Little is known about the neurobiological mechanisms that mediate the development and expression of abnormal repetitive behaviors (e.g., stereotypies, rituals) in children with autism spectrum, and related neurodevelopmental, disorders. This lack of knowledge precludes effective early intervention and prevention strategies. We propose to build on the biochemical and pharmacological findings from our previous grant that support our hypothesis of reduced indirect basal ganglia pathway activity in animals that develop high levels of repetitive behavior. Thus, the overall goal of this project wil be to identify specific morphological and proteomic alterations that mediate the reduced indirect pathway activation associated with high rates of repetitive behavior. Specifically, we will identif alterations in dendritic morphology and protein expression that mediate reduced indirect pathway activation and development of persistent repetitive behavior (Aim #1). Next, we will test the hypothesis that experience dependent attenuation of the development of repetitive behavior will result in higher levels of indirect pathway activation, an outcome mediated by altered dendritic spine density and protein expression (Aim #2). Finally, we will test the hypothesis that exacerbation or attenuation of repetitive behavior by select pharmacological agents alters indirect pathway activity, an effect mediated by alteration of key proteins expressed in this pathway (Aim #3). Successful completion of these aims will provide new and important information about specific neurobiological mechanisms that mediate the development and expression of repetitive behavior and provide novel therapeutic targets for the development of efficacious pharmacotherapies.

Public Health Relevance

Little is known about the neurobiological mechanisms that mediate the development and expression of abnormal repetitive behaviors (e.g., stereotypies, rituals) in children with autism spectrum and related neurodevelopmental disorders. This lack of knowledge precludes effective early treatment and prevention strategies. This project will use an animal model to provide important, new information about the brain circuitry that underlies the development of repetitive behavior and what new drug treatments can be developed for these behaviors.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Developmental Brain Disorders Study Section (DBD)
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Rossi, Andrew
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University of Florida
Schools of Medicine
United States
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Wilkes, B J; Lewis, M H (2018) The neural circuitry of restricted repetitive behavior: Magnetic resonance imaging in neurodevelopmental disorders and animal models. Neurosci Biobehav Rev 92:152-171
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Bechard, Allison R; Bliznyuk, Nikolay; Lewis, Mark H (2017) The development of repetitive motor behaviors in deer mice: Effects of environmental enrichment, repeated testing, and differential mediation by indirect basal ganglia pathway activation. Dev Psychobiol 59:390-399
Bechard, Allison R; Lewis, Mark H (2016) Transgenerational effects of environmental enrichment on repetitive motor behavior development. Behav Brain Res 307:145-9
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Tanimura, Yoko; King, Michael A; Williams, Dustin K et al. (2011) Development of repetitive behavior in a mouse model: roles of indirect and striosomal basal ganglia pathways. Int J Dev Neurosci 29:461-7
Tanimura, Yoko; Yang, Mark C K; Ottens, Andrew K et al. (2010) Development and temporal organization of repetitive behavior in an animal model. Dev Psychobiol 52:813-24

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