Circuits for deviance detection in V1

项目总结 大脑对刺激的反应不是随着时间的推移而是静态的，而是被并发的上下文动态调制的 以及之前的刺激。这有助于快速检测可能是关键的行为相关信息 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质(V1) 增加为背离背景模式的刺激，这种现象被称为“异常检测”。在……里面 在人类脑电记录中，这种异常检测反映在“失配负波”，一种早期的头皮电位 由罕见的刺激引起的，例如，“奇怪的”序列。视觉不匹配的负性，以及可能的偏差 在许多神经和精神疾病中，检测是改变的，索引基本的视觉处理 赤字可能会破坏受影响的个人与他们的世界的关系。 尽管有这些基本和临床意义，但产生异常检测的神经回路尚不清楚。 我们过去的工作是利用小鼠在基础水平上解决这个问题，因为有一组强大的基因和 这种动物身上有光学工具。我们在小鼠V1中发现了稳健的异常检测，特别是在 皮质浅层(第2/3层)的锥体神经元(PYRs)。然后我们展示了V1异常检测 依赖于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 扣带状；ACA)。这些电路元件究竟是如何相互作用来调节上下文中的V1活动的，产生 对新刺激的异常检测，目前尚不清楚。 目前的项目将建立这些初步的见解，以测试关于偏差如何的详细电路假说 检测响应出现在第2/3层的V1中。具体地说，我们建议自顶向下输入到V1(来自ACA) 参与相互抑制的神经元间回路，涉及血管活性肠肽(VIP)和 生长抑素(SST)神经元。这用于瞬时调制依赖于PYRs的子集的兴奋性 关于它们的特征选择性、对冗余刺激的衰减反应和对异常的增强反应 刺激物。为了验证这一假设，我们将向清醒的小鼠呈现视觉上的“古怪”和控制序列(这是 使我们能够从缺乏简单的神经适应中解析出真正的异常检测)。我们将雇用两名- 记录光子钙成像和时空精确的光遗传干预(单光子和双光子) 并在V1中操纵细胞类型的特定活动动态。在目标1中，我们将用光学方法探测PYR的兴奋性 单细胞分辨率在古怪范例的特定阶段，评估PYR响应相对于其 功能选择性。接下来，我们将光学抑制V1(目标2)中的SST和VIP，然后自上而下地输入ACA以 V1(目标3)在古怪范例的特定阶段，同时记录PYR、SST和VIP以进行精确测试 我们的电路假说的预测。这种专注的、技术先进的方法，应用于被动的 和高度可翻译的感觉刺激范式，将提供可能改变的基本见解 在健康和疾病中如何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.