Intrinsic amplification of synaptic inputs to nigral dopamine cells

描述（由申请人提供）：我们的日常运动和习惯依赖于中脑多巴胺（DA）的释放。这是因为DA细胞与整个大脑的感觉运动区域有着错综复杂的联系，包括基底神经节、海马、杏仁核和额叶皮质。许多兴奋性和抑制性输入汇聚到DA细胞，DA细胞必须整合这些信息。因此，单个DA神经元的内在兴奋性对于信息处理至关重要。这个项目将探讨DA神经元如何放大或抑制突触输入，以及哪些膜通道决定对输入的反应。切片生理学和药理学将结合起来操纵单个DA细胞。我们推测，最近的特点TRP通道提高阶段性多巴胺释放和几个钾通道调节释放的时间。此外，DA神经元的子集可能致力于阶段性释放，而其余的神经元保持被认为是重要的动机的基线DA。这项研究将证明阶段性释放的机制，这与强化学习相关。突触后靶点（如纹状体和前额叶皮层）释放的DA量最终影响目标导向行为中的动作选择。大脑中不适当数量的DA会导致各种动机和奖励学习的精神障碍，包括重度抑郁症，注意力缺陷多动障碍（ADHD），精神分裂症和药物成瘾。每天都有数千种处方药用于治疗这些疾病（例如Wellbutrin，Ritalin，Adderall，Zyban），但没有详细了解其长期影响。这些大规模销售的药物可能会导致线路的永久性变化，使药物戒断变得复杂。对DA细胞生理学的研究可能有助于为从短期治疗中恢复的患者定制药物方案。此外，帕金森病（PD）通过损害行走，说话和完成简单任务的能力来影响数百万人。目前的左旋多巴治疗增加DA水平，但往往过量，导致不必要的和无序的运动。因此，通过靶向内在膜特性来微调DA释放量的能力可能有助于恢复这些患者的协调运动。

DESCRIPTION (provided by applicant): Our daily movements and habits rely on midbrain dopamine (DA) release. This is because DA cells are intricately connected to sensorimotor regions throughout the brain, including the basal ganglia, hippocampus, amygdala, and frontal cortex. Many excitatory and inhibitory inputs converge onto the DA cells, which must integrate this information. Therefore, the intrinsic excitability of single DA neurons is critical for information processing. This project will explore how the DA neuron amplifies or dampens synaptic inputs, and which membrane channels determine the responsiveness to input. Slice physiology and pharmacology will be combined to manipulate single DA cells. We hypothesize that a recently characterized TRP channel boosts phasic dopamine release and that several potassium channels regulate the timing of release. Furthermore, subsets of DA neurons may be dedicated to phasic release, while the remaining neurons maintain the baseline DA thought to be important for motivation. This study will demonstrate the mechanism of phasic release, which has been correlated with reinforcement learning. The amount of DA release at post-synaptic targets, such as the striatum and prefrontal cortex, ultimately affects action selection in goal-directed behaviors. Inappropriate amounts of DA in the brain cause various psychiatric disorders of motivation and rewardlearning, including Major Depression, Attention-deficit Hyperactivity Disorder (ADHD), Schizophrenia, and drug addiction. Thousands of prescription medications are given out daily for these disorders (e.g. Wellbutrin, Ritalin, Adderall, Zyban) without a detailed understanding of their long-term effects. These massmarketed drugs may cause permanent changes in wiring that complicate withdrawal from medication. Research on DA cell physiology may help tailor drug regimens for patients recovering from short-term treatment. Furthermore, the loss of DA cells is Parkinson's disease (PD) affects millions of people by impairing the ability to walk, talk, and complete simple tasks. Current L-DOPA therapy increases DA levels, but often to excess, causing unwanted and disordered movements. Thus, the ability to fine-tune the amount of DA release by targeting intrinsic membrane properties may help restore coordinated movement in these patients.