Role of Parabrachial Nucleus Benzodiazepines in Gustatory Coding and Behavior

描述(申请人提供)：肥胖仍然是一个主要的健康问题，影响越来越多的美国人。肥胖症药物治疗的进展将取决于对食物适口性和消费行为的神经控制和调节的更好理解。最近的研究发现，神经肽Y和AGRP从下丘脑到臂旁核(PBN)的投射是影响摄食行为的重要调节因素。这些纤维共表达GABA，并在这些纤维中敲除GABA，从而显著减少摄食和体重。先前的研究表明，苯二氮类药物(BZD；GABAA受体激动剂)通过增加适口性而有效地增加消费量，其作用的一个关键部位可能是PBN。这项提议将阐明BZD在PBN味觉功能中的作用。我们将表征BZD诱导的PBN神经味觉编码的变化，并确定这些变化与BZD诱导的味觉评估行为指标的变化如何对应。具体地说，这项提议将采用双管齐下的方法，使用参数匹配的行为和电生理实验。这些行为实验将表征注入BZD的PBN对所有质量类别的不同味觉强度的短期和长期消耗性行为反应的剂量依赖效应。我们将评估PBN内注射的BZD受体拮抗剂是否阻止了对全身BZD治疗的适口性反应，以确定PBN是否对于BZD诱导的品尝者消费模式的变化是必要的。电生理学实验将表征直接在核内神经元上微量应用BZDS前后PBN神经元的味觉反应。基于初步数据，我们假设BZD改变了PBN内的味觉神经编码，使得甜味反应增加，对酸和苦刺激的反应减少，从而产生更窄的调谐宽度。我们的初步行为数据预测，味觉刺激消费的变化与味觉神经信号的变化一致，因此对正常接受的味道(如糖果)和通常避免的味道(如酸和苦)的舔将增加。拟议的研究应该有助于澄清PBN GABA处理对味觉引导行为的调制的相对贡献，该行为可能介导来自前脑结构(如下丘脑)的摄取调制信号。 与公共健康相关：肥胖是一个主要的国民健康问题，在很大程度上是由于过度消费高口感、高能量的食物。控制肥胖的药物治疗的发展依赖于对调节我们所消费食物的适口性的神经系统的了解。这项提议将确定大脑中特定的神经化学机制，这些机制涉及味觉对食物消费的影响。

DESCRIPTION (provided by applicant): Obesity continues to be a major health concern affecting increasing numbers of Americans. Advances in the pharmacological treatment of obesity will dependent on a better understanding of the neural control and regulation of food palatability and consummatory behavior. Recent research has identified neuropeptide-Y and AGRP projections from the hypothalamus to the parabrachial nucleus (PBN) as important regulators of feeding behavior. These fibers coexpress GABA and knockout of GABA in these fibers profoundly reduces feeding and body weight. Prior studies showed that benzodiazepines (BZDs; GABAA receptor agonists) potently increase consumption by enhancing palatability, and a key site of their action may be the PBN. This proposal will clarify the role of BZDs in PBN gustatory functions. We will characterize BZD- induced changes in PBN neural gustatory coding and identify how these changes correspond with BZD-induced changes in behavioral measures of taste evaluation. Specifically, this proposal will employ a dual-pronged approach using parametrically matched behavioral and electrophysiological experiments. The behavioral experiments will characterize the dose- dependent effects of PBN infusions of BZDs on brief-access and long-term consummatory behavioral responses to varied intensities of tastants across all quality categories. We will evaluate whether an intraPBN injected BZD receptor antagonist blocks palatability responses to systemic BZD treatment to determine if the PBN is necessary for BZD-induced changes in consummatory patterns for tastants. The electrophysiological experiments will characterize the gustatory responses of PBN neurons prior to and after microapplication of BZDs directly on neurons within the nucleus. Based on preliminary data, we hypothesize that BZDs alter the gustatory neural coding within the PBN such that sweet responses increase and responses to sour and bitter stimuli are reduced, producing a narrowed tuning breadth. Our preliminary behavioral data predict changes in consumption of taste stimuli consistent with the changes in gustatory neural signaling such that licking to normally accepted tastants, such as sweets, and to normally avoided tastants, such as sour and bitter will be increased. The proposed studies should help to clarify the relative contributions of PBN GABA processing to the modulation of taste-guided behavior that possibly mediates intake modulatory signals from forebrain structures such as the hypothalamus. PUBLIC HEALTH RELEVANCE: Obesity, a primary national health concern, is due in large part to the overconsumption of highly palatable, energy dense foods. Development of pharmacological treatments to control obesity is dependent on understanding the neural systems that regulate the palatability of foods we consume. This proposal will identify specific neurochemical mechanisms in the brain involved in taste-mediated influences on food consumption.