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Mutant Fish Help Reveal How Testosterone Works in the Brain

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Most people have some idea about the hormone testosterone –how it regulates male behavior or how too little of it might cause a decrease in libido and too much might cause aggressive and irritable behavior. Turns out, no one yet knows how testosterone really does all that.   

With a $1.9 million grant from the National Institute of General Medical Sciences, Beau Alward, assistant professor of psychology with a joint appointment in biology at the University of Houston, is set to find out. 

“We know androgens like testosterone control social behavior, but in reality, we still do not know precisely what aspects of social behavior androgens regulate and how this is done. We know they affect neurons, but not how they do it,” said Alward.   

Alward will use the highly social African cichlid fish, Astatotilapia burtoni (A. burtoni) along with cutting-edge techniques such as single-cell genomics, whole-brain imaging, and rich social behavior paradigms to address these questions. 

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. 

Alward 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,” said Alward. “Males mutant for both receptors lack all of these traits and actually perform female-typical behaviors.” 

Using the AR-mutant burtoni combined with pharmacology, Alward will use naturalistic social behavior paradigms that tax the genes and neurons that control social behavior. The specific genes and neurons involved will be identified using single-cell genomics and whole-brain imaging, respectively. The combination can elucidate the molecular and neural basis of social behavior and uncover the connections between steroid hormones, gene expression in the brain, and neuroplasticity, the brain's ability to modify, change, and adapt.

“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,” said Alward. "We will be able to address fundamental questions regarding the hormonal control of the brain and social behavior.” 

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.

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