Project 1. Uncovering the developmental genetic programs for establishment of limbic system neuronal diversity and connectivity.
Proper displays of social interaction between members of the same species are required for species propagation and survival. These behaviors are regulated by the limbic system, an interconnected set of brain nuclei that are generally highly conserved across mammals. Alterations in specific aspects limbic system development are a hallmark feature of human disorders such as autism and schizophrenia.While environmental inputs shape social behaviors, many components of these behaviors are hard-wired. Thus, it is likely that developmental genetic programs pattern the wiring of brain circuits that control these behaviors. However, the genetic programs that drive formation of limbic system neuronal identity and circuitry remain largely unknown. We are currently addressing this question using a combination of developmental genetic, gene profiling, electrophysiological and behavioral approaches.
Project 2. Determination of how developmentally defined limbic subcircuits control sex-specific innate social behaviors.
Despite a general understanding of how different brain structures control innate behaviors, the subcircuit logic for regulation of different innate behaviors remains generally unknown. Moreover, many of these behaviors differ between sexes suggesting different patterns of connectivity and/or circuit function in males and females.From our studies, we have discovered that parcellation of amygdala progenitor pools by transcription factor expression predicts neuronal subtype identity as defined by molecular and intrinsic electrophysiological characteristics, and quite interestingly sex differences in innate behavior-tuning specificity. Using a combination of viral, electrophysiological and optogenetic approaches our goal is to generate a comprehensive limbic system neuronal circuit map based on developmental genetic criteria. Moreover, we are employing a combination of in vivo optogenetic and pharmacological approaches to define the necessity and sufficiency of developmentally defined limbic subcircuits in regulation of sex-specific innate behaviors.
Project 3. Translation of our knowledge of limbic system development toward understanding genotype to phenotype links in autism spectrum disorders.
Currently, autism diagnosis is solely based on behavioral criteria. The lack of biological criteria for diagnosis represents a severe limitation for both the design of rational therapeutic approaches to treat underlying neurological dysfunction and predict outcomes for individuals with autism. Thus, there is a pressing unmet need to understand how mutations in autism susceptibility genes relate to neuroatypical behavior that defines autism. Recently, my laboratory in collaboration with the Center for Autism Spectrum Disorders at Children’s National, NICHD and Yale University has begun a cross model analysis (mouse, zebrafish, iPSCs) linking autism gene function to altered trajectories of amygdala development. This project leverages our knowledge of developmental genetics of the social brain, combined with recent advances in cataloguing of autism susceptibility genes from large sequencing efforts to elucidate how subsets of autism susceptibility genes function in the development and function of the amygdala, a central brain structure implicated in the social dysfunction in autism.
Project 4. Investigation of neurological consequences of COVID-19 on the pediatric brain.
One of the main consequences of COVID-19 infection in affected individuals in the pediatric population is a syndrome dubbed MISC (multi-inflammatory syndrome in children). Although relatively rare, hyperactive immune responses can have secondary consequences for brain development due to a comprised blood-brain-barrier. Additionally, recent evidence suggests that COVID-19 can also directly infect brain cells. Our lab is embarking on a new initiative to study this phenomenon in animal models.