0283 Aging Impact on SubC and A7 Noradrenergic Innervation of the Hypoglossal Nucleus may Contribute to the Increased Prevalence of Obstructive Sleep Apnea

Abstract Introduction Aging has been associated with the neurodegeneration of noradrenergic neurons. We hypothesized that aging may also reduce the excitatory drive from pontine noradrenergic neurons to the hypoglossal nucleus (HN) that innervates upper airway motoneurons, which would contribute to the increased prevalence of obstructive sleep apnea (OSA) in the aging population. We sought to investigate whether aging, one of the major risk-factors of OSA, affects the noradrenergic innervation of the HN originating from A7 and Subcoeruleus (SubC) neurons. Methods The young (6-7 months; n=13) and aged (20-28 months; n=8) dopamine β-hydroxylase-(DBH)-cre mice received single unilateral microinjections of AAV8-EF1a-DIO-hChR2-(H134R)-mCherry (10-50 nl) aimed at the A7 and SubC nuclei. Four weeks following AAV-injection, mice were perfused, and brainstem sections were processed with DsRed and tyrosine hydroxylase immunohistochemistry. We counted all A7 and SubC ChR2-transduced neurons. Then, we counted ChR2-positive axonal projections within the functionally different ventral and dorsal subdivisions of the HN at three anteroposterior (AP) levels: -7.2 mm (rostral), -7.48 mm (middle) and -7.76 mm (caudal) from Bregma. We used the linear regression analysis between the number of ChR2-transduced neurons and the axonal counts, and the analysis of covariates (one-way ANCOVA) to assess the impact of age on the projections to the HN. Results In both young and aged mice, the total number of ChR2-positive axonal projections counted within the HN at all three AP levels positively correlated with the number of ChR2-positive neurons located in both SubC and A7 nuclei (R2=0.66, p< 0.001, linear regression). The projections from A7 neurons to the HN were abolished in aged mice (slope=-0.30 vs. 1.92 in young mice), which was significant at AP-7.48 (p=0.046, ANCOVA). However, SubC innervation of the HN was either unchanged (AP-7.2) or showed an unexpected increase in the regression slope with aging at AP-7.48 (p=0.045) and AP-7.76 (p=0.021, ANCOVA). Conclusion Our results suggest that aging leads to degeneration of the A7 noradrenergic innervation of the HN. The SubC innervation of the HN was augmented in aging brain providing partial compensation for the loss of A7-noradrenergic innervation. However, it may not be sufficient to overcome the age-related increase of upper-airway collapsibility in OSA patients. Support (if any) NIH-NIA-R01AG065233