Neural Mechanisms of Predictive Impairments in Autism

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Autism spectrum disorders (ASDs) are characterized by altered sensory processing and intellectual disability. Atypical sensory processing has been recognized as an important diagnostic criterion for autism and is predictive of social communication deficits later in life. ASDs are also associated with impaired structural and functional connectivity within and between neocortical areas. However, how impaired neural connectivity, which is present in ASDs, leads to impaired sensory processing and learning is not understood. Recently, we have discovered new visual familiarity-evoked theta oscillations in the primary visual cortex (V1). In Fmr1 KO mice, a mouse model of Fragile X syndrome, these oscillations are weaker, shorter, and frequency shifted. Furthermore, we have shown a similar emergence of visually cued theta oscillations in the anterior cingulate cortex (ACC), an area connected to V1 and involved in social interaction, decision making and error detection. We have also started mapping the neural circuit underlying these oscillations. Our prior studies suggest that these familiarity-evoked theta oscillations and the underlying changes in the neural circuit connectivity may be the cause of impairments in visual learning and perception. Our preliminary data also suggest that Fmr1 KO mice demonstrate impaired theta oscillations in a visual discrimination task. We have developed a computational model to reproduce theta oscillations in the cortex. This proposal builds on foundational advances by dissecting the mechanisms of theta oscillations in WT and Fmr1 KO mice. Using an integrated approach combining mapping of neuronal connectivity in brain slices, in vivo extracellular recordings, and behavior, we will: 1) map the circuitry necessary to form a theta oscillator in V1 and identify altered connectivity patterns within V1 and between V1 and ACC in Fmr1 KO mice, 2) examine how the strength of theta oscillations in V1 and ACC correlates with behavior in WT and Fmr1 KO mice following learning, and 3) rescue theta oscillations by restoring FMRP expression selectively only in the specific neuronal groups in Fmr1 KO mice guided by the computational model. Based on our prior studies, preliminary data, and computational model, we expect to see familiarity-evoked theta oscillations correlate with successful behavior in a visual discrimination task. We also expect to identify the critical parts of the neural circuit required for the generation of theta oscillations and its impairment in Fmr1 KO mice. Results from this proposal will help inform the development of targeted neural circuit-based behavioral and pharmacological therapeutics to enable personalized medicine for individuals with ASDs.