健康与遗传心理学研究室知识库

动物和人类的某些行为反复发生之后，其行为模式能够完成从目标导向模式向习惯化模式的转变。这个转变具有提高机体反应效率、节约脑力与体力资源的优势。同时，根据情景的实际需要，机体可以实现目标导向与习惯化策略之间的灵活转换。然而，在某些异常状况下，这种转变可能失灵活，机体不能根据具体环境与条件做出相应的行为反应，表现出不适宜的习惯化行为，或称之为习惯化偏好。慢性应激即是这样一种能够导致习惯化行为偏好的风险因子。然而，慢性应激通过怎样的神经生物学机制导致习惯化偏好的仍然未知。

为回答上述问题，本研究采用10天社交挫败模型作为慢性应激处理模式，在经过10-15天的奖赏获得操作行为训练后，通过奖赏贬值的方式评价动物的行为方式——目标导向行为或习惯化行为，之后对下边缘皮质（infralimbic cortex, IL）的促肾上腺皮质激素释放因子I型受体（corticotropin-releasing factor receptor-1, CRFR1）系统进行重点研究。首先，通过对比糖水、糖丸和食丸三种不同感觉和质地的奖赏物进行操作行为训练与测试，我们证明了慢性应激可以导致不受奖赏物类型依赖的习惯化偏好行为；接下来，通过对于行为相关的即早基因cFos蛋白表达进行分析，我们明确了前额叶皮质中参与慢性应激导致习惯行为偏好的主要调控亚区为IL，而前边缘皮质（prelimbic cortex, PL）和前扣带回（anterior cingulate cortex, ACC）的参与度较低；最后，采用行为药理学方法，我们阐明了选择性拮抗IL的CRFR1能够逆转慢性应激导致的习惯化行为偏好，与之相反，选择性激活IL的CRFR1可以诱导出类似于慢性应激导致的习惯化偏好行为。

综上，本研究揭示了IL脑区在慢性社会应激导致习惯化行为偏好中的重要作用，IL的CRF系统高活性状态可能是长期应激导致行为策略转化失灵活的重要脑机制之一。这些研究结果不仅揭示了慢性应激导致行为僵化的神经机制，也为更深入地理解应激相关疾患（如，抑郁症、强迫症、成瘾行为等）的病理机制提供了新路径。

In human and animal, after repeated occurrence of certain behaviors, the transition from goal-oriented mode to habitual mode can be completed. This transformation has the advantages of improving the efficiency of body's response, saving the brain resources and physical strength. For the normal individuals, behaviors should be flexible depending on the environments around them. They can easily conduct a flexible conversion between goal-orientated and habitual behavior. However, in some special situations, the body is unable to respond to the changed circumstances and conditions, and the behavior becomes rigid. Chronic stress is such a risk factor for damaging behavioral flexibility. The individuals, who had ever exposed to the stressed condition, show a habitual bias. However, the neuronal mechanisms underlying this impairment remain unknown.

To answer this question, the present study focused on the corticotropin-releasing factor (CRF) system in the medial prefrontal cortex, which is one of the most sensitive brain area to stress. A ten or fifteen-days’ social defeat protocol was used for establishing chronic stress model in mice. Firstly, we found that the mice which had a chronic stress experience preferred to use a habitual behavior, compared with the control mice. And this behavioral preference was independent on the type of rewards. And then, by analyzing the expression of immediate early gene cFos protein, we revealed that altered neuronal activity in the infralimbic cortex (IL), a subregion of the mPFC, was more relative to the habitual behavior choice in stress-treated mice, while the behavior-associated neuronal activation was not observed in the anterior limbic cortex (PL) or anterior cingulated cortex (ACC). Finally, by using behavioral pharmacology, we demonstrated that selective blockade of corticotropin-releasing factor receptors-1 (CRFR1) in IL reversed stress-induced habitual behavior bias, whereas selective activation of CRFR1 facilitated habitual behavior formation.

Altogether, the present study suggest that altered function in the CRF system of the IL may play an important role in chronic stress-change behavioral strategy. These results may provide a new way to better understand the pathological mechanism of stress-related disorders (e.g., depression, obsessive-compulsive disorder, addictive behavior, etc.).