Peptidergic modulation of thermoregulation and energy expenditure

 描述(申请人提供)：间脑的精确带(ZI)与其他脑区有广泛的联系，并参与控制内脏活动、体温调节、唤醒和运动活动等功能。尽管ZI具有重要的功能，但它是脑内研究最少的区域之一，迄今还没有关于ZI神经元的细胞和突触电生理特性的研究报道。维持体温是哺乳动物能量平衡的核心，因为体温是生物体能量消耗的主要部分。它由直接或间接投射到吻部的视前区/下丘脑前部(PO/AH)神经元控制。 中缝苍白球。解剖和功能证据清楚地表明，视前区是体温调节中心，投射到ZI神经元。联合逆行标记/免疫染色实验表明，投射到ZI的视前神经元是多肽能神经元。ZI神经元投射到中缝苍白带，因此它们可以代表视前生热输出到控制温度效应过程的脑干神经元的中继站。我们的主要假设是Zi GABA能神经元介导PO/AH神经元对体温调节的多肽能调制。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，并增加细胞内钙浓度。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神经元。利用转基因模型和遥测技术，我们计划研究ZI神经元在神经肽(Sp目标1)调节体温调节中的作用。我们计划在脑片上鉴定温度调节ZI神经元，并研究它们的放电和突触特征以及参与温度调节的神经肽对它们的调节作用，然后进行单细胞RT/PCR分析，以确定这些受体(Sp。目标2)。通过使用药理学工具、钙成像、电生理学和转基因模型，我们将研究神经肽对ZI神经元(Sp.目标3)。总之，在这项研究中，我们将讨论体温调节的神经控制的基本和未被探索的方面。

 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.