The fundamental hypothesis guiding this proposal is that chronic treatments, known to enhance serotonergic modulation of respiratory motor output, strengthen respiratory synaptic pathways to spinal (phrenic) motoneurons, thereby improving respiratory function during recovery from spinal cord injury. In specific, we will investigate the effects of Chronic Intermittent Hypoxia (CIH) and spinal deafferentation via Cervical Dorsal Rhizotomy (CDR) on synaptic pathways to phrenic motoneurons prior to acute spinal hemisection or following chronic spinal hemisection. Our laboratory has previously shown that both CIH and CDR enhance serotonergic modulation of phrenic motor output, but appear to do so by different mechanisms. We have also shown that spinal serotonin receptor activation enhances both functional and ineffective (crossed-spinal) synaptic pathways in rats. Thus, we will apply these unique models of serotonin-dependent respiratory plasticity to test the hypothesis that they will restore respiratory drive to phrenic motoneurons on the injured (hemisected) side.
In Aims 1 and 2, we will test the hypotheses that pretreatment with either CIH or CDR enhances evoked and spontaneous phrenic activity in intact and crossed-spinal pathways in anesthetized rats. In the next three aims, we will apply CIH following chronic spinal hemisection to test the hypotheses that CIH enhances evoked and spontaneous phrenic activity in anesthetized rats (Aims 3), restores ventilatory responses to chemoreceptor stimulation in unanesthetized rats (Aims 4), and increases ventral spinal concentrations of brain derived neurotrophic factor below the hemisection (Aim 5). This study provides an unprecedented opportunity to determine whether two experimental treatments restore respiratory motor function below a well-defined cervical spinal injury, provides the basis for highly novel therapeutic approaches in the treatment of respiratory insufficiency following spinal cord injury.
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