经由小鼠中缝背核表达BDNF促进情绪和代谢调控的研究

Mood disorders and metabolic diseases have significant comorbidities; furthermore, they can enhance the risk of the other ones. Both brain derived neurotrophic factor (BDNF) and serotonin (5-HT) can regulate moods in the limbic system and metabolism in the hypothalamus. After expressing BDNF in dorsal raphe, the biggest nucleus of the central 5-HT system, preliminary data from our group found that mice showed significant anti-depressant and anxiolytic behaviors in chronic unpredictable mild stress model of depression. The manipulation also remarkably ameliorated obesity and hyperglycemia in high-fat diet induced obesity (DIO) and leptin receptor-deficient (db/db) mice. To further test the hypothesis that BDNF overexpressed in dorsal raphe improves moods and metabolism, the moods-regulating role of BDNF will be confirmed in social defeat stress model, and the concurrent modulation of moods and metabolism by BDNF will be investigated in streptozotocin-induced depression and diabetes comorbid mice. More work will employ tool mice related to central 5-HT functions and TrkB.T1 that can block the BDNF signaling pathway as a dominant-negative receptor, to dissect the neural mechanisms underlying the above mentioned phenotypes. To corroborate our findings, chemogenetic approach by hM3Dq will be used. Our research surmounts the “hypothalamocentric” paradigm dominating in metabolism research by connecting moods and metabolism via dorsal raphe.

情感障碍性和代谢性疾病常合并发生，且增加彼此的发病风险。脑源性神经营养因子BDNF和五羟色胺（5-HT）均能在边缘系统调控情绪，在下丘脑调控代谢。本组前期工作在中枢5-HT系统最大核团中缝背核表达BDNF，发现慢性不可预知应激模型中小鼠产生明显的抗抑郁和抗焦虑表型；高脂摄食诱导的肥胖模型（DIO）和瘦素受体突变（db/db）小鼠中产生明显的抗肥胖和降血糖表型。为进一步验证中缝背核表达BDNF同时促进情绪和代谢调控的假说，本申请将在社交挫败应激模型中确证BDNF促进情绪调控的作用；在链脲佐菌素诱导的抑郁症和糖尿病共病模型中研究BDNF同时促进情绪和代谢调控的作用；利用中枢5-HT系统工具鼠和阻断BDNF信号通路的受体TrkB.T1解析上述表型的神经基础；最后利用化学遗传学（hM3Dq）方法辅证BDNF的作用。本课题突破了以下丘脑为中心的代谢研究范式，通过中缝背核将情绪和代谢调控研究联系起来。

情感障碍如抑郁症和代谢性疾病如肥胖症和糖尿病常合并发生，且每种疾病增加另一种的发病风险，持续抗抑郁药物作用增加二型糖尿病的患病风险和变胖，另一方面，减肥药物也可导致不同的精神副反应。因此，研发针对情感障碍疾病和代谢性疾病研发安全有效的疗法且具有最小副作用在目前是迫切需要的。脑源性神经营养因子BDNF和五羟色胺在边缘系统调控情绪，在下丘脑调控代谢。中脑区的中缝背核拥有脑内合成五羟色胺最多的神经元，其所包含的五羟色胺和非五羟色胺神经元向前脑包括边缘系统和下丘脑有广泛投射。本项研究旨在探讨BDNF在中缝背核过表达后是否对情绪和代谢具有促进作用。结果显示，中缝背核过表达BDNF具有抗抑郁和抗焦虑的作用。同时，中缝背核过表达BDNF可以显著缓解高脂摄食诱导的或者瘦素受体缺失的肥胖和糖尿病小鼠的肥胖和高血糖表型，表现为体重减轻，摄食降低，能量消耗增加，糖耐量和胰岛素耐受获得改善。中缝背核参与五羟色胺合成和转运的tph2和vmat2的表达显著升高。同时，参与代谢调控的多个基因在下丘脑，脂肪组织和肝脏也发生改变。然而，条件性敲除tph2并不影响BDNF调控代谢的作用，化学遗传学活化中缝背核神经元同样可以促进代谢调控。中缝背核表达BDNF可以促进情绪和代谢调控，本项研究突破了以往以下丘脑为中心的代谢研究，通过中缝背核将代谢和情感调控联系起来。.第二部分工作：海马区过表达BDNF可以减少一型糖尿病小鼠海马区的神经炎症反应，而且提示HMGB1/RAGE/NF-kB信号通路可能参与了BDNF的作用。