Plasticity is a hallmark of neural systems, including those controlling breathing. One well-studied model of spinal, respiratory neuroplasticity is phrenic long-term facilitation (pLTF), a long-lasting (>90min) increase in phrenic motor output following acute intermittent hypoxia (AIH; 3, 5-min episodes with 5-min intervals). Modest AIH (PaO2 35-45 mmHg) elicits pLTF which requires serotonin type 2 (5-HT2) receptor activation. Since these receptors canonically activate protein kinase C (PKC), I hypothesized that activation of classical/novel PKC isoform(s) is/are required for pLTF. Cervical spinal PKC inhibition demonstrated that activation of PKCθ (but not other isoforms) is necessary for pLTF. Intrapleural delivery of small interfering RNAs targeting PKCθ decreased cervical spinal PKCθ expression, preventing pLTF. Conversely, pharmacological activation of spinal PKC with a diacylglycerol analog causes a phrenic motor facilitation (pMF), phenotypically similar to AIH-induced pLTF. However, the pharmacological profile of this pMF suggests that it requires activation of a distinct PKC isoform. While multiple, distinct mechanisms giving rise to pMF have recently been appreciated, their biological significance is unknown. I hypothesize that competition between diverse mechanisms generates emergent properties of pLTF, such as pattern sensitivity. Severe hypoxic episodes elicits a distinct, serotonin-independent pLTF (PaO2 25-35 mmHg) which requires adenosine 2A (A2A) receptor activation. Paradoxically, with moderate AIH, A2A receptor activation constrains pLTF, demonstrating that the serotonin- and adenosine-dependent mechanisms interact via cross-talk inhibition. Such inhibitory interactions may reach a balance during moderate ASH, preventing pLTF expression (ie. pattern sensitivity). pLTF is pattern sensitive since it is induced by moderate AIH, but not moderate acute sustained hypoxia (ASH; 25 min, P2O2 45-55 mmHg). Since longer hypoxia may increase adenosine formation/release, I hypothesized 5-HT2 and A2A receptor activation is balanced during ASH, preventing pLTF. Disrupting this balance during moderate ASH with spinal A2A receptor blockade revealed serotonin-dependent pLTF. Additionally, severe ASH shifted the 5-HT2/A2A balance, revealing A2A receptor-dependent pLTF presumably by greater adenosine formation/release. Understanding mechanisms of pLTF and its hallmark features (ie. pattern sensitivity) is of fundamental biological importance, and may facilitate efforts to harness spinal, respiratory motor plasticity in devastating clinical disorders, such as sleep apnea, cervical spinal injury and motor neuron disease.