Medial septum differentially regulates spontaneous dopamine neuron activity in the ventral tegmental area and substantia nigra pars compacta via distinct neurochemical pathways

项目摘要/摘要 多巴胺(DA)信号的中断是几种破坏性的 神经心理障碍，如精神分裂症、抑郁症、帕金森氏症和成瘾，使 DA信号的正常化是心理健康的主要问题(1-3)。然而，伴随着令人不安的副作用 这可以发生在直接的多巴胺能操纵(4；3)和电路内的病理识别 控制DA神经元(6)，许多研究的焦点已经转向DA系统的传入调节。 通过这一努力，已经发现了一条来自腹侧下丘脑腹下丘的关键通路。 通过伏隔核(NAC)和苍白球腹侧核(Vp)将海马体投射到腹侧被盖区。 这规范了VTA中的人口活动(7)。群体活动很重要，因为只有活跃的DA神经元 可以在突发性放电(8)，DA系统的行为显著输出(9-11)，允许海马体调节 阶段性DA释放的“收益”(8)。海马体功能的一个相对未被研究的调节器是内侧隔 (Ms)；胆碱能基底前脑的一个亚区，尽管它在精神病学中具有已知的重要性 障碍、认知功能和DA系统相互作用(13)，还没有得到充分的评估 途径特定的方式。MS主要通过胆碱能和GABA能神经支配海马区 投射(14)，驱动海马theta节律(14)，影响目标导向的学习和记忆(15；16)。 尽管如此，MS是否是中脑DA系统的传入调节器一直没有被确定。 此外，还没有研究比较VsubNAC-VP通路对VTA和VTA的调节 黑质(SNC)，这一区域也与精神病理学有关(3)。因此，确定(1)是至关重要的 MS是否调节VTA和SNc中的DA活性，(2)其机制和途径 发生，(3)该回路是否在传入驱动的DA失调模型中被中断，从而突出显示 MS与治疗策略相关，(4)该回路的行为影响，以及(5)该回路是否 雄性和雌性大鼠的调节是不同的。为了测试这一点，我们将使用体内电生理学来测量DA 用NMDA或DREADDS(HM3Dq)激活MS后，VTA和SNc的神经元放电。路径和 神经递质机制将通过Vsubor VP的失活和通过注入特定的 拮抗者分别进入VSub。MAM模型将被用来在传入模型中测试该电路。 被驱使的DA失调。此电路的行为影响将通过使用以下命令激活MS来测试 DREADDS(HM3Dq)和与VTA(苯丙胺诱导的)DA活动相关的操作行为 和SNC(苯丙胺诱导的刻板印象)和目标导向的空间记忆任务(T迷宫 反转学习)。这些研究将为发现与以下相关的新的治疗靶点奠定基础 DA驱动的症状和疾病，通过描述一个新的中脑DA活动调节区和通过 展示了中脑DA调节中基于不同神经递质的区域特异性。

Project Summary/Abstract Disruptions in dopamine (DA) signaling are central to symptom presentation of several devastating neuropsychological disorders, such as schizophrenia, depression, Parkinson’s, and addiction, making normalization of DA signaling a primary concern in mental health(1-3). However, with the troubling side effects that can occur with direct dopaminergic manipulation(4; 3), and the identification of pathology within the circuits controlling DA neurons(6), the focus of much research has turned to the afferent regulation of the DA system. Through this effort, a critical pathway has been discovered from the ventral subiculum (Vsub) of the hippocampus to the ventral tegmental area (VTA), via the nucleus accumbens (NAc) and ventral pallidum (VP), that regulates population activity in the VTA(7). Population activity is important because only active DA neurons can fire in bursts(8), the behaviorally-salient output of the DA system(9-11), allowing the hippocampus to regulate the “gain” of phasic DA release(8). A relatively unstudied regulator of hippocampal function is the medial septum (MS); a sub-region of the cholinergic basal forebrain, which, despite its known importance in psychiatric disorders, cognitive functions, and DA system interactions(13), has not been adequately evaluated in a pathway-specific manner. The MS innervates the hippocampus via primarily cholinergic and GABAergic projections(14), drives hippocampal theta rhythms(14), and affects goal-directed learning and memory(15; 16). Despite this, it has never been determined if the MS is an afferent regulator of the midbrain DA system. Additionally, no studies have drawn comparisons between Vsub-NAc-VP pathway regulation of VTA and substantia nigra (SNc), a region also implicated in psychopathology(3). Thus, it is critical to determine (1) whether the MS regulates DA activity in the VTA and SNc, (2) the mechanism and pathway by which this occurs, (3) whether this circuit is disrupted in a model of afferent-driven DA dysregulation, thereby highlighting the MS as relevant to treatment strategies, (4) the behavioral impact of this circuit, and (5) whether this circuit regulation is different in male and female rats. To test this, we will use in vivo electrophysiology to measure DA neuron firing in the VTA and SNc following MS activation with NMDA or DREADDs (hM3Dq). Pathway and neurotransmitter mechanism will be determined by inactivation of the Vsub or VP and by infusing specific antagonists into the VSub, respectively. The MAM model will be used to test this circuit in a model of afferent- driven DA dysregulation. The behavioral impact of this circuit will be tested by activating the MS with DREADDs (hM3Dq) and performing behaviors correlated to DA activity in the VTA (amphetamine-induced hyperlocomotion) and SNc (amphetamine-induced stereotypy) and a goal-direct, spatial memory task (T-maze reversal learning). These studies will lay the groundwork for the discovery of new treatment targets related to DA-driven symptoms and diseases by describing a novel regulator region of midbrain DA activity and by demonstrating differential neurotransmitter-based regional specificity in midbrain DA regulation.