Systematic in vivo Testing of the Fast-Spiking Synchrony Hypothesis

描述(申请人提供)：快峰细胞(FS)是新皮质中最常见的中间神经元类型，其活动被广泛认为是健康和疾病中锥体神经元(PYR)功能的关键调节因素。FS活性很高，很可能与PYR结合，并产生快速而强烈的超极化，支持FS活性对抑制PYR至关重要的观点。在这里，我们测试了这样的假设，即FS活动的变化也可以增强PYR的敏感性，具体地说，FS的同步性可以驱动对微弱甚至亚阈值感觉输入的更高的PYR反应。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的敏感性。我们还预测，在持续数百毫秒的纪元内，FS在整个当地人口中的同步性会增加，并且在这些事件期间，PYR的敏感度会增强。在目标I中，我们将使用我们开发的新的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。除了直接测量FS活性和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，而不依赖于与FS同步表达自然共生的协变量。我们还将实现三个密切相关的目标。在AIM II中，我们将详细量化FS同步性的空间和时间表达。尽管对这一动态的意义进行了重大的理论研究，但在清醒状态下表现为新皮质的情况下，从来没有系统地进行过这样的测量。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的亚阈值影响，以及网络级别的影响，特别是FS同步是否通过更有效地抑制FS而导致去抑制。在目标四中，我们将直接测试FS的同步性和提高的灵敏度可以增强感觉处理的假设，特别是振动检测的性能。这些目标将直接检验FS同步假说。他们还将独立于假设检验的结果，在几个层面上产生关于FS同步的影响的重要新数据，这种动态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.