Nuclear Receptor Mechanism in the Brain
Our work has revealed that estrogen receptor alpha (ERα) activates persistent male-biased gene expression programs in the developing brain. Some regions of the genome increase chromatin accessibility at birth and remain open into adulthood. We also observe that adult sex differences in gene expression are a consequence of acute hormone state; as hormones change, so do genes, and removal of the gonads abrogates nearly all sex differences in chromatin accessibility. Essentially, the neuronal genome of adult mice with no gonads resembles that of a prepubescent mouse. So how do hormone receptors generate both persistent and plastic effects on the genome? How does cooperation with cell-type-specific transcription factors and coregulators give rise to diverse transcriptional responses in distinct neuronal types? Understanding the gene regulatory strategies employed by hormone receptors in the brain is one of our key interests.
ERα genomic binding on the day of birth (P0) specifies sustained male-specific enhancer usage and gene expression at P4. From Gegenhuber et al. 2022
Development of Social Behavior Circuitry
Connecting individual genes to specific behaviors is challenging, especially in mammalian model organisms. We study innate, sex-variable, social behaviors that are modulated by steroid hormones. We are inspired by the rich history of behavioral genetics in worms and flies, comparative studies of morphological traits, and extensive prior dissection of “the social behavior network” in rodents. We explore how hormone receptor target genes contribute to the development and function of pathways that regulate aggression, sexual behavior, parenting and pair-bonding.
Expression pattern of Avpr1a in a prairie vole pup brain
Hormonal Modulation of Brain Health and Disease
We believe that characterization of sex-variable developmental trajectories in the brain will reveal gene programs that underlie sex- and gender-biased susceptibility to psychiatric and neurological conditions. For example, sex-specific regulation of serotonin receptor genes may contribute to the 2:1 incidence of major depressive disorder (MDD) in women compared to men. Estrogen in particular has many beneficial and neuroprotective effects: mood, cognition, and sleep quality are all enhanced by estrogen. Loss of ERα signaling, either through menopause or via some cancer treatments, can lead to profound alterations in brain function, as well as an increased risk for Alzheimer’s disease. Having identified an extensive repertoire of hormone-regulated genes, we are now investigating how select genes contribute to established sex-variable phenotypes. We have already demonstrated that selective modulation of a single ERα target gene increases physical activity in ovariectomized female mice. Our long-term goal is to facilitate the development of more targeted hormone replacement therapies to improve quality of life without increasing cancer risk.
Morphology of ERα cortical neurons