Neural plasticity in chronic hypoxemia due to lung disease

Chronic sustained hypoxia (CSH) is a major complication of chronic obstructive pulmonary disease. The body’s first line of defence against hypoxemia, or lack of oxygen supply,  is the hypoxic ventilatory response (HVR), a reflex increase in respiration. With prolonged hypoxemia due to issues such as chronic lung disease, ventilatory drive and the HVR are further increased. This secondary increase is termed ventilatory acclimatization to hypoxia (VAH) and persists for weeks after re-oxygenation. VAH thus represents a form of functional memory in respiratory control circuits. Although systemic hypoxemia can be alleviated with oxygen therapy, it is costly and unwieldy. One promising alternative is to control the internal VAH response in a patient-specific manner to reduce hypoxemia; however, altering VAH requires knowledge of the synaptic pathways that mediate VAH, which are currently unknown.

Dr. Pamenter’s research aims to seek out the neural mechanisms that increase ventilatory drive and enhance arterial oxygen  during chronic hypoxemia. This project will determine the cellular signals for plasticity in the central nervous system mechanisms of ventilatory reflexes  caused by chemicals during CSH in rats.

In pilot experiments, Dr. Pamenter has examined a role for glutamatergic receptors in CSH in rats. Glutamatergic receptors are synaptic receptors located primarily on the membranes of neuronal cells. During the experminent, plasticity pathways are manipulated by direct microinjection of drugs into the Nucleus tractus solitarius (NTS), a nucleus in the brainstem. He will then examine changes of related second messengers (calcium and nitric oxide) in the NTS using an in vivo imaging system. Finally, he will examine glutamatergic mechanisms of synaptic plasticity directly in NTS neurons in isolated respiratory brainstem slices taken from control and CSH rats.

This research is a first step towards understanding the role of neural plasticity in systemic responses to hypoxemia due to chronic lung disease. Thus, elucidating these pathways is physiologically and clinically significant.