A leptin-responsive lateral hypothalamus to ventrolateral periaqueductal gray circuit for palatable food overconsumption

项目总结/摘要 肥胖是一个全球性的公共卫生危机，在过去三年中， 几十年虽然许多因素影响体重，但过度食用可口的食物（例如， 高脂饮食（HFD）是导致肥胖的主要危险因素。值得注意的是，大多数获得 成功饮食并从这些食物中戒断显示出高的HFD过度消费复发率。鉴于 这一过程与人们对可口食物的偏好增加、对神经回路的理解 导致戒断后HFD过度消耗的机制可以说是治疗性糖尿病的核心问题。 肥胖症的长期治疗策略。然而，无论是特定的神经回路通路， 这一过程的分子机制已被充分理解。瘦素是一种脂肪组织产生的激素， 通过作用于下丘脑中的受体来发挥其抗抑郁作用。长瘦素受体（LepR）的激活 刺激多种信号传导途径，抑制食物摄入和体重增加。虽然减少了 下丘脑组织对瘦素的敏感性的特征在于LepR激活的能力受到干扰 下游效应或LepR表达受损，我们不了解有关原发性 大脑回路发展瘦素不敏感，这可能有助于HFD过度消费的复发。所以针对本 我们的目标是提出一个跨学科的方法来了解电路的具体作用瘦素 在戒断此类食物后，对HFD过度消费的敏感性。我们将主要关注 连接外侧下丘脑（LH）和中脑导水管周围灰质腹外侧的瘦素反应回路 （vlPAG），并在功能上探测其在HFD暴露后的神经适应。这项建议的中心目标是 目的是利用LepR LH神经元投射到vlPAG的神经功能障碍， HFD的间歇性访问时间表，以更好地了解HFD的神经机制 当食物变得更加突出时，过度消费。为了实现我们的目标，我们将首先描述 目标特异性LepR LH神经元在不同食物阶段的HFD消耗期间的体内活性。我们将 检查投射vlPAG的LepR LH神经元是否参与禁欲后HFD过度消耗 (Aim 1）。其次，使用分子分析方法，我们将研究HFD禁欲如何诱导回路- 与HFD过度消耗相关的LepR信号传导中的特异性神经适应（Aim 2）。三是 确定LepR敲低诱导的LepR LH神经元中的瘦素不敏感性如何调节HFD消耗 和体重之间的关系（目标3）。这项研究的意义是实质性的，因为它 代表了理解瘦素响应LH-vlPAG电路如何控制HFD的第一步 因禁欲而加剧的消费。这种贡献是创新的，因为它将首先提供 时间，一个研究瘦素敏感性在HFD过度消耗复发中的回路特异性作用的框架， 以及开发用于治疗进食障碍和肥胖症的病理症状的靶向疗法。

PROJECT SUMMARY/ABSTRACT Obesity is a global public health crisis, and its prevalence continued to increase dramatically during the last three decades. Although numerous factors influence on body weight, excessive consumption of palatable foods (e.g., high-fat diet, HFD) is a major risk factor leading to obesity. Notably, most of the individuals who achieved a successful diet with withdrawal from such foods show high rates of relapse to HFD overconsumption. Given that this process is highly associated with the increased preference for palatable foods, understanding neural circuit mechanisms leading to HFD overconsumption after abstinence is arguably the core issue in therapeutic strategies for the long-term treatment of obesity. However, neither the specific neural circuit pathway nor the molecular mechanisms underlying this process are well understood. Leptin, an adipose tissue-derived hormone, exerts its anorexic effects by acting on its receptors in the hypothalamus. Activation of long leptin receptor (LepR) stimulates multiple signal transduction pathways to suppress food intake and weight gain. While a decrease in hypothalamic tissue sensitivity to leptin is characterized by a disturbance in the ability of LepR to activate downstream effectors or impairment in LepR expression, we do not understand critical issues concerning primary brain circuit that develops leptin insensitivity which can subserve relapse to HFD overconsumption. Thus, in this proposal we aim to propose an interdisciplinary approach to understand the circuit-specific role of leptin sensitivity in driving HFD overconsumption following abstinence from such foods. We will primarily focus on the leptin-responsive circuit that connects the lateral hypothalamus (LH) to the ventrolateral periaqueductal gray (vlPAG) and functionally probe its neural adaptation after HFD exposure. The central objective of this proposal is to determine the neural dysfunction of LepR-expressing LH (LepR LH) neurons projecting to the vlPAG using the intermittent access schedule of HFD to better understand the neural mechanisms underlying HFD overconsumption when the food becomes more salient. To achieve our objective, we will first characterize in vivo activity of target-specific LepR LH neurons during HFD consumption at different food stages. We will examine whether the vlPAG-projecting LepR LH neurons are engaged in post-abstinence HFD overconsumption (Aim 1). Secondly, using molecular profiling methods, we will examine how HFD abstinence induces circuit- specific neural adaptation in the LepR signaling associated with HFD overconsumption (Aim 2). Third, we will determine how LepR knockdown-induced leptin insensitivity in the LepR LH neurons regulates HFD consumption and body weight with a circuit-specific manner (Aim 3). The significance of this study is substantial because it represents the first steps towards understanding how leptin-responsive LH-vlPAG circuitry controls HFD consumption that is exacerbated by abstinence. The contribution is innovative because it will provide, for the first time, a framework for studying the circuit-specific role of leptin sensitivity in relapse to HFD overconsumption, and in developing targeted therapies for the treatment of pathological symptoms in eating disorders and obesity.