Steroid hormone dependent gene expression and neuroplasticity in the brain

PROJECT SUMMARY
Steroid hormones in humans and other animals coordinate physiological and behavioral processes underlying
optimal responses to the social environment. The brain is a major site of steroid hormone action; however, our
knowledge of the role of steroid hormones in regulating gene expression and neuroplasticity in the brain is in
its infancy. It has been a challenge to disentangle the role of steroid hormones on brain function because they
broadly influence physiology and behavior, making it difficult to characterize direct versus indirect effects.
Thus, researchers wishing to use animal models of the hormonal modulation of the brain should have the
ability to study separately the physiological and behavioral effects of steroid hormones. My research program
aims to uncover the connections between steroid hormones, gene expression in the brain, and neuroplasticity
using Astatotilapia burtoni, a cichlid fish that exhibits sophisticated social dynamics. In the wild as in the
laboratory, male A. burtoni stratify along a social hierarchy where dominant males possess bright coloration,
aggressively defend a territory, and mate with females, while non-dominant males do not. Female A. burtoni do
not form a social hierarchy but behave aggressively towards one another for mating opportunities. Social rank
is in flux, as dominant and non-dominant males can change their status depending on the social milieu. These
complex social interactions are tightly linked to levels of a class of steroid hormones called androgens. My
research program will leverage the social dynamics of A. burtoni in the laboratory to discover the role of
androgens in controlling genes in the brain and neuroplasticity. We will tackle these questions using cutting-
edge techniques such as single-cell genomics, whole-brain imaging, and rich social behavior paradigms. For
these experiments, I have used CRISPR/Cas9 gene editing technology to genetically delete distinct androgen
receptors (ARs) in A. burtoni. These mutant A. burtoni lack functional genes for ARα, ARβ, or both. Findings in
these mutants reveal ARα and ARβ are required for distinct physiological and behavioral aspects of social
status, making them ideal for the proposed projects. For example, ARα mutant males do not perform dominant
social behaviors but have large testes and bright coloration, while ARβ mutant males perform dominant social
behaviors but possess small testes and drab coloration. Males mutant for both receptors lack all of these traits
and actually perform female-typical behaviors. As no other laboratory in existence possesses these AR
mutants, my research program is highly innovative and in a unique position for addressing these questions.
These experiments will be performed in both males and females, yielding novel results about the role of steroid
hormones in regulating fundamental brain and behavioral functions. With foundational data from AR mutant A.
burtoni, we will be able to address fundamental questions regarding the hormonal control of the brain and
social behavior. Indeed, these questions may connect naturally to those on the hormonal control of social
behavior in other species such as humans and how social systems emerge throughout evolution.

Grant Number: 5R35GM142799-05
NIH Institute/Center: NIH
Principal Investigator: Beau Alward