To eat or run? The role of GABA in the hippocampus-prefrontal cortex circuit for decision making

吃饭还是跑步？

• 批准号: 8809593
• 负责人: CHIYE J AOKI
• 金额: $ 26.47万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8809593
• 关键词: Adaptive Behaviors; Adolescence; Adolescent; Adult; Animal Model; Animals; Anorexia; Anorexia Nervosa; Anxiety; Anxiety Disorders; Axon; Behavior; Behavioral; Biological; Body Weight decreased; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cessation of life; Child; Comorbidity; Data; Decision Making; Disease; Eating; Eating Disorders; Electron Microscopy; Electrons; Environment; Enzymes; Exercise; Exhibits; Female; Female Adolescents; Food; Food Access; GABA Receptor; Goals; Gonadal Hormones; Health; Hippocampus (Brain); Hour; Impairment; Individual; Individual Differences; Learning; Life; Link; Major Depressive Disorder; Measurement; Measures; Mental disorders; Microscopic; Molecular; Mus; Panic Disorder; Plague; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Progesterone; Puberty; Regulation; Rodent; Role; Running; Social Phobia; Stress; Structure; Suicide; Synapses; System; Testing; Time; Up-Regulation; addiction; base; childhood anxiety; cognitive control; environmental stressor; excessive exercise; exhaustion; food restriction; gamma-Aminobutyric Acid; indexing; knock-down; male; nerve supply; neural circuit; public health relevance; response; stem; therapy design; trait

DESCRIPTION (provided by applicant): Our aim is to understand the neural circuit underlying the cognitive control over the mal-adaptive behaviors that stem from stress-induced anxiety, especially among female adolescents. We also aim to understand why adolescent females are more vulnerable than males, adults and children to mental illnesses that are co-morbid with anxiety disorders. We have shown that adolescent female rodents that are exposed to the stress of food restriction (FR) exhibit individual differences in vulnerability to an anxiety disorer-like behavior, consisting of abnormality on the elevated plus maze, voluntary food restriction and excessive exercise, the latter of which contribute to severe weight loss and for some, death. This compilation of FR-evoked abnormalities, called activity-based anorexia (ABA) differs widely among individuals and correlate strongly with changes in the GABAergic inhibitory system (axons and alpha4betadelta-GABA receptors) in the prefrontal cortex and hippocampus. What remains unknown is whether the behavioral and anatomical changes are causally linked and if so, the mechanism for the stress (in this study, FR)-evoked up-regulation of the GABAergic system that protects animals from the mal-adaptive behavior. We hypothesize that (1) up-regulation to the GABAergic system of the prefrontal cortex and hippocampus is causal to the animal's ability to make decisions regarding responses to stressful environments (e.g., to eat or to run) that are more adaptive and to regulate the stress-evoked anxiety; and (2) individual differences in the GABAergic system of the prefrontal cortex and hippocampus arise from gonadal hormone fluctuations at puberty and the activity-dependent BDNF release. We will test these hypotheses by (1) determining the extent to which experimentally boosting the GABA system in the hippocampus and prefrontal cortex reduces ABA vulnerability and trait anxiety; and (2) determining whether systemic progesterone or the systemic or local alterations of BDNF level increase the strength of the GABA system and with it, reductions in the mal-adaptive behavior of voluntary FR, excessive exercise, and anxiety measures on the elevated plus maze. These goals will be achieved by quantifying the mal-adaptive behaviors of mice that are globally or locally knocked down of or boosted of the expression of GABAR subunits or of the GABA synthesizing enzyme or of BDNF and verifying the ultrastructure of GABAergic synapses by electron microscopy.

描述（由申请人提供）：我们的目的是了解对因压力引起的焦虑而产生的适应不良行为进行认知控制的神经回路，特别是在女性青少年中。我们还旨在了解为什么青春期女性比男性、成人和儿童更容易患上与焦虑症共存的精神疾病。我们已经表明，暴露在食物限制（FR）压力下的青春期雌性啮齿动物在易受焦虑症样行为影响方面表现出个体差异，包括高架十字迷宫异常、自愿食物限制和过度运动，后者其中会导致体重严重减轻，甚至导致某些人死亡。这种由 FR 引起的异常的集合，称为基于活动的厌食症 (ABA)，在个体之间存在很大差异，并且与前额皮质和海马中 GABA 能抑制系统（轴突和 α4βδ-GABA 受体）的变化密切相关。目前尚不清楚的是，行为和解剖学变化是否存在因果关系，如果是，则压力（在本研究中为 FR）引起 GABA 能系统上调的机制，该系统可以保护动物免受适应不良行为的影响。我们假设 (1) 前额叶皮层和海马体 GABA 能系统的上调导致动物能够做出有关应激环境反应的决策（例如，吃饭或跑步），这些决策更具适应性并能够调节压力引起的焦虑； (2) 前额皮质和海马 GABA 能系统的个体差异是由青春期性腺激素波动和活动依赖性 BDNF 释放引起的。我们将通过以下方式检验这些假设：(1) 确定通过实验增强海马和前额皮质中的 GABA 系统可在多大程度上降低 ABA 脆弱性和特质焦虑； (2) 确定全身黄体酮或 BDNF 水平的全身或局部改变是否会增加 GABA 系统的强度，并随之减少自愿 FR 的适应不良行为、过度运动和高架十字迷宫上的焦虑措施。这些目标将通过量化全局或局部 GABAR 亚基或 GABA 合成酶或 BDNF 表达被敲低或增强的小鼠的适应不良行为并通过电子显微镜验证 GABA 能突触的超微结构来实现。