Dopaminergic Projection from Ventral Tegmental Area to Substantia Nigra Pars Reticulata Mediates Chronic Social Defeat Stress-Induced Hypolocomotion
Dopaminergic Projection from Ventral Tegmental Area to Substantia Nigra Pars Reticulata Mediates Chronic Social Defeat Stress-Induced Hypolocomotion
复制标题
从腹侧被盖区到黑质网状部的多巴胺能投射介导慢性社交失败压力引起的运动减退
DOI：
10.1007/s12035-021-02522-7
复制
发表时间：
2021-08-12
影响因子：
5.1
通讯作者：
Tian, Bo
中科院分区：
文献类型：
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作者：
He, Feng;Zhang, Pei;Tian, Bo
许多人类临床研究表明，自主活动减少是重度抑郁症（MDD）以及其他精神疾病的常见症状。在MDD中，中脑腹侧被盖区（VTA）的多巴胺（DA）神经元与奖赏、动机、认知和厌恶等信息加工的调节密切相关。然而，VTA-DA神经元和MDD相关运动障碍，特别是运动功能减退之间关系的神经回路机制在很大程度上仍然是未知的。在此，我们研究了腹侧被盖区DA神经元如何在慢性社会失败应激（CSDS），抑郁症相关的神经行为状态的小鼠模型的hypolocomotion性能。结果表明，CSDS对小鼠自发活动有影响，但对小鼠握力和强迫运动能力无影响。化学发生激活腹侧被盖区DA能神经元可减轻CSDS诱导的运动功能减退。随后，定量全脑映射显示CSDS治疗后VTA-DA神经元向黑质网状部（SNr）的投射减少。用相位放电而不是强直放电刺激，光遗传激活从VTA到SNr的多巴胺能投射，可以显著增加小鼠的运动活动。此外，化学激活CSDS小鼠的VTA-SNr多巴胺能回路也可以挽救自发活动的下降。综上所述，我们的数据表明，腹侧被盖区-SNr多巴胺能投射介导的CSDS诱导的运动功能减退，这为MDD提供了理论基础和潜在的治疗靶点。
Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.