Modeling the Neurogenetics of Serotonin Regulation

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DESCRIPTION (provided by applicant): Serotonergic tone plays an important role in mental health, with dysfunction implicated in many prominent mental health disorders including depression, schizophrenia, and addictive personality disorders. This application seeks to explore the neurogenetic diversity of serotonin transporter (SERT) and Monoamine Oxidase A (MAOA) genes in rhesus monkeys. In humans, variance in these genes is associated with an individual's relative vulnerability to or protection from a range of mental health disorders. The objective here is to characterize functional polymorphisms and haplotypes in these genes in rhesus monkeys in vitro, and to identify variations that naturally mimic in effect specific human polymorphisms implicated in neuropsychiatric dysfunction. Specific Aims are to assess the incidence of polymorphisms and haplotypes in rhesus monkey SERT and MAOA genes, to explore whether certain rhesus monkey SERT, and MAOA variants have parallel functionality to human orthologous haplotypes in vitro, and to develop the use of naturally-occurring rhesus monkey genetic variations to create non-human primate models of human neurogenetic variance underlying mental health disorders. The broad ambition of the research program is to identify cohorts of rhesus monkeys that harbor multiple allelic variants which functionally parallel human allelic variants and associate with primate-specific phenotypes relevant to mental health disorders. The identification and characterization of functional SERT and MAOA polymorphisms across our colony of more than 1100 genetically diversified rhesus monkeys at NEPRC will enhance our growing genotype/phenotype assessments in this animal population by accelerating our ability to use this unique and valuable resource to clarify genetic interactions influencing distinct phenotypic, physiological, behavioral and trait variances influencing mental health. In this regard, this application explores the feasibility of using selected cohorts of NEPRC rhesus monkeys as a "naturalistic" animal model with extraordinary translational validity for human mental health research, and their appropriateness as a preclinical platform for the development of human pharmacogenomics-based therapeutics. Relevance: Understanding the genetic basis of neuropsychiatric disease will not only facilitate diagnosis and treatment options, but the elucidation of differences between individuals will increase efficacy. Developing non-human primate models of this variation allows not only for a greater examination of the mechanisms and pathologies of the disease, but also allows for the development of highly translational novel treatments.