Dendritic alterations precede age-related dysphagia and nucleus ambiguus motor neuron death

Abstract

Motor neurons (MNs) within the nucleus ambiguus innervate the skeletal muscles of the larynx, pharynx and oesophagus, which are essential for swallow. Disordered swallow (dysphagia) is a serious problem in elderly humans, increasing the risk of aspiration, a key contributor to mortality. Despite this importance, very little is known about the pathophysiology of ageing dysphagia and the relative importance of frank muscle weakness compared to timing/activation abnormalities. In elderly humans and in aged Fisher 344 (F344) rats, a variety of motor pools exhibit weakness and atrophy (sarcopenia), contemporaneous to MN death. Synchronisation of swallow is dependent on the stability of MN dendrites, which integrate neural circuits. Dendritic derangement occurs in many neuromotor degenerative conditions prior to MN death. We hypothesise behavioural weakness and death of nucleus ambiguus MNs will occur by age 24 months in F344 rats and that this will be preceded by swallow-respiration dyscoordination and dendritic arbour degenerations from 18 months compared to controls at 6 months. Using pressure catheters to estimate laryngeal and diaphragm function during naturalistic water bolus applications, we show that swallow number and post-swallow apnoeas are altered from 18 months. Swallow pressure (weakness) and nucleus ambiguus MN numbers (evaluated via stereological assessments of Nissl staining) were reduced at 24 months. Dendritic lengths, surface areas and dendritic spines were reduced in nucleus ambiguus MNs from 18 months (evaluated by confocal imaging of Golgi-Cox impregnated brainstem). These results show that synapse loss occurs prior to MN death and behavioural weakness. Strategies to preserve synapses may be of utility in ameliorating sarcopenia.

Key points

• Dysphagia is a major contributor to ageing morbidity and mortality, but the underling pathophysiology is unexplored.
• Here, in Fischer 344 rats, we use pressure and timing evaluations of swallow-respiration, showing timing impairments occur prior to frank pressure defects.
• In nucleus ambiguus motor neurons, dendritic defects were apparent with the onset of swallow–respiration dyscoordination, with frank motor neuron loss occurring subsequently to synapse loss.
• Our results show that synapse loss occurs prior to motor neuron death and behavioural impairments. Strategies to preserve synapses may be of utility in ameliorating sarcopaenia.