Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Virus Injection and Cannula Implantation
2.3. Drugs (CNO, OXA, Muscimol and Bicuculline)
2.4. Metabolic and Behavioral Profiling (Indirect Calorimetry)
2.5. Experimental Design
2.6. Orexin Neuron Excitation Study
2.7. Direct DRN Orexin Injection Study
2.8. Statistical Analysis
3. Results
3.1. Expression of DREADD-mCherry in Lateral LH Orexin Neurons
3.2. Chemogenetic Activation of Orexin Neurons Enhances SPA in Mice
3.3. Injecting the DRN with Orexin-A Enhances SPA and EE in Mice
3.4. Enhanced SPA Is Positively Correlated with Increased EE
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Kotz, C.M.; Perez-Leighton, C.E.; Teske, J.A.; Billington, C.J. Spontaneous Physical Activity Defends Against Obesity. Curr. Obes. Rep. 2017, 6, 362–370. [Google Scholar] [CrossRef] [PubMed]
- Garland, T., Jr.; Schutz, H.; Chappell, M.A.; Keeney, B.K.; Meek, T.H.; Copes, L.E.; Acosta, W.; Drenowatz, C.; Maciel, R.C.; van Dijk, G.; et al. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: Human and rodent perspectives. J. Exp. Biol. 2011, 214, 206–229. [Google Scholar] [CrossRef] [PubMed]
- Shay, D.A.; Welly, R.J.; Givan, S.A.; Bivens, N.; Kanaley, J.; Marshall, B.L.; Lubahn, D.B.; Rosenfeld, C.S.; Vieira-Potter, V.J. Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice. Horm. Behav. 2020, 121, 104719. [Google Scholar] [CrossRef]
- Messina, A.; Monda, M.; Valenzano, A.; Messina, G.; Villano, I.; Moscatelli, F.; Cibelli, G.; Marsala, G.; Polito, R.; Ruberto, M.; et al. Functional Changes Induced by Orexin A and Adiponectin on the Sympathetic/Parasympathetic Balance. Front. Physiol. 2018, 9, 259. [Google Scholar] [CrossRef] [PubMed]
- Polito, R.; Nigro, E.; Elce, A.; Monaco, M.L.; Iacotucci, P.; Carnovale, V.; Comegna, M.; Gelzo, M.; Zarrilli, F.; Corso, G.; et al. Adiponectin Expression Is Modulated by Long-Term Physical Activity in Adult Patients Affected by Cystic Fibrosis. Mediat. Inflamm. 2019, 2019, 2153934. [Google Scholar] [CrossRef] [PubMed]
- Teske, J.A.; Mavanji, V. Energy expenditure: Role of orexin. Vitam. Horm. 2012, 89, 91–109. [Google Scholar] [CrossRef] [PubMed]
- Mavanji, V.; Pomonis, B.; Kotz, C. Orexin, serotonin, and energy balance. WIRES Mech. Dis. 2021, 14, e1536. [Google Scholar] [CrossRef] [PubMed]
- Thorpe, A.J.; Mullett, M.A.; Wang, C.; Kotz, C.M. Peptides that regulate food intake: Regional, metabolic, and circadian specificity of lateral hypothalamic orexin A feeding stimulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 284, R1409–R1417. [Google Scholar] [CrossRef] [PubMed]
- Hagan, J.J.; Leslie, R.A.; Patel, S.; Evans, M.L.; Wattam, T.A.; Holmes, S.; Benham, C.D.; Taylor, S.G.; Routledge, C.; Hemmati, P.; et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc. Natl. Acad. Sci. USA 1999, 96, 10911–10916. [Google Scholar] [CrossRef] [PubMed]
- Perez-Leighton, C.; Little, M.R.; Grace, M.; Billington, C.; Kotz, C.M. Orexin signaling in rostral lateral hypothalamus and nucleus accumbens shell in the control of spontaneous physical activity in high- and low-activity rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2017, 312, R338–R346. [Google Scholar] [CrossRef] [PubMed]
- Teske, J.A.; Levine, A.S.; Kuskowski, M.; Levine, J.A.; Kotz, C.M. Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006, 291, R889–R899. [Google Scholar] [CrossRef] [PubMed]
- Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.M.; Tanaka, H.; Williams, S.C.; Richardson, J.A.; Kozlowski, G.P.; Wilson, S.; et al. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92, 573–585. [Google Scholar] [CrossRef] [PubMed]
