Action Potentials; Eating Disorders; Hypothalamus; Membrane Potentials; Neurophysiology; Sleep Disorders; Glutamic Acid; Synaptic Potentials
Obstetrics, Gynecology & Reproductive Sciences: Discovery to Cure Internship | Reproductive Neurosciences Group
The lateral hypothalamus (LH) plays a substantial role in a number of functions including sensorimotor integration, energy homeostasis, sleep-wake regulation, addiction, emotion and regulation of the autonomic nervous system. It has been shown that the LH is a central hub receiving physiological, behavioral and environmental inputs from and sending outputs to other brain structures to participate in homeostatic and behavioral functions. Our long-term goal is to understand how signaling at molecular, cellular and circuit levels leads to the emergence of instinctive behaviors critical for animal survival and how adaptive and maladaptive changes in the LH lead to diseases and conditions such as obesity, diabetes, sleep disorders, etc.
Specialized Terms: Neurotransmission; Neurotransmitter response and synaptic plasticity; Cellular physiology of neuropeptides (hypocretin/orexin, melanin concentrating hormone, neuropeptide Y, ghrelin, leptin, and a-MSH); Ion channels (Na+, Ca2+, K+ channels); Electrophysiology/patch clamp recording; calcium imaging; Hypothalamus/lateral hypothalamic area; Energy homeostasis/feeding regulation; Sleep homeostasis and regulation; Drug addiction
Extensive Research Description
The lateral hypothalamus (LH) plays a substantial role in a number of functions including sensorimotor integration, energy homeostasis, sleep-wake regulation, addiction, emotion and regulation of the autonomic nervous system. It has been shown that the LH is a central hub receiving physiological, behavioral and environmental inputs from and sending outputs to other brain structures to participate in homeostatic and behavioral functions.
Despite its critical role in the survival of individuals and species, it is largely unclear how the LH integrates information from internal and external environments to exert its actions. Moreover, it is also not clear how the neural circuitry centered on neurons in the LH make adaptive changes to accommodate physiological, behavioral and environmental changes. Our long-term goal is to understand the logic of how signaling at molecular, cellular and circuit levels leads to the emergence of instinctive behaviors critical for animal survival.
Specifically, the questions that we are pursuing include: 1) how neural circuitry in the LH participates in the regulation of homeostatic and behavioral functions of the brain; 2) how neural circuitry in the LH is modified by physiological, behavioral and environmental changes in mature animals; 3) how maternal and early postnatal experience leads to changes in the development of neural circuitry responsible for dysfunctions of the LH during adulthood. 1. Crosstalk of Hypocretin and MCH in Feeding
Regulation. This study investigates neuropeptides (hypocretin/orexin and MCH) and their receptors involved in regulatory pathways controlling feeding behavior. Supported by the NIH/NIDDK.
Deficiency in Prader-Willi Syndrome Animal Models. This study investigates the functional deficiency in hypocretin/orexin neurons in Prader-Willi Syndrome animal models. Supported by the Foundation for Prader-Willi Research.
Direct evidence for wake-related increases and sleep-related decreases in synaptic strength in rodent cortex
Liu, Z.W., Faraguna, U., Cirelli, C., Tononi, G., Gao, X.B. (2010) Direct evidence for wake-related increases and sleep-related decreases in synaptic strength in rodent cortex. J Neuroscience 30: 8671-8675.
Regulation of synaptic efficacy in hypocretin/orexin containing neurons by melanin concentrating hormone in the lateral hypothalamus
Rao, Y., M. Lu, F. Ge, D.J. Marsh, S. Qian, A.H. Wang, M.R. Picciotto, X.-B. Gao. (2008) Regulation of synaptic efficacy in hypocretin/orexin containing neurons by melanin concentrating hormone in the lateral hypothalamus. Journal of Neuroscience 28: 9101-9110.
Prolonged wakefulness induces experience-dependent synaptic plasticity in hypocretin/orexin neurons
Rao, Y., Z.-W. Liu, E. Borok, R.L. Rabenstein, M. Shanabrough, M. Lu, M.R. Picciotto, T.L. Horvath, and X.-B. Gao. (2007) Prolonged wakefulness induces experience-dependent synaptic plasticity in hypocretin/orexin neurons. Journal of Clinical Investigation 117: 4022-4033.
Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect
Liu, Z.W. and X.-B. Gao. (2007) Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. Journal of Neurophysiology 97: 837-848.
