DESTABILIZATION OF HYPOTHALAMIC SLEEP/WAKE NEURONAL SYSTEM IN THE EXPERIMENTAL SCI

Spinal cord injury (SCI) produces dramatic, life-long impairment of multiple basic physiological processes, including the regulation of sleep. Chronic sleep disturbances are hypothesized to initiate wide-ranging co-morbidities in the able-bodied population. It is well regarded that the physiological consequence of insufficient sleep includes elevated stress, increased levels of inflammatory markers, diminished protein synthesis, reduced wound healing, increased pain sensitivity, elevated risk for obesity/type II diabetes, and results in cognitive impairment. As such, the post-injury pathophysiology of SCI patients may be exacerbated by diminished sleep efficiency. Wakefulness is associated with neural activity across several ascending arousal systems. In contrast, the inhibition of the arousal system is coordinated by comparatively few populations of neurons. The ventrolateral preoptic nucleus (VLPO) contains sleep-active neurons and has been implicated in transitioning between sleep/wake states. The VLPO may be the functional counterpart to ascending monoaminergic arousal systems such as the locus coeruleus (LC) and raphe nuclei. These competing neural circuits serve to rapidly gate the complete transition between sleep and wake states. Interestingly, experimental perturbations to this neural switch do not produce exclusive somnolence or wakefulness, but rather frequent transitions between sleep/wake states. In the present proposal we will use an animal model of T3-SCI with the overarching aim to elucidate the neural mechanisms responsible for reduced sleep efficiency after SCI. Specifically, we will experimentally test our hypotheses that (1) EEG analysis will quantify sleep quality and reveal that SCI animals display more frequent arousals during sleep periods, reduced sleep efficiency, and reduced time spent in rapid eye movement (REM) sleep compared to surgical controls; (2) chronic T3-SCI interrupts the functioning of the neural systems that regulate sleep and wakefulness. We predict that SCI rats will have reduced expression of c-Fos in the VLPO during the light phase when compared to surgical controls. We further predict that microdialysis-HPLC analysis of the VLPO region of SCI rats will reveal higher norepinephrine and serotonin levels in SCI rats compared to surgical controls. These neurotransmitters are released by fibers originating in the LC and raphe nuclei and act to inhibit sleep by reducing activity in the VLPO. The current project will validate our ability to quantify sleep disturbances in our experimental model of SCI. Indeed, while descriptive reports have revealed sleep disturbances in experimental models of SCI; to date, no study of the neural mechanisms responsible for the observed sleep disorders have been conducted. This research will begin to establish that reduced sleep efficiency is a critical secondary pathology of SCI and will provide insights into the complex neural sleep/wake mechanisms altered by SCI. Ultimately, the model that will be developed in this project may be used toward understanding diminished sleep quality in human SCI and provide the basis for identifying the influence of sleep upon post-SCI co-morbidities in the clinical setting.