Homeostatic synaptic plasticity of respiratory motor output

In normal animals, the pattern of respiratory muscle activation remains largely the same throughout development, from birth until old age. Yet, the excitability of the neurons driving breathing may change dramatically throughout life, as changes occur in cell size, intrinsic excitability, dendritic field, synaptic number or synaptic strength. How does the respiratory control system maintain the appropriate pattern and strength of respiratory muscle activation in the face of continual physiological and environmental pressures that alter neuronal excitability? The hypothesis guiding our efforts in this direction is that local negative feedback mechanisms sense respiratory motor neuron activity and adjust synaptic efficacy to maintain motor output within an optimal range. This “self-tuning” ability may stabilize neural output in the face of internal and external perturbations while preserving the capacity for plasticity.

Current research efforts are directed at understanding the role of glial-derived TNFa and all-trans retinoic acid synthesis within respiratory motor neurons in homeostatic regulation of respiratory motor output. This research has direct implications for understanding compensatory mechanisms that help to preserve respiratory motor output following the onset ventilatory control disorders (i.e, obstructive sleep apnea, neurodegenerative disease, spinal injury), and may identify promising therapeutic targets to restore ventilation when endogenous mechanisms of plasticity are insufficient.

Recovery of respiratory motor output following spinal injury

Our goal is to use endogenous mechanisms of plasticity to elicit functional recovery of respiratory motor output following spinal injury. The fundamental hypothesis guiding our efforts in this direction is that disruption of descending inspiratory drive to phrenic motor neurons following spinal injury initiates homeostatic increases in synaptic efficacy designed to “ramp up” phrenic motor output. When spinal injuries are incomplete, these homeostatic mechanisms may strengthen spared pathways and/or reveal previously silent crossed phrenic pathways. Other forms of respiratory plasticity, such as long-term facilitation following intermittent hypoxia, may then be used to further strengthen these residual pathways, thereby leading to a partial functional recovery of ventilation following high cervical spinal injuries.

Ventilatory control following prenatal alcohol exposure

Infants exposed to ethanol during gestation may develop Fetal Alcohol Spectrum Disorder (FASD). Infants with FASD have an increased risk for catastrophic health disorders, such as sudden death syndrome (SIDS). However, very little is known regarding the effects of early chronic ethanol exposure on the control of breathing in any model system. We are investigating the mechanisms that underlie long-term deficits in the ventilatory control system following developmental ethanol exposure.