Abstract

Neurobiological mechanisms that influence emotional reactivity: a developmental study of the hippocampus

Coleman S, Hilde KL, Maras PM, Hagenauer MH, Stefanov AV, Birt I, Kumar V, Hebda-Bauer EK, Watson SJ, Akil H
50th Annual Meeting of the Society for Neuroscience, Virtual. 2021.

Abstract

Debilitating psychiatric disorders such as major depression and chronic anxiety have a major personal and societal impact. Both prevention and treatment strategies require a better understanding of the relationship between genetic predisposition and brain function. For instance, while it is known that there is a genetic component to emotional reactivity, the neurobiological mechanisms through which gene expression patterns shape these behavioral traits remain largely unknown. Using a selective breeding model in rodents, this study aims to elucidate potential cellular mechanisms that link genetic predisposition and the emergence of vulnerable or resilient behavioral traits.

Our laboratory has selectively bred rats for over 60 generations in order to select for locomotor responses to novelty, ultimately generating a robust behavioral model of emotional reactivity and temperament. Bred low responder (bLR) animals and bred high responder (bHR) animals represent extreme ends of emotional reactivity. bLRs represent an internalizing phenotype, are behaviorally inhibited, with a high level of anxiety- and depressive-like behaviors. In contrast, bHRs represent an externalizing phenotype, with low behavioral inhibition and high levels of impulsivity.

Our lab has characterized genetic variants as well as hippocampal gene expression changes in the bLR/bHR model and identified candidate genes that differentiate between the lines. A top candidate gene is the Bone Morphogenetic Protein 4 (Bmp4), which has diverse roles in nervous system development. Preliminary results demonstrate that differences in Bmp4 in the bLR/bHR model arise early in life and are maintained throughout the lifetime of the animals. We perform a comprehensive analysis of cell-type composition and gene expression in the bLR/bHR model using a combination of multiplexed fluorescent in situ hybridization, immunohistochemistry, and confocal imaging. We test the hypothesis that Bmp4 is important for establishing cell-type balance within the developing hippocampus, and that these differences, in turn, play a role in shaping adult behavior.