Cochlear Implants Stimulate Activity-Dependent CREB Pathway in the Deaf Auditory Cortex: Implications for Molecular Plasticity Induced by Neural Prosthetic Devices

Abstract

Neural activity modulates the maturation of synapses and their organization into functional circuits by regulating activity-dependent signaling pathways. Phosphorylation of cyclic AMP/Ca²⁺-responsive element-binding protein (CREB) is widely accepted as a stimulus-inducible event driven by calcium influx into depolarized neurons. In turn, phosphorylated CREB (pCREB) activates the transcription of brain-derived neurotrophic factor (BDNF), which is needed for synaptic transmission and long-term potentiation. We examined how these molecular events are influenced by sensorineural hearing loss and long-term reactivation via cochlear implants. Sensorineural hearing loss reduced the expression of pCREB and BDNF. In contrast, deafened animals subject to long-term, unilateral intracochlear electrical stimulation exhibited an increased expression of pCREB and BDNF in the contralateral auditory cortical neurons, relative to ipsilateral ones. These changes induced by cochlear implants are further accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which has been implicated in long-lasting forms of synaptic plasticity. Because CREB and BDNF are critical modulators of synaptic plasticity, our data describe for the first time possible molecular candidate genes, which are altered in the auditory cortex, following cochlear implantation. These findings provide insights into adaptive, molecular mechanisms recruited by the brain upon functional electrical stimulation by neural prosthetic devices.