Balancing motivation through VTA GABA/Glutamate co-transmission

通过 VTA GABA/谷氨酸共同传输平衡动力

• 批准号: 10759702
• 负责人: Shelley May Warlow
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10759702
• 关键词: Address; Affect; American; Amygdaloid structure; Automobile Driving; Axon; Behavior Control; Behavioral; Behavioral Assay; Bipolar Depression; Bipolar Disorder; Brain; CRISPR/Cas technology; Calcium; Calcium Signaling; Cells; Chronic; Complex; Compulsive Behavior; Development; Disease; Dissection; Dopamine; Equilibrium; Exposure to; Fiber; Genes; Genetic; Glutamates; Goals; Habenula; Hyperactivity; Incentives; Lateral; Life; Major Depressive Disorder; Manic; Measures; Mediating; Membrane Potentials; Mental Depression; Modeling; Monitor; Moods; Motivation; Mus; Negative Reinforcements; Neurons; Neurotransmitters; Phase; Photometry; Physiological; Physiology; Population; Population Heterogeneity; Positive Reinforcements; Psychological reinforcement; Regulation; Research; Rewards; Role; Shapes; Signal Transduction; Somatostatin; Stress; Structure; Sucrose; Testing; Training; Ventral Tegmental Area; cell type; depressive symptoms; designer receptors exclusively activated by designer drugs; dopaminergic neuron; experience; experimental study; faculty mentor; gamma-Aminobutyric Acid; genetic approach; in vivo; in vivo calcium imaging; insight; motivated behavior; neural circuit; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; patch clamp; postsynaptic; prevent; programs; protein kinase C-delta; reduce symptoms; response; reward circuitry; skill acquisition; therapeutic target; therapeutically effective; tool; transmission process

PROJECT SUMMARY Identifying the neural circuit mechanisms underlying both homeostatic and uncontrolled motivation are crucial for developing more targeted and effective therapeutic treatments for neuropsychiatric disorders like major depression or bipolar disorder. Within mesolimbic brain reward circuitry, the ventral tegmental area (VTA) is a major regulator of both reward and aversion. While generally reduced to its dopamine projection neurons, the VTA also contains neurons that co-release inhibitory GABA and excitatory glutamate and, similar to dopamine projections, can modulate motivation. However, the functional role of this GABA/glutamate co- release is still not well understood, and major questions regarding their role in positive vs. negative reinforcement remain. In particular, why would neurons simultaneously send an inhibitory and excitatory signal? This set of proposed experiments will systematically test the hypothesis that VTA GABA/glutamate co- release serves as a mechanism to balance postsynaptic activity and motivation in a homeostatic manner. Using optogenetics to drive VTA GABA/glutamate co-release in downstream structures that regulate mood and motivation, I will apply gene-editing tools (CRISPR/Cas9) to test the selective contribution of GABA vs. glutamate release in behavioral reinforcement (Aim 1). I will then apply chemogenetic approaches and chronic behavioral manipulations that alter postsynaptic activity to test the net in vivo effect of optogenetically driving VTA GABA/glutamate co-release using in vivo calcium imaging (Aim 2). These experiments will reveal basic mechanisms of neurotransmitter co-release and uncover their role within mesolimbic circuitry in balancing motivation and preventing prolonged excitation/inhibition of efferent structures associated with extreme motivational states. The capability of GABA/glutamate co-release to normalize activity can provide a novel target for treating disorders of imbalanced motivation such as bipolar disorder or depression. A strong interdisciplinary team of faculty mentors and experts will provide the scientific training required for these proposed experiments (gene-editing and fiber photometry) as well as professional development training to facilitate a successful transition to the R00 phase of this proposal. During the R00 phase, I will unify my prior expertise with newly acquired skills to determine the physiological and behavioral role of a newly-described VTA GABA/glutamate projection to amygdala. Using in vivo calcium imaging, I will first monitor activity of VTA GABA/glutamate terminals in amygdala during an effort-based instrumental sucrose task, and will then identify the net effect of optogenetically stimulating VTA GABA/glutamate terminals on cell-defined amygdala populations (Aim 3). These results will significantly expand our understanding of the role of VTA co-release in complex motivated behavior relevant to models of bipolar disorder and depression, and will crucially pave the way for more targeted approaches that form the basis my independent research program.

项目摘要 识别稳态动机和不受控制动机背后的神经回路机制， 对于开发更有针对性和更有效的神经精神疾病治疗方法至关重要， 重度抑郁症或躁郁症在中脑边缘脑奖励回路中，腹侧被盖区 (VTA)是奖赏和厌恶的主要调节器虽然一般减少到其多巴胺投射 除了神经元外，腹侧被盖区还含有共同释放抑制性GABA和兴奋性谷氨酸的神经元， 多巴胺投射，可以调节动机。然而，这种GABA/谷氨酸协同作用的功能作用， 释放仍然没有得到很好的理解，关于它们在积极与消极方面的作用的主要问题 增援仍在。特别是，为什么神经元会同时发送抑制性和兴奋性信号， 信号？这组拟议的实验将系统地测试VTA GABA/谷氨酸共- 释放作为一种机制，以自我平衡的方式平衡突触后活动和动机。 使用光遗传学驱动VTA GABA/谷氨酸在调节情绪和神经元的下游结构中共同释放 动机，我将应用基因编辑工具（CRISPR/Cas9）来测试GABA与 谷氨酸释放行为强化（目的1）。然后，我将应用化学遗传学方法和慢性 改变突触后活动的行为操作，以测试光遗传学驱动的净体内效应 使用体内钙成像的VTA GABA/谷氨酸盐共释放（Aim 2）。这些实验将揭示 神经递质共同释放的机制，并揭示其在中脑边缘回路中的作用， 动机和防止与极端相关的传出结构的长期兴奋/抑制 动机状态。GABA/谷氨酸共释放使活性正常化的能力可以提供一种新的方法。 用于治疗不平衡动机障碍如双相情感障碍或抑郁症的靶点。一个强大 由教师导师和专家组成的跨学科团队将提供这些所需的科学培训。 建议的实验（基因编辑和纤维光度学）以及专业发展培训， 促进成功过渡到本提案的R 00阶段。在R 00阶段，我将统一我的先验 具有新获得的技能的专业知识，以确定新描述的 VTA GABA/谷氨酸投射到杏仁核。使用体内钙成像，我将首先监测VTA的活动 在基于努力的工具蔗糖任务中，杏仁核中的GABA/谷氨酸末端，然后将识别 光遗传学刺激腹侧被盖区GABA/谷氨酸终末对细胞限定杏仁核的净效应 人口（目标3）。这些结果将大大扩展我们对VTA共同释放在 与双相情感障碍和抑郁症模型相关的复杂动机行为， 更有针对性的方法，形成了我的独立研究计划的基础。