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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Gnadt, James W
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University of Massachusetts Amherst
Schools of Arts and Sciences
United States
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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
Ikeda, Maaya Z; Jeon, Sung David; Cowell, Rosemary A et al. (2015) Norepinephrine Modulates Coding of Complex Vocalizations in the Songbird Auditory Cortex Independent of Local Neuroestrogen Synthesis. J Neurosci 35:9356-68
Chao, Andrew; Paon, Ashley; Remage-Healey, Luke (2015) Dynamic variation in forebrain estradiol levels during song learning. Dev Neurobiol 75:271-86
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Remage-Healey, Luke (2014) Frank Beach Award Winner: Steroids as neuromodulators of brain circuits and behavior. Horm Behav 66:552-60
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Schlinger, Barney A; Remage-Healey, Luke; Rensel, Michelle (2014) Establishing regional specificity of neuroestrogen action. Gen Comp Endocrinol 205:235-41
Remage-Healey, Luke; Jeon, Sung D; Joshi, Narendra R (2013) Recent evidence for rapid synthesis and action of estrogens during auditory processing in a songbird. J Neuroendocrinol :
Remage-Healey, Luke (2012) Brain estrogen signaling effects acute modulation of acoustic communication behaviors: A working hypothesis. Bioessays 34:1009-16
Schlinger, B A; Remage-Healey, L (2012) Neurosteroidogenesis: insights from studies of songbirds. J Neuroendocrinol 24:16-21

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