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)：我们的目标是了解认知控制不良适应行为的神经回路，这些行为源于压力诱导的焦虑，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、成年人和儿童更容易受到与焦虑症并存的精神疾病的影响。我们发现，暴露在食物限制(FR)应激下的青春期雌性啮齿动物对焦虑失调者样行为的易感性存在个体差异，包括高架+迷宫异常、自愿食物限制和过度运动，后者导致严重体重减轻，对一些人来说，甚至死亡。这种FR诱发的异常称为基于活动的厌食症(ABA)，个体差异很大，与前额叶皮质和海马区GABA能抑制系统(轴突和α4β-GABA受体)的变化密切相关。目前尚不清楚的是，行为和解剖学的变化是否存在因果联系，如果是的话，应激的机制(在本研究中为FR)-引起GABA能系统的上调，以保护动物免受不良适应行为的影响。我们假设：(1)前额叶皮质和海马区GABA能系统的上调是动物对应激环境(如进食或跑步)做出更适应的反应并调节应激引起的焦虑的能力的原因；以及(2)前额叶皮质和海马区GABA能系统的个体差异源于青春期性激素的波动和依赖活动的BDNF的释放。我们将通过(1)确定通过实验增强海马体和前额叶皮质中的GABA系统降低ABA脆弱性和特质焦虑的程度；以及(2)确定全身孕酮或全身或局部BDNF水平的变化是否增加了GABA系统的强度，以及随之而来的是自愿FR的不良适应行为的减少、过度运动和高架+迷宫上的焦虑措施，以检验这些假说。这些目标将通过量化GABAR亚单位或GABA合成酶或BDNF表达的全局或局部下调或增强的小鼠的不良适应行为，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.