Inhibitory regulation of visual processing and plasticity in visual cortex

描述（由申请人提供）：皮质抑制回路对于感觉信息的处理至关重要，例如，需要在大范围刺激强度下控制反应增益。增益控制对于所有感觉模式都是必不可少的，介导增益控制的细胞机制可能代表了整个皮层中用于执行多模态整合和认知任务等功能的典型电路安排。对增益控制过程中驱动抑制性神经元活动的局部连通性的理解是缺乏的。以前的进展受到无法识别和操纵体内特定抑制细胞类型的限制。在这里，我们将采用最先进的双光子成像技术，结合体内电生理学和小鼠转基因，直接记录和操纵特定抑制细胞类型的神经活动。引人注目的是，特定抑制细胞亚型的遗传扰动再现了许多神经发育疾病特征的感知和行为缺陷。目前尚不清楚这些发育早期抑制性神经元中定义明确的分子缺陷如何在成人中表现为感觉编码缺陷。我们弥合这一差距的策略是：(1)研究一种特别重要的抑制性细胞类型——小蛋白表达神经元（PV）的经验依赖性成熟，以及(2)精确量化PV神经元在出生后发育过程中调节增益的程度。具体来说，我们将通过结合体内双光子成像引导的鉴定细胞类型记录、药物遗传学和光遗传学操作以及体外切片电生理学，确定正常和视觉剥夺小鼠中负责募集PV神经元的局部连接。接下来，使用相同的技术，我们将评估PV神经元在基因受损背景下发展和维持其成熟连接概况的能力。最后，我们将通过使用基因编码的钙指示剂GCaMP6测量兴奋性神经元的对比饱和度和定向选择性的对比不变调节，分析层状特异性PV神经元的药物遗传学操作对整个发育过程中增益控制的影响。这些特定目标的成功完成将揭示视觉经验与PV反应特性成熟和皮质网络增益控制的出生后发育相结合的分子机制。

DESCRIPTION (provided by applicant): Cortical inhibitory circuits are critically important for processing of sensory information, for example, are required for controlling response gain across a wide range of stimulus intensities. Gain control is essential for all sensory modalities, and the cellular mechanisms mediating gain control may represent a canonical circuit arrangement used throughout the cortex to perform functions such as multimodal integration and cognitive tasks. An understanding of the local connectivity that drives inhibitory neuron activity during gain control is lacking. Previously progress was limited by an inability to identif and manipulate specific inhibitory cell types in-vivo. Here we will employ state-of-the-art two-photon imaging technology in combination with in-vivo electrophysiology and mouse transgenics to directly record and manipulate the neural activity of specific inhibitory cell types. Strikingly genetic perturbation of specific inhibitory cell subtypes reproduces many perceptual and behavioral deficits that characterize neurodevelopmental disease. Currently it is unknown how these well-defined molecular defects in inhibitory neurons early in development manifest as deficits in sensory encoding in the adult. Our strategy to bridge this gap is to (1) study experience-dependent maturation of a particularly important inhibitory cell type, the parvalbumin-expressing neuron (PV), and (2) precisely quantify the extent to which PV neurons regulate gain across postnatal development. Specifically, we will identify the local connectivity responsible for recruiting PV neurons in normal and visually deprived mice, using a combination of in-vivo two-photon imaging guided recording of identified cell types, pharmacogenetic and optogenetic manipulation, in addition to in-vitro slice electrophysiology. Next, using the same techniques we will assess the ability of PV neurons to develop and maintain their mature connectivity profile in a genetically compromised background. Finally, we will assay the impact of laminar-specific pharmacogenetic manipulation of PV neurons on gain control across development by measuring contrast saturation and contrast invariant tuning of orientation selectivity in excitatory neurons using the genetically encoded calcium indicator GCaMP6. Successful completion of these specific aims will reveal the molecular mechanisms that couple visual experience to the maturation of PV response properties and postnatal development of cortical network gain control.