- Kotz, C.M.; Teske, J.A.; Billington, C.J. Neuroregulation of nonexercise activity thermogenesis and obesity resistance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 294, R699–R710. [Google Scholar] [CrossRef] [PubMed]
- Thorpe, A.J.; Kotz, C.M. Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res. 2005, 1050, 156–162. [Google Scholar] [CrossRef] [PubMed]
- Hara, J.; Beuckmann, C.T.; Nambu, T.; Willie, J.T.; Chemelli, R.M.; Sinton, C.M.; Sugiyama, F.; Yagami, K.; Goto, K.; Yanagisawa, M.; et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001, 30, 345–354. [Google Scholar] [CrossRef] [PubMed]
- Hara, J.; Yanagisawa, M.; Sakurai, T. Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Neurosci. Lett. 2005, 380, 239–242. [Google Scholar] [CrossRef] [PubMed]
- Zhang, S.; Zeitzer, J.M.; Sakurai, T.; Nishino, S.; Mignot, E. Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy. J. Physiol. 2007, 581, 649–663. [Google Scholar] [CrossRef] [PubMed]
- Fujiki, N.; Yoshida, Y.; Zhang, S.; Sakurai, T.; Yanagisawa, M.; Nishino, S. Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models. Peptides 2006, 27, 2326–2331. [Google Scholar] [CrossRef] [PubMed]
- Kotz, C.M.; Teske, J.A.; Levine, J.A.; Wang, C. Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul. Pept. 2002, 104, 27–32. [Google Scholar] [CrossRef] [PubMed]
- Bunney, P.E.; Zink, A.N.; Holm, A.A.; Billington, C.J.; Kotz, C.M. Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet. Physiol. Behav. 2017, 176, 139–148. [Google Scholar] [CrossRef] [PubMed]
- Zink, A.N.; Perez-Leighton, C.E.; Kotz, C.M. The orexin neuropeptide system: Physical activity and hypothalamic function throughout the aging process. Front. Syst. Neurosci. 2014, 8, 211. [Google Scholar] [CrossRef] [PubMed]
- Funato, H.; Tsai, A.L.; Willie, J.T.; Kisanuki, Y.; Williams, S.C.; Sakurai, T.; Yanagisawa, M. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. 2009, 9, 64–76. [Google Scholar] [CrossRef] [PubMed]
- Novak, C.M.; Levine, J.A. Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obes. Silver Spring 2009, 17, 1493–1498. [Google Scholar] [CrossRef] [PubMed]
- Kotz, C.M. Integration of feeding and spontaneous physical activity: Role for orexin. Physiol. Behav. 2006, 88, 294–301. [Google Scholar] [CrossRef] [PubMed]
- Teske, J.A.; Perez-Leighton, C.E.; Billington, C.J.; Kotz, C.M. Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013, 305, R1337–R1345. [Google Scholar] [CrossRef] [PubMed]
- Novak, C.M.; Kotz, C.M.; Levine, J.A. Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet-resistant rats. Am. J. Physiol. Endocrinol. Metab. 2006, 290, E396–E403. [Google Scholar] [CrossRef] [PubMed]
- Xiao, J.; Song, M.; Li, F.; Liu, X.; Anwar, A.; Zhao, H. Effects of GABA microinjection into dorsal raphe nucleus on behavior and activity of lateral habenular neurons in mice. Exp. Neurol. 2017, 298, 23–30. [Google Scholar] [CrossRef] [PubMed]
- Yabut, J.M.; Crane, J.D.; Green, A.E.; Keating, D.J.; Khan, W.I.; Steinberg, G.R. Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule. Endocr. Rev. 2019, 40, 1092–1107. [Google Scholar] [CrossRef] [PubMed]
- Burke, L.K.; Heisler, L.K. 5-hydroxytryptamine medications for the treatment of obesity. J. Neuroendocrinol. 2015, 27, 389–398. [Google Scholar] [CrossRef] [PubMed]
- Mavanji, V.; Teske, J.A.; Billington, C.J.; Kotz, C.M. Elevated sleep quality and orexin receptor mRNA in obesity-resistant rats. Int. J. Obes. 2010, 34, 1576–1588. [Google Scholar] [CrossRef] [PubMed]
- Tao, R.; Ma, Z.; McKenna, J.T.; Thakkar, M.M.; Winston, S.; Strecker, R.E.; McCarley, R.W. Differential effect of orexins (hypocretins) on serotonin release in the dorsal and median raphe nuclei of freely behaving rats. Neuroscience 2006, 141, 1101–1105. [Google Scholar] [CrossRef] [PubMed]
