Lu Chen, Feng Yifan, Li Hongxia, Gao Zilong, Zhu Xiaona, Hu Ji
School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Front Hum Neurosci. 2022 Aug 10;16:945912. doi: 10.3389/fnhum.2022.945912. eCollection 2022.
Deep brain stimulation (DBS) is a clinical intervention for the treatment of movement disorders. It has also been applied to the treatment of psychiatric disorders such as depression, anorexia nervosa, obsessive-compulsive disorder, and schizophrenia. Psychiatric disorders including schizophrenia, bipolar disorder, and major depression can lead to psychosis, which can cause patients to lose touch with reality. The ventral tegmental area (VTA), located near the midline of the midbrain, is an important region involved in psychosis. However, the clinical application of electrical stimulation of the VTA to treat psychotic diseases has been limited, and related mechanisms have not been thoroughly studied. In the present study, hyperlocomotion and stereotyped behaviors of the mice were employed to mimic and evaluate the positive-psychotic-like behaviors. We attempted to treat positive psychotic-like behaviors by electrically stimulating the VTA in mice and exploring the neural mechanisms behind behavioral effects. Local field potential recording and fiber photometry to observe the behavioral effects and changes in neural activities caused by DBS in the VTA of mice. Optogenetic techniques were used to verify the neural mechanisms underlying the behavioral effects induced by DBS. Our results showed that electrical stimulation of the VTA activates local gamma-aminobutyric acid (GABA) neurons, and dopamine (DA) neurons, reduces hyperlocomotion, and relieves stereotyped behaviors induced by MK-801 (dizocilpine) injection. The results of optogenetic manipulation showed that the activation of the VTA GABA neurons, but not DA neurons, is involved in the alleviation of hyperlocomotion and stereotyped behaviors. We visualized changes in the activity of specific types in specific brain areas induced by DBS, and explored the neural mechanism of DBS in alleviating positive psychotic-like behaviors. This preclinical study not only proposes new technical means of exploring the mechanism of DBS, but also provides experimental justification for the clinical treatment of psychotic diseases by electrical stimulation of the VTA.
深部脑刺激（DBS）是一种用于治疗运动障碍的临床干预手段。它也已被应用于治疗诸如抑郁症、神经性厌食症、强迫症和精神分裂症等精神疾病。包括精神分裂症、双相情感障碍和重度抑郁症在内的精神疾病可导致精神病，这会使患者与现实脱节。腹侧被盖区（VTA）位于中脑中线附近，是参与精神病的一个重要区域。然而，VTA电刺激治疗精神病性疾病的临床应用一直有限，相关机制也尚未得到充分研究。在本研究中，利用小鼠的运动亢进和刻板行为来模拟和评估类阳性精神病行为。我们试图通过电刺激小鼠的VTA并探索行为效应背后的神经机制来治疗类阳性精神病行为。采用局部场电位记录和光纤光度法来观察小鼠VTA中DBS引起的行为效应和神经活动变化。运用光遗传学技术来验证DBS诱导的行为效应背后的神经机制。我们的结果表明，VTA电刺激可激活局部γ-氨基丁酸（GABA）能神经元和多巴胺（DA）能神经元，减少运动亢进，并减轻由注射MK-801（地卓西平）诱导的刻板行为。光遗传学操作的结果表明，VTA GABA能神经元而非DA能神经元的激活参与了运动亢进和刻板行为的缓解。我们可视化了DBS诱导的特定脑区特定类型活动的变化，并探索了DBS减轻类阳性精神病行为的神经机制。这项临床前研究不仅提出了探索DBS机制的新技术手段，还为通过VTA电刺激临床治疗精神病性疾病提供了实验依据。
