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

精神分裂症是一种以多巴胺(DA)中脑系统功能障碍和包括工作记忆(WM)损害在内的严重认知功能障碍为特征的慢性破坏性精神疾病。我们的目的是了解DA系统如何与前额叶皮质(PFC)相互作用来指导小鼠的WM行为，以及这些相互作用在精神分裂症小鼠模型中是如何受到影响的。具体地说，我们将关注我们在前一个资助期发现的4赫兹振荡，它以一种依赖于WM的方式同步腹侧被盖区(VTA)和PFC的神经元活动，并且在精神分裂症小鼠模型中被干扰。我们将使用以前开发的病毒工具来光遗传学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，在单个神经元和神经元群体的水平上表征它们各自与WM相关的放电模式。最后，对VTA和PFC内投射特定神经元亚群的光遗传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激活来挽救精神分裂症小鼠模型中VTA-PFC网络活动和WM行为的缺陷。综上所述，我们的结果将对VTA-PFC的相互作用、它们在正常认知功能中的作用以及它们在精神疾病模型中的崩溃产生重要的机械见解。

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.