Regulation of dopamine neuronal activity and depressive behavior by HCN channels

描述(申请人提供)：临床上可用的抗抑郁药具有相同的核心机制，即阻止5-羟色胺和去甲肾上腺素在大脑中的再摄取。然而，约50%的患者对可用的治疗没有完全反应，这表明其他神经递质也参与了抑郁症。中脑边缘多巴胺系统控制奖赏和动机，多巴胺能传递功能障碍可能是快感减退、缺乏动力和其他抑郁症状的原因。这项应用的总体目标是了解在类抑郁状态下多巴胺能传递是如何改变的，以及这种改变是如何导致抑郁行为的。中脑边缘多巴胺由腹侧被盖区(VTA)的多巴胺神经元合成，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)作为抑郁的小鼠模型，我们的初步研究表明，CUS减少了VTA中AP的放电和VTA中催化cAMP水解酶的磷酸二酯酶4(PDE4)的活性。中脑多巴胺神经元的自发AP放电主要由起搏器通道--超极化激活的环核苷酸门控通道(HCN)驱动。顾名思义，HCN感知化学(CAMP)和电信号(电压)。我们推测，CUS引起的VTA内cAMP的减少损害了HCN的激活，导致AP放电和多巴胺释放的减少；多巴胺能传递的受损可能参与了快感缺失和其他抑郁样行为。为了检验这一假说，本文提出了两个具体目标。目的I的目的是探讨CUS导致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CUS导致VTA多巴胺神经元AP放电的减少。目的II的目的是验证这样一种假设，即VTA中的HCN通道病变有助于CUS诱导的抑郁样行为。具体地说，我们将研究HCN在VTA中功能丧失和功能获得的细胞和行为影响。该项目的完成有望提供将慢性应激与多巴胺能传递不足和抑郁样行为联系起来的关键机制。此外，本研究有可能为抑郁症的药物治疗发现新的治疗靶点。

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.