焦慮與抑郁的神經環路和分子機制羅敏敏張二荃占成

北京生命科學研究所

摘要：焦慮和抑郁癥是人群中最常見的情緒情感障礙，而情緒和情感的神經機制是公認的重大科學問題之一。本研究利用小鼠作為模式動物，研究焦慮和抑郁癥的神經環路和分子機理這個關鍵科學問題，通過多學科交叉，分為三個研究展開，試圖從分子到個體多層次研究焦慮和抑郁癥行為的神經生物學機制。 本研究第一個子研究是動物焦慮和抑郁行為的細胞生理學研究。五羥色胺（5-HT）系統紊亂會導致焦慮、快感缺失和抑郁，而且5-HT轉運體是現有的治療抑郁得主要靶點，因此在第一個子研究中，研究組成員研究了激活腦內5-HT主要來源的背側中縫核（DRN）5-HT細胞的行為效果。通過運用光遺傳學、清醒動物單細胞記錄、藥理學、轉基因小鼠遺傳操作、以及多種行為學分析，發現激活DRN的5-HT細胞產生強烈的獎賞效應，而且此一效應通過5-HT以及谷氨酸這兩種神經遞質來完成。這些結果證明中縫背核直接介導獎賞效應，而且為從多神經遞質的角度分析中縫背核的功能提供了良好的開端；為快感缺失及其相關的抑郁、精神分裂等情緒紊亂和精神疾病癥候群的機理和治療揭示了新的途徑。 本研究第二個子研究主要研究生物節律對人類情緒等行為的影響。生物節律包括近日節律（晝夜）、近月節律（潮汐）、近年節律（季節）等等周期在生物體內的表征。我們重點研究對象是近日周期、近年周期，與人類情緒調控的互作。本年度報告中，我們主要在三個方面有明顯進展：1. 近年節律對情緒調控的影響方面，我們發現小鼠C3H品系對于模擬人類季節性抑郁癥方面有較好的吻合；2. 近日節律對情緒調控的影響方面，我們發現VTA腦區的生物鐘基因Bmal1和Clock都有很重要的作用；3. 藥物治療方面，我們運用高通量方面對約9000個化合物進行了篩選，找到了一批生物鐘調節相關的化合先導物，可能為通過對生物鐘進行調節進而緩解人類情緒疾病提供一種嶄新的嘗試。 本研究的第三個子研究開展與動物焦慮和抑郁行為相關的神經環路的影像學研究。初步完成了焦慮和抑郁神經環路的影像學研究方法和平臺的建立，有效開展了去甲腎上腺素（NE）和腎上腺素（E）神經細胞的全腦連接和投射研究以及光功能成像研究，完成了大腦阿片-促黑素細胞皮質素原（POMC）神經細胞的功能研究。 以上研究在過去的一年中，圓滿完成了本研究的年度計劃，且為下一年度有效開焦慮和抑郁癥的神經生物學研究打下了堅實的基礎。

關鍵詞：焦慮， 抑郁， 神經環路， 分子機制，光學成像， 電生理，鈣成像，晝夜節律

Neural circuits and molecular mechanisms underlying anxiety and depression

Abstract：Anxiety and depression are common human emotion and mood disorders， and their underlying neural mechanisms remain largely unknown. In this project， we plan to use mouse as the model system to study the neural circuits and molecular mechanisms of anxiety and depression， at the levels ranging from molecules to animal behaviors. The first team carries out the cellular physiological studies of animal anxiety and depression. The malfunctions of the serotonin （5-HT） system are related to anxiety， anhedonia， and depression. We examined the behavioral effects of activating 5-HT neurons in the dorsal raphe nucleus （DRN）， the major source of 5-HT in the forebrain. By combining optogenetics， single-unit recordings， pharmacology， mouse genetic， and behavioral assays， we find that the activation of DRN 5-HT neurons produces strong reward signals that are mediated through the release of 5-HT and glutamate. Our results demonstrate that the DRN directly mediates reward， provides new insights into the intervention of depression and schizophrenia， which often manifest as the disorders of emotion and mood. The second team mainly focus on the interactions between circadian/circannual rhythms and the mood regulation. Here we present some substantial progresses on three aspects. First， we discovered that the C3H mouse strain is particularly suitable for studying seasonal affective disorders （SAD）， highlighting the light-entrainment， or seasonal-mimicking， in mood regulation. Second， we found that the deletion of Bmal1 or Clock gene in the brain VTA area developed a counter-depression effect in mice， suggesting the engagement of the circadian clock in mood regulation. Finally， we have developed a cell-based high-throughput screen assay to identify clock modifier drugs， which are potentially useful to cure or relieve the mood disorders such as depression in humans. The third team is tasked to perform optical imaging studies of the neural circuits. We have established the optical methods and platforms to study the neural circuits underlying anxiety and depression， carried out the preliminary experiments of studying the whole-brain projection patterns as well as calcium imaging of NE/E neurons in the brain. In addition， we have completed the study of the behavioral functions of POMC neurons in the adult brain. In summary， we are smoothly on the track of our research schedules， and are well-positioned to make more exciting findings in the future years.

Keywords：Anxiety， Depression， Neural Circuit， Molecular mechanisms， Optical imaging， Electrophysiology， Calcium imaging， Circadian Rhythm

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