Nucleus reuniens regulation of ventral tegmental area dopamine neuron activity: relevance to psychosis

核团对腹侧被盖区多巴胺神经元活动的调节：与精神病的相关性

• 批准号: 9047529
• 负责人: Eric Zimmerman
• 金额: $ 5.19万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047529
• 关键词: Acute; Address; Adverse effects; Amphetamines; Animals; Antipsychotic Agents; Behavioral; Bipolar Disorder; Brain; Cells; Communication; Data; Development; Disease; Dopamine; Dopamine Antagonists; Effectiveness; Exhibits; Functional disorder; Globus Pallidus; Hippocampus (Brain); Hyperactive behavior; Infusion procedures; Knowledge; Lead; Link; Measures; Medial; Mediating; Mental disorders; Methylazoxymethanol Acetate; Modeling; N-Methylaspartate; Neurobiology; Nucleus Accumbens; Patients; Personality; Pharmaceutical Preparations; Plague; Population; Prefrontal Cortex; Psychotic Disorders; Regulation; Reporting; Reuniens Thalamic Nucleus; Role; Schizophrenia; Schizotypal Personality Disorder; Signal Transduction; Site; Structure; Subthalamic structure; Symptoms; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Thalamic structure; Therapeutic Intervention; Ventral Tegmental Area; base; design; dopaminergic neuron; experience; novel; novel therapeutic intervention; optogenetics; presynaptic; psychotic symptoms; public health relevance

 DESCRIPTION (provided by applicant): Schizophrenia is a prevalent and debilitating mental illness. The psychotic or "positive" symptoms of the disease can sometimes be addressed by treatment with antipsychotic medications. However, antipsychotic medications have limited effectiveness and treat only a subset of symptoms, deficiencies that have not been addressed since these medications were developed over 50 years ago. In addition, psychosis is observed in many other psychiatric illnesses, including schizotypal personality disorder, bipolar disorder, and temporal lobe epilepsy. The fact that antipsychotic medications act by blocking dopamine (DA), along with other lines of evidence, suggests that the symptoms schizophrenia might be caused by excess DA release in the brain. It has been proposed that this DA excess could be caused by dysfunction in afferent regions governing ventral tegmental area (VTA) DA neuron activity. However, these regions have not been fully characterized. My project is therefore designed to enhance our knowledge of afferent regions involved in controlling activity of VTA DA cells, and which of these afferent regions could contribute to the aberrant neurobiology seen in schizophrenia. Previous findings from our group and others have described a tripartite circuit containing the ventral subiculum (vSub), nucleus accumbens (NAc), and ventral pallidum (VP), which governs the proportion of VTA DA neurons that are spontaneously active, ie "population activity." Population activity is a key parameter of VTA activity, because DA cells can only exhibit burst firing if they are spontaneously active. Recently, our group reported that inhibition of the infralimbic subdivision of the medial prefrontal cortex (ilPFC) increases population activit, and that this effect depends on vSub. However, there is no direct projection from ilPFC to the ventral hippocampus. We propose that communication between the two structures is mediated by the nucleus reuniens of the midline thalamus (RE). Several anatomical studies have characterized dense, reciprocal connections between RE and ilPFC/vSub. This suggests that RE could be involved in controlling VTA DA neuron population activity, and that ilPFC might exert its influence on VTA via RE. In addition, dysfunction in prefrontal cortex, hyperactivity in thalamus, and hyperactivity in ventral hippocampus have been proposed to underlie the psychotic symptoms of schizophrenia and other disorders. However, the idea that hyperactivity in RE could lead to overdrive of vSub and aberrantly high VTA DA neuron activity has never been tested directly. We will address these questions with the following specific aims: 1) Determine the role of RE in regulating VTA DA neuron population activity 2) Determine if ilPFC control of VTA DA population activity is mediated by RE 3) Determine how altered signaling in the ilPFC-RE-vSub circuit contributes to hyperdopaminergic states, using circuit-based electrophysiological and behavioral approaches.

 描述（适用提供）：精神分裂症是一种普遍且令人衰弱的精神疾病。该疾病的精神病或“阳性”症状有时可以通过抗精神病药治疗来解决。但是，抗精神病药物的有效性有限，并且仅治疗一部分症状，由于这些药物是50年前开发的，这些缺陷尚未解决。此外，在许多其他精神病疾病中也观察到精神病，包括精神分裂型人格障碍，躁郁症和临时叶癫痫。抗精神病药通过阻断多巴胺（DA）以及其他证据表明，精神分裂症可能是由大脑中的DA释放过多引起的，这一事实表明，精神分裂症可能引起。已经提出，该DA超过可能是由控制腹侧盖区域（VTA）DA神经元活动的传入区域功能障碍引起的。但是，这些区域尚未完全表征。因此，我的项目旨在增强我们对控制VTA DA细胞活动的传入区域的了解，这些传入区域中的哪个可能有助于精神分裂症中看到的异常神经生物学。我们小组和其他人的先前发现描述了一个包含腹侧下调（VSUB），伏隔核（NAC）和腹侧pallidum（VP）（VP）的三方回路，该基础是赞助的VTA DA神经元的比例，它是赞助的。人口活动是VTA活性的关键参数，因为DA细胞只有主动赞助，才能暴露出爆发。最近，我们的小组报告了抑制作用 培养基前额叶皮层（ILPFC）的输液细分增加了人口活性，并且这种效果取决于VSUB。但是，ILPFC对腹侧海马没有直接投影。我们提出，这两种结构之间的通信是由中线丘脑的核团聚介导的（re）。几项解剖学研究表征了RE和ILPFC/VSUB之间的密集，相互的联系。这表明RE可能参与控制VTA DA神经元人口活动，并且ILPFC可能通过RE对VTA产生影响。此外，已经提出，已经提出，已经提出，腹侧海马的功能障碍，丘脑的多动症和腹侧海马的多动症是为基于精神分裂症和其他疾病的精神病症状的基础。 However, the idea that hyperactivity in RE could lead to overdrive of vSub and aberrantly high VTA DA neuron activity has never We will address these questions with the following specific aims: 1) Determine the role of RE in determining VTA DA neuron population activity 2) Determine if ilPFC control of VTA DA population activity is mediated by RE 3) Determine how altered signaling in the ilPFC-RE-vSub circuit contributes to使用基于电路的电生理和行为方法的高胺能状态。