Input organization and plasticity of hypocretin neurons: Possible clues to obesity’s association with insomnia
Horvath, T.L. and X.-B. Gao. (2005) Input organization and plasticity of hypocretin neurons: Possible clues to obesity’s association with insomnia. Cell metabolism 1: 279-286.
Melanin-Concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus
Gao, X.-B. and A.N. van den Pol. (2001) Melanin-Concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus. Journal of Physiology (Lond.) 533: 237-252.
Full List of PubMed Publications
- Khrimian L, Obri A, Ramos-Brossier M, Rousseaud A, Moriceau S, Nicot AS, Mera P, Kosmidis S, Karnavas T, Saudou F, Gao XB, Oury F, Kandel E, Karsenty G: Gpr158 mediates osteocalcin's regulation of cognition. J Exp Med. 2017 Aug 29; 2017 Aug 29. PMID: 28851741
- Suyama S, Ralevski A, Liu ZW, Dietrich MO, Yada T, Simonds SE, Cowley MA, Gao XB, Diano S, Horvath TL: Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons. Elife. 2017 Aug 1; 2017 Aug 1. PMID: 28762946
- Varela L, Suyama S, Huang Y, Shanabrough M, Tschöp MH, Gao XB, Giordano FJ, Horvath TL: Endothelial HIF-1α Enables Hypothalamic Glucose Uptake to Drive POMC Neurons. Diabetes. 2017 Jun; 2017 Mar 14. PMID: 28292966
- Gao XB, Horvath TL: Feeding Behavior: Hypocretin/Orexin Neurons Act between Food Seeking and Eating. Curr Biol. 2016 Sep 26. PMID: 27676302
- Onorati M, Li Z, Liu F, Sousa AM, Nakagawa N, Li M, Dell'Anno MT, Gulden FO, Pochareddy S, Tebbenkamp AT, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N: Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Rep. 2016 Sep 6; 2016 Aug 24. PMID: 27568284
- Gao XB, Hermes G: Neural plasticity in hypocretin neurons: the basis of hypocretinergic regulation of physiological and behavioral functions in animals. Front Syst Neurosci. 2015; 2015 Oct 21. PMID: 26539086
- Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL: Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015 Mar 5; 2015 Feb 18. PMID: 25707796
- Zhou WL, Gao XB, Picciotto MR: Acetylcholine Acts through Nicotinic Receptors to Enhance the Firing Rate of a Subset of Hypocretin Neurons in the Mouse Hypothalamus through Distinct Presynaptic and Postsynaptic Mechanisms. eNeuro. 2015 Jan-Feb. PMID: 26322330
- Gao XB, Horvath T: Function and dysfunction of hypocretin/orexin: an energetics point of view. Annu Rev Neurosci. 2014; 2014 Apr 24. PMID: 24821311
- D'Agostino G, Kim JD, Liu ZW, Jeong JK, Suyama S, Calignano A, Gao XB, Schwartz M, Diano S: Prolyl endopeptidase-deficient mice have reduced synaptic spine density in the CA1 region of the hippocampus, impaired LTP, and spatial learning and memory. Cereb Cortex. 2013 Aug; 2012 Jul 5. PMID: 22767632
- Rao Y, Mineur YS, Gan G, Wang AH, Liu ZW, Wu X, Suyama S, de Lecea L, Horvath TL, Picciotto MR, Gao XB: Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin-producing neurons in the lateral hypothalamus in mice. J Physiol. 2013 Apr 1; 2013 Jan 14. PMID: 23318871
- Dietrich MO, Bober J, Ferreira JG, Tellez LA, Mineur YS, Souza DO, Gao XB, Picciotto MR, Araújo I, Liu ZW, Horvath TL: AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nat Neurosci. 2012 Jun 24; 2012 Jun 24. PMID: 22729177
- Aldad TS, Gan G, Gao XB, Taylor HS: Fetal radiofrequency radiation exposure from 800-1900 mhz-rated cellular telephones affects neurodevelopment and behavior in mice. Sci Rep. 2012; 2012 Mar 15. PMID: 22428084
- Gao XB: Plasticity in neurons synthesizing wake/arousal promoting hormone hypocretin/orexin. Vitam Horm. 2012. PMID: 22640607
- Liu ZW, Gan G, Suyama S, Gao XB: Intracellular energy status regulates activity in hypocretin/orexin neurones: a link between energy and behavioural states. J Physiol. 2011 Sep 1; 2011 Jul 4. PMID: 21727218
- Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL: Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med. 2011 Aug 28; 2011 Aug 28. PMID: 21873987
- Mineur YS, Abizaid A, Rao Y, Salas R, DiLeone RJ, Gündisch D, Diano S, De Biasi M, Horvath TL, Gao XB, Picciotto MR: Nicotine decreases food intake through activation of POMC neurons. Science. 2011 Jun 10. PMID: 21659607
- Wolff EF, Gao XB, Yao KV, Andrews ZB, Du H, Elsworth JD, Taylor HS: Endometrial stem cell transplantation restores dopamine production in a Parkinson's disease model. J Cell Mol Med. 2011 Apr. PMID: 20406327
- Gao XB, Horvath TL: An arousing discovery on catalepsy: orexin regulates vestibular motor functions. Neuron. 2011 Feb 24. PMID: 21338870
- Trinko R, Gan G, Gao XB, Sears RM, Guarnieri DJ, DiLeone RJ: Erk1/2 mediates leptin receptor signaling in the ventral tegmental area. PLoS One. 2011; 2011 Nov 4. PMID: 22076135
- Gyengesi E, Liu ZW, D'Agostino G, Gan G, Horvath TL, Gao XB, Diano S: Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology. 2010 Nov; 2010 Sep 15. PMID: 20843996
- Dietrich MO, Antunes C, Geliang G, Liu ZW, Borok E, Nie Y, Xu AW, Souza DO, Gao Q, Diano S, Gao XB, Horvath TL: Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci. 2010 Sep 1. PMID: 20810901
- Liu ZW, Faraguna U, Cirelli C, Tononi G, Gao XB: Direct evidence for wake-related increases and sleep-related decreases in synaptic strength in rodent cortex. J Neurosci. 2010 Jun 23. PMID: 20573912
- Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, Elsworth JD, Savitt JM, DiMarchi R, Tschoep M, Roth RH, Gao XB, Horvath TL: Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J Neurosci. 2009 Nov 11. PMID: 19906954
- Gao XB: Electrophysiological effects of MCH on neurons in the hypothalamus. Peptides. 2009 Nov; 2009 May 20. PMID: 19463877
- Wallingford N, Perroud B, Gao Q, Coppola A, Gyengesi E, Liu ZW, Gao XB, Diament A, Haus KA, Shariat-Madar Z, Mahdi F, Wardlaw SL, Schmaier AH, Warden CH, Diano S: Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents. J Clin Invest. 2009 Aug; 2009 Jul 20. PMID: 19620781
- Rao Y, Lu M, Ge F, Marsh DJ, Qian S, Wang AH, Picciotto MR, Gao XB: Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. J Neurosci. 2008 Sep 10. PMID: 18784290
- Rao Y, Liu ZW, Borok E, Rabenstein RL, Shanabrough M, Lu M, Picciotto MR, Horvath TL, Gao XB: Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. J Clin Invest. 2007 Dec. PMID: 18060037
- Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, Diano S: A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab. 2007 Jan. PMID: 17189204
- Liu ZW, Gao XB: Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol. 2007 Jan; 2006 Nov 8. PMID: 17093123
- Gao Q, Mezei G, Nie Y, Rao Y, Choi CS, Bechmann I, Leranth C, Toran-Allerand D, Priest CA, Roberts JL, Gao XB, Mobbs C, Shulman GI, Diano S, Horvath TL: Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med. 2007 Jan; 2006 Dec 31. PMID: 17195839
- Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschöp MH, Gao XB, Horvath TL: Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest. 2006 Dec; 2006 Oct 19. PMID: 17060947
- Horvath TL, Gao XB: Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia. Cell Metab. 2005 Apr. PMID: 16054072
- Gao XB, Ghosh PK, van den Pol AN: Neurons synthesizing melanin-concentrating hormone identified by selective reporter gene expression after transfection in vitro: transmitter responses. J Neurophysiol. 2003 Dec; 2003 Oct 22. PMID: 14573562
- Li Y, Gao XB, Sakurai T, van den Pol AN: Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron. 2002 Dec 19. PMID: 12495630
- Gao XB, van den Pol AN: Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons. J Physiol. 2002 Jul 1. PMID: 12096069
- van den Pol AN, Ghosh PK, Liu RJ, Li Y, Aghajanian GK, Gao XB: Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol. 2002 May 15. PMID: 12015428