The role of VTA neurotransmitter co-release in health and disease

项目总结 阐明动态平衡和失控动机背后的神经回路机制是 对于开发更好的治疗抑郁症或躁郁症等神经精神疾病的治疗方法至关重要 无序。 作为边缘中脑奖励回路的一部分，腹侧被盖区(VTA)通常被缩小到其 多巴胺投射神经元。然而，VTA也含有共同释放抑制性GABA和 兴奋性谷氨酸，能够有力地调节动力。然而，这一功能的作用 GABA/谷氨酸在健康和疾病中的共同释放还不是很清楚。为什么这些神经元 同时发出‘STOP’和‘GO’信号？ 这组拟议的实验将系统地检验VTA GABA/谷氨酸共同- 释放作为一种机制，以一种稳态的方式使突触后活动正常化。vbl.使用 光遗传学驱动VTA、GABA/谷氨酸在下游结构中共同释放，这些结构调节情绪和 动机，我将使用化学遗传学方法和改变突触后的慢性行为操作 活性，然后测试光遗传驱动VTA GABA/谷氨酸的生理和行为效应 联合发行。这些实验将揭示神经递质共释放的基本机制，并揭示其 在调节奖赏和厌恶之间的转换中，在中脑边缘回路中扮演的角色。建议数 实验还将为研究人员提供细胞贴附和全细胞贴片方面的广泛培训 钳夹电生理学和小鼠遗传学。 展示一种能够使活动正常化并进而激发动机的大脑机制可以提供一种新的 治疗神经精神疾病的靶点，以及阐明神经递质共同的神秘作用- 超越神经精神疾病的释放。

PROJECT SUMMARY Elucidating the neural circuit mechanisms underlying both homeostatic and uncontrolled motivation are crucial for developing better therapeutic treatments for neuropsychiatric disorders like depression or bipolar disorder. As part of mesolimbic brain reward circuitry, the ventral tegmental area (VTA) is generally reduced to its dopamine projection neurons. However, VTA also contains neurons that co-release inhibitory GABA and excitatory glutamate that are capable of powerfully modulating motivation. However, the functional role of this GABA/glutamate co-release in health and disease is not well understood. Why would these neurons simultaneously send both a `stop' and `go' signal? This set of proposed experiments will systematically test the hypothesis that VTA GABA/glutamate co- release serves as a mechanism to normalize postsynaptic activity in a homeostatic manner. Using optogenetics to drive VTA GABA/glutamate co-release in downstream structures that regulate mood and motivation, I will use chemogenetic approaches and chronic behavioral manipulations that alter postsynaptic activity, and then test the physiological and behavioral effect of optogenetically driving VTA GABA/glutamate co-release. These experiments will reveal basic mechanisms of neurotransmitter co-release and uncover their role within mesolimbic circuitry in modulating the switch between reward and aversion. The proposed experiments will also provide the investigator with extensive training in cell-attached and whole-cell patch clamp electrophysiology, and mouse genetics. Showing a brain mechanism capable of normalizing activity and in turn motivation can provide a novel target for treating neuropsychiatric diseases, as well as elucidate the mysterious role of neurotransmitter co- release beyond neuropsychiatric disease.