0285 Impact of Aging on A1C1 Catecholaminergic Innervation of the Hypoglossal Nucleus and the Nucleus of the Solitary Tract (NTS)

Abstract Introduction Aging is associated with neurodegeneration of pontine noradrenergic neurons, which may reduce the excitatory noradrenergic drive to upper airway motoneurons and increase prevalence of obstructive sleep apnea (OSA) in the aging population. We hypothesized that innervation of the hypoglossal nucleus that originates from the medullary A1C1 neurons may contribute to OSA pathophysiology in elderly. We sought to quantify projections from A1/C1 neurons to the hypoglossal nucleus and the adjacent viscero-sensory NTS. Methods The young (3-4 months; n=13) and old (20-23 months; n=8) dopamine β-hydroxylase-(DBH)-cre mice received unilateral microinjections of AAV8-EF1a-DIO-hChR2-(H134R)-mCherry (100 nl) into the A1/C1 nucleus. Four weeks after the injection, mice were perfused, and medullary sections were processed with both DsRed and tyrosine hydroxylase immunohistochemistry. We counted ChR2-transduced A1C1 neurons. Then we calculated ChR2-positive axonal projections within the functionally different ventral and dorsal subdivisions of the hypoglossal nucleus at three anteroposterior (AP) levels: -7.2 mm (rostral), -7.48 mm (middle) and -7.76 mm (caudal) from Bregma. In the NTS, we measured the percentage area of the ChR2-positive axons at these AP levels. We used the linear regression analysis between the number of ChR2-transduced A1C1 neurons and the axonal counts, and the analysis of covariates (one-way ANCOVA) to assess the impact of age on the A1C1 catecholaminergic projections to the hypoglossal nucleus and NTS. Results We found that the number of ChR2-positive neurons within the A1C1 nucleus positively correlated with the combined ChR2-positive axonal projections within both the ipsilateral hypoglossal nucleus (p=0.0006) and NTS (p=0.0004) in young and old mice (Pearson correlation). The ANCOVA analysis demonstrated that linear regressions were significantly reduced in older mice in the ipsilateral ventral (p=0.004) and dorsal (p=0.026) subdivisions of the hypoglossal nucleus at AP -7.2. Similarly, aging negatively impacted the ChR2-positive A1C1 projections to the NTS bilaterally at AP -7.2 (p=0.026). Conclusion Our results suggest that the catecholaminergic innervation of the hypoglossal nucleus and the NTS, which originates from the A1C1 catecholaminergic neurons, decreases in older mice. The age-related weakening of the A1C1catecholaminergic drive to the hypoglossal nucleus and NTS may negatively impact the functioning of upper airway muscles and cardio-respiratory function in aging OSA patients, respectively. Support (if any) NIH-NIA-R01AG065233