- Darwinkel, A.; Stanić, D.; Booth, L.C.; May, C.N.; Lawrence, A.J.; Yao, S.T. Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: Co-localization with tyrosine hydroxylase and neuronal nitric oxide synthase. Neuroscience 2014, 278, 253–264. [Google Scholar] [CrossRef] [PubMed]
- Yaswen, L.; Diehl, N.; Brennan, M.B.; Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 1999, 5, 1066–1070. [Google Scholar] [CrossRef] [PubMed]
- Tupone, D.; Madden, C.J.; Cano, G.; Morrison, S.F. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J. Neurosci. 2011, 31, 15944–15955. [Google Scholar] [CrossRef] [PubMed]
- Muraki, Y.; Yamanaka, A.; Tsujino, N.; Kilduff, T.S.; Goto, K.; Sakurai, T. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. J. Neurosci. 2004, 24, 7159–7166. [Google Scholar] [CrossRef] [PubMed]
- Yamanaka, A.; Muraki, Y.; Tsujino, N.; Goto, K.; Sakurai, T. Regulation of orexin neurons by the monoaminergic and cholinergic systems. Biochem. Biophys. Res. Commun. 2003, 303, 120–129. [Google Scholar] [CrossRef] [PubMed]
- Nonogaki, K.; Memon, R.A.; Grunfeld, C.; Feingold, K.R.; Tecott, L.H. Altered gene expressions involved in energy expenditure in 5-HT(2C) receptor mutant mice. Biochem. Biophys. Res. Commun. 2002, 295, 249–254. [Google Scholar] [CrossRef] [PubMed]
- Nonogaki, K.; Nozue, K.; Takahashi, Y.; Yamashita, N.; Hiraoka, S.; Kumano, H.; Kuboki, T.; Oka, Y. Fluvoxamine, a selective serotonin reuptake inhibitor, and 5-HT2C receptor inactivation induce appetite-suppressing effects in mice via 5-HT1B receptors. Int. J. Neuropsychopharmacol. 2007, 10, 675–681. [Google Scholar] [CrossRef] [PubMed]
- Romanova, I.V.; Derkach, K.V.; Mikhrina, A.L.; Sukhov, I.B.; Mikhailova, E.V.; Shpakov, A.O. The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents. Neurochem. Res. 2018, 43, 821–837. [Google Scholar] [CrossRef] [PubMed]
- Pei, Y.; Rogan, S.C.; Yan, F.; Roth, B.L. Engineered GPCRs as tools to modulate signal transduction. Physiology 2008, 23, 313–321. [Google Scholar] [CrossRef] [PubMed]
- Zink, A.N.; Bunney, P.E.; Holm, A.A.; Billington, C.J.; Kotz, C.M. Neuromodulation of orexin neurons reduces diet-induced adiposity. Int. J. Obes. 2018, 42, 737–745. [Google Scholar] [CrossRef] [PubMed]
- Korczeniewska, O.A.; James, M.H.; Eliav, T.; Katzmann Rider, G.; Mehr, J.B.; Affendi, H.; Aston-Jones, G.; Benoliel, R.T. Chemogenetic inhibition of trigeminal ganglion neurons attenuates behavioural and neural pain responses in a model of trigeminal neuropathic pain. Eur. J. Pain 2022, 26, 634–647. [Google Scholar] [CrossRef] [PubMed]
- Stanojlovic, M.; Pallais, J.P.; Kotz, C.M. Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease. Front. Neurosci. 2019, 13, 702. [Google Scholar] [CrossRef] [PubMed]
- Stanojlovic, M.; Pallais Yllescas, J.P.; Vijayakumar, A.; Kotz, C. Early Sociability and Social Memory Impairment in the A53T Mouse Model of Parkinson’s Disease Are Ameliorated by Chemogenetic Modulation of Orexin Neuron Activity. Mol. Neurobiol. 2019, 56, 8435–8450. [Google Scholar] [CrossRef] [PubMed]
- Stanojlovic, M.; Pallais, J.P.; Lee, M.K.; Kotz, C.M. Pharmacological and chemogenetic orexin/hypocretin intervention ameliorates Hipp-dependent memory impairment in the A53T mice model of Parkinson’s disease. Mol. Brain 2019, 12, 87. [Google Scholar] [CrossRef] [PubMed]
- Stanojlovic, M.; Pallais Yllescas, J.P., Jr.; Mavanji, V.; Kotz, C. Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 316, R571–R583. [Google Scholar] [CrossRef] [PubMed]
