Reduced respiratory neural activity elicits a long-lasting decrease in the CO2 threshold for apnea in anesthetized rats.

Two critical parameters that influence breathing stability are the levels of arterial pCO2 at which breathing ceases and subsequently resumes - termed the apneic and recruitment thresholds (AT and RT, respectively). Reduced respiratory neural activity elicits a chemoreflex-independent, long-lasting increase in phrenic burst amplitude, a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF). The physiological significance of iPMF is unknown. To determine if iPMF and neural apnea have long-lasting physiological effects on breathing, we tested the hypothesis that patterns of neural apnea that induce iPMF also elicit changes in the AT and RT. Phrenic nerve activity and end-tidal CO2 were recorded in urethane-anesthetized, ventilated rats to quantify phrenic nerve burst amplitude and the AT and RT before and after three patterns of neural apnea that differed in their duration and ability to elicit iPMF: brief intermittent neural apneas, a single brief "massed" neural apnea, or a prolonged neural apnea. Consistent with our hypothesis, we found that patterns of neural apnea that elicited iPMF also resulted in changes in the AT and RT. Specifically, intermittent neural apneas progressively decreased the AT with each subsequent neural apnea, which persisted for at least 60min. Similarly, a prolonged neural apnea elicited a long-lasting decrease in the AT. In both cases, the magnitude of the AT decrease was proportional to iPMF. In contrast, the RT was transiently decreased following prolonged neural apnea, and was not proportional to iPMF. No changes in the AT or RT were observed following a single brief neural apnea. Our results indicate that the AT and RT are differentially altered by neural apnea and suggest that specific patterns of neural apnea that elicit plasticity may stabilize breathing via a decrease in the AT.

Inactivity-induced respiratory plasticity: protecting the drive to breathe in disorders that reduce respiratory neural activity.

Multiple forms of plasticity are activated following reduced respiratory neural activity. For example, in ventilated rats, a central neural apnea elicits a rebound increase in phrenic and hypoglossal burst amplitude upon resumption of respiratory neural activity, forms of plasticity called inactivity-induced phrenic and hypoglossal motor facilitation (iPMF and iHMF), respectively. Here, we provide a conceptual framework for plasticity following reduced respiratory neural activity to guide future investigations. We review mechanisms giving rise to iPMF and iHMF, present new data suggesting that inactivity-induced plasticity is observed in inspiratory intercostals (iIMF) and point out gaps in our knowledge. We then survey conditions relevant to human health characterized by reduced respiratory neural activity and discuss evidence that inactivity-induced plasticity is elicited during these conditions. Understanding the physiological impact and circumstances in which inactivity-induced respiratory plasticity is elicited may yield novel insights into the treatment of disorders characterized by reductions in respiratory neural activity.

Inactivity-induced phrenic and hypoglossal motor facilitation are differentially expressed following intermittent vs. sustained neural apnea.

Reduced respiratory neural activity elicits a rebound increase in phrenic and hypoglossal motor output known as inactivity-induced phrenic and hypoglossal motor facilitation (iPMF and iHMF, respectively). We hypothesized that, similar to other forms of respiratory plasticity, iPMF and iHMF are pattern sensitive. Central respiratory neural activity was reversibly reduced in ventilated rats by hyperventilating below the CO2 apneic threshold to create brief intermittent neural apneas (5, ∼1.5 min each, separated by 5 min), a single brief massed neural apnea (7.5 min), or a single prolonged neural apnea (30 min). Upon restoration of respiratory neural activity, long-lasting (>60 min) iPMF was apparent following brief intermittent and prolonged, but not brief massed, neural apnea. Further, brief intermittent and prolonged neural apnea elicited an increase in the maximum phrenic response to high CO2, suggesting that iPMF is associated with an increase in phrenic dynamic range. By contrast, only prolonged neural apnea elicited iHMF, which was transient in duration (<15 min). Intermittent, massed, and prolonged neural apnea all elicited a modest transient facilitation of respiratory frequency. These results indicate that iPMF, but not iHMF, is pattern sensitive, and that the response to respiratory neural inactivity is motor pool specific.