丘脑室旁核兴奋性神经元驱动强迫进食行为的机制研究

Since the last two decades, overweight/obesity has become a serious public health problem in China. The availability of high-calorie food is a major factor contributing to this obesity epidemic. In this field, the mechanisms relating to the disturbed homeostatic regulation of food intake have been well understood. However, the mechanisms underlying increased motivation to consume food, particularly the compulsive eating behavior, are still unclear.We have shown that 1-week high-fat diet consumption is sufficient to induce compulsive eating behavior in mice, suggesting that compulsive eating may contribute to high-fat diet-induced obesity. Importantly, high-fat diet-induced compulsive eating caused a high level of c-Fos activation in the paraventricular nucleus of the thalamus (PVT) in mice. In this project, we will use a combination of behavioral, electrophysiology, immunohistochemistry, and optogenetics/pharmacogenetics methods, to explore the central role of PVT, along with its inputs and outputs, in high-fat diet-induced compulsive eating, to provide a new insight into the pathogenesis of obesity.

近年来，由于无节制摄入高热量饮食，超重/肥胖已成为我国非常严重的公共卫生问题。本领域的相关工作多集中于对能量代谢和进食行为的内稳调控机制进行研究，而对食物奖赏的过度寻求以及由此而来的强迫进食等摄食障碍则关注较少。强迫进食很有可能与目前高热量的膳食结构相关：高热量食物可能通过影响中枢奖赏系统诱发强迫进食，但涉及的脑区和具体机制我们知之甚少。我们的预实验发现，高脂食物喂养一周就足以诱发小鼠的强迫进食行为，提示强迫性进食可能是高脂食物诱发肥胖的行为机制之一。我们的c-Fos染色结果表明，强迫进食小鼠的丘脑室旁核（PVT）被过度激活，提示高脂食物诱发的强迫进食与PVT的活动密切相关。我们将以高脂食物诱发的强迫进食小鼠为模型，采用行为学、电生理、免疫组化及光遗传学/药理遗传学等实验技术，研究PVT及其相关核团-主要是下丘脑腹内侧核-在强迫进食中的作用，为肥胖的防治提供新的、基于中枢的理论和应用依据。

高热量食物可能通过影响中枢奖赏系统诱发强迫进食，但涉及的脑区和具体机制我们知之甚少。本研究中，我们发现高脂食物喂养（HFD）一周就足以诱发小鼠的强迫进食行为，提示强迫性进食可能是高脂食物诱发肥胖的行为机制之一。我们的c-Fos染色结果表明，强迫进食小鼠的丘脑室旁核（PVT）被过度激活，提示高脂食物诱发的强迫进食与PVT的活动密切相关。我们以高脂食物诱发的强迫进食小鼠为模型，通过行为学、电生理、免疫组化及光遗传学/药理遗传学等实验技术，发现激活PVT兴奋性神经元可诱导小鼠强迫性进食行为，功能上论证了PVT参与强迫进食行为的可能性。病毒追踪实验发现，腹内侧下丘脑（VMH）是PVT的一个下游脑区，后续实验发现激活PVT- VMH环路可诱发正常喂养小鼠强迫进食行为，而不影响其条件性奖赏获取，提示PVT-VMH环路激活会引起强迫性进食行为。另外，Iba-1染色结果表明，HFD引起PVT脑区小胶质细胞数量增加。抑制小胶质细胞的增生则可以逆转强迫性进食行为，而侧脑室注射十六碳棕榈酸诱导小胶质细胞增生可诱发一定程度的强迫性进食。综上所述，我们研究表明，HFD引起的中枢炎症反应导致了PVT-VMH神经环路异常，最终导致强迫性进食。这一发现阐释了食源性肥胖的一种神经环路机制；为进食障碍的防治提供新的、基于中枢的理论和应用依据。