The roles of distinct nucleus basalis projections in cognition

 描述（由申请人提供）：我们的长期目标是了解前脑神经调节区，基底核（NB）如何支持认知功能。NB被认为在学习和注意力方面起着重要作用，它的退化与一系列痴呆患者的认知功能下降平行。然而，识别的投射细胞类型从未被记录。我们的目标是确定哪些信息是由不同的NB长距离皮层投射所代表和发出的，并建立它们的因果行为功能。 为了研究这个问题，我们已经开发了一个定量的心理物理听觉检测任务的小鼠，改编自人类和灵长类动物的工作，使我们能够评估一些行为相关的NB神经元。此外，我们将使用我们最近开发的光遗传学工具包首次记录所有三种已知的NB投射细胞类型：胆碱能，GABA能和多巴胺能神经元。我们的中心假设是NB以特定于细胞类型的方式广播不同的认知信号。首先，我们将不同的认知变量操作化，以便对编码特定认知变量的每个神经元的活动进行统计评估。具体来说，我们将评估每时每刻，试验到试验之间的相关性放电率和不同的行为措施（如准确性或反应时间，RT）。其次，在这三个目标中，我们将考虑一个主要的投射系统，并评估它们在行为过程中何时被招募以及它们编码了哪些认知变量。最后，使用从这些记录中收集的时间信息，我们将使用光遗传学获得和功能丧失操作来测试不同NB投射细胞类型的因果作用。 在完成这些目标后，我们期望从NB建立特定于细胞类型的广播信号及其在认知的定义方面的作用。

 DESCRIPTION (provided by applicant): Our long-term goal is to understand how the forebrain neuromodulatory region, nucleus basalis (NB) supports cognitive functions. NB is thought to play significant roles in learning and attention, and its degeneration parallels the decline of cognitive functions in patients in a range of dementias. However, identified projection cell-types have never been recorded. Our objective is to determine what information is represented in and signaled by distinct NB long- range cortical projections and establish their causal behavioral function. To study this issue, we have developed a quantitative psychophysical auditory detection task for mice, adapted from human and primate work, enabling us to assess a number of behavioral correlates of NB neurons. In addition, we will use our recently developed optogenetic toolkit to record from all the three known NB projection cell-types: cholinergic, GABAergic and glutamatergic neurons during behavior for the first time. Our central hypothesis is that NB broadcasts distinct cognitive signals in a cell-type-specific manner. First, we operationalized different cognitive variables so that the activity of every neuron encoding a particular cognitive variable can be statistically evaluated. Specifically we will assess the moment-to-moment, trial-to-trial correlations between firing rates and different behavioral measures (e.g. accuracy or reaction time, RT). Second, in each of the three aims we will consider one of the major projection systems and evaluate when they are recruited during behavior and what cognitive variables they encode. Finally, using the temporal information gleaned from these recordings we will test the causal role of different NB projection cell- types using optogenetic gain and loss of function manipulations. Upon completion of these aims, we expect to establish the cell-type specific broadcast signals from NB and their role in defined aspects of cognition.