The hypocretin/orexin (Hcrt) system is a neuropeptide system involved in behavioral arousal, metabolism, addiction, stress-induced analgesia (SIA) and neuroendocrine function. Hcrt deficiency results in narcolepsy, a CNS disorder characterized by impaired alertness, excessive sleepiness, restricted social activities, and increased body mass index. Given the functional significance of this system, identification of the inputs that control the Hcrt system and functional Hcrt efferent pathways is of clinical relevance. We will use a combination of optogenetics, transgenic mice in which light-sensitive proteins are expressed specifically in Hcrt neurons, and conditional transgenic mouse strains to further understand the Hcrt system. Using a novel transgenic mouse that expresses the light-sensitive proton pump Archaerhodopsin-3 specifically in Hcrt neurons, we will test the hypotheses that: (1) optogenetic inactivation of the Hcrt neurons will induce changes in cortical activity, muscle tone and behavior indicative of sleep, and (2), that homeostatic sleep pressure modulates the efficacy of optogenetic inactivation of Hcrt neurons to induce sleep. Using a transgenic mouse in which the 5HT1A receptor is conditionally overexpressed in Hcrt neurons, we will test the hypothesis that the negative feedback loop between Hcrt neurons and the serotonergic dorsal raphe nucleus has functional significance for the regulation of sleep and wakefulness. Lastly, we will exploit a newly created transgenic mouse in which conditional expression of diphtheria toxin A (DTA) occurs specifically in Hcrt neurons to establish and validate a novel mouse model of human narcolepsy that more closely resembles the human disorder. The research proposed here represents an integrated systems neurobiology approach to elucidate control of a neurotransmitter system implicated in a number of behaviors and whose pathology is clearly linked to CNS dysfunction and may lead to novel pharmacotherapeutic approaches for the treatment of disorders of Hcrt insufficiency such as narcolepsy.
The hypocretin/orexin (Hcrt) system is a hypothalamic neuropeptide system that is involved in behavioral arousal, metabolism, addiction, stress-induced analgesia, and neuroendocrine function. Degeneration of Hcrt neurons results in the sleep disorder narcolepsy. Given the clinical relevance of this system, identification of the input that control the Hcrt neurons and functional Hcrt efferent pathways is of significance. We will use a combination of optogenetics, transgenic mice in which light-sensitive proteins are expressed specifically in Hcrt neurons, and conditional transgenic mouse strains to further understand the Hcrt system and to generate new models that may lead to novel pharmacotherapeutic approaches for the treatment of disorders of Hcrt insufficiency including narcolepsy.
| Williams, Rhîannan H; Vazquez-DeRose, Jacqueline; Thomas, Alexia M et al. (2018) Cortical nNOS/NK1 Receptor Neurons are Regulated by Cholinergic Projections From the Basal Forebrain. Cereb Cortex 28:1959-1979 |
| Williams, Rhîannan H; Black, Sarah W; Thomas, Alexia M et al. (2018) Excitation of Cortical nNOS/NK1R Neurons by Hypocretin 1 is Independent of Sleep Homeostasis. Cereb Cortex : |
| Peyron, Christelle; Kilduff, Thomas S (2017) Mapping the Hypocretin/Orexin Neuronal System: An Unexpectedly Productive Journey. J Neurosci 37:2268-2272 |
| Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S (2017) Challenges in the development of therapeutics for narcolepsy. Prog Neurobiol 152:89-113 |
| Schwartz, Michael D; Nguyen, Alexander T; Warrier, Deepti R et al. (2016) Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep. eNeuro 3: |
| Parks, Gregory S; Warrier, Deepti R; Dittrich, Lars et al. (2016) The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems. Neuropsychopharmacology 41:1144-55 |
| Black, Sarah Wurts; Kilduff, Thomas S (2016) H1N1 infection of sleep/wake regions results in narcolepsy-like symptoms. Proc Natl Acad Sci U S A 113:476-7 |
| Schwartz, Michael D; Kilduff, Thomas S (2015) The Neurobiology of Sleep and Wakefulness. Psychiatr Clin North Am 38:615-44 |
| Black, Sarah Wurts; Morairty, Stephen R; Chen, Tsui-Ming et al. (2014) GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy. J Neurosci 34:6485-94 |
| Tabuchi, Sawako; Tsunematsu, Tomomi; Black, Sarah W et al. (2014) Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci 34:6495-509 |
Showing the most recent 10 out of 14 publications
