Dorsal raphe dopaminergic neurons target CaMKII+ neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors.

IF 5.8 1区 医学 Q1 PSYCHIATRY
Wentao Wang, Dan Wang, Di Zhao, Lihong Xu, Shujun Jiang, Yu Zhang, Minghu Cui, Jing Liu, Fantao Meng, Cuilan Liu, Dunjiang Liu, Wei Li, Chen Li
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Abstract

Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II+ (CaMKII+) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRNDA → dBNSTCaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.

背侧剑突多巴胺能神经元以纹状体末端背侧床核的 CaMKII+ 神经元为靶点,介导抑郁相关行为。
多巴胺(DA)神经元在抑郁症的发展和表现以及对抗抑郁治疗的反应中起着至关重要的作用。虽然主要分布在腹侧被盖区(VTA)的多巴胺神经元的功能已得到证实,但背侧剑突核(DRN)中的一小部分多巴胺神经元在抑郁症中的贡献仍不清楚。在这项研究中,我们发现慢性不可预知应激(CUS)会诱发抑郁相关行为,并降低DRN中DA神经元的自发发射率、兴奋性和抑制性突触后电流,这与雌雄小鼠兴奋性突触传递的减少有关。化学抑制 DRN 中的 DA 神经元会产生抑郁表型。相反,激活这些神经元则可完全逆转 CUS 所诱发的厌世和绝望行为。此外,我们还发现,投射到纹状体末端背侧床核(dBNST)的DRN多巴胺能通过调节dBNST中的多巴胺神经递质和多巴胺受体2(DR2),影响钙/钙调蛋白依赖性蛋白激酶II+(CaMKII+)靶神经元的神经活动和N-甲基-D-天冬氨酸受体(NMDAR)介导的EPSC,从而选择性地控制抑郁行为。总之,这些发现凸显了 DRNDA → dBNSTCaMKII+ 神经回路在双向介导应激诱导的抑郁相关行为中的重要作用。我们的研究结果表明,DRN DA神经元是参与调节抑郁相关行为的神经回路的关键组成部分,使其成为抑郁症的潜在治疗靶点。
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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