# Investigating the role of Bmp4 in glial subtype specification and temperament

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $88,426

## Abstract

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.

## Key facts

- **NIH application ID:** 10318440
- **Project number:** 3U01DA043098-05S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** HUDA AKIL
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $88,426
- **Award type:** 3
- **Project period:** 2017-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318440

## Citation

> US National Institutes of Health, RePORTER application 10318440, Investigating the role of Bmp4 in glial subtype specification and temperament (3U01DA043098-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10318440. Licensed CC0.

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