Intersection of causal neurodevelopmental disorder risk genes, cortical circuit function, and cognitive processing required for behavioral adaptions

项目总结

PROJECT SUMMARY Neurodevelopmental disorders (NDDs), like most neuropsychiatric disorders, are defined in general terms through cognitive impairment and behavioral alterations. Advances in genome sequencing from large patient populations has led to the identification of genes that cause complex NDDs. As a result, a major area of basic research related to NDDs is to understand how these high-impact genetic risk factors disrupt molecular and cellular mechanisms in brain cells and how these cellular alterations translate to changes in circuitry and behavior. This ongoing R01 has historically focused on the neurobiological impact of a consensus NDD risk gene, Syngap1, on the assembly and function of cortical synaptic connectivity in mice. In the current budget period, we have made progress toward understanding the extent of touch-mediated behavioral deficits and dysfunction within cortical circuitry that processes touch in the Syngap1 mouse model. The upcoming budget period seeks to understand the cause-and-effect relationships between altered assembly, function, and plasticity of cortical circuits and touch-associated behavioral maladaptations in this model. Based on mounting published and unpublished preliminary data, we will test the overarching hypothesis that Syngap1 regulates cognitive function and behavior by sculpting cortical circuits that promote tactile perception. This hypothesis is relevant to NDD etiology because altered sensory processing is a ubiquitous manifestation of NDDs, including ASD, SCZ, and ADHD. An idea gaining momentum in the field is that alterations to cognitive function and behavior are caused, at least in part, through impaired sensory processing within cortical circuits. This research topic is relevant to mental health disorders because cognitive function is a major domain of brain function and perception is a construct that defines it. However, the circuits that support perception, how they directly impact behaviors relevant to mental health disorders, and how major genetic risk factors regulate them, remains poorly understood. Aim 1 will determine how Syngap1 expression within tactile processing cortical neurons contributes to tactile learning and behavioral phenotypes in Syngap1 mice. Aim 2 studies will determine how Syngap1 regulates mesoscale cortical plasticity during tactile learning. Aim 3 is designed to provide insight into how Syngap1 expression in forebrain excitatory neurons contributes to modulation of hindbrain arousal centers that support reinforcement learning. Overall Impact: The proposed research has the potential to define cortical circuits that causally link impaired sensory processing directly to NDD-associated cognitive and behavioral impairments. Such studies are expected to inform the growing idea in the field that impaired cortical sensory processing directly leads to behavioral maladaptations common to NDDs.