- Matsuki, T.; Nomiyama, M.; Takahira, H.; Hirashima, N.; Kunita, S.; Takahashi, S.; Yagami, K.; Kilduff, T.S.; Bettler, B.; Yanagisawa, M.; et al. Selective loss of GABA(B) receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc. Natl. Acad. Sci. USA 2009, 106, 4459–4464. [Google Scholar] [CrossRef] [PubMed]
- Mahler, S.V.; Aston-Jones, G. CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience. Neuropsychopharmacology 2018, 43, 934–936. [Google Scholar] [CrossRef]
- Gomez, J.L.; Bonaventura, J.; Lesniak, W.; Mathews, W.B.; Sysa-Shah, P.; Rodriguez, L.A.; Ellis, R.J.; Richie, C.T.; Harvey, B.K.; Dannals, R.F.; et al. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 2017, 357, 503–507. [Google Scholar] [CrossRef]
- Chohan, M.O.; Fein, H.; Mirro, S.; O’Reilly, K.C.; Veenstra-VanderWeele, J. Repeated chemogenetic activation of dopaminergic neurons induces reversible changes in baseline and amphetamine-induced behaviors. Psychopharmacology 2023, 240, 2545–2560. [Google Scholar] [CrossRef] [PubMed]
- Scammell, T.E.; Winrow, C.J. Orexin receptors: Pharmacology and therapeutic opportunities. Annu. Rev. Pharmacol. Toxicol. 2011, 51, 243–266. [Google Scholar] [CrossRef] [PubMed]
- Hong, C.; Byrne, N.J.; Zamlynny, B.; Tummala, S.; Xiao, L.; Shipman, J.M.; Partridge, A.T.; Minnick, C.; Breslin, M.J.; Rudd, M.T.; et al. Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Nat. Commun. 2021, 12, 815. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Perrey, D.A.; Decker, A.M.; Langston, T.L.; Mavanji, V.; Harris, D.L.; Kotz, C.M.; Zhang, Y. Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists. J. Med. Chem. 2021, 64, 8806–8825. [Google Scholar] [CrossRef] [PubMed]
- Hao, Y.Y.; Yuan, H.W.; Fang, P.H.; Zhang, Y.; Liao, Y.X.; Shen, C.; Wang, D.; Zhang, T.T.; Bo, P. Plasma orexin-A level associated with physical activity in obese people. Eat Weight Disord. 2017, 22, 69–77. [Google Scholar] [CrossRef] [PubMed]
- Gac, L.; Butterick, T.A.; Duffy, C.M.; Teske, J.A.; Perez-Leighton, C.E. Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A. Peptides 2016, 76, 14–18. [Google Scholar] [CrossRef] [PubMed]
- Teske, J.A.; Billington, C.J.; Kotz, C.M. Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neuroscience 2014, 256, 91–100. [Google Scholar] [CrossRef] [PubMed]
- Kukkonen, J.P.; Holmqvist, T.; Ammoun, S.; Akerman, K.E. Functions of the orexinergic/hypocretinergic system. Am. J. Physiol. Cell Physiol. 2002, 283, C1567–C1591. [Google Scholar] [CrossRef] [PubMed]
- Mavanji, V.; Butterick, T.A.; Duffy, C.M.; Nixon, J.P.; Billington, C.J.; Kotz, C.M. Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice. Neurobiol. Learn. Mem. 2017, 146, 21–30. [Google Scholar] [CrossRef] [PubMed]
- Perez-Leighton, C.E.; Boland, K.; Billington, C.J.; Kotz, C.M. High and low activity rats: Elevated intrinsic physical activity drives resistance to diet-induced obesity in non-bred rats. Obesity 2013, 21, 353–360. [Google Scholar] [CrossRef] [PubMed]
- Kaiyala, K.J.; Wisse, B.E.; Lighton, J.R.B. Validation of an equation for energy expenditure that does not require the respiratory quotient. PLoS ONE 2019, 14, e0211585. [Google Scholar] [CrossRef] [PubMed]
- Azeez, I.A.; Del Gallo, F.; Cristino, L.; Bentivoglio, M. Daily Fluctuation of Orexin Neuron Activity and Wiring: The Challenge of “Chronoconnectivity”. Front. Pharmacol. 2018, 9, 1061. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, A.; Kwa, C.; Debold, J.F.; Miczek, K.A. GABA(A) receptors in the dorsal raphé nucleus of mice: Escalation of aggression after alcohol consumption. Psychopharmacology 2010, 211, 467–477. [Google Scholar] [CrossRef] [PubMed]
