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

描述（由申请人提供）：我们的目的是了解神经回路的认知控制的适应不良的行为，源于压力引起的焦虑，特别是在女性青少年。我们还旨在了解为什么青少年女性比男性，成人和儿童更容易患上与焦虑症共病的精神疾病。我们已经表明，暴露于食物限制（FR）的压力的青春期雌性啮齿动物表现出个体差异的脆弱性焦虑disorer样行为，包括异常的高架十字迷宫，自愿食物限制和过度运动，后者导致严重的体重减轻和一些，死亡。这种FR诱发的异常，称为基于活动的厌食症（阿坝），在个体之间差异很大，并与前额叶皮层和海马中GABA能抑制系统（轴突和α 4 β-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，如果是这样，应激（在本研究中，FR）诱发GABA能系统上调的机制，保护动物免受适应不良行为的影响。我们假设（1）前额叶皮质和海马的GABA能系统的上调与动物对压力环境（例如，（2）前额叶皮层和海马GABA能系统的个体差异源于青春期性腺激素的波动和活动依赖性BDNF的释放。我们将通过（1）确定实验性地增强海马和前额皮质中的GABA系统在多大程度上降低阿坝脆弱性和特质焦虑来验证这些假设;和（2）确定全身孕酮或BDNF水平的全身或局部改变是否增加GABA系统的强度，并随之减少随意FR，过度运动，以及高架十字迷宫的焦虑测试这些目标将通过量化GABAR亚基或GABA合成酶或BDNF的表达被整体或局部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。

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.