The lateral hypothalamus (LH) serves as a central hub, integrating a wide range of inputs from various brain regions and projecting neuropeptide-containing nerve fibers all over the brain. The LH has long been recognized as a feeding center. The regulation of food intake plays an important role in energy-balance homeostasis. Unbalanced energy accumulation leads to obesity, which has been recognized as a risk factor in many diseases and disorders. Despite the overwhelming importance of this structure, it remains poorly understood how the LH integrates different sources of signals and exerts its functions via hypocretin/orexin and melanin-concentrating hormone (MCH) systems in the LH. Both hypocretin and MCH have been implicated as orexigenic: Previous studies have suggested that hypocretin/orexin is an excitatory peptide while MCH is inhibitory. Given their opposite actions at the cellular level, it is intriguing to understand how these two systems interact dynamically to determine the final output and hence to determine the behavioral states of animals. The long-term goal of this project is to understand how these neurons interact with each other to form specific functional organizations for regulating different behaviors. In this proposal, we will use molecular biological, electrophysiological, immunocytochemical and electron microscopic methods as well as digital calcium imaging to address the interaction or hypocretin/orexin and MCH at the cellular level in both normal animals and transgenic mouse models. The chief hypothesis is that the excitatory role of hypocretin/orexin in the LH may serve as the engine to propel this brain region, while the inhibitory modulation induced by MCH may substantially adjust the tone of neuronal activity in the LH area and thus may shape the decision making of the LH and the arcuate nucleus. The following hypotheses will be examined: 1. Hypocretin/orexin serves as a major excitatory force to both hypocretin/orexin and MCH systems. 2. MCH modulates excitability in both hypocretin/orexin and MCH containing neurons. 3. Crosstalk of hypocretin and MCH underlies appropriate regulation of the melanocortin system in the arcuate nucleus. This proposal will begin to bridge the gap between studies at the molecular level and the systemic level on the role of the LH in regulation of food intake. We hope that results generated from this proposal will complement to the current framework in understanding energy homeostasis in mammals. Ultimately, we hope that our research will benefit those suffering from obesity and obesity-related diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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Yale University
Schools of Medicine
New Haven
United States
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Rao, Yan; Mineur, Yann S; Gan, Geliang et al. (2013) Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin-producing neurons in the lateral hypothalamus in mice. J Physiol 591:1951-66
Gao, Xiao-Bing (2012) Plasticity in neurons synthesizing wake/arousal promoting hormone hypocretin/orexin. Vitam Horm 89:35-59
Mineur, Yann S; Abizaid, Alfonso; Rao, Yan et al. (2011) Nicotine decreases food intake through activation of POMC neurons. Science 332:1330-2
Liu, Zhong-Wu; Gan, Geliang; Suyama, Shigetomo et al. (2011) Intracellular energy status regulates activity in hypocretin/orexin neurones: a link between energy and behavioural states. J Physiol 589:4157-66
Gao, X-B; Wang, A H (2010) Experience-dependent plasticity in hypocretin/orexin neurones: re-setting arousal threshold. Acta Physiol (Oxf) 198:251-62
Liu, Zhong-Wu; Faraguna, Ugo; Cirelli, Chiara et al. (2010) Direct evidence for wake-related increases and sleep-related decreases in synaptic strength in rodent cortex. J Neurosci 30:8671-5
Korosi, Aniko; Shanabrough, Marya; McClelland, Shawn et al. (2010) Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone. J Neurosci 30:703-13
Gao, Xiao-Bing (2009) Electrophysiological effects of MCH on neurons in the hypothalamus. Peptides 30:2025-30
Rao, Yan; Lu, Min; Ge, Fei et al. (2008) Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. J Neurosci 28:9101-10
Liu, Zhong-Wu; Gao, Xiao-Bing (2007) Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol 97:837-48

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