Regulation of dopamine neuronal activity and depressive behavior by HCN channels

HCN 通道对多巴胺神经元活动和抑郁行为的调节

• 批准号: 8925142
• 负责人: Qing-song Liu
• 金额: $ 38.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925142
• 关键词: Accounting; Action Potentials; Anhedonia; Antidepressive Agents; Behavior; Behavioral; Brain; Chemicals; Chronic; Chronic stress; Cyclic AMP; Disease; Dopamine; Enzymes; Functional disorder; Goals; Health; Hydrolysis; Knowledge; Lead; Life; Link; Mediating; Mental Depression; Midbrain structure; Motivation; Names; Neurons; Neurotransmitters; Norepinephrine; Pacemakers; Patients; Pharmacotherapy; Regulation; Rewards; Role; Serotonin; Signal Transduction; Stress; Synapses; Testing; Ventral Tegmental Area; cyclic-nucleotide gated ion channels; depressive behavior; depressive symptoms; dopaminergic neuron; gain of function; inhibitor/antagonist; insight; mesolimbic system; mouse model; new therapeutic target; novel; phosphodiesterase IV; reuptake; transmission process; voltage; voltage gated channel

DESCRIPTION (provided by applicant): Clinically available antidepressants share the same core mechanisms of blocking serotonin and noradrenaline reuptake in the brain. However, ~50% of patients do not fully respond to available treatments, suggesting other neurotransmitters are also involved in depression. The mesolimbic dopamine system governs reward and motivation, and dysfunction of dopaminergic transmission could account for anhedonia, lack of motivation and other symptoms of depression. The overall goal of this application is to understand how dopaminergic transmission is altered in depressive-like states and how this alteration contributes to depressive behavior. Mesolimbic dopamine is synthesized by dopamine neurons in the ventral tegmental area (VTA), and dopamine release is triggered by action potential (AP) firing. Using chronic unpredictable stress (CUS) as a mouse model of depression, our preliminary studies indicate that CUS decreased AP firing and an increase in the activity of phosphodiesterase 4 (PDE4), the enzyme that catalyzes the hydrolysis of cAMP, in the VTA. Spontaneous AP firing in midbrain dopamine neurons is driven primarily by the pacemaker channel--the hyperpolarization-activated cyclic nucleotide-gated channel (HCN). As its name indicates, HCN senses chemical (cAMP) and electrical (voltage) signals. We hypothesize that the CUS-induced decrease in cAMP in the VTA impairs the activation of HCN, leading to decreases in AP firing and dopamine release; the impaired dopaminergic transmission may contribute to anhedonia and other depressive-like behavior. Two Specific Aims are proposed to test this hypothesis. The objective of Aim I is to investigate the mechanisms for CUS-induced decrease in action potential firing in VTA dopamine neurons. We will examine whether changes in activation of HCN and other voltage-gated channels and excitatory and inhibitory synaptic inputs contribute to CUS-induced decrease in AP firing in VTA dopamine neurons. The objective of Aim II is to test the hypothesis that HCN channelopathy in the VTA contributes to CUS-induced depressive-like behaviors. Specifically, we will examine the cellular and behavioral effects of loss- and gain-of-function of HCN2 in the VTA. Completion of this project is expected to provide key mechanisms linking chronic stress to deficiency in dopaminergic transmission and depressive-like behaviors. Furthermore, this study has the potential to uncover novel therapeutic targets for pharmacotherapy of depression.

描述（由申请人提供）：临床可用的抗抑郁药具有阻断大脑中血清素和去甲肾上腺素再摄取的相同核心机制。然而，约50%的患者对现有的治疗没有完全反应，这表明其他神经递质也与抑郁症有关。中脑边缘多巴胺系统控制奖励和动机，多巴胺能传递功能障碍可能导致快感缺乏、动机缺乏和其他抑郁症症状。这项应用的总体目标是了解多巴胺能传递在抑郁样状态下是如何改变的，以及这种改变是如何导致抑郁行为的。中边缘多巴胺由腹侧被盖区（VTA）的多巴胺神经元合成，并通过动作电位（AP）放电触发多巴胺释放。使用慢性不可预测应激（CUS）作为小鼠抑郁症模型，我们的初步研究表明，CUS减少了VTA中AP的发射，并增加了磷酸二酯酶4 （PDE4）的活性，PDE4是催化cAMP水解的酶。中脑多巴胺神经元的自发AP放电主要由起搏器通道驱动——超极化激活的环核苷酸门控通道（HCN）。顾名思义，HCN可以感知化学（cAMP）和电气（电压）信号。我们假设cusu诱导的VTA cAMP降低会损害HCN的激活，导致AP放电和多巴胺释放减少；多巴胺能传递受损可能导致快感缺乏和其他类似抑郁的行为。提出了两个具体目标来检验这一假设。目的：探讨cu诱导的VTA多巴胺神经元动作电位放电减少的机制。我们将研究HCN和其他电压门控通道的激活以及兴奋性和抑制性突触输入的变化是否有助于cu诱导的VTA多巴胺神经元AP放电的减少。Aim II的目的是检验VTA中HCN通道病变导致cuss诱导的抑郁样行为的假设。具体来说，我们将研究HCN2在VTA中功能丧失和获得对细胞和行为的影响。该项目的完成有望提供慢性应激与多巴胺能传递缺乏和抑郁样行为之间的关键机制。此外，这项研究有可能为抑郁症的药物治疗发现新的治疗靶点。