Brain function depends on precisely organized neural networks. A central problem in contemporary neuroscience has been to determine how the specific organization of synaptic inputs is established in the brain during development. Uncovering the identity of key molecules involved in this process and elucidating how they are dynamically engaged as a result of development and experience is fundamental for a comprehensive understanding of the mechanisms underlying the establishment, maturation and functionality of the synaptic circuitry. Previous studies conducted in sensory systems have shown that both intrinsic and experiential factors are required for the adequate formation of synaptic circuitry and its performance. In particular, significant research into these questions has been carried out in the mammalian auditory brainstem, where a series of post-natal developmental changes underlie the adequate establishment of neuronal connectivity and, consequently, intact hearing. Much of these studies have focused in the medial nucleus of the trapezoid body (MNTB), a relay station of the ascending auditory pathways involved in the localization of sounds in the horizontal plane, and embedded in the superior olivary complex. Input into MNTB neurons occurs through a highly specialized synaptic terminal adapted for high-fidelity transmission of auditory information. This synaptic terminal is known as the Calyx of Held and consists of the largest known synaptic terminal in the mammalian central nervous system. Due to its size, known neurochemical properties and convenient anatomical localization, this synaptic contact on MNTB neurons has been extensively used to determine the biophysical and ultrastructural underpinnings of synaptic transmission supporting hearing. Despite a large body of literature on the biophysical changes that correlate with the development of the MNTB circuitry, the underlying molecular substrates responsible for such modifications are largely unknown. Furthermore, no systematic studies to date have attempted to identify and dissociate the molecular events are regulated by developmental stage (age) from those that are impacted by sensory experience. In this application, we aim to significantly fill this current gap in knowledge. We propose to use high-throughput quantitative proteomics and mass spectrometric approaches to uncover the cascade of protein regulatory events associated with the post-natal development of MNTB circuitry. More specifically, we intend to use two-dimensional differential in-gel expression (2D-DIGE)-based proteomics to identify age- and experience-regulated proteins in the MNTB, both before and after hearing onset. In addition, we propose to investigate how abnormal sensory experience impacts the dynamic regulation of the MNTB proteome throughout post-natal development. To achieve this goal, we intend to combine high-throughput quantitative proteomics and mass spectrometry to study mouse models of early- and late-onset deafness and, consequently, identify protein regulatory events that are altered in these conditions. We predict that the results of this research will significantly contribute to the emergence of a coherent picture of the molecular and cellular processes underlying the development of central auditory pathways. Moreover, this research is expected to provide open new avenues for the development of pharmacological and/or molecular strategies aimed at ameliorating or recovering hearing dysfunction, as in the case of deafness. We propose to systematically investigate how the coordinated activation of key molecules guide the maturation of neuronal circuits that control hearing function, and how interference with normal audition impacts these molecular programs. A thorough understanding of the molecular events that underlie the establishment and maturation of hearing-related circuits may open potential avenues for ameliorating or restoring dysfunctional audition, as in the case of deafness.
We propose to systematically investigate how the coordinated activation of key molecules guide the maturation of neuronal circuits that control hearing function, and how interference with normal audition impacts these molecular programs. A thorough understanding of the molecular events that underlie the establishment and maturation of hearing-related circuits may open potential avenues for ameliorating or restoring dysfunctional audition, as in the case of deafness.
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