Synaptic and Behavioral Correlates of Early Life Stress in the BLA

BLA 中早期生活压力的突触和行为相关性

• 批准号: 8684993
• 负责人: Mary Jane Skelly
• 金额: $ 4.26万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684993
• 关键词: Adolescence; Adolescent; Adult; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Anxiety; Anxiety Disorders; Attention; Attenuated; Back; Behavior; Behavioral; Brain region; Cells; Characteristics; Chronic; Chronic stress; Comorbidity; Data; Development; Disease; Doctor of Philosophy; Equilibrium; Ethanol; Etiology; Exposure to; Extinction (Psychology); Fellowship; Fright; Funding; Glutamates; Housing; Individual; Inhibitory Synapse; Interneurons; Lateral; Lead; Life Stress; Link; Literature; Long-Evans Rats; Mediating; Memory; Methods; National Research Service Awards; Neurobiology; Neurons; Norepinephrine; Output; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Physiology; Population; Post-Traumatic Stress Disorders; Relative (related person); Research; Research Training; Risk; Risk Factors; Rodent Model; Self Administration; Signal Transduction; Social isolation; Stress; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; Time; Training; Universities; addiction; alcohol behavior; alcohol use disorder; attenuation; base; conditioned fear; design; feeding; forest; insight; learning extinction; male; medical schools; new therapeutic target; noradrenergic; novel; osmotic minipump; pre-doctoral; prevent; professor; public health relevance; reinforced behavior; relating to nervous system; research study; stem; stress related disorder; transmission process

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.

描述（由申请人提供）：本申请露丝L。基尔施斯坦NRSA的个人博士前奖学金是由玛丽简斯凯利提交，寻求研究培训的指导下杰弗里L。韦纳博士，维克森林大学医学院生理学和药理学系教授。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，并确定这些障碍的典型适应不良行为的突触相关性。本文所包含的实验将扩展这项研究的调查，为第一次，慢性发展压力的青少年社会隔离的抑制性肾上腺素受体（AR）信号在基底外侧杏仁核（BLA）的形式的影响。我们已经表明，青少年的社会隔离导致焦虑样行为和乙醇自我管理的表达增加，并闭塞灭绝的成年雄性Long-Evans大鼠的条件性恐惧。 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AR信号中断，我们假设BLA是表达这种中断的重要神经位点。具体来说，我们建议，平衡的兴奋和抑制作用的去甲肾上腺素对BLA AR的社会隔离改变，导致增加BLA兴奋输出，这反过来又增强了焦虑和酒精饮用。简言之，目标1将研究社会隔离对BA抑制性输入（局部反馈中间神经元和前馈外侧囊旁细胞（LPC））的信号传导的影响，并确定在这些输入处的GABA能信号传导的AR促进是否在社会隔离后改变。已知局部抑制性中间神经元活动会因恐惧条件反射而减少，并在消退后增加-因为我们的数据表明社会隔离会阻止消退学习，我们假设局部和LPC突触的GABA能信号传导中断可能是罪魁祸首。 因此，该目标还将研究相对于群体饲养的对照组，社交隔离后的恐惧条件反射和消退训练是否会对BLA抑制性突触产生差异性改变，以及AR抑制的改变是否会导致任何观察到的差异。重要的是，目标2将使用渗透微泵来确定增强AR介导的LPC GABA能信号传导，单独或同时阻断BLA AR的兴奋作用，是否逆转了社会隔离症状的应激相关行为。拟议的实验将大大推进我们对这些常见共病疾病的理解，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。