Spiral ganglion neurons transmit auditory information from cochlear hair cells to the neurons of the cochlear nucleus. Thus, spiral ganglion and cochlear nucleus neurons are essential for normal hearing and for restoration of hearing via cochlear or cochlear nucleus implants in deaf individuals. However, in some circumstances these neurons may degenerate or die after deafening, limiting the potential efficacy of these devices. The reasons for this neurodegeneration and its variable nature after hair cell death remain unclear. Recent findings from our labs have revealed that elements of the innate immune system are recruited to the spiral ganglion and cochlear nucleus after deafening and suggest that the activation status of immune cells is an important determinant of neuronal survival in both structures. We also show that these elements of the innate immune system have profound effects on the survival of the auditory neurons, in some cases being cytotoxic, in others possibly neuroprotective. In at least one deafness model, the immune response, remarkably, may be a principal cause of spiral ganglion neuronal death after deafening. To resolve these complex and disparate effects of the innate immune system on auditory neuronal survival – with the long-term goal of developing immunotherapies for neuroprotection – we propose to systematically delete specific components of the innate immune system involving Natural Killer (NK) cells, macrophages, or microglia to determine their effect on neuronal survival. The experiments will use transgenic mice and, in some cases, inhibitory antibodies. Both macrophages and NK cells are recruited into the spiral ganglion in response to hair cell injury. The proposed experiments will determine whether macrophages and NK cells are neurotoxic or neuroprotective in the injured cochlea and the roles of specific cytokines and chemokines in stimulation and potential neurotoxicity of these immune cells. A parallel series of studies will focus on neuroimmune interactions in the cochlear nucleus, in which extensive research by one of the co-PI's has shown that neuronal survival depends on afferent input during a `critical period' in early postnatal maturation. In contrast, mature cochlear nucleus neurons survive deafferentation. Preliminary data suggest that this may be due to neuroprotection by microglia (the resident immune cells of the CNS.) The proposed experiments will test this hypothesis. Together, these studies will test fundamentally new hypotheses implicating specific components of the innate immune system as critical, if not optimal, targets for neuroprotective therapies to promote survival of cochlea and auditory brainstem neurons after cochlear pathology.