Deafferentiation‐associated changes in afferent and efferent processes in the guinea pig cochlea and afferent regeneration with chronic intrascalar brain‐derived neurotrophic factor and acidic fibroblast growth factor

Abstract

Deafferentation of the auditory nerve from loss of sensory cells is associated with degeneration of nerve fibers and spiral ganglion neurons (SGN). SGN survival following deafferentation can be enhanced by application of neurotrophic factors (NTF), and NTF can induce the regrowth of SGN peripheral processes. Cochlear prostheses could provide targets for regrowth of afferent peripheral processes, enhancing neural integration of the implant, decreasing stimulation thresholds, and increasing specificity of stimulation. The present study analyzed distribution of afferent and efferent nerve fibers following deafness in guinea pigs using specific markers (parvalbumin for afferents, synaptophysin for efferent fibers) and the effect of brain derived neurotrophic factor (BDNF) in combination with acidic fibroblast growth factor (aFGF). Immediate treatment following deafness was compared with 3-week-delayed NTF treatment. Histology of the cochlea with immunohistochemical techniques allowed quantitative analysis of neuron and axonal changes. Effects of NTF were assessed at the light and electron microscopic levels. Chronic BDNF/aFGF resulted in a significantly increased number of afferent peripheral processes in both immediate- and delayed-treatment groups. Outgrowth of afferent nerve fibers into the scala tympani were observed, and SGN densities were found to be higher than in normal hearing animals. These new SGN might have developed from endogenous progenitor/stem cells, recently reported in human and mouse cochlea, under these experimental conditions of deafferentation-induced stress and NTF treatment. NTF treatment provided no enhanced maintenance of efferent fibers, although some synaptophysin-positive fibers were detected at atypical sites, suggesting some sprouting of efferent fibers.

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

“…However, the effects on soma area associated with neurotrophin administration are much greater than the cell size changes elicited with electrical stimulation. In fact, several previous studies in guinea pigs have shown that 4 weeks of intracochlear infusion of BDNF resulted in large increases in SG perikaryal size compared to deafened cochleae and cross-sectional areas that were even significantly larger than in normal controls (Agterberg et al 2008;Glueckert et al 2008;McGuinness and Shepherd 2005;Shepherd et al 2005Shepherd et al , 2008. The mechanism(s) underlying this alteration are unclear, but we agree with the suggestion by ) that it may be related to the high concentrations of exogenous neurotrophin applied in these studies using osmotic pumps.…”

“…Profound deafness has been reported to result in reduction in the size of SG neuron perikarya in many previous studies and in various deaf animal models (Agterberg et al 2008(Agterberg et al , 2009Araki et al 1998;Elverland and Mair 1980;Glueckert et al 2008;Leake et al 1999Leake et al , 2007Leake et al , 2011; Leake and Hradek 1988;McGuinness and Shepherd 2005;Shepherd et al 2005;Wise et al 2005). Presumably, reduction in somatic size reflects reduced metabolic requirements of these neurons due to reduced spike activity after deafness (Hartmann et al 1984;Liberman and Kiang 1978;Shepherd and Javel 1997).…”

“…Because several previous studies (Agterberg et al 2008(Agterberg et al , 2009Glueckert et al 2008;Leake et al 2011;Shepherd et al 2005Shepherd et al , 2008 have reported that BDNF results in increased SG cell soma size, we utilized a physical disector stereological method that accurately estimates the number of objects (nucleoli of SG neurons) in a given volume of tissue, independent of their size (Mouton 2002) as described previously (Leake et al 2011). Four sets of six serial sections (5 μm thickness) were collected at each of 9 locations representing 10 % sectors of the cochlea.…”

“…Recent studies have shown highly significant effects of BDNF in promoting SG survival (Agterberg et al 2008;Glueckert et al 2008;Miller et al 2007;Shepherd et al 2008;Wise et al 2005), and trophic effects also have been reported with other neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) (Kanzaki et al 2002;Maruyama et al 2008;Yagi et al 2000;Ylikoski et al 1998) and fibroblast growth factor (FGF) (Glueckert et al 2008). Other studies have reported that the survival-promoting effects of NTs are enhanced by concomitant electrical stimulation and that these effects can be maintained by stimulation after cessation of NT infusion (Kanzaki et al 2002;.…”

Auditory-Nerve Responses to Varied Inter-Phase Gap and Phase Duration of the Electric Pulse Stimulus as Predictors for Neuronal Degeneration

“…This degeneration has been associated with discontinued neurotrophic support from the organ of Corti (Ernfors et al 1995;Fritzsch et al 1999;Zilberstein et al 2012). Administration of exogenous neurotrophic factors has prevented SGC degeneration in multiple animal models of SNHL (for a review, see Ramekers et al 2012); SGCs are larger and more numerous after neurotrophic treatment than in untreated controls (Ernfors et al 1996;Richardson et al 2005;Shepherd et al 2005;Glueckert et al 2008;Agterberg et al 2008Agterberg et al , 2009Leake et al 2011;van Loon et al 2013).…”