: The functional properties of sensory cortical neurons, as reflected in their response selectivity to stimulus attributes, are primarily determined by the spatiotemporal integration of sensory-evoked excitatory and inhibitory synaptic inputs to the cell. The objective of this project is to provide an understanding of excitatory and inhibitory synaptic mechanisms underlying the cortical cells'functional properties. The role of synaptic inhibition in shaping visual cortical processing has remained controversial. In addition, due to the difficulties in identifying and targeting cortical inhibitory neurons in vivo, the receptive field (RF) properties of these neurons, which are crucial to the function of synaptic inhibition, remain largely elusive. We propose to combine the in vivo whole-cell recording and two-photon imaging techniques, and exploit mouse genetic models, to determine the response properties of excitatory and inhibitory inputs in visual cortical neurons. In Aim 1, using "blind" whole-cell voltage-clamp recording coupled with histology, we will dissect the excitatory and inhibitory synaptic conductances of cortical excitatory neurons evoked by sparse flash stimuli. We will determine how simple and complex receptive field structures are determined by the spatial distribution of synaptic inputs. By reconstituting the membrane potential changes that result from these synaptic inputs, we will test the hypothesis that inhibitory inputs play a crucial role in sharpening the spatial discreteness of spike On and Off receptive fields. In Aim 2, we will perform two-photon imaging guided loose patch recording in a transgenic mouse line where inhibitory neurons are labeled with green fluorescence protein. We will examine visually evoked spike responses of both fluorescent inhibitory neurons and non-fluorescent excitatory neurons, and test the hypothesis that there are functional differences between these two groups of neurons, i.e. inhibitory neurons are less selective to stimulus attributes such as spatial phase and orientation. In Aim 3, by applying imaging guided whole-cell current-clamp and voltage-clamp recordings, we will test the hypothesis that the functional differences between excitatory and inhibitory neurons can be attributed to the difference in the strength of synaptic inputs they receive, rather than in the structure of synaptic input circuitry. These studies will provide novel insights into functional cortical circuitry. PUBLIC HEALTH RELEVANCE In the central nervous system inhibitory synaptic inputs control the gain of network activity and play a critical role in information processing. Abnormality in synaptic inhibition has been implicated in several cognitive disorders and age-related reduction in perceptual functions. The proposed project will advance our understanding of the role of inhibitory circuits in visual processing, and may provide important insights into how functional changes of inhibitory neurons can lead to deterioration of cognitive functions.