Adrian Rodriguez-Contreras - US grants

DESCRIPTION (provided by applicant): PROJECT SUMMARY The medial nucleus of the trapezoid body (MNTB) plays a key role in sound localization by delivering fast and precise synaptic inhibition to auditory neurons in the mammalian brainstem. Previous studies indicate that activity-dependent mechanisms are involved in the refinement of this auditory pathway during early development. However, a fundamental issue that remains puzzling concerns the nature of the activity, since the refinement begins before the onset of hearing. We have identified spontaneous burst firing as the major form of spontaneous electrical activity before hearing onset. The major goal of this proposal is to use innovative electrophysiological and imaging techniques to determine the cellular and synaptic mechanisms of activity-dependent development in the MNTB in vivo. In the first aim, we will study the mechanisms that underlie bursting activity. Using electrophysiological techniques we will test the role of different types of synapses in bursting activity. For example, we predict that antagonists of synaptic transmission will block bursting activity during early postnatal development. In additional electrophysiological and immunostaining experiments we will study the developmental properties and roles of the voltage-activated conductance Ih, which could be involved in the fine tuning of electrical properties of MNTB cells and their responses to synaptic stimulation. In the second aim we will use two-photon calcium imaging to measure the activity of cellular ensembles in the MNTB of prehearing rats. We will validate this approach with electrophysiology experiments and will describe the spatial and temporal properties of the spontaneous ensemble activity, and how these patterns change during postnatal development. Finally, in the third aim, and in collaboration with Drs. Peqa, Tchernikovsky and Smotherman we will use similar methods described in the first and second aims in combination with sound stimulation to determine the responses of MNTB ensembles to simple and complex sounds. By manipulating the spectral content of sound stimuli we will study the capacity and limitations for short-term adaptation in the mammalian brainstem. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Tinnitus, a prevalent and poorly understood condition where sounds are perceived in the absence of auditory stimulation affects ~20% of Americans, and has debilitating effects in as many as 2 million citizens. Our experiments will directly determine how parts of the auditory system activate in the absence of sound, and could help explain why some people hear sounds when they shouldn't.

? DESCRIPTION (provided by applicant): Tonotopy is the map-like representation of sound frequency in the auditory system. Previous electrophysiology studies from this research and the work of others identified a precise pattern of spontaneous action potential bursts in auditory neurons of the medial nucleus of the trapezoid body (MNTB) that originates in the immature cochlea. Spontaneous action potential bursts are important for short-term synaptic plasticity and refinement of auditory synaptic connections before the onset of hearing. However, the cellular mechanisms of ensemble spontaneous activity in tonotopic maps remain unclear. To address this scientific issue, cellular activity will be measured with calcium indicators, molecules that emit fluorescence in response to changes in intracellular calcium ion concentration. Using state-of-the-art fluorescence two-photon microscopy it will be possible to measure calcium signals in the living brain of anesthetized rodent pups with cellular resolution at different stages of development. The overall hypothesis is that activity-dependent mechanisms, local cellular interactions and experience interact to determine the patterns of ensemble map activity during auditory system development. The aims are: 1) To define developmental patterns of neuronal ensemble activity in the MNTB; 2) To define developmental patterns of astrocyte differentiation and activity in the MNTB; and 3) To determine the relationship between maternal care, auditory development and MNTB auditory map activity. Altogether, these studies will determine the contribution of glial cells to the maturation of central auditory circuits in mammals, and increase our understanding of how experience and intrinsic programs interact to generate developmental plasticity in the auditory system. Auditory impairments such as deafness are caused by defects in different cellular and molecular components of the ear. However, recent evidence suggests that central nervous system malfunction in the auditory system contributes to neuropsychiatric diseases and other forms of neurologic disease with a developmental onset. The work in this proposal will define how patterns of activity in brain auditory maps change during development, providing clues to understand how these patterns may be affected in disease conditions such as autism and schizophrenia.