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.
There is a division of labor among brain cell types;this diversity of cell types is essential for proper signal transformation and sensory encoding. Understanding the process by which experience drives the differentiation of cell types during postnatal development is an important step in designing treatment strategies for neurodevelomental diseases such as autism and schizophrenia. Furthermore, results from these studies may identify molecular pathways that can be targeted in the treatment of amblyopia in adults.
|Pafundo, Diego E; Nicholas, Mark A; Zhang, Ruilin et al. (2016) Top-Down-Mediated Facilitation in the Visual Cortex Is Gated by Subcortical Neuromodulation. J Neurosci 36:2904-14|