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

促进厌食行为的精氨酸加压素受体 1A 电路的功能图谱

基本信息

批准号：
10321547
负责人：
Lori M Zeltser
金额：
$ 46.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321547
关键词：
Adolescence Adolescent Alleles Amygdaloid structure Anorexia Anorexia Nervosa Argipressin Behavior Biological Body Weight decreased Brain Brain region Brain-Derived Neurotrophic Factor Caloric Restriction Cell Nucleus Cessation of life Cholera Toxin Protomer B Collaborations Cre driver Development Diagnosis Disease Eating Eating Behavior Epidemiology Exhibits Exposure to Fasting Feeding behaviors Female Foundations Future Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic study Goals Human Injections Knock-out Lead Life Malnutrition Maps Medical Mental disorders Methods Microinjections Modeling Mood Disorders Mouse Strains Mus Neurobiology Neurons Neurosecretory Systems Onset of illness Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Pharmacology Phase II Clinical Trials Physiological Population Predisposition Prevalence Risk Risk Factors Severities Signal Transduction Site Social isolation Source Stains Stress Symptoms Techniques Time V1a vasopressin receptor Variant Visualization Wild Type Mouse anorexic antagonist anxiety-related disorders arginine treatment base comorbidity design designer receptors exclusively activated by designer drugs dietary restriction effective therapy environmental stressor experimental study feeding gene environment interaction insight interest mortality mouse model nestin protein new therapeutic target phase II trial psychologic receptor social stress

项目摘要

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.

项目摘要厌食症神经（AN）在任何精神病中的死亡率最高，并且没有有效的治疗方法。识别新的治疗靶标的主要障碍是缺乏洞察力成为病理生理饮食行为的原因。营养不良和合并精神病疾病会导致大脑和外围的巨大变化，使努力揭露的精力复杂化负责疾病发作的因素。 Zeltser实验室开发了一种新的鼠标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结果 - 青少年的遗传敏感性。携带的雌鼠与遗传易感性相关的等位基因（BDNF-VAL66MET）暴露于社会青少年期间的隔离应力和热量限制。这些小鼠中约有40％表现出严重的自我施加的饮食限制，有时会死亡。使用此研究的研究预验状态的小鼠模型确定了治疗的新型治疗靶点：精氨酸加压素受体1A（AVPR1A）。提出的实验将绘制大脑中必要的AVP→AVPR1A圆圈足以抑制进食，并将确定基因X环境的潜在促进对厌食性行为敏感的相互作用。 AIM 1中概述的研究将使用定义AVPR1A种群的药理，遗传和药物遗传学方法必要且足以抑制野生型小鼠喂养的神经元。并联， AIM 2中的实验将结合逆行追踪和药物遗传学鉴定传递厌食症AVP信号的神经元种群的技术。因为有许多不同的调节进食的不同电路，AIM 3中的研究将确定厌食症的影响 AVP和AVPR1A途径成分的表达在HBDNFMet/中得到增强？女性暴露于聚会周围的社会隔离压力。在我们的小鼠模型中阐明促进厌食性行为的脑电路的阐明将提供未来努力探索目前是否正在探索的AVPR1A拮抗剂的坚实基础其他精神病学适应症的II期临床试验可能会使某些患者受益。教训学到的还将大大提高人们对公共BDNF-VAL66met的理解变体加剧了社会压力对青少年大脑的影响以提高易感性到各种与动画有关的和情感障碍。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rethinking the Approach to Preclinical Models of Anorexia Nervosa.

DOI：
10.1007/s11920-022-01319-2
发表时间：
2022-01
期刊：
Current psychiatry reports
影响因子：
6.7
作者：
François M;Zeltser LM
通讯作者：
Zeltser LM

Corrigendum: MC4R-dependent suppression of appetite by bone-derived lipocalin 2.

勘误表：骨源性脂质运载蛋白 2 对 MC4R 依赖性食欲的抑制。

DOI：
10.1038/nature22808
发表时间：
2017
期刊：
Nature
影响因子：
64.8
作者：
Mosialou,Ioanna;Shikhel,Steven;Liu,Jian-Min;Maurizi,Antonio;Luo,Na;He,Zhenyan;Huang,Yiru;Zong,Haihong;Friedman,RichardA;Barasch,Jonathan;Lanzano,Patricia;Deng,Liyong;Leibel,RudolphL;Rubin,Mishaela;Nickolas,Thomas;Chung,Wen
通讯作者：
Chung,Wen

A Framework for Developing Translationally Relevant Animal Models of Stress-Induced Changes in Eating Behavior.