Corticosterone Signaling and a Lateral Habenula–Ventral Tegmental Area Circuit Modulate Compulsive Self-Injurious Behavior in a Rat Model

被盖腹侧区 腹侧苍白球 神经科学 麝香醇 皮质酮 人口 生物 心理学 内分泌学 内科学 医学 多巴胺能 兴奋剂 中枢神经系统 多巴胺 基底神经节 激素 苍白球 受体 环境卫生
作者
Yujie Guo,Xun Tang,Jichuan Zhang,Sen Jin,Jinnan Li,Lufeng Ding,Keming Zhang,Chao‐Yu Yang,Hua Zhou,Xiaobin He,Fuqiang Xu,Guo‐Qiang Bi,Lin Xu,Pak-Ming Lau
出处
期刊:The Journal of Neuroscience [Society for Neuroscience]
卷期号:38 (23): 5251-5266 被引量:7
标识
DOI:10.1523/jneurosci.2540-17.2018
摘要

Self-injurious behavior (SIB) is commonly observed in patients with neuropsychiatric disorders, as well as in nonclinical populations with stress-related mental-health problems. However, the exact circuitry mechanisms underlying SIB have remained poorly understood. Here, with bilateral injection of muscimol into the entopeduncular nucleus (EP), we established a rat model of SIB. Following the muscimol injection, the male rats exhibited in a dose-dependent manner stereotypic self-biting behavior that lasted for hours and often resulted in wounds of various severities. The SIB was associated with an elevated level of serum corticosterone and could be exacerbated by enhancing the corticosterone signaling and, conversely, alleviated by inhibiting the corticosterone signaling. Activity mapping using c-fos immunostaining, combined with connectivity mapping using herpes simplex virus-based anterograde tracing from the EP and pseudorabies virus-based retrograde tracing from the masseter muscle, revealed the potential involvement of many brain areas in SIB. In particular, the lateral habenula (LHb) and the ventral tegmental area (VTA), the two connected brain areas involved in stress response and reward processing, showed a significant increase in neuronal activation during SIB. Furthermore, suppressing the LHb activity or modulating the GABAergic transmission in the VTA could significantly reduce the occurrence of SIB. These results demonstrate the importance of stress hormone signaling and the LHb–VTA circuit in modulating SIB resulting from EP malfunction, and suggest potential targets for therapeutic intervention of SIB and related disorders. SIGNIFICANCE STATEMENT Self-injurious behavior (SIB) occurs in ∼4% of the general population, with substantially higher occurrence among adolescents and patients of neuropsychiatric disorders. Stress has been linked to the occurrence of SIB, yet the underlying mechanisms have remained unclear. Using a rat model of SIB induced by disruption of activity in the entopeduncular nucleus (EP), we found that the behavior is regulated by stress and linked to corticosterone signaling. Viral tracing and c-fos immunostaining revealed the involvement of various subcortical areas, especially the EP–lateral habenula (LHb)–ventral tegmental area (VTA) circuit, in SIB. Furthermore, regulating activity in the LHb or the VTA alleviates SIB. These results may have implications in the development of new strategies for treating SIB.

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