Gerashchenko D, Murillo-Rodriguez E, Blanco-Centurion C, Lin L, Nishino S, Mignot E, Shiromani PJ (2005) Adenosine levels do not increase with 6 h waking in rats with lesions of the lateral hypothalamus. Neuroscience 2005 Abstracts 63.9. Society for Neuroscience, Washington, DC.
Summary: The hypocretin neurons in the lateral hypothalamus (LH) have been implicated in wakefulness, but it is not clear which projection is responsible for the arousal. One possibility is that the LH neurons induce wakefulness by driving the basal forebrain (BF) wake-active neurons (Gerashchenko and Shiromani, Cellular & Molec Neurosci, 29: 41, 2004). Here we measure adenosine (AD) levels in the BF as a marker of arousal and test the LH-BF circuit in Sprague-Dawley rats with lesions of the LH induced by hypocretin-2-saporin. 64 days after lesions the rats were kept awake (gentle handling) for six hours (ZT 3-9) and microdialysis samples (5ul) were collected hourly for 9 hours (24h after probe stabilization). AD levels were assessed using HPLC. Hypocretin-saporin ablated 95% of the hypocretin neurons and reduced CSF hypocretin levels (-75% versus control). AD levels increased with 6h waking in saline control rats (n=9), consistent with previous studies in cats (Strecker et al., Behav Brain Res 115: 183, 2000) and rats (Murillo-Rodriguez et al., Neuroscience 123: 361, 2004). However, in rats with LH lesions (n=5) such an increase with waking did not occur. Sleep drive was measured by conducting a rodent version of a multiple sleep latency test (MSLT). In this test, conducted over 10h (from ZT2-ZT12) the rats were kept awake for 20min and then allowed 20min to sleep. The lesioned rats had more sleep during the 20min sleep periods indicating a higher sleep drive. These results suggest that in narcolepsy when the HCRT LH neurons die, there is a loss of stimulation of the wake-active BF neurons and the decline in this pathway may be the cause of the increased sleep attacks. Supported by VA Medical Research and NIH
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