- Picker, M.J.; Allen, R.M.; Morgan, D.; Levine, A.S.; O’Hare, E.; Cleary, J.P. Effects of neuropeptide Y on the discriminative stimulus and antinociceptive properties of morphine. Pharmacol. Biochem. Behav. 1999, 64, 161–164. [Google Scholar] [CrossRef] [PubMed]
- Nicholson, C. Diffusion from an injected volume of a substance in brain tissue with arbitrary volume fraction and tortuosity. Brain Res. 1985, 333, 325–329. [Google Scholar] [CrossRef] [PubMed]
- Ehrström, M.; Levin, F.; Kirchgessner, A.L.; Schmidt, P.T.; Hilsted, L.M.; Grybäck, P.; Jacobsson, H.; Hellström, P.M.; Näslund, E. Stimulatory effect of endogenous orexin A on gastric emptying and acid secretion independent of gastrin. Regul. Pept. 2005, 132, 9–16. [Google Scholar] [CrossRef] [PubMed]
- Mavanji, V.; Perez-Leighton, C.E.; Kotz, C.M.; Billington, C.J.; Parthasarathy, S.; Sinton, C.M.; Teske, J.A. Promotion of Wakefulness and Energy Expenditure by Orexin-A in the Ventrolateral Preoptic Area. Sleep 2015, 38, 1361–1370. [Google Scholar] [CrossRef] [PubMed]
- Jalewa, J.; Joshi, A.; McGinnity, T.M.; Prasad, G.; Wong-Lin, K.; Hölscher, C. Neural circuit interactions between the dorsal raphe nucleus and the lateral hypothalamus: An experimental and computational study. PLoS ONE 2014, 9, e88003. [Google Scholar] [CrossRef] [PubMed]
- Stanzani, S.; Russo, A. Afferent and efferent connections between the hypothalamus and raphe. Study using the technic of retrograde transport of peroxidases. Boll. Soc. Ital. Biol. Sper. 1981, 57, 993–998. [Google Scholar] [PubMed]
- Brown, R.E.; Sergeeva, O.A.; Eriksson, K.S.; Haas, H.L. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J. Neurosci. 2002, 22, 8850–8859. [Google Scholar] [CrossRef] [PubMed]
- Xiao, X.; Yeghiazaryan, G.; Hess, S.; Klemm, P.; Sieben, A.; Kleinridders, A.; Morgan, D.A.; Wunderlich, F.T.; Rahmouni, K.; Kong, D.; et al. Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity. Nat. Commun. 2021, 12, 5249. [Google Scholar] [CrossRef] [PubMed]
- Adidharma, W.; Deats, S.P.; Ikeno, T.; Lipton, J.W.; Lonstein, J.S.; Yan, L. Orexinergic modulation of serotonin neurons in the dorsal raphe of a diurnal rodent, Arvicanthis niloticus. Horm. Behav. 2019, 116, 104584. [Google Scholar] [CrossRef] [PubMed]
- Khodabande, F.; Akbari, E.; Ardeshiri, M.R. The modulation of the spatial reference memory by the orexinergic system of the dorsal raphe nucleus. Life Sci. 2021, 265, 118777. [Google Scholar] [CrossRef] [PubMed]
- Kawashima, T. The role of the serotonergic system in motor control. Neurosci. Res. 2018, 129, 32–39. [Google Scholar] [CrossRef] [PubMed]
- Kotz, C.; Nixon, J.; Butterick, T.; Perez-Leighton, C.; Teske, J.; Billington, C. Brain orexin promotes obesity resistance. Ann. N. Y. Acad. Sci. 2012, 1264, 72–86. [Google Scholar] [CrossRef] [PubMed]
- Weiss, J.M.; West, C.H.; Emery, M.S.; Bonsall, R.W.; Moore, J.P.; Boss-Williams, K.A. Rats selectively-bred for behavior related to affective disorders: Proclivity for intake of alcohol and drugs of abuse, and measures of brain monoamines. Biochem. Pharmacol. 2008, 75, 134–159. [Google Scholar] [CrossRef] [PubMed]
- Elliott, P.; Wallis, D.I. Serotonin and L-norepinephrine as mediators of altered excitability in neonatal rat motoneurons studied in vitro. Neuroscience 1992, 47, 533–544. [Google Scholar] [CrossRef] [PubMed]
- Dringenberg, H.C.; Vanderwolf, C.H. Involvement of direct and indirect pathways in electrocorticographic activation. Neurosci. Biobehav. Rev. 1998, 22, 243–257. [Google Scholar] [CrossRef] [PubMed]
- Brown, R.E.; Sergeeva, O.; Eriksson, K.S.; Haas, H.L. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001, 40, 457–459. [Google Scholar] [CrossRef]
- Lucki, I. The spectrum of behaviors influenced by serotonin. Biol. Psychiatry 1998, 44, 151–162. [Google Scholar] [CrossRef] [PubMed]
