负性情绪调控摄食行为的神经机制

Food intake is a kind of instinctive behavior essential to individual survival. Besides being regulated by visceral sensory signals, energy homeostasis, and motivational behaviors, feeding behavior is also influenced by emotions, especially negative emotions. However, the underlying mechanism is still unclear. Our preliminary data showed that cued fear could acutely inhibit feeding behavior in mice, and further results suggested that pontine central gray (PCG) may play a key role. But what is the neural mechanism by which PCG works? Can PCG integrate negative emotional and energy homeostasis signals to regulate feeding behavior? Is PCG function abnormal in anorexia nervosa models? To further answer these scientific problems, by employing multi-disciplinary approaches involved in light/chemical genetics, electrophysiology, behavior analysis, molecular genetics and transgenosis, we will study the key issues that negative emotion how to regulate feeding behavior at multiple levels, namely, neural circuit, cell type and molecular mechanism, and further analyze whether the abnormalities of these neural mechanisms contribute to the occurrence of related diseases such as anorexia nervosa. The results are expected to further reveal the neural regulation mechanism of feeding behavior and provide new ideas/potential drug targets for the treatment of anorexia nervosa.

摄食是一种对于个体生存至关重要的本能行为，除了受到内脏感受信号、能量内稳态、动机行为等调节外，还受到情绪特别是负性情绪的调节，然而，其调控机制仍不清楚。我们最近的预实验发现，恐惧情绪可抑制小鼠的摄食行为，并可能是通过脑桥中央灰质（pontine central gray，PCG）起作用。但是PCG发挥作用的神经机制是什么？PCG能否整合负性情绪和能量内稳态信号而调控摄食行为？在神经性厌食症模型，PCG功能是否发生异常？为了进一步回答这些科学问题，拟综合应用光/化学遗传学、电生理学、行为学、分子遗传学和转基因等多种方法，围绕负性情绪如何调节摄食行为这一核心科学问题，从神经环路的功能和可塑性机制、细胞类型、分子机制等多个层次展开研究，并分析这些神经机制的异常是否贡献于神经性厌食症等疾病发生，预期研究结果将进一步揭示摄食行为的情绪神经调控机制，并为神经性厌食症的治疗提供新思路和潜在药物靶标。

食物消耗，即进食，是维持人和动物生存所必需的行为。在自然界动物往往需克服一些危险因素所引起的负性情绪而顺利进食。临床上也存在进食相关的情绪调控，如神经性贪食症作为一种进食障碍，也被认为是与负性情绪密切相关的精神疾病。部分研究提示，负性情绪处理失衡在贪食症发作中起重要作用。患者往往在负性情绪下产生暴食行为，并通过食物消耗缓解负性情绪或转移注意力。因此，我们探索了伴随着食物消耗的情绪调控机制。我们首先发现，食物消耗可下调恐惧情绪表达。c-fos染色结果提示，外侧下丘脑（lateral hypothalamus，LH）和脑干不定核（nucleus incertus，NI）在其中可能发挥关键作用。已有文献报道，外侧下丘脑GABA能神经元参与了食物消耗及奖赏行为。利用光纤记录技术，我们发现，动物食物消耗期间给予恐惧刺激或在恐惧状态下开始摄食，LH GAD2神经元活性都有显著增加。进一步的环路示踪和mRNA原位杂交实验，我们发现LH GAD2神经元投射到NI RLN3神经元。光遗传激活这条环路可促进食物消耗，降低恐惧情绪；相反地，光遗传抑制这条环路可抑制食物消耗，增加恐惧情绪。光纤记录实验进一步发现，动物食物消耗期间给与恐惧刺激，NI RLN3神经元活性显著增加；且其活性增加依赖于LH神经输入。研究进食调控负性情绪的机制，不仅对于理解进食和情绪之间的神经环路和分子机制非常重要，更为理解神经性贪食症的发病机制，提供新的治疗靶点和思路具有重要意义。