Circuits for deviance detection in V1

项目概要 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。这支持快速检测可能是关键的行为相关信息 为了在复杂的环境中生存。在视觉系统中，神经活动早在初级视觉皮层（V1） 偏离情境模式的刺激会增加，这种现象称为“偏差检测”。在 人类脑电图记录中，这种偏差检测反映在“失配负性”中，这是一种早期头皮电位 例如，由“奇怪”序列中的罕见刺激引起。视觉不匹配的负面影响和可能的偏差 检测，在许多神经和精神疾病中发生改变，索引基本的视觉处理 可能会破坏受影响的个人与世界的关系的赤字。 尽管具有这一基本和临床意义，但用于生成偏差检测的神经回路仍是未知的。 考虑到强大的遗传和基因组，我们过去的工作利用小鼠在基本层面上解决了这个问题。 这种动物可以使用光学工具。我们在小鼠 V1 中发现了强大的偏差检测，特别是在 浅层皮质层（第 2/3 层）的锥体神经元 (PYR)。然后我们展示了 V1 偏差检测 取决于 i) 局部 GABA 能中间神经元和 ii) 来自较高皮质区域（前部）的自上而下的输入 扣带回； ACa）。这些电路元件究竟如何相互作用来调节上下文中的 V1 活动，产生 对新刺激的偏差检测尚不清楚。 当前的项目将建立这些初步见解来测试偏差如何的详细电路假设 检测响应出现在第 2/3 层的 V1 中。具体来说，我们建议对 V1 进行自上而下的输入（来自 ACa） 参与相互抑制的中间神经元回路，包括血管活性肠肽（VIP）和 生长抑素（SST）神经元。这用于瞬时调节依赖于 PYR 的子集的兴奋性 关于它们的特征选择性，减弱对冗余刺激的反应并增强对异常刺激的反应 刺激。为了检验这个假设，我们将向清醒的小鼠呈现视觉“奇怪”和控制序列（这 允许我们在缺乏简单神经适应的情况下解析真正的偏差检测）。我们将聘用两名—— 光子钙成像和时空精确光遗传学干预（一光子和二光子）来记录 并操纵 V1 中细胞类型的特定活性动态。在目标 1 中，我们将光学探测 PYR 兴奋性 在奇怪范式的特定阶段进行单细胞分辨率，评估相对于其的 PYR 反应 特征选择性。接下来，我们将光学抑制 V1 中的 SST 和 VIP（目标 2），然后自上而下的 ACa 输入 V1（目标 3）在奇怪范式的特定阶段，同时记录 PYR、SST 和 VIP 以进行精确测试 我们的电路假设的预测。这种重点突出、技术先进的方法在被动 和高度可转化的感官刺激范式，将提供可以改变的基本见解 如何在健康和疾病中研究和理解基本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.