- Sasaki-Adams, D.M.; Kelley, A.E. Serotonin-dopamine interactions in the control of conditioned reinforcement and motor behavior. Neuropsychopharmacology 2001, 25, 440–452. [Google Scholar] [CrossRef] [PubMed]
- Jacobs, B.L.; Azmitia, E.C. Structure and function of the brain serotonin system. Physiol. Rev. 1992, 72, 165–229. [Google Scholar] [CrossRef] [PubMed]
- Donovan, M.H.; Tecott, L.H. Serotonin and the regulation of mammalian energy balance. Front. Neurosci. 2013, 7, 36. [Google Scholar] [CrossRef] [PubMed]
- Matsuzaki, I.; Sakurai, T.; Kunii, K.; Nakamura, T.; Yanagisawa, M.; Goto, K. Involvement of the serotonergic system in orexin-induced behavioral alterations in rats. Regul. Pept. 2002, 104, 119–123. [Google Scholar] [CrossRef]
- Duxon, M.S.; Stretton, J.; Starr, K.; Jones, D.N.; Holland, V.; Riley, G.; Jerman, J.; Brough, S.; Smart, D.; Johns, A.; et al. Evidence that orexin-A-evoked grooming in the rat is mediated by orexin-1 (OX1) receptors, with downstream 5-HT2C receptor involvement. Psychopharmacology 2001, 153, 203–209. [Google Scholar] [CrossRef] [PubMed]
- Hassanain, M.; Levin, B.E. Dysregulation of hypothalamic serotonin turnover in diet-induced obese rats. Brain Res. 2002, 929, 175–180. [Google Scholar] [CrossRef] [PubMed]
- Sinton, C.M. Orexin/hypocretin plays a role in the response to physiological disequilibrium. Sleep Med. Rev. 2011, 15, 197–207. [Google Scholar] [CrossRef] [PubMed]
- de Lecea, L.; Sutcliffe, J.G.; Fabre, V. Hypocretins/orexins as integrators of physiological information: Lessons from mutant animals. Neuropeptides 2002, 36, 85–95. [Google Scholar] [CrossRef] [PubMed]
- Moriguchi, T.; Sakurai, T.; Nambu, T.; Yanagisawa, M.; Goto, K. Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia. Neurosci. Lett. 1999, 264, 101–104. [Google Scholar] [CrossRef] [PubMed]
- Williams, R.H.; Jensen, L.T.; Verkhratsky, A.; Fugger, L.; Burdakov, D. Control of hypothalamic orexin neurons by acid and CO2. Proc. Natl. Acad. Sci. USA 2007, 104, 10685–10690. [Google Scholar] [CrossRef] [PubMed]
- Yamanaka, A.; Beuckmann, C.T.; Willie, J.T.; Hara, J.; Tsujino, N.; Mieda, M.; Tominaga, M.; Yagami, K.; Sugiyama, F.; Goto, K.; et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003, 38, 701–713. [Google Scholar] [CrossRef] [PubMed]
- Monti, J.M. The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness. Sleep Med. Rev. 2010, 14, 307–317. [Google Scholar] [CrossRef] [PubMed]
- Liu, R.J.; van den Pol, A.N.; Aghajanian, G.K. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J. Neurosci. 2002, 22, 9453–9464. [Google Scholar] [CrossRef] [PubMed]
- Schneeberger, M.; Parolari, L.; Das Banerjee, T.; Bhave, V.; Wang, P.; Patel, B.; Topilko, T.; Wu, Z.; Choi, C.H.J.; Yu, X.; et al. Regulation of Energy Expenditure by Brainstem GABA Neurons. Cell 2019, 178, 672–685.e612. [Google Scholar] [CrossRef] [PubMed]
- Thorpe, A.J.; Doane, D.F.; Sweet, D.C.; Beverly, J.L.; Kotz, C.M. Orexin A in the rostrolateral hypothalamic area induces feeding by modulating GABAergic transmission. Brain Res. 2006, 1125, 60–66. [Google Scholar] [CrossRef] [PubMed]
- van den Pol, A.N.; Gao, X.B.; Obrietan, K.; Kilduff, T.S.; Belousov, A.B. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J. Neurosci. 1998, 18, 7962–7971. [Google Scholar] [CrossRef] [PubMed]
- Ohno, K.; Sakurai, T. Orexin neuronal circuitry: Role in the regulation of sleep and wakefulness. Front. Neuroendocrinol. 2008, 29, 70–87. [Google Scholar] [CrossRef] [PubMed]
- Seo, C.; Guru, A.; Jin, M.; Ito, B.; Sleezer, B.J.; Ho, Y.Y.; Wang, E.; Boada, C.; Krupa, N.A.; Kullakanda, D.S.; et al. Intense threat switches dorsal raphe serotonin neurons to a paradoxical operational mode. Science 2019, 363, 538–542. [Google Scholar] [CrossRef] [PubMed]
