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

 描述(申请人提供)：精神分裂症是一种流行的、使人衰弱的精神疾病。这种疾病的精神病或“阳性”症状有时可以通过抗精神病药物治疗来解决。然而，抗精神病药物的疗效有限，只能治疗部分症状，自50多年前开发这些药物以来，这些缺陷一直没有得到解决。此外，在许多其他精神疾病中也观察到精神病，包括分裂型人格障碍、双相情感障碍和颞叶癫痫。抗精神病药物通过阻断多巴胺(DA)发挥作用的事实，以及其他证据表明，精神分裂症的症状可能是由大脑中过量释放DA引起的。有研究认为，这种DA过量可能是由于支配腹侧被盖区(VTA)DA神经元活动的传入区域功能障碍所致。然而，这些地区还没有得到充分的描述。因此，我的项目旨在增强我们对参与控制VTA DA细胞活动的传入区域的了解，以及这些传入区域中的哪些可能导致精神分裂症中出现的异常神经生物学。我们小组和其他人以前的发现描述了一个包含腹侧下丘(VSub)、伏隔核(Nac)和腹侧苍白球(Vp)的三部分回路，它控制着VTA DA神经元自发活动的比例，即“群体活动”。群体活动是VTA活动的一个关键参数，因为DA细胞只有在自发激活的情况下才能表现出爆发式放电。最近，我们小组报告说，抑制 内侧前额叶皮质(IlPFC)的边缘下亚区(IlPFC)增加了群体活动，这种作用依赖于vSub。然而，ilPFC并不直接投射到腹侧海马区。我们认为，这两种结构之间的通讯是由丘脑中线核(RE)的核团介导的。一些解剖学研究表明，RE和ilPFC/vSub之间存在紧密的相互联系。提示RE可能参与控制VTA DA神经元的活动，而ilPFC可能通过RE对VTA产生影响。此外，前额叶皮质功能障碍、丘脑多动和腹侧海马体多动被认为是精神分裂症和其他疾病的精神症状的基础。然而，RE中的过度活动可能导致vSub过度驱动和异常高的VTA DA神经元活动的想法从未被直接验证过。我们将以以下具体目标来解决这些问题：1)确定RE在调节VTA DA神经元群体活动中的作用2)确定ilPFC对VTA DA群体活动的控制是否由RE介导3)使用基于电路的电生理学和行为学方法，确定ilPFC-RE-vSub回路中的信号改变如何促进高多巴胺能状态。

 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.