Systematic in vivo Testing of the Fast-Spiking Synchrony Hypothesis

描述（申请人提供）：快速尖峰细胞（Fast-spiking cells， 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锥体神经元（PYR）功能在健康和疾病中的关键调节因子。FS高度活跃，与PYR有高概率连接，并产生快速而强烈的超极化，支持FS活性对PYR抑制至关重要的观点。在这里，我们验证了FS活动的变化也可以增强PYR敏感性的假设，特别是FS同步可以驱动PYR对弱甚至阈下感觉输入的反应增加。基于FS和RS之间的强大互联性，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的敏感性。我们还预测，在持续数百毫秒的epoch中，整个本地种群的FS同步增加，并且在这些事件期间PYR灵敏度得到增强。在Aim I中，我们将使用我们开发的新型慢性四极阵列直接测量FS同步性的内源性表达及其与PYR敏感性的关系，该阵列允许行为小鼠耐受高电极数量。除了直接测量FS活性与PYR敏感性之间的自然相关性外，我们还将使用外部输入（FS的选择性光遗传刺激）来直接测试我们感兴趣的变量，独立于与FS同步表达自然共存的协变。我们还将开展三个密切相关的目标。在Aim II中，我们将详细量化FS同步的空间和时间表达。尽管对这一动态的重要性有重要的理论解释，但这种测量从未在清醒行为的新皮层中系统地进行过。在Aim III中，我们将测试两种可能导致FS同步以增强PYR敏感性的机制。我们将测试这种现象对PYR的阈下影响，以及网络层面的影响，特别是FS同步是否会通过更有效地抑制FS而导致去抑制。在Aim IV中，我们将直接检验FS同步性和灵敏度增加可以增强感觉加工，特别是振动检测性能的假设。这些目标将直接检验FS同步性假设。它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，这一动态已被广泛假设为对信息处理和健康的网络功能很重要。

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.