[R35] Steroid hormone dependent gene expression and neuroplasticity in the brain.
Ente: National Institute of General Medical Sciences
Scadenza: 2031-06-30
Importo max: 421.922 EUR
Paese: US
Descrizione
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, but our
understanding of how steroid hormones regulate gene expression and neuroplasticity in the brain remains
limited. My research program aims to uncover the connections between steroid hormones, gene expression in
the brain, and cellular functions using Astatotilapia burtoni, a cichlid fish with sophisticated social dynamics. In
both the wild and lab, A. burtoni stratify along a social hierarchy: dominant males (DOM) display bright
coloration, defend territories, and mate, while subordinate males (SUB) do not. Females (F) do not form a
hierarchy but compete aggressively for mates. Social rank is in flux, as it can shift depending on the social
milieu. These dynamics are closely tied to levels of androgens (e.g., testosterone) and estrogens (e.g.,
estradiol). My research program will leverage the social dynamics of A. burtoni to discover the role of steroid
hormones in controlling genes in the brain and neuroplasticity. We engineered androgen receptor (AR) and
brain-aromatase mutant A. burtoni to address these questions. ARα mutants do not perform DOM social
behaviors but have large testes and bright coloration, while ARβ mutants perform DOM social behaviors but
possess small testes and drab coloration. Mutants lacking both receptors exhibit F-typical traits. Single-nucleus
RNA-sequencing (snRNA-seq) of the ARβ mutant hypothalamus revealed oxytocin (oxt) as a candidate
modulator of ARβ-regulated traits. In brain-aromatase mutants, DOM show normal aggression, but F attack
DOM, suggesting estrogenic modulation of F behavior. These findings offer new avenues for uncovering
molecular and neural mechanisms of steroid hormone action. We will use genetic mutants, cutting-edge
sequencing technologies, neurobiological profiling, and rich social behavior paradigms to discover genes in the
brain and neuroplasticity controlled by androgens and estrogens. Using snRNA-seq and spatial transcriptomics
of the hypothalamus in AR mutants, we will determine cell-type-specific, spatially resolved gene expression
regulated by androgens. We will leverage AR and brain-aromatase mutants to investigate how androgenic and
estrogenic signaling control neuroplasticity. Social behaviors will be explored in brain-aromatase mutants to
discover the role of estrogen signaling in regulating aggression and reproductive behavior in A. burtoni.
Moreover, oxt mutants will be used to determine the role of oxytocin in regulating optimal behavioral responses
to social cues. Our novel approach and innovative methodological toolkit position us well to uncover
fundamental principles of the hormonal control of genes in the brain and neuroplasticity underlying behavior.
Data from our studies will allow us to address central questions regarding the hormonal control of the br
Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES
PI: Beau Alward
Progetto: 2R35GM142799-06
Settori: National Institute of General Medical Sciences
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