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 在大多数人中，冲动性（通常被定义为无思考的行为）是一种先前存在的人格特征。 可能是有利的；但是，超过它会成为适应不良的。病理冲动行为（IB）是 饮食失调及其发病机理的病因的基本因素之一。饮食对于 生存，但是不良适应的食物摄入量可以改变食物和食物相关的提示的奖励价值。 暴饮暴食是喂养行为的功能失调模式，通常包括食用可口的食物 富含甜食和脂肪。 研究表明，在暴饮暴食障碍中可能会改变岛状皮质（IC）电路。 IC具有 与冲动行动有关，并被归类为脉冲发展的神经生物学门 相关疾病。前IC（也称为味皮层（GC））也参与了处理 品味，对奖励的期望以及有关食品消费的决策。这个证据表明 GC是一个理想的区域电路，用于研究可能构成冲动控制中缺陷的机制， 特别是与食物摄入有关。 该提案的目的是检验以下假设，即改变了补品GABA能抑制的水平，这是 有助于调节神经回路的兴奋性，在介导味道依赖性冲动中起着核心作用 选择。该假设将通过使用神经固醇丙酮酮作为药物来解决 研究补品抑制在GC电路刺激和IB上的作用的工具。评估中立 IB的机制，我将使用组织学检查GC在GC中的表达模式 测定，量化外部刺激性GABAARS对神经类固醇的敏感性的可能差异，并使用选择性 GABAARS亚基表达的操纵以确定外部抑制对IB的贡献。 我的初步数据表明，在 GC，以及神经类固醇输注GC中舔行为的变化。 该提案的发现将为神经网络生理的差异提供重要的见解 依赖味道IB的属性。对基本机制定义的机制有更清晰的理解 抑制性控制将为诊断，治疗和预防冲动 - 相关的神经精神疾病改善了患者及其家人的生活。