- Meeusen, R.; Piacentini, M.F.; Van Den Eynde, S.; Magnus, L.; De Meirleir, K. Exercise performance is not influenced by a 5-HT reuptake inhibitor. Int. J. Sports Med. 2001, 22, 329–336. [Google Scholar] [CrossRef] [PubMed]
- Strüder, H.K.; Weicker, H. Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance. Part II. Int. J. Sports Med. 2001, 22, 482–497. [Google Scholar] [CrossRef] [PubMed]
- Davis, J.M. Central and peripheral factors in fatigue. J. Sports Sci. 1995, 13, S49–S53. [Google Scholar] [CrossRef] [PubMed]
- Maier, S.F.; Seligman, M.E. Learned helplessness at fifty: Insights from neuroscience. Psychol. Rev. 2016, 123, 349–367. [Google Scholar] [CrossRef] [PubMed]
- Waters, F.; Naik, N.; Rock, D. Sleep, fatigue, and functional health in psychotic patients. Schizophr. Res. Treat. 2013, 2013, 425826. [Google Scholar] [CrossRef] [PubMed]
- Davis, J.M.; Bailey, S.P. Possible mechanisms of central nervous system fatigue during exercise. Med. Sci. Sports Exerc. 1997, 29, 45–57. [Google Scholar] [CrossRef] [PubMed]
- Yamashita, M. Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit. Int. J. Tryptophan. Res. 2020, 13, 1178646920936279. [Google Scholar] [CrossRef] [PubMed]
- Perrier, J.F.; Rasmussen, H.B.; Jørgensen, L.K.; Berg, R.W. Intense Activity of the Raphe Spinal Pathway Depresses Motor Activity via a Serotonin Dependent Mechanism. Front. Neural Circuits 2017, 11, 111. [Google Scholar] [CrossRef] [PubMed]
- Perrier, J.F. If serotonin does not exhaust you, it makes you stronger. J. Physiol. 2019, 597, 5–6. [Google Scholar] [CrossRef]
- Roelands, B.; Meeusen, R. Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature. Sports Med. 2010, 40, 229–246. [Google Scholar] [CrossRef] [PubMed]
- Henderson, T.T.; Taylor, J.L.; Thorstensen, J.R.; Tucker, M.G.; Kavanagh, J.J. Enhanced availability of serotonin limits muscle activation during high-intensity, but not low-intensity, fatiguing contractions. J. Neurophysiol. 2022, 128, 751–762. [Google Scholar] [CrossRef]
- Cotel, F.; Exley, R.; Cragg, S.J.; Perrier, J.F. Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation. Proc. Natl. Acad. Sci. USA 2013, 110, 4774–4779. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.W.; Kim, Y.S.; Jun, T.W.; Seo, J.H.; Kim, K.; Shin, M.S.; Kim, C.J. The impact of duration of one bout treadmill exercise on cell proliferation and central fatigue in rats. J. Exerc. Rehabil. 2013, 9, 463–469. [Google Scholar] [CrossRef] [PubMed]
- Kavanagh, J.J.; Taylor, J.L. Voluntary activation of muscle in humans: Does serotonergic neuromodulation matter? J. Physiol. 2022, 600, 3657–3670. [Google Scholar] [CrossRef] [PubMed]
- Fernstrom, J.D.; Fernstrom, M.H. Exercise, serum free tryptophan, and central fatigue. J. Nutr. 2006, 136, 553S–559S. [Google Scholar] [CrossRef] [PubMed]
- Mackay-Phillips, K.; Orssatto, L.B.R.; Polman, R.; Van der Pols, J.C.; Trajano, G.S. Effects of α-lactalbumin on strength, fatigue and psychological parameters: A randomised double-blind cross-over study. Eur. J. Appl. Physiol. 2023, 123, 381–393. [Google Scholar] [CrossRef] [PubMed]
- Amann, M.; Sidhu, S.K.; McNeil, C.J.; Gandevia, S.C. Critical considerations of the contribution of the corticomotoneuronal pathway to central fatigue. J. Physiol. 2022, 600, 5203–5214. [Google Scholar] [CrossRef] [PubMed]
- Thorstensen, J.R.; Taylor, J.L.; Tucker, M.G.; Kavanagh, J.J. Enhanced serotonin availability amplifies fatigue perception and modulates the TMS-induced silent period during sustained low-intensity elbow flexions. J. Physiol. 2020, 598, 2685–2701. [Google Scholar] [CrossRef] [PubMed]
