Systematic in vivo Testing of the Fast-Spiking Synchrony Hypothesis

描述（由申请人提供）：快速尖峰细胞（FS）是新皮层中最常见的中间神经元类型，其活性被广泛认为是健康和疾病中锥体神经元（PYR）功能的关键调节因子。FS是高度活跃的，以高概率连接到PYR，并产生快速和强烈的超极化，支持FS活性对抑制PYR至关重要的观点。在这里，我们测试的假设，FS活动的变化也可以提高PYR的敏感性，特别是FS同步可以驱动增加PYR反应弱，甚至阈下的感觉输入。基于FS和RS之间强大的互连性，以及我们的初步数据，我们假设单个FS同步事件可以增强PYR敏感性。我们还预测，FS同步增加整个当地人口的历元持续数百毫秒的顺序，PYR的敏感性增强，在这些事件。在目的I中，我们将直接测量FS同步性的内源性表达及其与PYR敏感性的关系，使用我们开发的新的慢性四极阵列，其允许在行为小鼠中耐受高电极数。除了直接测量FS活性和PYR敏感性之间的天然相关性之外，我们还将使用外部输入（FS的选择性光遗传学刺激）来直接测试我们感兴趣的变量，而不依赖于与FS同步表达天然共发生的共变体。我们还将实施三个密切相关的目标。在目标II中，我们将详细量化FS同步的空间和时间表达。尽管关于这种动态的重要理论化，但这种措施从未在清醒行为的新皮层中系统地进行过。在目标III中，我们将测试两种机制，可以导致FS同步，以提高PYR的敏感性。我们将测试这种现象对PYR的阈下影响，以及网络水平的影响，特别是FS同步是否通过更有效的FS抑制导致去抑制。在目的四，我们将直接测试的假设，FS同步和敏感性的增加，可以提高感觉处理，特别是触须检测的性能。这些目标将直接测试FS同步假设。他们还将独立于假设检验的结果，在几个层面上产生重要的新数据，以影响FS同步，一个动态的，已被广泛假设为是重要的信息处理和健康的网络功能。

DESCRIPTION (provided by applicant): Fast-spiking cells (FS) are the most common interneuron type in the neocortex, and their activity is widely regarded as a key regulator of pyramidal neuron (PYR) function in health and disease. FS are highly active, connected at high probability to PYR, and generate rapid and strong hyperpolarization, supporting the view that FS activity is crucial for suppression of PYR. Here, we test the hypothesis that changes in FS activity can also enhance PYR sensitivity, specifically that FS synchrony can drive increased PYR responses to weak or even subthreshold sensory input. Based on the robust interconnectivity between FS and RS, and our Preliminary Data, we hypothesize that individual FS synchrony events can enhance PYR sensitivity. We also predict that FS synchrony increases across the local population for epochs lasting on order of hundreds of milliseconds, and that PYR sensitivity is enhanced during these events. In Aim I, we will directly measure the endogenous expression of FS synchrony and its relation to PYR sensitivity using new chronic tetrode arrays we have developed that allow tolerance of high-electrode numbers in behaving mice. In addition to directly measuring the natural correlations between FS activity and PYR sensitivity, we will also use external input (selective optogenetic stimulation of FS) to directly test our variable of interest, independent of the co-variants that natural co-occur with FS synchrony expression. We will also conduct three closely related Aims. In Aim II, we will quantify in detail the spatial and temporal expression of FS synchrony. Despite significant theorization as to the import of this dynamic, such measures have never been systematically made in awake behaving neocortex. In Aim III, we will test two mechanisms that could lead FS synchrony to enhance PYR sensitivity. We will test the subthreshold impact of this phenomenon on PYR, and the network level impact, specifically whether FS synchrony leads to disinhibition through more efficacious suppression of FS. In Aim IV, we will directly test the hypothesis that FS synchrony and increased sensitivity can enhance sensory processing, specifically the performance of vibrissal detection. These Aims will directly test the FS synchrony hypothesis. They will also, independent of the outcome of hypothesis testing, generate important new data at several levels as to the impact of FS synchrony, a dynamic that has been widely hypothesized to be important for information processing and healthy network function.