Time delimited neural silencing to dissect the basis of visual object perception

描述（由申请人提供）：视觉物体识别是健康和疾病的生活质量的核心，但它并没有在深层次上被理解。例如，虽然灵长类动物的下颞叶皮层（IT）可能是一个关键的神经元处理瓶颈，但我们仍然有 只有一个模糊的理解其因果作用在一个精细的空间和时间颗粒。这个探索性的建议（R21）的目的是部署，表征和行为验证新的工具，以产生空间上精确的，时间上划定沉默的神经元活动在IT皮层的清醒，行为灵长类动物。具体地说，我们想在非人类灵长类动物大脑的磁共振图像上选择一个毫米级的位置，然后问：在支持给定行为任务的过程中，该位置正常诱发的神经元活动的重要性是什么？而不是试图注入 神经元信号，我们的策略是开发方法来短暂地（10-300 ms）阻断神经元活动，通常干预之间的视觉刺激发作和动物的反应时间。为此，这个探索性的建议有两个协同的目标：首先，我们的初步结果表明，病毒传递的光门控沉默分子确实可以在IT皮层产生强烈的神经元活动沉默，但我们对这种沉默的可靠性，空间范围和时间限制知之甚少。因此，我们将（目的1）进行X射线靶向病毒注射，然后进行X射线靶向光纤植入，并在IT皮质的多个部位进行光纤尖端内和周围的神经元沉默（或增强）效应的空间精确（~10 um）映射。预期的结果是光诱导的神经元沉默的光纤尖端周围的时空地图，其依赖于光强度，持续时间和延迟。其次，我们不知道IT子区域的光学沉默是否会对物体识别任务产生可测量的行为影响。因此，我们已经开发了可能受IT沉默影响的识别任务，并且我们已经发现，在特定IT子区域（蝇蕈醇）的药理学神经元沉默导致至少一个识别任务（但不是所有这些任务）中的行为缺陷。我们现在的目标（目标2）是测试光学沉默工具在相同位置的相同任务中产生行为缺陷的能力。预期的结果是一个示范，光学沉默的IT子区域可以产生特定的行为识别缺陷，以及与ESTA诱导的赤字比较。如果成功，拟议的工作将使全新的干预工作线， 系统地测试IT皮层在视觉物体识别中的因果作用，并将为灵长类动物系统级问题的光学技术提供一个仍处于萌芽状态但很有前途的工具箱。

DESCRIPTION (provided by applicant): Visual object recognition is central to quality of life in health and disease, but it is not understood at a deep, mechanistic level. For example, while primate inferior temporal cortex (IT) is likely a key neuronal processing bottleneck, we still have only a dim understanding of its causal role at a fine spatial and temporal grain. This exploratory proposal (R21) aims to deploy, characterize, and behaviorally validate novel tools to produce spatially precise, temporally delimited silencing of neuronal activity in the IT cortex of the awak, behaving primate. Concretely, we want to choose a mm-scale location on a magnetic resonance image of a non-human primate brain, and then ask: what is the importance of normally-evoked neuronal activity at that location in supporting a given behavioral task? Rather than try to inject neuronal signals, our strategy is to develop methods to briefly (10-300 ms) block the neuronal activity that normally intervenes between visual stimulus onset and the animal's reaction time. To that end, this exploratory proposal has two synergistic aims: First, our preliminary results show that virally delivered optically-gated silencing molecules can indeed produce strong silencing of neuronal activity in IT cortex, but we have little understanding of the reliability, spatial extent and temporal limits of this silencing. Thus, we will (Aim 1) make x-ray targeted viral injections, followed by x-ray targeted optical fiber implantation, and spatially precise (~10 um) maps of neuronal silencing (or enhancement) effects in and around the optical fiber tip at multiple sites in IT cortex. The expected outcome is a spatiotemporal map of light-induced neuronal silencing around the optical fiber tip, and its dependence on light intensity, duration and latency. Second, we do not know if optical silencing of IT sub-regions leads to measurable behavioral effects on object recognition tasks. Thus, we have developed recognition tasks that are likely to be affected by IT silencing, and we have already discovered that pharmacological neuronal silencing at specific IT sub-regions (muscimol) leads to behavioral deficits in at least one recognition task (but not all such tasks). We now aim (Aim2) to test the ability of optical silencing tools to produce behavioral deficits in that same task at those same locations. The expected outcome is a demonstration that optical silencing of IT sub-regions can produce specific behavioral recognition deficits, as well as a comparison with pharmacologically induced deficits. If successful, the proposed work will enable entirely new lines of interventional work to systematically test the causal role of IT cortex in visual object recognition, and will contribute o a still nascent, but promising toolbox of optical techniques for systems-level questions in primates.