PROJECT SUMMARY The overarching goal of this project is to better understand the links between ASD genetic risk, resulting distributed brain connectivity impairments, and the impact of this on ASD-relevant behaviors. We will do this by performing state-of-the art in vivo electrophysiology studies in awake-behaving animals that model a monogenic form of ASD. This research project is significant because altered brain connectivity is routinely observed in ASD patients, though it remains unknown how brain connectivity alterations cause abnormal behaviors relevant to ASD. In the animal model, we will focus on behaviors that optimize active touch. This is approach is valid because altered sensory function, including touch, is a core manifestation of ASD and somatomotor brain areas display altered activation in ASD patients. An emerging idea is that altered functioning of sensory systems directly impairs the functions of other major neural domains, such as cognitive and social systems. Active touch arises through rapid adaptions in the dynamics of touch organs in response to physical contact with objects. This behavioral transformation optimizes touch-related input into the brain and is an emergent behavior resulting from sensorimotor integration at various levels in the nervous system. Therefore, we generally hypothesize that genetic variants that cause ASD disrupt key points of functional connectivity within the somatomotor system, which in turn causes altered active touch behaviors, leading to altered acquisition of tactile information. This hypothesis is significant because it could define a neural process (i.e. altered distributed functional connectivity) that explains how sensory-guided adaptive behaviors are impaired by genetic variants that cause ASD. Our modeling studies also have the potential to define how altered brain connectivity can disrupt relevant behaviors. We will test this hypothesis in the first aim by recording the flow of information throughout the major areas of the somato-motor system in a mouse model for a monogenic form of ASD. The proposed in vivo recordings in awake-behaving animals will utilize state-of-art silicon neural probes that will enable us to measure local and long-range functional connectivity of neurons during distinct behaviors, including during active touches of objects. These sophisticated measurements will identify circuits that are functionally impaired during ASD-relevant behaviors. The second aim takes a distinct, but complementary approach by regionally and temporally disrupting expression of the causal ASD gene and then observing the impact of these perturbations on behaviors that define etiologically-relevant active touch. We expect to find that proper expression of the ASD gene is required in developing s...