Dissecting the neural circuitry for spatial working memory

 描述（由申请人提供）：工作记忆是一种基本的认知功能，几乎对所有行为都至关重要。尽管我们知道哪些大脑区域和哪些神经调质参与了工作记忆，但我们对哪些神经元需要激活才能启动工作记忆知之甚少。我们知识中的这一差距是由于在足够高的时间分辨率下操纵和监测遗传和解剖学定义的细胞类型中的神经活动的技术困难而产生的。为了克服这一挑战并阐明工作记忆的一些因果神经动力学，我们建议将联合收割机多种协同方法结合起来，包括我们先前开发的靶向多巴胺能神经元的大鼠光遗传学模型，体内电生理记录，以及基于荧光的自由行为动物神经活动监测（使用gCaMP6）。在目的1中，我们将在工作记忆的更新、维持或读出过程中，通过光遗传学方法抑制几个皮层和纹状体回路，以确定每个回路支持工作记忆的哪个方面。在目标2中，我们将使用gCaMP6监测多巴胺能神经元的神经活动，以确定多巴胺能动力学如何与工作记忆表现相关。在目标3中，我们将产生不同的多巴胺能刺激模式（例如，强直与相位），以确定工作记忆表现和多巴胺能活动动力学之间的因果关系。在目标4中，我们将整合多巴胺能刺激与背侧纹状体和边缘前皮层的电生理记录， 由多巴胺能活性介导的神经活性的下游变化。总之，这项工作将为工作记忆的神经回路机制提供新的见解，对基础科学和理解各种精神疾病中的工作记忆功能障碍都有影响。

 DESCRIPTION (provided by applicant): Working memory is an essential cognitive function central to virtually all behaviors. Despite the fact that we know which brain areas and which neuromodulators are involved in working memory, we know very little about which neurons need to be activated when to enable working memory. This gap in our knowledge arose because of the technical difficulty in manipulating and monitoring neural activity in genetically- and anatomically- defined cell-types with sufficiently high temporal resolution. In order to overcome this challenge and elucidate some of the causal neural dynamics for working memory, we propose to combine multiple synergistic approaches, including a rat optogenetic model that we have previously developed to target dopaminergic neurons, in vivo electrophysiological recordings, and fluorescence-based monitoring of neural activity in freely behaving animals (with gCaMP6). In Aim 1, we will optogenetically inhibit several cortical and striatal circuits eiter during the updating, maintenance, or readout of working memory to determine which aspect of working memory each circuit supports. In Aims 2, we will monitor neural activity in dopaminergic neurons using gCaMP6 to determine how dopaminergic dynamics correlate with working memory performance. In Aim 3, we will generate different patterns of dopaminergic stimulation (e.g. tonic vs phasic) to determine the causal relationship between working memory performance and dopaminergic activity dynamics. In Aim 4, we will integrate dopaminergic stimulation with electrophysiological recordings in dorsal striatum and prelimbic cortex to isolate the downstream changes in neural activity mediated by dopaminergic activity. Together, this work will provide new insights into the neural circuit mechanisms underlying working memory, with implications for both basic science and an understanding of the working memory dysfunction in various psychiatric disorders.