- Mavanji, V.; Teske, J.A.; Kotz, C.M.; Pellizzer, G. Changes in sensorimotor cortex oscillatory activity by orexin-A in the ventrolateral preoptic area of the hypothalamus reflect increased muscle tone. J. Neurosci. Res. 2023, 101, 1305–1323. [Google Scholar] [CrossRef] [PubMed]
- Stanojlovic, M.; Pallais, J.P.; Kotz, C.M. Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 795. [Google Scholar] [CrossRef] [PubMed]
- Mullett, M.A.; Billington, C.J.; Levine, A.S.; Kotz, C.M. Hypocretin I in the lateral hypothalamus activates key feeding-regulatory brain sites. Neuroreport 2000, 11, 103–108. [Google Scholar] [CrossRef] [PubMed]
- Maehara, S.; Furukawa, J.; Ota, T. Orexin 2 receptor is involved in orexin A-induced hyperlocomotion in rats. Pharmacol. Rep. 2019, 71, 1147–1150. [Google Scholar] [CrossRef] [PubMed]
- Wang, Q.P.; Koyama, Y.; Guan, J.L.; Takahashi, K.; Kayama, Y.; Shioda, S. The orexinergic synaptic innervation of serotonin- and orexin 1-receptor-containing neurons in the dorsal raphe nucleus. Regul. Pept. 2005, 126, 35–42. [Google Scholar] [CrossRef] [PubMed]
- Yang, C.; Zhang, L.; Hao, H.; Ran, M.; Li, J.; Dong, H. Serotonergic neurons in the dorsal raphe nucleus mediate the arousal-promoting effect of orexin during isoflurane anesthesia in male rats. Neuropeptides 2019, 75, 25–33. [Google Scholar] [CrossRef] [PubMed]
- Soffin, E.M.; Gill, C.H.; Brough, S.J.; Jerman, J.C.; Davies, C.H. Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus. Neuropharmacology 2004, 46, 1168–1176. [Google Scholar] [CrossRef]
- Périer, C.; Tremblay, L.; Féger, J.; Hirsch, E.C. Behavioral consequences of bicuculline injection in the subthalamic nucleus and the zona incerta in rat. J. Neurosci. 2002, 22, 8711–8719. [Google Scholar] [CrossRef] [PubMed]
- Naudé, T.W.; Berry, W.L. Suspected poisoning of puppies by the mushroom Amanita pantherina. J. S. Afr. Vet. Assoc. 1997, 68, 154–158. [Google Scholar] [CrossRef] [PubMed]
- Madden, C.J.; Morrison, S.F. Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 296, R831–R843. [Google Scholar] [CrossRef] [PubMed]
- Willie, J.T.; Takahira, H.; Shibahara, M.; Hara, J.; Nomiyama, M.; Yanagisawa, M.; Sakurai, T. Ectopic overexpression of orexin alters sleep/wakefulness states and muscle tone regulation during REM sleep in mice. J. Mol. Neurosci. 2011, 43, 155–161. [Google Scholar] [CrossRef] [PubMed]
- Nollet, M.; Leman, S. Role of orexin in the pathophysiology of depression: Potential for pharmacological intervention. CNS Drugs 2013, 27, 411–422. [Google Scholar] [CrossRef] [PubMed]
- España, R.A.; Baldo, B.A.; Kelley, A.E.; Berridge, C.W. Wake-promoting and sleep-suppressing actions of hypocretin (orexin): Basal forebrain sites of action. Neuroscience 2001, 106, 699–715. [Google Scholar] [CrossRef] [PubMed]
- Nixon, J.P.; Kotz, C.M.; Novak, C.M.; Billington, C.J.; Teske, J.A. Neuropeptides controlling energy balance: Orexins and neuromedins. Handb. Exp. Pharmacol. 2012, 209, 77–109. [Google Scholar] [CrossRef] [PubMed]
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Mavanji, V.; Pomonis, B.L.; Shekels, L.; Kotz, C.M. Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance. Brain Sci. 2024, 14, 464. https://doi.org/10.3390/brainsci14050464
Mavanji V, Pomonis BL, Shekels L, Kotz CM. Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance. Brain Sciences. 2024; 14(5):464. https://doi.org/10.3390/brainsci14050464
Chicago/Turabian StyleMavanji, Vijayakumar, Brianna L. Pomonis, Laurie Shekels, and Catherine M. Kotz. 2024. "Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance" Brain Sciences 14, no. 5: 464. https://doi.org/10.3390/brainsci14050464