氯胺酮介导cAMP/PKA/CREB信号通路调控青幼期抑郁大鼠自杀特征行为机制研究

Suicide seriously endangers the physical and mental health and lives of juveniles, while its pathogenesis is still not clear. Recent research of suicide autopsy specimens reported that cAMP/PKA/CREB signaling pathway is the important part of the molecular mechanism of suicide brain regulation. And, ketamine, as a new targeted drugs, has anti-depression and anti-suicide effects. Based on the previous work of the first childhood rats depression model with “suicide-trait behavior”, preliminary experiments found that cAMP/PKA signaling pathway changed significantly in prefrontal cortex of this model and the suicide-trait behaviors can be reversed after injection of ketamine. Thus, based on above research, we proposed scientific hypothesis that regulation of cAMP/PKA/CREB signaling pathway induced by ketamine in the pathogenesis of suicide-trait behavior in the rates model of childhood depression. We plan to carry out the following work: ① we will integrate the expression changes of gene and protein, and confirm the molecular changes of cAMP/PKA/CREB signaling pathway in the key brain area of childhood rats with “suicide characteristics”; ② we will inject antagonist of key protein to verify the regulation of childhood rats suicide-trait behavior by cAMP/PKA/CREB signaling pathway. Through the above research work , we aim to explore the brain molecular mechanism of suicide, and find out important therapeutic target of anti-suicide drugs.

自杀严重危害我国青少年人群的生命健康，其内在生物学机制迄今不清。最近大量基于自杀者尸检标本研究发现，cAMP/PKA/CREB信号通路参与是调控自杀脑分子机制的重要环节。氯胺酮作为新型靶向药物，发现其具有抗抑郁和抗自杀的生物学作用。课题组基于自主研发“伴自杀特征”青幼期抑郁大鼠模型，预实验发现cAMP/PKA通路在该模型的前额叶中改变最显著，且注射氯胺酮可逆转伴青幼期抑郁大鼠自杀行为。基于此，提出科学假设，氯胺酮通过cAMP/PKA/CREB信号通路调控青幼期抑郁大鼠自杀特征行为。拟开展以下工作：①整合基因和蛋白表达水平变化，证实cAMP/PKA/CREB通路在伴自杀特征青幼期大鼠关键脑区的分子改变；②注射关键蛋白拮抗剂，验证氯胺酮通过cAMP/PKA/CREB通路调控青幼期大鼠自杀特征行为。通过上述研究，有望探索青少年自杀发生的脑分子机制，寻找抗自杀药物研发的重要分子靶点。

自杀严重危害我国青少年人群的生命健康，其内在生物学机制迄今不清。最近大量基于自杀者尸检标本研究发现，cAMP/PKA/CREB信号通路参与是调控自杀脑分子机制的重要环节。课题组基于自主研发“伴自杀特征”青幼期抑郁大鼠模型，预实验发现cAMP/PKA通路在该模型的前额叶中改变最显著，且注射氯胺酮可逆转伴青幼期抑郁大鼠自杀行为。基于此，课题组以“伴自杀特征”青幼期抑郁大鼠模型为载体，以cAMP/PKA信号通路为研究主线，探索儿童青少年抑郁自杀行为发病机制及干预靶点，开展了以下工作：①成功构建期伴自杀特征抑郁青幼期大鼠，并进行前额叶蛋白质组学检测，发现PKA和GABA信号通路的蛋白改变与自杀行为有关；②基于我们的“伴自杀特征”青幼期抑郁大鼠模型，通过脑区RNA测序，发现在自杀过程中青幼期抑郁大鼠自杀样行为与大脑Cnih2、Ppp6r3和Ugt1a3基因相关。③通过动物行为学进行机器学习分析，发现快感缺失、攻击性和易怒是五个自杀特征的前三位效应因子。本项目研究围绕“伴自杀特征”青幼期抑郁大鼠模型，进行行为、转录、蛋白层面的研究，为进一步探索调控自杀的病理机制，从而预防和减少自杀行为提供前期理论基础。