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

内侧隔膜通过不同的神经化学途径差异调节腹侧被盖区和黑质致密部的自发多巴胺神经元活动

• 批准号: 9769877
• 负责人: David Michael Bortz
• 金额: $ 6.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769877
• 关键词: Affect; Amphetamines; Animals; Behavior; Behavioral; Cognitive; Complex; Critical Pathways; Data; Disease; Dopamine; Electrophysiology (science); Female; Fire - disasters; Globus Pallidus; Goals; Hippocampus (Brain); Interneurons; Knowledge; Learning; Measures; Medial; Mediating; Memory; Mental Depression; Mental Health; Mental disorders; Midbrain structure; Modeling; N-Methylaspartate; Neurons; Neuropsychology; Neurotransmitters; Nucleus Accumbens; Output; Parkinson Disease; Pathology; Pathway interactions; Perinatal; Periodicity; Pharmacology; Phase; Population; Psychopathology; Pyramidal Cells; Rattus; Regulation; Research; Reversal Learning; Role; Schizophrenia; Signal Transduction; Specificity; Substantia nigra structure; Symptoms; Synapses; System; Techniques; Testing; Theta Rhythm; Ventral Tegmental Area; addiction; basal forebrain; base; cholinergic; cognitive function; designer receptors exclusively activated by designer drugs; dopamine system; dopaminergic neuron; improved; in vivo; male; neurochemistry; novel; pars compacta; prenatal; sex; side effect; spatial memory; stereotypy; treatment strategy

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.

项目总结/摘要 多巴胺（DA）信号传导的中断是几种毁灭性疾病症状表现的核心。 神经心理障碍，如精神分裂症，抑郁症，帕金森氏症和成瘾， DA信号正常化是心理健康的主要问题（1-3）。然而，由于它的副作用 直接多巴胺能操作（4; 3）和回路内病理学的鉴定 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，已经发现了一个关键的途径，从腹下托（Vsub）的 海马通过腹侧苍白球（VP）和腹侧丘脑（NAc）到腹侧被盖区（VTA）， 调节VTA中的种群活动（7）。群体活动很重要，因为只有活跃的DA神经元 可以突然放电（8），这是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“增益”（8）。一个相对未被研究的海马功能调节器是内侧隔 (MS)胆碱能基底前脑的一个亚区域，尽管它在精神病中的重要性是众所周知的， 疾病，认知功能和DA系统相互作用（13），尚未在一项研究中得到充分评价。 具体的方式。MS主要通过胆碱能和GABA能神经支配海马 投射（14），驱动海马theta节律（14），并影响目标导向的学习和记忆（15; 16）。 尽管如此，它从来没有被确定，如果MS是中脑DA系统的传入调节器。 此外，还没有研究比较Vsub-NAc-VP通路对VTA的调节和 黑质（SNc），也涉及精神病理学的区域（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）这一机制和途径 发生，（3）在传入驱动的DA失调模型中，该回路是否中断，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 调节在雄性和雌性大鼠中是不同的。为了验证这一点，我们将使用体内电生理学来测量DA 在用NMDA或DREADD（hM 3Dq）激活MS后，VTA和SNc中的神经元放电。途径和 神经递质机制将通过Vsub或VP的失活和通过输注特异性的 拮抗剂分别进入VSub。MAM模型将用于在传入神经模型中测试该回路- 驱动的DA失调该电路的行为影响将通过激活MS进行测试， DREADDs（hM 3Dq）和与VTA中DA活性相关的行为（安非他明诱导的 运动过度）和SNc（安非他明诱导的刻板）以及目标导向的空间记忆任务（T-迷宫 逆向学习）。这些研究将为发现新的治疗靶点奠定基础， DA驱动的症状和疾病，通过描述中脑DA活性的一个新的调节区域， 证明了中脑DA调节中基于不同神经递质的区域特异性。