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J. Neurosci. 32 (46): 16478-16495

Copyright © 2012 by the Society for Neuroscience.


Behavioral/Systems/Cognitive

Mechanistic Basis and Functional Roles of Long-Term Plasticity in Auditory Neurons Induced by a Brain-Generated Estrogen

Liisa A. Tremere,1 Ryan F. Kovaleski,1 Kaiping Burrows,2 Jin Kwon Jeong,3 , and Raphael Pinaud1

1Department of Neurobiology, Northwestern University, Evanston, Illinois 60208, 2Department of Physiology, University of Oklahoma, Oklahoma City, Oklahoma 73190, and 3Department of Neurobiology, Yale University, New Haven, Connecticut 06520

Correspondence should be addressed to Dr. Raphael Pinaud, Department of Neurobiology, 2200 Campus Drive, Pancoe 2-411, Northwestern University, Evanston, Illinois 60208. Email: pinaud{at}northwestern.edu

Abstract: The classic estrogen 17β-estradiol (E2) was recently identified as a novel modulator of hearing function. It is produced rapidly, in an experience-dependent fashion, by auditory cortical neurons of both males and females. This brain-generated E2 enhances the efficiency of auditory coding and improves the neural and behavioral discrimination of auditory cues. Remarkably, the effects of E2 are long-lasting and persist for hours after local rises in hormone levels have subsided. The mechanisms and functional consequences of this E2-induced plasticity of auditory responses are unknown. Here, we addressed these issues in the zebra finch model by combining intracerebral pharmacology, biochemical assays, in vivo neurophysiology in awake animals, and computational and information theoretical approaches. We show that auditory experience activates the MAPK pathway in an E2-dependent manner. This effect is mediated by estrogen receptor β (ERβ), which directly associates with MEKK1 to sequentially modulate MEK and ERK activation, where the latter is required for the engagement of downstream molecular targets. We further show that E2-mediated activation of the MAPK cascade is required for the long-lasting enhancement of auditory-evoked responses in the awake brain. Moreover, a functional consequence of this E2/MAPK activation is to sustain enhanced information handling and neural discrimination by auditory neurons for several hours following hormonal challenge. Our results demonstrate that brain-generated E2 engages, via a nongenomic interaction between an estrogen receptor and a kinase, a persistent form of experience-dependent plasticity that enhances the neural coding and discrimination of behaviorally relevant sensory signals in the adult vertebrate brain.


Received for publication July 6, 2012. Revision received Sept. 22, 2012. Accepted for publication Sept. 25, 2012.

Correspondence should be addressed to Dr. Raphael Pinaud, Department of Neurobiology, 2200 Campus Drive, Pancoe 2-411, Northwestern University, Evanston, Illinois 60208. Email: pinaud{at}northwestern.edu


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