Audrey Christine Brumback, MD, PhD - US grants

? DESCRIPTION (provided by applicant): Autism spectrum disorder is a prevalent and devastating neuropsychiatric condition characterized by disabilities in social communication and repetitive, restricted interests and behaviors. Though many genetic changes have been linked to autism, it is unclear how the implicated genes translate into clinical symptoms. In the proposed studies, I will use cutting-edge techniques to discover how diverse genetic causes of autism connect at the level of neuronal circuits to drive autism-associated behaviors. I am a board-certified Child Neurologist with a PhD in Neuroscience. I have extensive training in neurobiology and the clinical evaluation and management of neurological diseases. My long-term goal is to understand the autistic brain through clinically-relevant basic science research. In order to become an independent investigator running my own productive research group elucidating the neurobiology of autism, there are several skills I need to master. Through the proposed research and career development plan, I will obtain the training, mentorship, and experience I need to launch my career as a successful independent investigator. My preliminary studies show a specific deficit in the excitability of prefrontal corticothalamic neurons that is common to three mouse models of autism (Fragile X knockout, CNTNAP2 knockout, and prenatal valproate exposure). Importantly, the social behavior of valproate-exposed mice can be bidirectionally modulated by acute ontogenetic activation or inactivation of these prefrontal corticothalamic neurons. In the proposed studies, I will use these mouse models of autism to test specific hypotheses about how the prefrontal corticothalamic circuit participates in autism-associated behaviors. In Aim 1, I will perform in vitro brain slice electrophysiology to test the hypothesis tat in autism, synaptic transmission is defective between the prefrontal cortex and thalamus. In Aim 2, I will perform in vivo electrophysiology and in vivo calcium imaging of the prefrontal cortex and thalamus during social behavior to determine how these regions interact in the normal and autistic brain. Finally, in Aim 3, I will perform ontogenetic manipulations in awake, behaving mice to test how the prefrontal corticothalamic circuit directly contributes to social behavior. I have assembled a stellar team of experts in neurobiology and autism to serve as mentors - Drs. Vikaas Sohal, Mattew State, and Elysa Marco. Two other world-renown experts will serve as advisors for the in vivo electrophysiology (Dr. Loren Frank) and behavioral experiments (Dr. Jacqueline Crawley). I will supplement the mentored research with coursework on signal processing, data analysis, computer programming, biostatistics, and bioethics. I will gain expertise in the clinical aspects of autism spectrum disorder through mentoring by Drs. State and Marco. Finally, I will hone my professional skills by publishing original research manuscripts, presenting my work at international meetings, and participating in formal courses on scientific leadership and management. By the completion of the career development award, I will have successfully applied for R01-level funding. As a result of the individually-tailored carer development plan, I will be able to launch my career as a physician- scientist and independent investigator leading a productive team of researchers focused on discovering the cellular and circuit-based mechanisms of autism spectrum disorder.

Project Summary The mediodorsal thalamus (MD) and its reciprocal connection with medial prefrontal cortex (mPFC) control important aspects of executive functioning and social behavior. Dysfunction of this neural circuit can cause developmental brain disorders and neuropsychiatric conditions. Understanding prefrontal thalamocortical (MD?mPFC) circuit function has been hampered by a lack of understanding of MD projection neuron types and how they integrate and process synaptic information. The central hypothesis is that differences in intrinsic properties and connectivity between the two major populations of neurons that provide ascending input to the mPFC causes them to extract and transmit different information to the mPFC. Thus, these two populations have different roles in behavior. The overall goal is to expand understanding of the circuits within MD. The rationale is that understanding of neural processing by the thalamus and thalamic inputs to prefrontal cortex is necessary for understanding the mechanisms of executive function and developing neuromodulation therapies targeting the prefrontal network for neuropsychiatric disorders. The central hypothesis will be tested with three specific aims: 1) Determine how intrinsic properties of MD neurons control synaptic integration of mPFC inputs. 2) Test how MD neurons differentially process synaptic inputs arising from different brain regions. 3) Determine how optogenetic manipulation of specific MD circuits affects cognitive, social, and affective behaviors in wildtype mice. The research proposed in this application is innovative, in the applicant's opinion, because it defines the function of an understudied but essential thalamic nucleus, from the level of membrane biophysics, to synaptic integration, to control of behavior. The work is significant because it will contribute to the anatomical and physiological map of prefrontal thalamocortical circuitry. Ultimately, such knowledge has the potential to guide the development of future neuromodulation strategies to treat the symptoms of neuropsychiatric disorders that localize to the prefrontal network.