Estrogens play a central role in the brain's regulation of reproductive behavior, sexual development and cognitive processes such as learning and memory formation. Recent evidence suggests that estradiol (E2) also impacts auditory processing and perception. Auditory event-related potentials correlate with the plasma E2 levels in humans during the menstrual cycle and auditory processing is more efficient in younger and older females relative to males. Hearing disorders and lower auditory processing efficiency also occur in women with Turner's syndrome, who are deficient in E2. Direct evidence for E2 as a regulator of hearing-driven neural activity and plasticity-associated gene expression was recently presented for central auditory circuits. Despite key advancements on the characterization of a novel sensory-neuroendocrine interaction, the intracellular mechanisms by which E2 regulates hearing-driven gene expression are unknown. It is also unclear how E2 modulates the tuning and effectiveness with which auditory signals are processed and encoded by central auditory neurons. Here we address this gap by studying the auditory system of songbirds, a unique model for the study of auditory processing of communication signals. We focus on the caudomedial nidopallium (NCM), a forebrain auditory area thought to be analogous to the mammalian auditory association cortex. NCM neurons are selective to species-specific auditory signals, are involved in the perceptual processing of songs, and the formation of auditory memories. NCM is also the site of a major overlap between the auditory and neuroendocrine systems. High levels of aromatase and estrogen receptors are found in NCM. E2 levels also rapidly increase in NCM with socially-relevant auditory experiences. Finally, locally-produced E2 regulates auditory-evoked activity and plasticity-related gene expression in NCM. The molecular bases of E2's effects on NCM neurons, and the functional outcomes of such modulation to NCM's physiology and auditory-based behaviors are unknown. This proposal has five objectives that, together, will address these gaps: First, in-situ hybridization will be used to determine if auditory stimulation activates neurons that either produce or are sensitive to E2 in NCM. Second, a combination of intracerebral pharmacology in awake birds and biochemical methods will determine the specific intracellular mechanisms by which E2 influences auditory-driven genomic responses in NCM neurons. Third, patch-clamp electrophysiological studies will determine how E2 exert rapid effects in synaptic transmission and plasticity within NCM circuitry. Fourth, in-vivo neurophysiology coupled to local pharmacology will determine how E2 impacts the spectrotemporal tuning, and the effectiveness with which NCM neurons encode auditory signals. Finally, local pharmacological manipulations in awake animals coupled to behavioral assays will determine if normal E2 modulation of NCM is required for auditory discrimination. Our long-term goal is to elucidate the mechanistic bases and functional roles of E2's modulation of NCM's physiology during the auditory and perceptual processing of songs. We also aim to uncover how manipulations of steroid hormone levels may be used to alter auditory processing towards recovery of abnormal auditory function. This proposal will yield significant information on how the vertebrate brain interprets behaviorally-relevant communication signals, and will shed light on the neural basis of experience- dependent changes that underlie critical auditory-based behavioral processes such as auditory discrimination. PUBLIC HEALTH RELEVANCE: We propose to thoroughly determine how a classic steroid hormone, 17-estradiol, impacts the cellular physiology and the processing of complex communication signals in the vertebrate brain. In addition, we aim to understand how this hormone engages sensory-regulated, plasticity-associated gene expression, and ultimately modulates higher-order behaviors such as auditory discrimination.