Substance use disorders (SUDs) are debilitating disorders that have a major personal and societal impact. Both prevention and treatment strategies require a better understanding of neurobiological and behavioral traits that predispose for drug taking as well as risk of addiction. Our laboratory has selectively bred rats for over 60 generations in order to select for particular behavioral traits, ultimately generating a robust behavioral model of emotional reactivity and addiction liability. Bred high responder (bHR) and bred low responder (bLR) animals represent extreme ends of emotional reactivity: bHR animals represent an externalizing phenotype, with low behavioral inhibition and high levels of impulsivity and drug-seeking behavior. bLR animals represent an internalizing phenotype, are behaviorally inhibited, with a high level of anxiety- and depressive-like behaviors, but less prone to drug seeking and relapse. Importantly the reproducibility of behavioral traits across generations allows for a predictive model and the investigation of developmental mechanisms that contribute to adult behavior. A major goal of the parent award (U01) is to understand the genetic basis of temperamental tendencies that predispose for addictive behaviors. In recent years, our lab has characterized genetic variants as well as hippocampal gene expression changes that arise early in development in the bHR/bLR model and strongly discriminate between the lines. A top candidate gene in development is the Bone Morphogenetic Protein 4 (Bmp4), which has well- established roles in patterning the developing nervous system, neurogenesis, and importantly, in specification of astrocytes and oligodendrocyte number during development. It is currently unknown whether glial specification and postnatal Bmp4 expression are important for shaping temperament and behavior. In this application we propose to study the role of Bmp4 in glial subtype specification and behavioral responses within the bHR/bLR model. We hypothesize that differences in Bmp4 arise early in development and contribute to a diverging glial phenotype in which the generation of oligodendrocytes and astrocytes is modified, and that differences in cell types, in turn, contribute to differences in temperament. This hypothesis will be tested using a combination of histological, viral, and behavioral approaches. This work has the potential to reveal a novel mechanism by which the developing hippocampus is patterned in the early postnatal window, and point to a new role for glial subtypes in shaping vulnerability to addictive and affective disorders.

Public Health Relevance

Only some people are tempted to experiment with drugs of abuse, and only a portion of them become true addicts. To understand the genetic and environmental reasons behind a person's vulnerability to addiction, we used selective breeding to generate two lines of rats that differ significantly in their tendency to experiment with drugs and become addicted. In this proposal, we will use innovative strategies to discover how developmental divergence within this model relates to their underlying differences, and provide insights into the biology of addiction in humans.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDA1)
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Lossie, Amy C
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Turner, Cortney A; Sharma, Vikram; Hagenauer, Megan H et al. (2018) Connective Tissue Growth Factor Is a Novel Prodepressant. Biol Psychiatry 84:555-562