#expbio APS Program: Chronic intermittent hypoxia suppresses adult neurogenesis and disrupts synaptic plasticity in the dentate gyrus of the hippocampus through a pro-oxidant state

Figure 1: Sleep apnea occurs slightly more often in men 

and causes substantial daytime sleepiness and can 

impair cognitive function. (Source: geralt)

Obstructive sleep apnea occurs in over 3 percent of people worldwide and is slightly more common in men. It occurs when the upper airway collapses during sleep, decreasing oxygen delivery to the brain, and causing disruptions in sleep. As you might expect, people with obstructive sleep apnea can have severe fatigue during the day. What you might not know is that cognitive functions, like short-term memory, can be impaired. The lab of Nino Ramirez at the University of Washington in Seattle and Seattle Children’s Research Institute is examining the cognitive aspect of sleep apnea. Dr. Alfredo J Garcia III (Senior Scientist) and Chelsea Pagan (graduate student) supervised this project, which also involved Maggie Khuu (post-bac research assistant) and Alexi Christakis (high school volunteer). Chelsea in particular was interested in the memory difficulties and overall cognitive impairment seen in patients with obstructive sleep apnea. She wondered the impaired memory could be due to a decrease in the number of new brain cells being created in the adult, a process called adult neurogenesis.

To study this question, the team used a model of obstructive sleep apnea called chronic intermittent hypoxia protocol. In this protocol, mice are exposed to many short episodes of low oxygen for a period of time. Chelsea wanted to know if chronic intermittent hypoxia would affect neurogenesis and the molecular correlate of learning, called long-term potentiation (LTP). Because a lack of oxygen can cause oxidative damage in the brain, she also wanted to know if any affect on neurogenesis could be prevented by treating with an anti-oxidative agent.

Mice underwent chronic intermittent hypoxia for 30 days and adult neurogenesis was studied 30 days later. The team found there were more new cells in the hippocampus of hypoxia animals but there were fewer cells becoming neurons, the type of brain cell that is known to modulate cognition. The new cells in the hypoxia animals were less complex than cells in the control mice, having far fewer “arms”, called dendrites, that reach out to other cells. The conclusion was that chronic intermittent hypoxia leads to “bad” neurogenesis. They then wanted to know if this could be prevented with an anti-oxidant.

They used a drug, called MnTMPyP (don’t worry, I can’t pronounce that either), which decreases oxidative stress. After treatment with MnTMPyP, the number of new neurons increased when compared with the hypoxic group that did not receive the drug. This suggests that the anti-oxidant drug was able to rescue immature neurons important for learning and memory. When they examined LTP, a molecular measure of learning, brain networks exposed to chronic intermittent hypoxia exhibited impaired potentiation; whereas, MnTMPyP treatment prevented the effects of chronic intermittent hypoxia on LTP.  

The Ramirez lab is continuing their work on this project by further examining the molecular signaling pathways involved with altering adult neurogenesis and neurophysiology following chronic intermittent hypoxia.