The Role of Extrasynaptic GABAAR Signaling in the Gustatory Cortex on Taste-Dependent Impulsive Behavior

项目摘要 冲动，通常被定义为不假思索的行为，是大多数人预先存在的性格特征。它 可以是有利的;然而，当过度时，它变得不适应。病理性冲动行为（IB） 饮食失调的病因和发病机制的基础因素之一。饮食对于 生存，但适应不良的食物摄入模式可以修改食物和食物相关线索的奖励价值。 暴饮暴食是一种功能失调的进食行为模式，通常包括食用可口的食物 富含糖和脂肪。 研究表明，岛叶皮层（IC）的电路可能会改变暴食症。该IC具有 与冲动行为有关，被归类为冲动发展的神经生物学大门 相关疾病。前IC -也称为味觉皮层（GC）-也参与对大脑皮层的加工。 味觉，期望奖励，以及关于食物消费的决策。这一证据表明， GC是研究可能导致冲动控制缺陷的机制的理想区域回路， 特别是在食物摄入方面。 本提案的目的是检验以下假设：强直性GABA能抑制水平的改变， 有助于调节神经回路的兴奋性，在介导味觉依赖性冲动中发挥核心作用 选择.这一假设将通过利用神经甾体别孕烯醇酮作为药理学 研究紧张性抑制对GC回路兴奋性和IB的作用的工具。为了评估神经系统 为了阐明IB的发病机制，我将利用组织学方法研究GC中突触外GABAARs的表达模式。 分析，量化突触外GABAAR对神经类固醇敏感性的可能差异，并使用选择性 GABAAR亚基表达的操作以确定突触外抑制对IB的贡献。 我的初步数据显示，突触外GABAARs和强直电流的大量表达， 的GC，和舔行为的变化，神经类固醇输注GC。 这项提案的发现将为神经网络生理学差异提供重要的见解。 特性潜在的味道依赖性IB。更清楚地了解这些缺陷的机制， 抑制控制将为冲动的诊断、治疗和预防提供新的生物标志物- 相关的神经精神疾病，改善患者及其家属的生活。

Project Summary Impulsivity, generally defined as acting without thinking, is a preexisting personality trait in most people. It can be advantageous; however, when excessive it becomes maladaptive. Pathological impulsive behavior (IB) is one of the factors underlying the etiology of dysregulated eating and its pathogenesis. Eating is essential for survival, but maladaptive patterns of food intake can modify the reward value of food and food-related cues. Binge eating is a dysfunctional pattern of feeding behavior that usually consists of consuming palatable foods rich in sweets and fats. Studies have shown that the insular cortex's (IC) circuitry may be altered in binge eating disorder. The IC has been associated with impulsive actions and classified as a neurobiological gate for the development of impulsivity related disorders. The anterior IC – also known as gustatory cortex (GC) – is also involved in the processing of taste, expectation of reward, and in decision making regarding food consumption. This evidence suggests that the GC is an ideal regional circuit to investigate the mechanisms that may underlie the deficits in impulse control, particularly in relation to food intake. The goal of this proposal is to test the hypothesis that altered levels of tonic GABAergic inhibition, which contributes to regulating neural circuit excitability, play a central role in mediating taste-dependent impulsive choices. This hypothesis will be addressed by utilizing the neurosteroid allopregnanolone as a pharmacological tool to investigate the role of tonic inhibition on GC circuit excitability and on IB. To assess the neural mechanisms for IB, I will examine the pattern of expression of extrasynaptic GABAARs in GC using histological assays, quantify possible differences in sensitivity of extrasynaptic GABAARs to neurosteroids, and use selective manipulations of GABAARs subunit expression to determine the contribution of extrasynaptic inhibition to IB. My preliminary data show substantial expression of extrasynaptic GABAARs and of tonic current in neurons of the GC, and changes in licking behavior by neurosteroid infusions in GC. The findings of this proposal will provide vital insights into differences in neural network physiological properties underlying taste-dependent IB. A clearer understanding of the mechanisms underlying deficits of inhibitory control will provide novel biomarkers for the diagnosis, treatment and prevention of impulsivity- related neuropsychiatric disorders improving the lives of patients and their families.