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

味觉皮层突触外 GABAAR 信号传导对味觉依赖性冲动行为的作用

• 批准号: 10436847
• 负责人: Priscilla Yevoo
• 金额: $ 3.89万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436847
• 关键词: Acute; Address; Adolescent; Adult; Affect; Allopregnanolone; Anatomy; Anterior; Automobile Driving; Behavior; Behavioral; Bilateral; Binge Eating; Binge eating disorder; Biological Assay; Brain region; Butyric Acids; Cardiovascular Diseases; Cells; Chemicals; Child; Consumption; Cues; Data; Decision Making; Development; Diagnosis; Disease; Eating; Eating Disorders; Electrophysiology (science); Etiology; Excision; Family; Fatty acid glycerol esters; Feeding Patterns; Feeding behaviors; Food; Food Patterns; GABA Receptor; Glutamates; Goals; Histologic; Human; Immunohistochemistry; Impulsive Behavior; Impulsivity; Infusion procedures; Injections; Insula of Reil; Link; Malignant Neoplasms; Mediating; Morbid Obesity; Mus; Neurobiology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Palate; Pathogenesis; Pathologic; Patients; Pattern; Personality Traits; Persons; Pharmacology; Physiological; Play; Prevention; Property; Receptor Signaling; Reporting; Research Proposals; Rewards; Rodent; Role; Slice; Stroke; Synaptic Transmission; Taste Perception; Testing; Therapeutic Intervention; Thinking; Training; Transgenic Mice; Transgenic Organisms; United States; Viral; Wild Type Mouse; Work; cardiovascular risk factor; cell type; expectation; experimental study; feeding; food consumption; genetic manipulation; improved; insight; neural circuit; neural network; neuromechanism; neuropsychiatric disorder; neurosteroids; novel; novel marker; patch clamp; potential biomarker; receptor; receptor expression; receptor sensitivity; sensory cortex; targeted treatment; testing access; tool; trait

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.

项目摘要 冲动，通常被定义为不加思考地行动，是大多数人预先存在的一种人格特征。它 可能是有利的；然而，当过度时，它就会变得不适应。病理冲动行为(IB)是 饮食失调的病因和发病机制之一。吃东西是必须的 但不适应的食物摄取模式会改变食物的奖赏价值和与食物相关的线索。 暴饮暴食是一种功能失调的进食行为模式，通常包括食用美味的食物。 富含甜食和脂肪。 研究表明，在暴饮暴食障碍中，岛叶皮质(IC)的电路可能会发生变化。集成电路有 与冲动行为联系在一起，被归类为冲动发展的神经生物学门 相关的障碍。前额叶--也称为味觉皮质(GC)--也参与 品味，对回报的期望，以及关于食物消费的决策。这一证据表明 GC是研究脉冲控制缺陷的可能基础机制的理想区域电路， 尤其是在食物摄入量方面。 这项提议的目标是检验这样一种假设，即改变了紧张性GABA能抑制水平，这是 有助于调节神经回路兴奋性，在调节味觉依赖冲动中发挥核心作用 选择。这一假说将通过使用神经类固醇别孕酮作为一种药理作用来解决。 研究紧张性抑制对GC回路兴奋性和IB的影响的工具。为了评估神经 IB的机制，我将用组织学方法研究突触外GABAARs在GC中的表达模式 检测，量化突触外GABA受体对神经类固醇敏感性的可能差异，并使用选择性 操纵GABAARs亚单位的表达，以确定突触外抑制对IB的贡献。 我的初步数据显示，突触外GABA受体和紧张性电流在大鼠的神经元中大量表达。 GC，以及GC中输注神经类固醇后舔食行为的变化。 这项提议的发现将为神经网络生理学的差异提供重要的见解。 品味依赖的IB的潜在属性。更清楚地了解存在缺陷的潜在机制 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。 相关的神经精神障碍改善患者及其家人的生活。