嗅球-嗅结节-杏仁核通路调控抑郁性睡眠障碍的作用及机制

Depression is a serious medical and social problem. Many patients with depression also suffer from rapid eye movement (REM) sleep disturbances. However the neural circuits and molecular mechanism for the interaction of REM sleep disturbances in depression remain unknown. We found that olfactory bulb (OB) is involved in the regulation of REM sleep disturbances in depression, inhibition the adenosine A2A receptors (A2ARs) in OB could lead to depressive behaviors and increased REM sleep, whereas activation of A2ARs decreased REM sleep. The A2AR-positive neurons in OB project to olfactory tubercle (OT), and OT also innervate amygdala which is one of the most important nucleis in the regulation of REM sleep and depression. Thus we hypothesized that A2AR neurons in the OB send fibers to the OT, and then OT projects to amygdala for regulating REM sleep disturbances in depression. This proposed study will use state-of-art sleep bioassay systems, Cre animals, specific nerve tracing technology, optogenetics and pharmacogenetics (designer receptors exclusively activated by designer drugs, DREADD), electrophysiology, spike recording and neurochemical technology to clarify the interactions of OB-OT-amygdala neural circuits in the regulation of REM sleep disturbances in depression, and try to manipulate the activity of these circuits to improve the REM sleep disturbances in depression. The expected findings will provide theoretical basis for its treatment and new therapeutic targets for REM sleep disturbances in depression.

抑郁症是严重的医学及社会问题。抑郁症伴发REM睡眠障碍，因机制未明，临床缺乏有效对策。我们发现抑制嗅球中的腺苷A2A受体导致抑郁行为及REM睡眠增高，反之，则降低。预实验提示嗅球中腺苷A2A受体阳性神经元投射至嗅结节，嗅结节与调控抑郁及REM睡眠的关键核团杏仁核存在神经支配。我们假说：嗅球-嗅结节-杏仁核神经环路，调节抑郁性REM睡眠障碍。本课题将利用睡眠和抑郁解析平台、Cre动物、特异性神经追踪技术、光遗传工学和DREADD特异性控制神经元活性法、电生理和Spike记录、神经化学等手段，阐明嗅球-嗅结节-杏仁核神经环路在抑郁性REM睡眠障碍中的作用和神经生物学机制，探索干预此环路对改善抑郁性REM睡眠障碍的作用。预期结果将为发现干预抑郁性REM睡眠障碍的有效方法和治疗新靶点提供理论依据。

抑郁症是严重的医学及社会问题。抑郁症伴发快眼动（Rapid eye movement，REM）睡眠障碍，因机制未明，临床缺乏有效对策。我们发现抑制嗅球中的腺苷A2A受体导致抑郁行为及REM睡眠增高，反之，则降低。预实验提示嗅球中腺苷A2A受体阳性神经元投射至嗅结节，嗅结节与调控抑郁及REM睡眠的关键核团杏仁核存在神经支配。我们假说：嗅球-嗅结节-杏仁核神经环路，调节抑郁性REM睡眠障碍。本课题将利用睡眠和抑郁解析平台、Cre动物、特异性神经追踪技术、光遗传工学和DREADD特异性控制神经元活性法、电生理和Spike记录、神经化学等手段，阐明嗅球-嗅结节-杏仁核神经环路在抑郁性REM睡眠障碍中的作用和神经生物学机制，探索干预此环路对改善抑郁性REM睡眠障碍的作用。预期结果将为发现干预抑郁性REM睡眠障碍的有效方法和治疗新靶点提供理论依据。研究结果显示：抑制嗅球局部的腺苷A2A受体增加REM睡眠，而激动嗅球局部的腺苷A2A受体降低REM睡眠；同时投射结果显示，嗅球中的腺苷A2A受体阳性神经元投射到嗅结节及梨状皮层等部位。进一步实验表明激动嗅结节局部的腺苷A2A受体增加非REM（Non-REM，NREM）睡眠，抑制嗅结节局部的腺苷A2A受体降低NREM睡眠，嗅结节中腺苷A2A受体阳性神经元投射到腹侧苍白球和外侧下丘脑等部位；而嗅结节中腺苷A2A受体阳性神经元正是通过抑制腹侧苍白球和外侧下丘脑来增加NREM睡眠的。以上研究结果表明了嗅球中的腺苷A2A受体调控了REM睡眠变化，而嗅结节中的腺苷A2A受体则调节NREM睡眠。该研究对丰富和发展睡眠觉醒调节理论、认识抑郁症性睡眠障碍机制及治疗药物开发提供依据。