Estrogens are a class of steroid hormones that can aid recovery from brain injury and reduce the impact of certain neurological disorders. Recently, the central nervous system of humans and other animals has been shown capable of generating its own local supply of estrogens, providing new opportunities for the targeted treatment of brain diseases. Historically, the clinical use of estrogens has produced mixed success, possibly because estrogenic drug treatments are designed to mimic long term actions of estrogens (days-weeks) whereas cognitive function may depend critically on the short-term actions of estrogens (seconds-minutes). Indeed, treating neurological disorders with systemic doses of estrogens is associated with adverse side effects and reduced patient compliance. The goal of this research program is to characterize the mechanisms for rapid estrogen production and action ('rapid estrogen signaling') within discrete brain regions, and to understand the consequences of these events for sensorimotor integration and behavior. Taking advantage of recent methodological advances, these studies will combine sensitive real-time measures of brain estrogen concentrations, acute recordings of identified neurons, and contemporary behavioral assessments to understand the functional significance of rapid estrogen signaling in brain circuits. This work will address a fundamental gap in our understanding of how estrogen production within the brain guides complex behavior, and will ultimately inform the development of highly-targeted estrogen therapies for cognitive and neurological disorders.

Public Health Relevance

The proposed research is relevant to public health because discoveries about how rapid estrogen signaling can guide higher brain function will yield new information about the way estrogens can be optimized for the prevention and/or treatment of neurological disorders that have been linked to dysfunction in estrogen actions, such as Alzheimer's, Parkinson's, dementia and stroke. Thus, the long-term goal of this research is consistent with the NIH mission to translate basic biomedical research outcomes into viable treatment strategies that can benefit millions of patients suffering from neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS082179-05
Application #
9465512
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Gnadt, James W
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Hadley
State
MA
Country
United States
Zip Code
Krentzel, Amanda A; Macedo-Lima, Matheus; Ikeda, Maaya Z et al. (2018) A Membrane G-Protein-Coupled Estrogen Receptor Is Necessary but Not Sufficient for Sex Differences in Zebra Finch Auditory Coding. Endocrinology 159:1360-1376
Lee, Vanessa; Pawlisch, Benjamin A; Macedo-Lima, Matheus et al. (2018) Norepinephrine enhances song responsiveness and encoding in the auditory forebrain of male zebra finches. J Neurophysiol 119:209-220
Hedges, Valerie L; Chen, Gang; Yu, Lei et al. (2018) Local Estrogen Synthesis Regulates Parallel Fiber-Purkinje Cell Neurotransmission Within the Cerebellar Cortex. Endocrinology 159:1328-1338
Balthazart, Jacques; Choleris, Elena; Remage-Healey, Luke (2018) Steroids and the brain: 50years of research, conceptual shifts and the ascent of non-classical and membrane-initiated actions. Horm Behav 99:1-8
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Vahaba, Daniel M; Macedo-Lima, Matheus; Remage-Healey, Luke (2017) Sensory Coding and Sensitivity to Local Estrogens Shift during Critical Period Milestones in the Auditory Cortex of Male Songbirds. eNeuro 4:
Ikeda, Maaya Z; Krentzel, Amanda A; Oliver, Tessa J et al. (2017) Clustered organization and region-specific identities of estrogen-producing neurons in the forebrain of Zebra Finches (Taeniopygia guttata). J Comp Neurol 525:3636-3652
Moseley, Dana L; Joshi, Narendra R; Prather, Jonathan F et al. (2017) A neuronal signature of accurate imitative learning in wild-caught songbirds (swamp sparrows, Melospiza georgiana). Sci Rep 7:17320
Tuscher, Jennifer J; Szinte, Julia S; Starrett, Joseph R et al. (2016) Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice. Horm Behav 83:60-67
Brenowitz, Eliot A; Remage-Healey, Luke (2016) It takes a seasoned bird to be a good listener: communication between the sexes. Curr Opin Neurobiol 38:12-7

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