NEUROANATOMIC MECHANIMS OF LEPTIN ACTION

加深了对精神分裂症的基本生理学和神经生物学的了解 能量代谢和动态平衡是预防肥胖的关键 以及进食障碍，如神经性厌食症。最近的研究表明 白色脂肪组织产生的瘦素在调节中起着关键作用。 能量平衡和神经内分泌功能。现在很明显， 中枢神经系统(CNS)，特别是下丘脑，与 参与对循环瘦素的反应，但特异性 这些反应背后的神经解剖学特征仍然很差。在……里面 这个提议，我们提供了一个独特的瘦素作用的神经解剖学模型 并描述了设计用来描述 下丘脑背内侧核(DMH)在下丘脑 对循环瘦素的生理反应。我们假设DMH 是产生瘦素的神经解剖途径的关键组成部分 反应，因为DMH含有瘦素受体，是由 静脉注射瘦素，并投射到下丘脑室旁 细胞核(PVH)。PVH的理想定位是受监管的多方面 对瘦素的反应和改变能量供应，因为它 拥有化学和解剖学上特定的自主神经投射 以及参与维持内环境平衡的内分泌控制部位。这 提案描述了旨在进行解剖和生理实验的 严格测试我们模型的特定组件。首先，我们将确定 饮食和禁食中瘦素激活神经元的化学表型 老鼠。这将使用FOS的免疫组织化学来完成 蛋白质，免疫组织化学或原位杂交检测神经元 表型标记。第二，使用逆行追踪技术， Fos蛋白的免疫组织化学，免疫组织化学或在 对于神经表型标记的原位杂交，我们将确定 支配下丘脑室旁核的瘦素激活神经元的化学表型。 第三，使用顺行示踪剂注入DMH，逆行示踪剂 延髓和脊髓内注射，免疫组织化学检测 FOS和神经元标志物，我们将确定DMH是否传出 支配瘦素激活的PVH神经元向自主神经投射 节前神经元。第四，使用一种新的实验制剂 这使我们能够评估生理反应和Fos分布 在下丘脑微量注射后，我们将直接 向DMH、下丘脑腹内侧核和 下丘脑弓状核(含瘦素的区域 受体和投射到下丘脑室旁核)。这些实验将决定 下丘脑不同部位瘦素受体的激活 会产生不同的生理反应。

An increased understanding of the basic physiology and neurobiology of energy metabolism and homeostasis is critical in the prevention of obesity and eating disorders such as anorexia nervosa. Recent studies indicate that leptin, produced by white adipose tissue, is critical in regulation of energy balance and neuroendocrine function. It is now clear that the central nervous system (CNS), particularly the hypothalamus, is intimately involved in responding to circulating leptin, but the specific neuroanatomy underlying these responses remain poorly characterized. In this proposal, we offer a unique neuroanatomical model of leptin action and describe experiments designed to characterize the role of the dorsomedial hypothalamic nucleus (DMH) in the production of the physiological responses to circulating leptin. We hypothesize that the DMH is a key component of a neuroanatomic pathway which produces leptin responses as the DMH contains leptin receptors, is activated by intravenous leptin, and projects to the paraventricular hypothalamic nucleus (PVH). The PVH is ideally positioned to regulated multiple aspects of responses to leptin and changing energy availability because it possesses chemically and anatomically specific projections to autonomic and endocrine control sites involved in maintenance of homeostasis. This proposal describes anatomic and physiologic experiments designed to critically test specific component of our model. First, we will determine the chemical phenotype of leptin-activated neurons in both fed and fasted rats. This will be accomplished using immunohistochemistry for the FOS protein, and immunohistochemistry or in situ hybridization for neuronal phenotypic markers. Second, using retrograde tracing techniques, immunohistochemistry for the Fos protein, and immunohistochemistry or in situ hybridization for neural phenotypic markers, we will determine the chemical phenotypes of leptin-activated neurons that innervate the PVH. Third, using anterograde tracer injections into the DMH, retrograde tracer injections into the medulla and spinal cord, and immunohistochemistry for Fos and neuronal markers, we will determine whether DMH efferents innervate leptin-activate PVH neurons that project to autonomic preganglionic neurons. Fourth, using a novel experimental preparation which allows us to assess physiological responses and Fos distributions following microinjections into the hypothalamus, we will directly microinject leptin into the DMH, ventromedial hypothalamic nucleus, and arcuate nucleus of the hypothalamus (regions which contain leptin receptors and project to the PVH). These experiments will determine whether activation of leptin receptors in different hypothalamic sites produces distinct physiological responses.