Dopamine function in working memory networks and its dysfunction in a mouse model of schizophrenia

精神分裂症小鼠模型工作记忆网络中的多巴胺功能及其功能障碍

• 批准号: 322169167
• 负责人: Dr. Sevil Duvarci
• 金额: --
• 依托单位: Physiologie II: Sinnes- und Neurophysiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/322169167?language=en
• 关键词: Dopamine; function; working; memory; networks

Schizophrenia is a chronic and devastating psychiatric disease characterized by a dysfunction of the dopamine (DA) midbrain system and severe cognitive dysfunctions including an impairment of working memory (WM). Our aim is to understand how the DA system interacts with the prefrontal cortex (PFC) to guide WM behavior in mice and how these interactions are affected in a mouse model of schizophrenia. Specifically, we will focus on a 4 Hz oscillation that we identified in the previous funding period that synchronizes neuronal activity in the ventral tegmental area (VTA) and the PFC in a WM-dependent manner and which is disrupted in a schizophrenia mouse model. We will use previously developed viral tools to optogenetically identify PFC and VTA projection neurons connecting the two structures. We will then use novel statistical tools to characterize their respective WM-related firing patterns at the level of individual neurons and neuronal populations. Finally, optogenetic manipulations of projection-specific neuronal subpopulations within the VTA and PFC will enable us to test their causal role in VTA-PFC synchrony and WM behavior. Based on these insights, we will attempt to rescue deficits in VTA-PFC network activity and WM behavior in our schizophrenia mouse model using cell-specific optogenetic activation. Taken together, our results will yield important mechanistic insights into VTA-PFC interactions, their role in normal cognitive functioning and their breakdown in psychiatric disease models.

精神分裂症是一种慢性和毁灭性的精神疾病，其特征是多巴胺（DA）中脑系统功能障碍和严重的认知功能障碍，包括工作记忆（WM）受损。我们的目的是了解DA系统如何与前额叶皮层（PFC）相互作用，以指导WM行为的小鼠和这些相互作用是如何影响的精神分裂症小鼠模型。具体来说，我们将专注于4 Hz的振荡，我们确定在前一个资助期，在腹侧被盖区（VTA）和PFC神经元活动的WM依赖性的方式，这是在精神分裂症小鼠模型中断。我们将使用先前开发的病毒工具来光遗传学地识别连接这两个结构的PFC和VTA投射神经元。然后，我们将使用新的统计工具来表征各自的WM相关的放电模式在单个神经元和神经元群体的水平。最后，VTA和PFC内投射特异性神经元亚群的光遗传学操作将使我们能够测试它们在VTA-PFC同步和WM行为中的因果作用。基于这些见解，我们将尝试使用细胞特异性光遗传学激活来挽救我们的精神分裂症小鼠模型中VTA-PFC网络活性和WM行为的缺陷。综上所述，我们的研究结果将产生重要的机制见解VTA-PFC的相互作用，他们在正常的认知功能和精神疾病模型中的崩溃的作用。