[R01] Spontaneous activity in the developing auditory system

Ente: National Institute on Deafness and Other Communication Disorders

Scadenza: 2031-03-31

Importo max: 417.875 EUR

Paese: US

Descrizione

Project Summary Neurons in the developing auditory system exhibit spontaneous activity prior to the onset of sensory experience. This activity is initiated within the cochlea when non-sensory inner supporting cells release ATP, triggering a cascade of events that ultimately induces trains of action potentials in spiral ganglion neurons (SGNs). Our prior studies revealed that this spatially restricted release of ATP triggers correlated firing of groups of SGNs that will later encode similar frequencies of sound, and showed that this burst firing propagates through the CNS to set the gain of auditory circuits, refine the frequency tuning of auditory neurons, and establish sound processing domains within the inferior colliculus and auditory cortex. Despite its role in maturation of the auditory system, the mechanisms that initiate this activity and its relationship to the dramatic structural transformation that occurs in the cochlea during this same time period remain poorly understood. We recently discovered a previously undescribed form of spontaneous activity in the developing cochlea involving local kinase activation within inner supporting cells (ISCs) – termed Spatiotemporally Restricted ERK Signaling (“SpaRKS”) – that is coincident with ATP induced activity. Here, we will leverage newly developed kinase reporter mice, in vivo genetic manipulations, and time lapse fluorescence imaging in ex vivo cochlear explants and in vivo central auditory centers to explore the mechanisms responsible for this signaling and its relationship to both thyroid hormone-induced maturation processes and ATP driven spontaneous activity. We will test the explicit hypothesis that thyroid hormone induced apoptosis of ISCs triggers both growth factor and ATP release to control the pace of cellular regression and initiate burst firing during this critical phase of development. Aim 1 will use pharmacological and genetic manipulations to define the mechanisms responsible for local ERK activity in ISCs, building on preliminary data implicating HB-EGF release from dying ISCs, as assess the importance of this signaling for functional maturation of the cochlea. Aim 2 will explore whether thyroid hormone T3 is necessary to initiate this activity and assess whether ERK signaling opposes T3-induced apoptosis. Aim 3 will investigate whether growth factors released from ISCs during this process also impact dendritic refinement and specification of SGNs. Aim 4 will then examine whether this process of cellular regression is mechanistically linked to the initiation of spontaneous electrical activity in the cochlea and central auditory neurons. Together, these studies will help define the mechanisms that control the structural and functional maturation of the cochlea, and establish a framework to explore how genetic mutations, trauma, and exposure to ototoxic drugs during early life alter the processing capabilities of central auditory circuits. Information gained from these studies m Istituzione: JOHNS HOPKINS UNIVERSITY PI: DWIGHT E BERGLES Progetto: 2R01DC008860-14

Settori: National Institute on Deafness and Other Communication Disorders

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.