In this project, we will examine the consequences of long-term sleep fragmentation/deprivation (SFD), a common problem in patients with sleep apnea, on cognitive, motor, neurophysiological, brain metabolic, and respiratory function, by using the recently developed model of the VLPO-lesioned rat. In the last term of this SCOR project, we found that the nerve cells in the ventrolateral preoptic nucleus (VLPO) are critical for maintaining normal sleep. Animals in which cell specific lesions have eliminated 70% or more of the VLPO cells bilaterally have severe sleep fragmentation (sleep bouts are twice as frequent, but one-quarter as long) and loss of sleep (more than 50% loss of NREM and REM sleep). These rats present an opportunity to examine the effects of long-term SFD on a variety of brain functions, without incurring stress from handling or hypoxic brain responses (as in models of chronic intermittent hypoxia). We hypothesize that these animals will have long-term rundown of glycogen and other metabolic stores and accumulation of adenosine, which will impair a variety of neuronal functions.
In Aim 1 we will examine the effects over a 12 week period of SFD on cognitive function (a battery of tests of hippocampal, prefrontal, and basal forebrain function), vigilance, and motor coordination.
In Aim 2, we will examine hippocampal slices from animals with long-term SFD to determine whether there is depression of synaptic transmission and long term potentiation, and whether this is due to accumulation of adenonsine in the hippocampus.
In Aim 3, we will measure adenosine levels by in vivo microdialysis in the hippocampus in rats with chronic SFD, and we will also measure glycogen levels in the gray matter of a number of cortical areas across the 12 weeks of sleep fragmentation/deprivation.
In Aim 4, we will examine the effects across 12 weeks of SFD on respiratory reflex responses to hypercarbia, hypoxia, and upper airway negative pressure. These studies will provide evidence for the role of long-term SFD on a range of cognitive, motor, and respiratory functions, including providing the first data on the rate of accumulation of these deficits, and whether there is adaptation to them. In addition, we will provide measurements of the effects of sleep fragmentation/deprivation on brain energy metabolism and adenosine levels, which may underlie many of the long-term impairments of cognitive and motor function seen in patients with obstructive sleep apnea.
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