Circuits for deviance detection in V1

项目摘要 大脑对刺激的反应并不是随着时间的推移而静态的，而是受到并发环境的动态调节。 和之前的刺激。这有助于快速检测行为相关信息，这可能是关键 在复杂的环境中生存。在视觉系统中，神经活动早在初级视皮层（V1） 对于偏离上下文模式的刺激，这种现象被称为“偏差检测”。在 在人类EEG记录中，这种异常检测反映在“失配负性”中，即早期头皮电位 由罕见的刺激引起，例如，“古怪”序列。视觉不匹配负性，和可能的偏差 检测，在许多神经和精神疾病中改变，索引基本视觉处理 这些缺陷可能会破坏受影响的个人与他们的世界的关系。 尽管有这种基本和临床意义，但产生异常检测的神经回路是未知的。 我们过去的工作已经利用小鼠在基本水平上解决了这个问题，考虑到强大的遗传和 光学工具。我们在小鼠V1中发现了强大的异常检测，特别是在 皮质浅层（2/3层）的锥体神经元（PYR）。然后，我们表明，V1偏差检测 依赖于i）局部GABA能中间神经元和ii）来自更高皮质区域（前皮质）的自上而下的输入。 扣带; ACa）。这些电路元件如何相互作用，在上下文中调节V1活动， 异常检测新的刺激，是不清楚的。 目前的项目将建立这些初步的见解，以测试一个详细的电路假设， 检测响应出现在层2/3中的V1中。具体来说，我们建议自上而下输入到V1（来自ACa） 参与相互抑制的中间神经元回路，即涉及血管活性肠肽（VIP）， 生长抑素（SST）神经元。这用于瞬时调节PYR依赖性神经元亚群的兴奋性。 在他们的特征选择性上，减弱了对冗余刺激的反应，增强了对异常刺激的反应。 刺激。为了验证这一假设，我们将向清醒的小鼠呈现视觉“古怪”和控制序列（ 允许我们从简单神经适应的缺失中解析真正的偏差检测）。我们会雇佣两个- 光子钙成像和时空精确的光遗传学干预（单光子和双光子）， 并操纵V1中的细胞类型特异性活性动力学。在目标1中，我们将光学探测PYR的兴奋性， 单细胞分辨率在特定阶段的oddball范例，评估PYR反应相对于他们的 特征选择性接下来，我们将在V1中光学抑制SST和VIP（目标2），然后自上而下ACa输入， V1（目标3）在古怪范式的特定阶段，同时记录PYR，SST和VIP，以精确测试 我们的电路假设的预测。这种集中的、技术先进的方法，在一个被动的 和高度可翻译的感官刺激范式，将提供基本的见解， 如何在健康和疾病中研究和理解基本的视觉处理和中央视觉回路。

PROJECT SUMMARY Brain responses to stimuli are not static over time but are dynamically modulated by the context of concurrent and preceding stimuli. This supports the rapid detection of behaviorally relevant information which may be key for survival in complex environments. In the visual system, neural activity as early as primary visual cortex (V1) is increased to stimuli that deviate from contextual patterns, a phenomenon termed “deviance detection.” In human EEG recordings, this deviance detection is reflected in the “mismatch negativity”, an early scalp potential elicited by rare stimuli in, for example, an “oddball” sequence. Visual mismatch negativity, and likely deviance detection, is altered in many neurological and psychiatric disorders, indexing fundamental visual processing deficits that may undermine how affected individuals relate to their world. Despite this basic and clinical significance, the neural circuitry for generating deviance detection is unknown. Our past work has utilized mice to address this question at a basic level, given the powerful set of genetic and optical tools available in this animal. We identified robust deviance detection in mouse V1, particularly in pyramidal neurons (PYRs) in superficial cortical layers (layer 2/3). We then showed that V1 deviance detection is dependent on i) local GABAergic interneurons and ii) top-down inputs from higher cortical areas (anterior cingulate; ACa). Exactly how these circuit elements interact to modulate V1 activity in context, producing deviance detection to novel stimuli, is unclear. The current project will build these preliminary insights to test a detailed circuit hypothesis of how deviance detection responses emerge in V1 in layer 2/3. Specifically, we propose that top-down input to V1 (from ACa) engages a mutually inhibitory interneuron circuit, involving namely vasoactive intestinal peptide- (VIP) and somatostatin- (SST) neurons. This serves to transiently modulate the excitability of subsets of PYRs dependent on their feature selectivity, attenuating responses to redundant stimuli and augmenting responses to deviant stimuli. To test this hypothesis, we will present visual “oddball” and control sequences to awake mice (which allows us to parse true deviance detection from the absence of simple neural adaption). We will employ two- photon calcium imaging and spatiotemporally precise optogenetic interventions (one and two-photon) to record and manipulate cell-type specific activity dynamics in V1. In aim 1, we will optically probe PYR excitability with single cell resolution during specific phases of the oddball paradigm, assessing PYR responses relative to their feature selectivity. Next, we will optically suppress SST and VIPs in V1 (aim 2) and then top-down ACa inputs to V1 (aim 3) at specific phases of the oddball paradigm while recording PYRs, SSTs, and VIPs to precisely test predictions of our circuit hypothesis. This focused, technologically advanced approach, applied during a passive and highly translatable sensory stimulation paradigm, will provide fundamental insights which could transform how basic visual processing and central visual circuitry is studied and understood in health and disease.