Plasticity is a hallmark of the neural system controlling breathing. One extensively studied form of respiratory
motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output after acute
intermittent hypoxia (AIH). Multiple, distinct cellular mechanisms contribute to AIH-induced pLTF. Unfortunately,
our understanding of how these mechanisms are regulated is limited. Two distinct mechanisms of AIH-induced
phrenic motor facilitation (pMF) are known as the Q and S pathways. The Q pathway requires phrenic motor
neuron 5-HT2 receptor activation, whereas the S pathway is initiated by phrenic motor neuron 5-HT7 receptors.
Q and S pathway co-activation elicits powerful cross-talk inhibition; in fact, equal Q and S pathway activation
cancels pMF expression. With moderate AIH (mAIH), the Q pathway dominates but is constrained by S pathway
inhibition; S pathway inhibition releases this “brake,” doubling mAIH-induced pLTF.
Repetitive AIH (rAIH) preconditioning enhances mAIH-induced pLTF through unknown mechanisms. This
property is essential in our translational efforts to harness rAIH as a treatment to improve breathing in people
with cervical spinal injury or neuromuscular disease. The fundamental goal of this proposal is to understand how
these cumulative rAIH benefits arise. Our central hypothesis is that rAIH minimizes Q-S pathway cross-talk
interactions, enabling both to contribute to AIH-induced phrenic motor plasticity.
AIH-induced phrenic motor plasticity exhibits profound age-dependent sexual dimorphism. However, we
know essentially nothing concerning how age and sex alter differentially affect pMF mechanisms, or their
response to rAIH preconditioning. Thus, we will compare Q and S pathway interactions in young (3 month) and
middle-aged (12 month) female vs male rats (when sexual dimorphisms are greatest). We will also investigate
differential rAIH preconditioning effects on diaphragm LTF in unanesthetized young and middle-aged female vs
male rats. Increased understanding of age and sex effects in normal rats will establish the “ground rules” for
translation to clinical disorders that afflict men and women of different ages.
We propose a working cellular model of rAIH-enhanced pLTF based on literature and exciting preliminary
data. Based on this model, we propose four specific aims to test the hypotheses that rAIH preconditioning: 1)
decreases Q and S pathway cross-talk inhibition, enabling contributions from both (Aim 1); and 2) strengthens
the Q pathway to pMF by increasing the expression of key pathway molecules (Aim 2). Since AIH-induced pLTF
exhibits profound age-dependent sexual dimorphisms, we will test the hypotheses that: 1) the Q and S pathways
to pMF are differentially affected by age and the estrus cycle female rats (Aim 3); and 2) age and sex are key
determinants of rAIH-enhanced diaphragm motor plasticity (Aim 4). These studies will greatly advance our
understanding of rAIH-enhanced phrenic motor plasticity, and accelerate our ability to harness rAIH as a
therapeutic modality to treat devastating clinical disorders that compromise breathing and threaten life itself.