Inhibitory regulation of visual processing and plasticity in visual cortex

描述（由申请人提供）：皮层抑制回路对于感觉信息的处理至关重要，例如，需要在宽范围的刺激强度上控制响应增益。增益控制对于所有感觉模态都是必不可少的，并且介导增益控制的细胞机制可以代表在整个皮层中用于执行诸如多模态整合和认知任务的功能的典型电路布置。缺乏对增益控制期间驱动抑制性神经元活动的局部连接的理解。以前的进展受到无法在体内鉴定和操纵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技术，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，特定抑制性细胞亚型的遗传干扰再现了许多神经发育疾病特征的感知和行为缺陷。目前尚不清楚这些明确的分子缺陷在抑制性神经元的早期发展表现为缺陷的感觉编码在成人。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--表达小白蛋白的神经元（PV）的经验依赖性成熟;（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。具体而言，我们将确定负责招募正常和视觉剥夺小鼠PV神经元的局部连接，使用体内双光子成像指导记录已识别的细胞类型，药物遗传学和光遗传学操作，以及体外切片电生理学。接下来，使用相同的技术，我们将评估PV神经元在遗传受损背景下发展和维持其成熟连接特征的能力。最后，我们将分析的影响，通过测量对比度饱和度和对比度不变的调整兴奋性神经元的方向选择性，使用遗传编码的钙指示剂GCaMP 6的PV神经元的板层特异性药物遗传操作的增益控制整个发展。这些特定目标的成功完成将揭示耦合视觉经验的PV响应特性的成熟和皮质网络增益控制的出生后发展的分子机制。

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.