背侧纹状体直接通路、间接通路神经元调控操作性行为的作用及机制研究

Instrumental learning involves two distinct associative learning processes: action-outcome(A-O) mediated goal-directed behaviour and stimulus-response(S-R) mediated habit behaviour. The dorsal striatum is a key neuronal locus to control instrumental learning with the dorsomedial striatum (DMS) is critically associated with the acquisition and expression of A-O goal-directed behavior whereas the dorsolateral striatum (DLS) is critical to S-R habit formation. The reinforcement learning mechanism predicts that concurrent activation of dopaminergic neurons and dopamine release triggered by motivationally significant event such as (reward delivery) and postsynaptic striatal neurons is critical to striatum-dependent instrumental learning. However, a critical question whether the transient activation of striatal neurons precisely at the time of reward delivery was sufficient to modulate instrumental learning has not been addressed due to the lack of method to control neurons activity with required spatiotemporal resolution to establish this temporal relationship. To work out this question, we’ll apply optogenetic approach to bi-directionally regulate specific striatal neurons(striatonigral neurons or striatopallidal neurons) of freely behaving animals in a temporally precise and reversible manner and critically evaluate the effect of optogenetic “time-locked” activation of striatonigral neurons or striatopallidal neurons on goal-directed behavior and habit formation. Furthermore, we will dissect out the possible subregion-specific, neuron type-specific contributions of striatonigral or striatopallidal neurons in the two anatomically and functionally distinct regions (DMS、DLS) of the striatum. Since drug addiction and obsessive-compulsive disorder (OCD) have been conceptualized as aberrant and pathological habit formation, demonstration of striatal striatonigral and striatopallidal neurons control of goal-directed and habitual action will provide necessary circuit mechanism and important rationale for a pharmacological or deep brain stimulation(DBS) strategy to intervene pathological instrumental behavior formation associated with these neuropsychiatric disorders.

操作性行为是重要适应性行为，其功能紊乱与系列神经精神疾病相关。背侧纹状体是调控操作性行为的关键节点，但背侧纹状体直接通路、间接通路神经元对操作性行为的具体作用未明。此外，强化性学习理论推测：给予奖赏时多巴胺释放与突触后膜纹状体神经元的同步激活对操作性学习至关重要。由于技术限制，与奖赏同步、瞬时性操控纹状体神经元活性，是否足以调控操作性行为，这一关键机制问题无法回答。基于光遗传学，本项目拟利用选择性在直接通路、间接通路神经元表达光敏蛋白的转基因小鼠，在操作性行为范式基础上，以“time-locked”方式，准确将两类神经元活性操控时间点与奖赏给予同步，对比不同步操控，将精确解析出背侧纹状体直接通路、间接通路神经元在操作性行为 “学习”和“表达”过程中的具体调控作用及关键性作用时间窗，本研究将提供强化性学习理论的直接实验证据，同时为研发干预手段治疗操作性行为相关神经精神疾病提供必要的环路机制。

操作性行为是重要适应性行为，其功能紊乱与系列神经精神疾病相关。背侧纹状体是调控操作性行为的关键节点，但背侧纹状体直接通路、间接通路神经元对操作性行为的具体作用未明。此外，强化性学习理论推测：给予奖赏时多巴胺释放与突触后膜纹状体神经元的同步激活对操作性学习至关重要。由于技术限制，与奖赏同步、瞬时性操控纹状体神经元活性，是否足以调控操作性为，这一关键机制问题无法回答。本项目基于光遗传学、化学遗传学，利用选择性在直接通路、间接通路神经元表达兴奋/抑制性光敏蛋白的转基因小鼠，结合操作性行为范式，以“time-locked”方式，准确将两类神经元活性操控时间点与奖赏给予同步，对比不同步操控，系统精确解析出了背侧纹状体（DMS、DLS）直接通路、间接通路神经元在操作性行为“学习”和“表达”过程中的具体调控作用及关键时间窗，研究结果表明：间接通路神经元对操作性行为的调控具有显著的亚区特异性及学习成分特异性，其主要通过其至外侧苍白球的投射末梢发挥调控作用，且调控的有效时间窗为给予奖赏2s内。而DMS直接通路活性与操作性行为形成过程中“行为-结果”联系的建立和编码关系密切，负调控操作性行为学习“获得”过程。总之，① 与奖赏同步、瞬时性（2s）操控直接通路、间接通路活性，足以调控操作性行为；② DMS两群神经元主导目标导向性行为调控，DLS两群神经元主导习惯性行为调控；③ 直接通路神经元主导操作性行为“获得”过程调控，间接通路神经元主导操作性行为“表达”调控。本研究将提供强化性学习理论的直接实验证据，同时为研发干预手段治疗操作性行为相关神经精神疾病提供必要的环路机制。