青春期可卡因滥用对成年时前额皮质内侧部锥体神经元功能的影响：GABA能突触传递的调控机制研究

Adolescence marks an important developmental period of neurobiological change. Drug abuse in adolescence may influence the development and function of brain as well as physical and psychological health, which contribute to later heightened vulnerability to develop mental disorders in adulthood, such as drug addiction, depression and cognitive disorder. Lots of studies began to explore the neurobiology of adolescent drug abuse. However, most of them focus on the short-term effects of abused drug exposure in adolescence on the development of brain. The medial prefrontal cortex (mPFC) is an important neural substrate for the development of drug addiction. Pyramidal neurons (PN) in mPFC project to several brain area, such as amygdale, ventral tegmental area, nucleus accumbens, hippocampus and dorsal striatum, and is involved in higher cognitive functions, such as reward, decision making, working memory and impulsive control. The output activity of PN is under the integrated control of excitatory and inhibitory (E-I) inputs. Imbalance of E-I control of PN lead to neurological disorders. The inhibitory inputs to PN are mainly from local γ-Aminobutyric acid (GABA) interneuron (IN) in mPFC. The aims of this study are : (1)Test the long-term effects of adolescent cocaine exposure on the structure and function of GABA IN—PN inhibitory synaptic circuit of mPFC in adulthood; (2)Examine the role of these adaptations of GABA IN—PN inhibitory synaptic circuit in later cocaine-related addiction behavior in adults; (3)Explore the molecular mechanism underlying these adaptations of GABA-IN—PN synaptic circuit in adult rats who have an adolescent cocaine exposure history. This study will contribute to better understand the neurobiology of drug addiction and will facilitate advances in prevention and treatment during adolescence.

青少年吸毒对脑功能损害的研究停留在毒品的短期效应水平。前额皮质内侧部(Medial prefrontal cortex，mPFC)是毒品作用的重要靶点。锥体神经元(Pyramidal neuron，PN)是mPFC中主要投射神经元，其输出活动受兴奋和抑制(Excitation-Inhibition，E-I)输入的整合调控。E-I失衡引起脑功能异常。γ-氨基丁酸能中间神经元（γ-Aminobutyric acidergic interneuron, GABA IN）是PN抑制输入的主要来源。本项目拟采用行为、形态、光遗传、分子生物和电生理等手段，探究青春期可卡因滥用对mPFC中GABA IN—PN突触传递路径发育和功能的长期影响；观察GABA IN—PN突触传递路径的可塑性变化，对成年时出现的病理行为的调控作用和机制。本项目研究结果将有助于为针对青少年吸毒患者的戒毒新药开发提供思路和方向

从世界各国药物滥用的流行情况来看，青少年是药物滥用的高危和高发人群。青春期的神经系统尚处于高速发育和未成熟阶段，对各种有害刺激十分敏感。毒品破坏青少年神经结构的正常发育，从而导致成长过程中脑的功能和精神状态异常，临床研究资料发现，有青春期毒品滥用史的患者，在成年期易出现焦虑和冲动的人格特征，增加其毒品复吸率和精神疾病罹患率，甚至伴随较高的违法犯罪率,对个人和社会带来了极大危害。近年来，人们开始注意到“个体化”戒毒治疗的重要性。探究青春期药物滥用对脑功能的影响的神经生物学机制，研发针对青少年吸毒患者这一特殊群体的新型戒毒药物，已成为精神依赖性药物成瘾研究领域的迫切要求。前额皮质内侧部（Medial prefrontal cortex, mPFC）是中枢神经系统中负责多种高级认知功能的一个重要脑区，也是精神依赖性药物发挥毒性作用的重要靶点。mPFC中锥体神经元（Pyramidal neuron，PN）活动接受兴奋和抑制(Excitation-Inhibition, E-I)输入的整合式调控。E-I的失衡会引起脑功能的异常，甚至增加罹患抑郁症、精神分裂症和药物成瘾等精神疾病的几率。γ-氨基丁酸（γ-Aminobutyric acid, GABA）是中枢主要的抑制性神经递质。本项目采用青春期暴露于可卡因的啮齿类动物模型，采用行为学、形态学、生物化学、化学遗传学、分子生物学和神经电生理学等研究手段，系统地探究了青春期可卡因滥用对mPFC的GABA IN—PN局部突触传递路径的发育、结构和功能的长期影响；并通过化学遗传学方法调控mPFC中GABA IN—PN局部突触传递，探究该通路对青春期接触毒品引发的异常行为的作用。研究发现，青春期接触看可卡因，可引起成年期动物的精神行为异常，同时伴有mPFC的PN的E/I失衡，表现为GABA能抑制性传入增强、兴奋性传入不便、PN的功能活性降低；通过条件性干预mPFC的GABA IN—PN通路活动，可以逆转青春期可卡因引发的成年期异常行为。本项目研究结果将有助于进一步理解可卡因成瘾和依赖的分子生物机制，为针对青少年吸毒患者的“个体化”戒毒治疗的新药开发提供新靶点。