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背后的认知控制的不良适应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春期女性比男性、成年人和儿童更容易患与焦虑症并存的精神疾病。我们已经证明，暴露于食物限制压力（FR）下的青春期雌性啮齿动物在对焦虑障碍样行为的脆弱性方面表现出个体差异，包括在升高的迷宫上的异常，自愿的食物限制和过度运动，后者导致严重的体重减轻，对一些人来说，死亡。fr诱发的异常，被称为活动性厌食症（ABA），在个体之间差异很大，与前额皮质和海马中gaba能抑制系统（轴突和α - β - gaba受体）的变化密切相关。目前尚不清楚的是，行为和解剖学上的变化是否存在因果关系，如果存在因果关系，那么应激（在本研究中，FR）诱发gaba能系统上调的机制是什么，而gaba能系统保护动物免受不良适应行为的影响。我们假设：(1)前额叶皮层和海马体gaba能系统的上调是动物对压力环境（例如，吃或跑）做出决策的能力的原因，这些决策更具适应性，并调节压力引起的焦虑；(2)青春期性激素波动和活动依赖性BDNF释放导致前额叶皮质和海马gaba能系统的个体差异。我们将通过以下方法来验证这些假设：(1)确定在多大程度上通过实验增强海马和前额叶皮层中的GABA系统可以降低ABA易感性和特质焦虑；(2)确定全身性黄体酮或BDNF水平的全身性或局部改变是否会增加GABA系统的强度，并随之减少自发性FR的不良适应行为、过度运动和升高+迷宫的焦虑措施。这些目标将通过量化小鼠的不良适应行为来实现，这些不良适应行为是GABAR亚基或GABA合成酶或BDNF表达的整体或局部下调或增强，并通过电子显微镜验证GABA能突触的超微结构。

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.