Flexiblebehavioriscentraltovirtuallyallcognitiveandsocialabilities.Recenttechnicaladvanceshaveopenedan unprecedentedopportunitytocomprehensivelydissecttheneuralcircuitmechanismsofthisabilityacrossmultiple brainareasinfreelybehavinganimals.Thisproposalfocusesonthecerebellum,astructurethatisamajorsiteof pathologyinautismspectrumdisorder.Damagetothecerebellumatbirthleadstoa36foldincreaseintheriskof autism, and this region is also a principal site for coexpression of autism risk genes. Thus cerebellar development may act as an intermediate mechanistic step in transducing inherited autism risk into neurodevelopmental phenotypes. In this project, a multidisciplinary team of leading experts proposes to investigate the neural basis of this disorder using advanced technologies, including unbiased automatic classification of behavior, largescale cellularresolutionimaginginbehavingrodents,mousegeneticmodelsfor autism,andmanipulationofneuralactivityinspecificcerebellarareasandcelltypes.Ingeneticmousemodelsof autism, the researchers will identify modes of behavior based on physical poses, and relate these modes to classical behavioral tests, such as eyeblink conditioning, and tocerebellarcircuitdysfunction.Inadultwildtype andautismmodelmice,theresearcherswilluseoptogeneticmethodstoperturbspecificcerebellarlobuleswhile quantifying the effects on behavioral dynamics and learning. In juvenile model mice, the researchers will use chemogeneticmethodstoidentifylonglastingpatternsofbehavioraldisruptionandrelatethesepatternsacross behaviorstobuildaquantitativemapoftheseperturbations.Inaddition,theywilluseinvivodendriticimagingto evaluatetheinfluencesofcerebellarperturbationonneocorticalneuronstructure.Alloftheseresultswillinform modeling of cerebellarneocortical interactions to better understandhowthesedifferentlywiredregionsinteract duringlearninganddevelopment.Thelongtermgoalofthisprojectistoarriveatachainofexplanation,centered on principles of convergent neuroscience, to understand causalmechanismsofneurodevelopmentaldisorders. This project will join genetics with circuit function, local cerebellar anatomy with behavioral outcomes, and classical behavioral tests with modern unbiased methods. Thisprojectisexpectedtoproduceanaccurateand detailed understanding of cerebellar contributions to normal and aberrant neurodevelopment. In addition, the proposedresearchwillenableresearcherstogenerateandtestavarietyofhypothesesabouttheneuralbasisof flexible behavior. Taken together, these achievements will represent a crucial step toward a mechanistic understanding of howthebraindevelopsitscomplexabilitytorespondflexiblytotheenvironment,frombirthto adulthood.
Impairments in flexible and social behavior are hallmarks of many neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorder, schizophrenia, mood disorders, and attention deficit/hyperactivity disorder. The major goal of this project is to determine how genetic susceptibility to autism spectrum disorder acts through neural mechanisms in the cerebellum to produce deficits in flexible and social behavior. Through a coordinated effort by multiple researchers to observe, map, perturb, and model brain circuits and behavior with state-of-the-art technologies, this project will provide critical clues to therapeutic approaches by establishing a causal, convergent framework for autism spectrum disorder from genes to circuits to systems to behavior.
| Badura, Aleksandra; Verpeut, Jessica L; Metzger, Julia W et al. (2018) Normal cognitive and social development require posterior cerebellar activity. Elife 7: |
| Deverett, Ben; Koay, Sue Ann; Oostland, Marlies et al. (2018) Cerebellar involvement in an evidence-accumulation decision-making task. Elife 7: |
