Gustatory Afferent Organization in the Solitary Nucleus

描述（由申请人提供）：阿片肽，与m阿片受体（MORs）相互作用，影响食物摄入。对这些影响的一种解释是，它们影响了食物的适口性。前脑结构，特别是伏隔核和腹侧白质，构成了MORs对摄食影响的关键基础。然而，内啡肽也通过脑干回路影响进食，尽管这些影响的位点、效果和机制尚不清楚。一个候选的脑干区域包括孤立束吻侧核（rNST）中的味觉神经元和下网状结构（RF）中的运动回路，这是一个功能整合的区域，我们称之为“吻侧孤立复合体”（RSC）。先前的研究表明，在这附近注射MOR激动剂会增加食物摄入量，而拮抗剂则会产生相反的效果。然而，通过更精确的注射和行为测量的初步数据表明，将MOR激动剂注入RSC会产生多种影响，包括更能表明抑制摄食的即时效应。我们假设这些复杂的效应反映了这些配体在多相电路中多点的相互作用。本建议的目标是精确定义在rNST和下RF中操纵MORs的行为后果，并指定这些影响的位置和细胞基础。具体目的是：(1)通过小剂量（60nl）输注MOR激动剂（DAMGO）和拮抗剂（CTOP），并使用多种行为测量，包括味觉反应性和短期味觉偏好测试，分析操纵rNST和下皮层MORs的感觉和运动后果。(2)在体内制备中，确定局部注射DAMGO和CTOP对rNST和RF中单个味觉和口腔体感反应的影响；(3)在体外，对rNST和下皮层进行膜片夹记录，以表征通过传入和传出连通性识别的神经元的MOR调节的细胞基础。先前的工作，包括在上一个项目期间完成的研究，已经阐明了脑干味觉神经元的神经生理反应特性和连通性，但对中央味觉回路的神经递质功能知之甚少。拟议中的实验将开始填补这一空白。此外，这些研究将有助于理解进食的神经控制，这是一种深刻影响人类健康的行为。调节饮食的神经基质是复杂的，涉及多个区域和中枢神经系统水平之间的相互作用。味觉对这种行为有重要影响，而rNST是处理这些感觉信号的第一个中枢部位。底层射频包含运动电路，包括一个最终的共同通路，整合前脑和后脑信号，决定食物摄入是继续还是停止。本提案的目标是了解一类在进食中重要的神经调节剂，阿片配体，如何在这些关键节点上相互作用。

DESCRIPTION (provided by applicant): Opiate peptides, interacting with m opiate receptors (MORs), affect food intake. One explanation for the basis of these effects is that they influence food palatability. Forebrain structures, especially nucleus accumbens and the ventral pallidum, comprise a critical substrate for the effect of MORs on feeding. Nevertheless, endorphins also impact eating through brainstem circuits, although the loci, effects, and mechanisms of these influences are less clear. One candidate brainstem region includes taste neurons in the rostral nucleus of the solitary tract (rNST) and oromotor circuitry in subjacent reticular formation (RF), a functionally-integrated region that we call the "rostral solitary complex" (RSC). Previous studies suggest that injecting MOR agonists into this vicinity increases food intake whereas antagonists have the opposite effect. Preliminary data with more precise injections and behavioral measures, however, instead suggest that MOR agonist infusions into the RSC exert multiple influences, including immediate effects more indicative of a suppression of feeding. We hypothesize that these complex effects reflect the interaction of these ligands at multiple points in this heterogeneous circuitry. The goal of the present proposal is to precisely define the behavioral consequences of manipulating MORs in the rNST and subjacent RF and to specify the sites and cellular basis of these effects. The Specific Aims are to: (1) Analyze the sensory and motor consequences of manipulating MORs in the rNST and subjacent RF by making small (60nl) infusions of MOR agonists (DAMGO) and antagonists (CTOP), and using multiple behavioral measures, including taste reactivity and short-term taste preference tests. (2) Establish the impact of local injections of DAMGO and CTOP on single-unit gustatory and oral somatosensory responses in the rNST and RF in an in vivo preparation, and (3) Perform in vitro, patch-clamp recordings from the rNST and subjacent RF to characterize the cellular basis of MOR modulation of neurons identified by their afferent and efferent connectivity. Previous work, including studies completed during the last project period, has clarified neurophysiological response properties and connectivity of brainstem taste neurons but knowledge about neurotransmitter function in central taste circuits is scarce. The proposed experiments will begin to fill this void. Moreover, these studies will contribute to understanding of the neural control of feeding, a behavior profoundly impacting human health. The neural substrate regulating eating is complex, involving interactions between multiple regions and levels of the central nervous system. Taste has a major influence on this behavior and the rNST is the 1st central site where these sensory signals are processed. The underlying RF contains motor circuitry comprising a final common pathway that integrates forebrain and hindbrain signals determining whether food intake continues or is aborted. The goal of this proposal is to understand how one class of neuromodulators important in feeding, m opiate ligands, interact at these critical nodes. PUBLIC HEALTH RELEVANCE: The rostral portion of the nucleus of the solitary tract is the initial termination site of all primary afferent fibers conveying gustatory information. Good nutrition is critical to health, and the sense of taste profoundly impacts the type and amount of food eaten. This project will focus on how one class of opiate peptides known to promote eating, influences this region of the brain.