Peptidergic modulation of thermoregulation and energy expenditure

温度调节和能量消耗的肽能调节

• 批准号: 9010800
• 负责人: Iustin Virgil Tabarean
• 金额: $ 41.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010800
• 关键词: Address; Anterior Hypothalamus; Arginine; Arousal; Biological Neural Networks; Body Temperature; Brain; Brain Stem; Brain region; Cell Nucleus; Cells; Characteristics; Data; Electrophysiology (science); Energy Metabolism; Future; Glutamates; Goals; Homeostasis; Hyperthermia; Image; Infusion procedures; Injection of therapeutic agent; Ions; Knowledge; Label; Ligands; Light; Maintenance; Mammals; Medial; Mediating; Motor Activity; Mus; Neurons; Neuropeptide Receptor; Neuropeptides; Neurotensin; Obesity; Organism; Output; Pathway interactions; Pattern; Peptides; Physiologic Thermoregulation; Physiology; Play; Preoptic Areas; Process; Property; Reporting; Research; Role; Signal Pathway; Signal Transduction; Site; Slice; Synapses; Telemetry; Testing; Therapeutic; Thermogenesis; Transgenic Model; Transgenic Organisms; Visceral; diencephalon; in vivo; induced hypothermia; medial preoptic nucleus; natural hypothermia; neuroregulation; optogenetics; public health relevance; receptor; research study; response; tool; zona incerta

 DESCRIPTION (provided by applicant): Zona incerta (ZI) of the diencephalon has extensive connections with other brain regions and has been involved in several functions such as controlling visceral activity, thermoregulation, arousal and locomotor activity. In spite of its important functions it is one of the most understudied regions of the brain and no studies of the cellular and synaptic electrophysiological properties of ZI neurons have been reported so far. Maintenance of body temperature is central to energy homeostasis in mammals because it represents a major part of the energy expenditure of the organism. It is controlled by neurons of the preoptic area/ anterior hypothalamus (PO/AH) that project directly or indirectly to the rostral raphe pallidus. Anatomical and functional evidence clearly indicate a projection from the preoptic area, the thermoregulatory center, to ZI neurons. Combined retrograde labeling/immunostaining experiments have revealed that preoptic neurons projecting to ZI are peptidergic. ZI neurons project to the raphe pallidus and thus they can represent a relay of the preoptic thermogenic output to the brainstem neurons controlling thermoeffector processes. Our overarching hypothesis is that ZI GABAergic neurons mediate the peptidergic modulation of thermoregulation by PO/AH neurons. Preliminary data indicate that ZI neurons express receptors for these neuropeptides. We have also found that thermoregulatory neuropeptides excite ZI GABAergic neurons by activating inward currents and that they increase intracellular Ca concentrations. Our preliminary data also show that preoptic neurons projecting to ZI GABAergic neurons are peptidergic. Using transgenic models and telemetry we plan to study the role of ZI neurons in mediating the modulation of thermoregulation by neuropeptides (Sp Aim 1). We plan to identify thermoregulatory ZI neurons in slices and study their firing and synaptic characteristics as well as their modulation by neuropeptides involved in thermoregulation, followed by single cell RT/PCR analysis to determine the expression patterns for these receptors (Sp. Aim 2). By employing pharmacological tools, Ca imaging, electrophysiology and transgenic models we will then study the signaling pathways and the ion conductances involved in the neuropeptides' actions on ZI neurons (Sp. Aim 3). In summary in this study we will address fundamental and unexplored aspects of neural control of thermoregulation.

 描述（由申请人提供）：间脑的未定带（ZI）与其他脑区域有广泛的联系，并参与多种功能，如控制内脏活动、体温调节、唤醒和运动活动。尽管它的重要功能，它是大脑的最欠研究的区域之一，没有研究的细胞和突触的电生理特性的ZI神经元已报道到目前为止。维持体温是哺乳动物体内能量平衡的核心，因为它代表了生物体能量消耗的主要部分。它是由视前区/下丘脑前部（PO/AH）的神经元直接或间接投射到吻侧核控制的。 苍白缝解剖和功能的证据清楚地表明，从视前区，温度调节中心，ZI神经元的投影。结合逆行标记/免疫染色实验表明，投射到ZI的视前神经元是肽能的。ZI神经元投射到苍白中缝，因此它们可以代表视前产热输出到控制热效应过程的脑干神经元的中继。我们的总体假设是ZI GABA能神经元介导PO/AH神经元对体温调节的肽能调节。初步数据表明，ZI神经元表达这些神经肽的受体。我们还发现，温度调节神经肽通过激活内向电流来兴奋ZI GABA能神经元，并且它们增加细胞内Ca浓度。我们的初步数据还表明，投射到ZI GABA能神经元的视前神经元是肽能的。使用转基因模型和遥测技术，我们计划研究ZI神经元在介导神经肽（Sp Aim 1）调节体温调节中的作用。我们计划确定热调节ZI神经元切片和研究其发射和突触特性，以及它们的调制参与温度调节的神经肽，然后通过单细胞RT/PCR分析，以确定这些受体的表达模式（SP。目的2）。通过使用药理学工具、Ca成像、电生理学和转基因模型，我们将研究神经肽对ZI神经元的作用所涉及的信号传导途径和离子电导（Sp. Aim 3）。总之，在这项研究中，我们将解决基本的和未探索的方面的神经控制的体温调节。