Invited Review: Neuroplasticity in respiratory motor control

Abstract

Although recent evidence demonstrates considerable neuroplasticity in the respiratory control system, a comprehensive conceptual framework is lacking. Our goals in this review are to define plasticity (and related neural properties) as it pertains to respiratory control and to discuss potential sites, mechanisms, and known categories of respiratory plasticity. Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. Respiratory neuroplasticity is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, the balance between opposing modulatory systems, age, gender, and genetics. Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury, stress, and pharmacological interventions or conditioning and occurs during development as well as in adults. Developmental plasticity is induced by experiences (e.g., altered respiratory gases) during sensitive developmental periods, thereby altering mature respiratory control. The same experience later in life has little or no effect. In adults, neuromodulation plays a prominent role in several forms of respiratory plasticity. For example, serotonergic modulation is thought to initiate and/or maintain respiratory plasticity following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory denervation, spinal cord injury, and at least some conditioned reflexes. Considerable work is necessary before we fully appreciate the biological significance of respiratory plasticity, its underlying cellular/molecular and network mechanisms, and the potential to harness respiratory plasticity as a therapeutic tool.

Breathing without CO2Chemosensitivity in ConditionalPhox2bMutants

“…This could reflect the loss of CO 2 chemical drive, but also the lack of entrainment of the pre-BötC by the embryonic RTN , as indicated by the slower than normal respiratory-like rhythm in late gestation. The breathing deficit normalized with age, probably because of maturation or plasticity of the respiratory system (Mitchell and Johnson, 2003). Similarly, CO 2 chemosensitivity had partly recovered in adult mutants.…”

Short- and Long-term Modulation of the Exercise Ventilatory Response

“…This persistent augmentation of the exercise ventilatory response is a form of serotonin-dependent respiratory plasticity termed long-term modulation (LTM) of the exercise ventilatory response (27;28;36;40). Although the name long-term modulation suggests rapid reversibility, the persistent nature of LTM is sufficient to categorize this mechanism as a form of plasticity (43). However, we suspect that repeated activation of the STM mechanism is a causal factor in establishing LTM since both are serotonin-dependent mechanisms (26).…”

“…Over the past few decades, we have come to realize that the neural system controlling breathing exhibits considerable capacity for modulation and plasticity, including the exercise ventilatory response (43). Here, we will discuss two of these adaptive mechanisms: short-term (STM) and long-term modulation (LTM) of the exercise ventilatory response (4;36;38).…”

Long-term effects of the perinatal environment on respiratory control

“…Plasticity is a persistent change in the morphology and/or function of the respiratory control system based on prior experience (e.g., neural activity, hypoxia, injury, or disease) (66). However, this broad definition belies the complexity of plasticity and the reality that there are different types.…”

“…LTF is a long-lasting increase in respiratory motor output following repeated episodes of hypoxia (see Ref. 66 for review), and previous studies have shown that pretreatment with CIH enhances phrenic and ventilatory LTF in adult rats (58,64). McGuire and Ling (63) observed that neonatal CIH (11-12% O 2 and 21% O 2 alternating at 5-min intervals, 12 h/day for 7 days beginning 2 days after birth) also enhanced ventilatory LTF, although the enhancement lasted considerably longer (Ͼ3 wk vs. Ͻ1 wk in adults; 64).…”