Thomas S. Kilduff

SRI International, USA

Abstract

[O17] Afferent regulation of hypocretin/orexin neurons

The hypocretin/orexin (Hcrt) neurons of the perifornical and lateral hypothalamus have been implicated in the control of wakefulness, energy metabolism, and addictive behaviors, among other CNS functions.  Hcrt neuron loss in humans results in the sleep disorder narcolepsy.  Narcoleptic patients are well known to suffer from both excessive daytime sleepiness (EDS) and a sudden loss of motor tone known as cataplexy that can be precipitated by positive emotional stimuli.  Narcoleptics also have a higher body mass index (BMI) than the general population and, although amphetamines have historically been prescribed for the treatment of EDS symptoms, narcoleptic patients are much less likely to escalate dosage than non-narcoleptics.  These clinical observations that suggest that Hcrt neurons are important for maintenance of wakefulness, normal BMI and for the development of addiction, concepts that have been supported by neuroscientific investigations in both wildtype and transgenic animals.

Given the apparent importance of the Hcrt neurons, we and others have sought to identify the afferent and neurochemical inputs that control these cells. Two transgenic mouse strains created by the Sakurai laboratory have been particularly useful in this regard.  Orexin/EGFP mice have allowed identification of Hcrt cells for in vitro patch clamp studies and determination of substances that excite or inhibit these cells.  Orexin/ataxin-3 mice undergo postnatal degeneration of the Hcrt neurons and exhibit cataplexy, thereby being a useful model of human narcolepsy.  The absence of the Hcrt neurons in these mice also allows determination whether substances found to excite or inhibit Hcrt neurons in vitro have functional significance in vivo.  Use of these complementary approaches to understand Hcrt neuron regulation by GABAB, nociceptin/orphanin FQ (N/OFQ) and thyrotropin releasing hormone (TRH) inputs will be discussed (Supported by NIH R01 MH61755, R01 AG020584 and R01 NS057464).

Biography

Thomas Kilduff, Ph.D., is Senior Director of the Center for Neuroscience at SRI International, a non-profit research institute, and a Consulting Professor in the Stanford University School of Medicine.  His research in sleep and circadian neurobiology has included studies on the suprachiasmatic nucleus, neurochemical and immunological studies of the sleep disorder narcolepsy, and gene expression studies across arousal states including mammalian hibernation. Along with researchers at the Scripps Research Institute, he is co-discoverer of the hypothalamic peptide hypocretin, also known as orexin.  His current work focuses on the hypocretin system and a novel population of sleep-active cortical neurons.