Thursday, January 27, 2022
1/27/2022
DESCRIPTION (provided by applicant): Restricted repetitive behaviors are seen in many different neurodevelopmental, neurological, and psychiatric disorders (e.g. autism, Fragile X syndrome, Rett syndrome, dementias, OCD, and schizophrenia). These behaviors are classified as highly repetitive, invariant, and without obvious function. In neurodevelopmental disorders specifically, there is a wide array of repetitive behaviors exhibited, ranging from rhythmic hand flapping or head banging to circumscribed interests and insistence of sameness. Although these behaviors are extremely common in these patient populations, the neurobiological basis of the behavior disorder is relatively unknown and treatment is challenging. The overarching goals of our lab are to elucidate the neurobiological mechanisms responsible for the expression of restricted repetitive behaviors and to reduce these behaviors in individuals with neurodevelopmental disorders. Animal models of restricted repetitive behaviors allow researchers to identify the neurobiological basis of these particular maladaptive behaviors without the influence or complication of other biological problems associated with the neurodevelopmental disorders. Animal models also allow for the determination of clinical efficacy of potential pharmacological therapies before clinical experimentation is attempted in these very vulnerable populations. Evidence from a mouse model of restricted repetitive behavior indicates that specific pathways in the brain that make up cortico-basal ganglia circuitry are disregulated. These two pathways, the direct and indirect pathways, normally work in a coordinated, yet antagonistic fashion to control cortical activation and behavioral output. Data from our lab suggests that the activation of the indirect pathway is reduced in mice that exhibit repetitive behavior and this leaves the direct pathway to overexcite the cortex and produce aberrant behaviors. To achieve our goals of elucidating the neurobiological basis of repetitive behavior, we will use mice that exhibit spontaneous repetitive behaviors and profile the gene and protein expression within the direct and indirect basal ganglia pathways. First, we will use fluorescence assisted cell sorting to separate direct from indirect pathway cells. Then we will use RT-PCR arrays to simultaneously measure the expression of 41 G-protein coupled receptors and 44 signal transduction molecules in the separate cell groups. We will then analyze the amount of those receptors that are inserted in to the cell membrane (and are therefore biologically active) and the amount of those receptors that are packaged in to intracellular vesicles. Measures from mice that exhibit high rates of repetitive behavior (C58/J mice) will be compared to measures from a closely related mouse strain (C57BL/6J mice) that express no repetitive behavior. Based on the results of our gene and protein analyses we will design drug challenge experiments to identify whether any of the targets elucidated by the first two experiments offer potential pharmacotherapy for restricted repetitive behaviors. PUBLIC HEALTH RELEVANCE: Many people with developmental disabilities, neurological problems, or psychiatric issues show restricted repetitive behaviors. These behaviors are repetitive in nature and serve no obvious function (e.g. hand flapping, head banging, insistence on sameness, and compulsions). We are investigating what genes and proteins are expressed differently in mice that show these kinds of behaviors and in mice that do not in order to learn how the brain controls these behaviors and what kind of drugs may be used to reduce them.
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