateral amygdala (BLA). We have shown that adolescent social isolation leads to increased expression of anxiety-like behaviors and ethanol self-administration, and occludes extinction of conditioned fear in adult male Long-Evans rats. Furthermore, evidence from our lab and many others implicates disrupted AR signaling in the etiology of these distinct but related behaviors, and we hypothesize that the BLA is an important neural locus where this disruption is expressed. Specifically, we propose that the balanced excitatory and inhibitory effects of norepinephrine acting on BLA ARs is altered by social isolation, resulting in increased BLA excitatory output, which in turn potentiates anxiety and ethanol drinking. Briefly, Aim 1 will investigate the effects of social isolation on signaling at BA inhibitory inputs (both local feed-back interneurons and feed-forward lateral paracapsular cells (LPCs)), and determine whether AR facilitation of GABAergic signaling at these inputs is altered following social isolation. Local inhibitory interneuron activity is known to be decreased by fear conditioning and increased following extinction~ as our data suggest that social isolation prevents extinction learning, we hypothesize that disrupted GABAergic signaling at local and LPC synapses may be to blame. Thus, this aim will also investigate whether BLA inhibitory synapses are differentially altered by fear conditioning and extinction training following social isolation, relative to group housed controls, and whether altered AR inhibition contributes to any observed differences. Importantly, Aim 2 will use osmotic minipumps to determine whether enhancing AR-mediated LPC GABAergic signaling, alone or while concomitantly blocking the excitatory effects of BLA ARs, reverses the stress-related behaviors symptomatic of social isolation. The proposed experiments stand to significantly advance our understanding of these commonly comorbid disorders, and could possibly point to new pharmacological targets for treating the symptoms of anxiety disorders, alcoholism, and PTSD.