Functional mapping of arginine vasopressin receptor 1A circuits that promote anorexic behavior

项目总结 神经性厌食症(AN)是所有精神疾病中死亡率最高的，而且没有 有效的治疗方法。寻找新的治疗靶点的一个主要障碍是缺乏洞察力 病理生理进食行为的原因。营养不良与共病精神病 疾病会导致大脑和外周发生戏剧性的变化，使发现疾病的努力复杂化。 导致疾病发生的因素。Zeltser实验室开发了一种新的小鼠模型来研究 在疾病转化之前的疾病阶段，利用流行病学 经常被忽视的观察--青春期的遗传易感性。雌性小鼠携带 一个与AN(BDNF-Val66Met)遗传易感性相关的等位基因暴露于社会 青春期隔离应激和热量限制。大约40%的这些老鼠 表现出严格的自我饮食限制，有时甚至到了死亡的地步。使用这一技术的研究 AN前状态的小鼠模型确定了一种新的治疗靶点：精氨酸 加压素受体1A(AVPR1A)。 拟议中的实验将绘制大脑中必要的avp→avpr1a电路的图谱。 足以抑制摄食，并将决定哪些被x基因环境增强 促进厌食症行为易感性的相互作用。目标1中概述的研究将利用 确定AVPR1a种群的药理学、遗传学和药物遗传学方法 抑制野生型小鼠进食所必需且足够的神经元。同时， 目标2中的实验将使用逆行追踪和药物遗传学的组合 识别传递厌食性AVP信号的神经元群的技术。因为有 许多不同的回路调节进食，目标3的研究将确定厌食症的影响 HBDNFMet/？hBDNFMet/？女性 暴露在青春期周围的社会孤立压力中。 在我们的小鼠模型中，促进厌食行为的大脑回路的阐明将提供 为未来努力探索目前正在使用的AVPR1A拮抗剂 其他精神病学适应症的II期临床试验可能会使一些AN患者受益。教训 所学到的知识也将大大促进对常见的BDNF-Val66Met如何 VARIANT加剧社会压力对青少年大脑的影响以增加易感性 各种与焦虑和情感障碍相关的疾病。

PROJECT SUMMARY Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, and there are no effective treatments. A major obstacle to identifying new therapeutic targets is the lack of insight into causes of the pathophysiological eating behavior. Malnutrition and co-morbid psychiatric illnesses cause dramatic changes in the brain and periphery that complicate efforts to uncover factors responsible for disease onset. The Zeltser lab developed a new mouse model to study AN at the stage of illness prior to disease conversion by taking advantage of an epidemiological observation that is often overlooked – genetic susceptibility in adolescence. Female mice carrying an allele associated with genetic susceptibility to AN (BDNF-Val66Met) were exposed to social isolation stress and caloric restriction during adolescence. Approximately 40% of these mice exhibit severe self-imposed dietary restriction, sometimes to the point of death. Studies using this mouse model of the pre-AN state identified a novel therapeutic target for AN treatment: arginine vasopressin receptor 1A (AVPR1A). The proposed experiments will map the AVP→ AVPR1A circuits in the brain that are necessary and sufficient to suppress feeding and will determine which are potentiated by gene x environment interactions that promote susceptibility to anorexic behavior. Studies outlined in Aim 1 will utilize pharmacological, genetic and pharmacogenetic approaches to define populations of AVPR1A neurons that are necessary and sufficient to suppress feeding in wild-type mice. In parallel, experiments in Aim 2 will use a combination of retrograde tracing and pharmacogenetic techniques to identify neuronal populations that transmit the anorexic AVP signal. Since there are many distinct circuits that regulate feeding, studies in Aim 3 will determine where anorexic effects of AVP and the expression of AVPR1A pathway components are enhanced in hBDNFMet/? females exposed to peri-pubertal social isolation stress. The elucidation of brain circuits that promote anorexic behavior in our mouse model would provide a strong foundation for future efforts to explore whether AVPR1A antagonists that are currently in Phase II clinical trials for other psychiatric indications could benefit some AN patients. Lessons learned will also significantly advance the understanding of how the common BDNF-Val66Met variant exacerbates the effects of social stress on the adolescent brain to increase susceptibility to a variety of anxiety-related and affective disorders.