During hearing development, auditory neurons are wired correctly, both qualitatively and quantitatively, with
specific types of spiral ganglion neurons (SGN; auditory afferents) and cochlear nucleus (CN) nerve fibers.
Maturation of the auditory neural pathway ensues along the functional tonotopic frequency axis, apparently
correlating with time and space/location-dependent gradients in neurotrophins (NTs). In addition, the SGNs
develop cochleotopic responses to sound and achieve cochleotopic projections to the cochlear nuclei (CN). The
activity of SGNs maintains the number, size and functions of cells in the CN. Previous studies suggest that this
process is regulated in part by neurotrophic factors (e.g. brain-derived neurotrophic factor (BDNF)). Expression
data show that BDNF expression undergo developmental and age-dependent shifts in their cellular and
longitudinal patterns of expression in the auditory pathway. This pattern was proposed to dictate distinct apico-
basal function of auditory neuron electrical properties, in turn requirements for cochleotopic and central auditory
neuron fine tuning. Despite the appeal of the NT-gradient and age-dependent hypothesis for auditory neural
properties, this idea rests on correlative evidence, disputed by some. We seek to unequivocally test and clarify
the NT-gradient predictions, and to understand BDNF-mediated auditory functional plasticity and how it sculpts
age-related hearing loss (ARHL).
We hypothesize that gradual decline in BDNF signaling is one of the common cause for ARHL.
We will unravel the function of BDNF in auditory neuronal plasticity using well-characterized cre lines (e.g.
Rosa26-creER; Fgf8-cre, Atoh1-cre) to selectively reduce or eliminate BDNF in floxed lines, to study the long-
term influence of BDNF levels on auditory signal processing in aging mice. In Aim 1, we will quantify BDNF
signaling expression in the auditory system, determine the source/s and the ensuing age-related changes in the
auditory neural pathway. Single molecule fluorescent in situ hybridization (SmFISH) and immunocytochemical
techniques will be used to quantify mRNA and protein expression and the age-related changes of BDNF.
Additionally, age-related changes in BDNF-receptors expression will be quantified. In Aim 2, we will determine
BDNF-mediated auditory plasticity with partial or delayed loss of BDNF. These goals will be accomplished using
inducible cre lines (e.g. Rosa26-creER) to eliminate all BDNF at various stages of aging from ~3-week to 2-year
old mice. We will determine the age-related cellular properties of auditory neurons (e.g. SGNs). Finally, in Aim
3, we will identify BDNF-mediated neural and synaptic plasticity with partial and delayed loss of BDNF. We will
use the animal models outlined in Aim 2 to identify changes in synaptic function at the calyx of Held, due to
BDNF loss/decline. This central auditory synapse, originates in the ventral cochlear nucleus (VCN), and project
contralaterally to the medial nucleus of the trapezoid body (MNTB), and is found to undergo morphological and
molecular alterations during aging. We will also examine CN functional changes.
Thus, we will resolve how the expression of BDNF impacts SGN/VCN/MNTB functions during aging,
providing evidence for BDNF signaling as a common cause for auditory decline. This knowledge will inform
efforts to use BDNF in therapeutic strategies to preserve auditory neuron viability and function after ARHL.