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（申请人提供）：临床上可用的抗抑郁药具有阻断大脑中5-羟色胺和去甲肾上腺素再摄取的相同核心机制。但是，约有50％的患者对可用治疗没有完全反应，这表明其他神经递质也参与抑郁症。中唇多巴胺系统控制奖励和动机，多巴胺能传播的功能障碍可能占阿内迪尼亚，缺乏动力和其他抑郁症状。该应用的总体目标是了解如何在类似抑郁症状态下改变多巴胺能传播，以及这种改变如何促进抑郁行为。中唇多巴胺是由腹侧盖区（VTA）中多巴胺神经元合成的，多巴胺释放是由动作电位（AP）触发的。使用慢性不可预测的应激（CUS）作为抑郁症的小鼠模型，我们的初步研究表明，CUS在VTA中催化CAMP水解的酶降低了AP发射和磷酸二酯酶4（PDE4）的活性的增加。中脑多巴胺神经元中的自发性AP发射主要由起搏器通道 - 超极化激活的循环核苷酸门控通道（HCN）驱动。顾名思义，HCN感应化学（CAMP）和电（电压）信号。我们假设VTA中CUS诱导的cAMP降低会损害HCN的激活，从而导致AP发射和多巴胺释放的降低。多巴胺能的传播受损可能导致Anhedonia和其他类似抑郁症的行为。提出了两个具体目标来检验这一假设。目标I的目的是研究VTA多巴胺神经元中CUS诱导的动作电势发射的减少的机制。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是否有助于CUS引起的VTA多巴胺神经元中AP发射的降低。 AIM II的目的是检验VTA中HCN通道病的假设有助于CUS诱导的抑郁样行为。具体而言，我们将检查HCN2在VTA中的损失和功能获得的细胞和行为影响。预计该项目的完成将提供关键机制，将慢性应激与多巴胺能传播和抑郁样行为的缺乏联系起来。此外，这项研究有可能发现抑郁症药物治疗的新型治疗靶点。