The anatomical changes responsible for narcolepsy remain unknown. While receptor abnormalities have been identified, it is unclear if these are the sole or major cause of the disease. The hypothesis to be tested in this project, is that narcolepsy is due to a localizable degenerative neuropathology that occurs prior to, or at the time of symptom onset. Using age and breed matched narcoleptic and control dogs, we will: l. Quantify the changes in the volume of a number of brainstem and forebrain nuclei to identify regional degeneration in narcolepsy. 2. Look for the expression of immediate early genes (IEG'S) (c-jun,jun-D and c-fos) prior to the onset of narcoleptic symptoms. Certain IEG's (c- jun and jun-D) have been shown to be expressed for prolonged periods during neuronal degeneration. 3. Use cupric silver staining technique to locate axonal degeneration. We will also use complementary histological stains (Hematoxylin-eosin and glial fibrillary acidic protein [GFAP]) to determine the nature of any localized or diffuse degeneration in narcolepsy. In pilot studies for this proposal using silver staining, we have found consistent and massive degeneration in certain limbic nuclei. specific to the narcoleptic dog. This finding encourages us to believe that we will be able to identify a localized neuropathology underlying this disease. However, even if the proposed volume, IEG and axonal degeneration studies are negative, these studies will be important in eliminating several major hypotheses of the etiology of narcolepsy.
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