Narcolepsy has now been linked to a lesion of neurons containing the neuropeptide hypocretin (HCRT), also named orexin. However, the loss of these neurons can only be determined upon autopsy. Cerebrospinal fluid (CSF) measurements of HCRT represent a potential marker of an underlying pathology, i.e., lesion of HCRT neurons. However, for this marker to be clinically significant it is vital that we determine the relationship between number of HCRT neurons and CSF HCRT levels. Narcoleptic patients have reduced CSF levels of HCRT, a finding consistent with the loss of HCRT neurons. However, new data from Mignot's group are beginning to show that in about 10 percent of narcoleptics the CSF levels of HCRT are normal. This raises important questions about loss of HCRT neurons, and the utility of CSF levels of HCRT as an assay to diagnose narcolepsy. For instance, if a human narcoleptic has normal CSF HCRT levels does it mean that HCRT neurons are intact? Or does it suggest that the disease has not progressed to a point where a certain threshold number of HCRT neurons have not been destroyed? Because such questions cannot be easily addressed using current murine knockout, rat knockout or canine models of narcolepsy, we will utilize the hypocretin-saporin (HCRT2-SAP) neurotoxin method to lesion hypocretin and adjacent lateral hypothalamic neurons and monitor sleep and CSF HCRT-1 levels in rats. We have designed a set of aims to provide critical data to the clinician, but also provide a framework for integrating the hypocretin neurons within an overall model of sleep regulation.
Specific aim 1 will test the hypothesis that a significant decrease in CSF HCRT levels is evident only after a threshold number of HCRT neurons are lost.
Specific aim 2 will determine the association between CSF HCRT levels and sleep. Specifically, we will investigate whether narcoleptic-like behavior, characterized by sleep onset REM sleep periods (SOREMPs), increased REM sleep at night, and hypersomnia is evident ahead of a decline in CSF HCRT levels.
Specific aim 3 will test the hypothesis that loss of a specific population of HCRT neurons is responsible for the symptoms of narcolepsy.
Specific aim 4 will determine the afferents and efferents of this population of HCRT neurons.
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