|
Nuclear Steroid Hormone Receptor Action in the Brain |
|
Pak Lab |
|
Research |
|
Toni R. Pak, Ph.D |
|
Assistant Professor |
|
Current Projects Ligand-independent signaling of estrogen receptor beta and the aging brain.
|
|
Menopause is characterized as a state of reproductive senescence coincident with sharply decreased circulating estrogen levels. Recently, the women’s health initiative (WHI) conducted a large-scale clinical study designed to evaluate the neurological benefits of estrogen replacement therapy for post-menopausal women. The results of that study, combined with other studies using animal models, have sparked a fervent debate about whether estrogen is beneficial or detrimental to normal brain function. Estrogen signaling in the brain is conveyed by two high specificity receptors, estrogen receptors alpha and beta (ERα, ERβ). Data from our laboratory have focused on the biological function of ERβ for two neuronal-specific genes that are estrogen-responsive and dramatically altered as a direct result of the aging process: gonadotropin-releasing hormone (GnRH) and arginine vasopressin (AVP). GnRH is the primary central regulator of reproduction and AVP is a critical regulator of several processes including: mood, circadian rhythms, and the stress response. Our data demonstrate that ERβ differentially regulates these genes in the presence and absence of estrogen, leading to our central hypothesis that the basic function of ERβ in the brain changes during the aging process. Understanding the molecular basis and the associated underlying consequences of changes in ERβ signaling is critical for evaluating the efficacy and necessity of exogenous hormone therapies. |
|
Interactive effects of ethanol and estrogen on brain vasopressin during puberty. |
|
Women who abuse alcohol are twice as likely to develop anxiety disorders compared with men, a phenomenon in which the underlying biological mechanisms are unknown. Our overall objective is to identify the interactive effects of alcohol and estrogen on arginine vasopressin (AVP), a well-established key molecular mediator of anxiety, in order to elucidate the molecular mechanisms predisposing women to increased risk of anxiety disorders. Adolescent binge drinking is a potential risk factor for the development of adult anxiety disorders due to the heightened stress reactivity that occurs as a direct result of increased circulating estrogens during pubertal development. Little is known about the long-term neurobiological consequences of alcohol consumption during puberty, which is a dynamic and important period of brain development that involves changes in cortical gray matter, synaptic connectivity, and increased neurogenesis. Exposure of alcohol during this critical period of extensive brain remodeling may result in permanent neuronal damage or disruptions in the formation of new neuronal connections, which might manifest as adult behavioral psychoses, including anxiety disorder. |
|
Department of Cell and Molecular Physiology |