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生活质量的核心，但人们对其缺乏深层次的机械理解。例如，虽然灵长类下颞叶皮质(IT)可能是神经元处理的关键瓶颈，但我们仍然有 对其因果作用只有一个模糊的空间和时间颗粒。这项探索性建议(R21)旨在部署、表征和行为验证新工具，以产生空间上精确的、时间上限定的对行为灵长类动物觉醒的IT皮质中的神经元活动的沉默。具体地说，我们想要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：在该位置正常诱发的神经元活动在支持给定行为任务方面的重要性是什么？而不是试图注入 对于神经元信号，我们的策略是开发方法来短暂地(10-300ms)阻断通常在视觉刺激开始和动物反应时间之间干预的神经元活动。为此，这一探索性的提议有两个协同目标：第一，我们的初步结果表明，病毒传递的光学门控沉默分子确实可以产生强烈的IT皮质神经元活动沉默，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(目标1)进行X光靶向病毒注射，然后X光靶向光纤植入，并在空间上(~10um)绘制IT皮质多个位置光纤末端及其周围的神经元沉默(或增强)效应图。预期的结果是一张光诱导的光纤末端周围神经元沉默的时空图，以及它对光强度、持续时间和潜伏期的依赖。第二，我们不知道IT子区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，我们开发了可能受到IT沉默影响的识别任务，我们已经发现，特定IT亚区(Muscimol)的药理神经元沉默会导致至少一个识别任务(但不是所有此类任务)的行为缺陷。我们现在的目标是(AIM2)测试光学沉默工具在相同地点的相同任务中产生行为缺陷的能力。预期的结果是，证明IT亚区的光学沉默可以产生特定的行为识别缺陷，并与药物诱导的缺陷进行比较。如果成功，拟议的工作将使全新的干预性工作能够 系统地测试IT皮层在视觉对象识别中的因果作用，并将为解决灵长类系统级问题的光学技术工具箱做出贡献，该工具箱仍处于萌芽阶段，但前景看好。

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.