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，寻求在维克森林大学医学院生理和药学系教授Jeffrey L. Weiner博士指导下的研究培训资金。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相关性。本文所包含的实验将通过首次调查青少年社会隔离形式的慢性发育应激对基底外侧杏仁核（BLA）中抑制性肾上腺素受体（AR）信号传导的影响来扩展这一研究。我们已经证明，青少年社会隔离导致焦虑样行为和乙醇自我管理的表达增加，并阻断了成年雄性Long-Evans大鼠条件恐惧的消退。此外，来自我们实验室和许多其他实验室的证据表明，这些不同但相关的行为的病因学中存在干扰AR信号，我们假设BLA是表达这种干扰的重要神经位点。具体来说，我们提出去甲肾上腺素作用于BLA ARs的平衡兴奋和抑制作用被社会隔离改变，导致BLA兴奋输出增加，进而增强焦虑和酒精饮酒。简而言之，目的1将研究社会隔离对BA抑制输入信号的影响（包括局部反馈中间神经元和前馈外侧囊旁细胞（LPCs）），并确定这些输入的gaba能信号的AR促进是否在社会隔离后发生改变。已知局部抑制性中间神经元活动因恐惧条件作用而减少，并在灭绝后增加~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能信号中断可能是罪魁祸首。因此，本研究还将调查在社会隔离后，相对于对照组，恐惧条件反射和灭绝训练是否会改变BLA抑制突触，以及改变的AR抑制是否会导致任何观察到的差异。重要的是，Aim 2将使用渗透性微型泵来确定增强ar介导的LPC gaba能信号，单独或同时阻断BLA ar的兴奋作用，是否能逆转社会孤立症状的压力相关行为。提出的实验将显著提高我们对这些常见的共病性疾病的理解，并可能为治疗焦虑症、酗酒和创伤后应激障碍的症状指明新的药理学靶点。

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.