Corticosterone Signaling and a Lateral Habenula-Ventral Tegmental Area Circuit Modulate Compulsive Self-Injurious Behavior in a Rat Model
Corticosterone Signaling and a Lateral Habenula-Ventral Tegmental Area Circuit Modulate Compulsive Self-Injurious Behavior in a Rat Model
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皮质酮信号传导和外侧缰核-腹侧被盖区回路调节大鼠模型中的强迫性自残行为
DOI：
10.1523/jneurosci.2540-17.2018
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发表时间：
2018-06-06
影响因子：
5.3
通讯作者：
Lau, Pak-Ming
中科院分区：
文献类型：
--
作者：
Guo, Yujie;Tang, Xun;Lau, Pak-Ming
自伤行为(SIB)通常见于神经精神障碍患者，以及与应激相关的心理健康问题的非临床人群。然而，SIB背后的确切电路机制仍然知之甚少。本实验采用双侧内丘脑内侧核(EP)注射蝇毒酚的方法，建立了大鼠SIB模型。注射麝香酚后，雄性大鼠表现出持续数小时的刻板印象的自咬行为，并经常导致不同严重程度的伤口。SIB与血清皮质酮水平升高有关，增强皮质酮信号可加重SIB，相反，抑制皮质酮信号可缓解SIB。C-fos免疫染色的活动图，以及单纯疱疹病毒为基础的EP顺行追踪和伪狂犬病病毒为基础的咬肌逆行追踪的连接性图谱，揭示了许多大脑区域在SIB中的潜在参与。尤其是参与应激反应和奖赏加工的两个相连的大脑区域--外侧缰核(LHb)和腹侧被盖区(VTA)，在SIB时神经元的激活显著增加。此外，抑制LHb活性或调节VTA内GABA能传递可以显著减少SIB的发生。这些结果证明了应激激素信号和LHb-VTA通路在调节由EP功能障碍引起的SIB中的重要性，并为SIB和相关疾病的治疗干预提供了潜在的靶点。
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.