2007 — 2009 |
Remage-Healey, Luke R |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Rapid Steroidogenesis in the Brain. @ University of California Los Angeles
[unreadable] DESCRIPTION (provided by applicant): Important behavioral and physiological changes occur on a timescale of minutes, yet the neuroendocrine mechanisms that underlie these fast changes are not well understood. Steroid hormones represent one group of candidate molecules for such rapid neural and behavioral effects. Although steroid hormones are powerful and pervasive neuromodulators, little is known about how steroid levels within the brain (neurosteroids) are regulated over rapid time periods. Narrowing the gap in understanding this entire class of neuromodulators will provide insight into how neurotransmitter systems and neurosteroids interact on a minute-by-minute basis. Preliminary clinical investigations have indicated that neurosteroid pathophysiologies are involved in disorders such as postpartum depression, pregnancy fatigue, and epilepsy. Thus, a greater appreciation of how neurosteroid levels change overtime may improve our understanding of social behavior, mental health and disease. In this proposal, characterizing the activity of steroidogenic enzymes in the brain, as well as in vivo measurement of brain steroid levels, are critical and complementary approaches toward understanding the neuromodulatory role of steroids and the function of steroid conversion by the brain. This proposal seeks to clarify how rapid changes in brain steroid levels contribute to changes in brain function and social behavior. In the zebra finch model, the proposed experiments will assess how singing behavior is related to rapid changes in both brain steroid levels in vivo and changes in steroidogenic enzyme activity. The proposed experiments will also examine rapid changes in brain steroid levels and steroidogenic enzyme activity during acute stress. Both humans and songbirds exhibit significant steroidogenesis from non-gonadal origins, including brain, and so these experiments provide an opportunity to improve our understanding of basic neurosteroid mechanisms. [unreadable] [unreadable] [unreadable]
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0.948 |
2009 — 2012 |
Remage-Healey, Luke R |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Modulation of Forebrain Circuits by Local Neurosteroid Production @ University of California Los Angeles
Modem neuroscience is only beginning to understand how the activity of forebrain circuits is modulated by neurochemicals, including steroids such as estrogen. Appreciation of the neuroprotective effects of steroids has led to ongoing clinical trials for steroid treatment of human neurocircuit pathologies. Current clinical treatments deliver steroids peripherally, and therapeutic steroids consequently reach the brain slowly in a uniform, global manner. However, only a subset of steroid treatments appears to be effective at reducing neurological disease progression. The most recent, emergent research on the actions of steroids within the brain emphasizes both local and acute effects on neurons and neurocircuits. In order to optimize our use of steroids as neuro-therapeutic agents, we must therefore consider the fine temporal and spatial scale of steroid regulation within neurocircuits. With the advancement of in vivo neurosteroid microdialysis, I have established that forebrain steroid levels can be experimentally monitored and manipulated in discrete neurocircuits. In this K99/R00 career development award, I will determine how local steroid actions contribute to forebrain circuit activity and function. During the Mentorship Phase, I will acquire skills in electrophysiological, functional, and developmental approaches to forebrain circuits, and combine them with recently- optimized in vivo neurosteroid microdialysis techniques. I have assembled a highly-qualified team of mentors and collaborators with a comprehensive set of skills to facilitate my training and maturation into an independent neuroscientist. During the Independent Phase, I will direct my laboratory to apply these innovative tools to a broad- scale, integrative study of how forebrain circuits are modulated by local, brain-derived steroids. Results of the training and research outlined in this K99/R00 Award will provide an integrated understanding of neural circuit regulation, and could have wide-ranging implications for the future development of novel therapeutic approaches to neurological diseases. PUBLIC HEALTH RELEVANCE: The research outlined in this K99/R00 PI Award will shed light on how brain-derived steroids contribute to the acute regulation of forebrain circuit function. The ultimate goal of this work is to improve our understanding of steroid actions within neural circuits, in order to optimize the future development of steroids as neuro- therapeutic agents for disorders such as epilepsy, stroke, and Alzheimer's disease.
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1 |
2014 — 2020 |
Remage-Healey, Luke R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Rapid Estrogen Signaling in Brain Circuits That Guide Complex Behavior @ University of Massachusetts Amherst
PROJECT SUMMARY 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.
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1 |
2014 — 2018 |
Remage-Healey, Luke |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Song Learning and Fluctuating Brain Estrogens @ University of Massachusetts Amherst
Learning is dependent on the actions of small molecules in the brain, called neuromodulators. Common neuromodulators include dopamine and serotonin, which are involved in learning and memory in animals from worms to humans. The current work will explore a recently-identified neuromodulator system: the production of estrogens within the brain. A series of studies will examine how brain estrogen production may support learning complex motor sequences. Understanding the brain's ability to produce its own supply of estrogens may open up new perspectives on cognition, memory, and the function of basic neural circuits that are common among vertebrate animals.
Estrogens are typically considered reproductive hormones secreted by the ovaries, yet it is now clear that estrogens are produced within the brain itself, in both males and females. A combination of approaches will test the hypothesis that estrogens can be produced within brain circuits to rapidly enhance the consolidation of recent experiences. Songbirds provide an exceptional opportunity to study the underlying brain mechanisms for the learning and memorization of song. There are substantial neural and behavioral parallels between song learning in songbirds and language/speech learning in humans. Juvenile songbirds typically learn songs from an adult tutor during a brief critical sensory period. A recently-optimized method enables the measurement and manipulation of brain estrogens in behaving songbirds while they learn from song tutors and consolidate new songs. Because estrogens have been associated with learning and memory in many animals, including human beings, this research therefore has potential for significant impacts. The work will also involve training students from underrepresented groups in multidisciplinary, integrative research and outreach activities.
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0.915 |