Orexin Signaling in Rostral Lateral Hypothalamus and Nucleus Accumbens Shell in the Control of Spontaneous Physical Activity in High- and Low-activity Rats

Overview

Journal Am J Physiol Regul Integr Comp Physiol

Publisher American Physiological Society

Specialty Physiology

Date 2017 Jan 1

PMID 28039192

Citations 12

Authors

Claudio Perez-Leighton

Morgan R Little

Martha Grace

Charles Billington

Catherine M Kotz

Affiliations

Soon will be listed here.

Abstract

Spontaneous physical activity (SPA) describes activity outside of formal exercise and shows large interindividual variability. The hypothalamic orexin/hypocretin peptides are key regulators of SPA. Orexins drive SPA within multiple brain sites, including rostral lateral hypothalamus (LH) and nucleus accumbens shell (NAcSh). Rats with high basal SPA (high activity, HA) show higher orexin mRNA expression and SPA after injection of orexin-A in rostral LH compared with low-activity (LA) rats. Here, we explored the contribution of orexin signaling in rostral LH and NAcSh to the HA/LA phenotype. We found that HA rats have higher sensitivity to SPA after injection of orexin-A in rostral LH, but not in NAcSh. HA and LA rats showed similar levels of orexin receptor expression in rostral LH, and activation of orexin-producing neurons after orexin-A injection in rostral LH. Also, in HA and LA rats, the coinjection of orexin-A in rostral LH and NAcSh failed to further increase SPA beyond the effects of orexin-A in rostral LH. Pretreatment with muscimol, a GABA receptor agonist, in NAcSh potentiated SPA produced by orexin-A injection in rostral LH in HA but not in LA rats. Our results suggest that a feedback loop from orexin-responsive neurons in rostral LH to orexin neurons and a the NAcSh-orexin neuron-rostral LH circuit regulate SPA. Overall, our data suggest that differences in orexin sensitivity in rostral LH and its modulation by GABA afferents from NAcSh contribute to individual SPA differences.

Citing Articles

Stimulation of Dopamine D4 Receptors in the Nucleus Accumbens Shell Increases Palatable Food Intake in Satiated Male Rats: Modulation by NMDA and AMPA Receptors.

Cruz-Trujillo R, Diaz-Urbina D, Diaz-Gandarilla J, Vidal-Lopez D, Escartin-Perez R, Mancilla-Diaz J Brain Sci. 2024; 14(11).

PMID: 39595865 PMC: 11592207. DOI: 10.3390/brainsci14111103.

Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation.

Mohammadkhani A, Mitchell C, James M, Borgland S, Dayas C Br J Pharmacol. 2024; 181(22):4430-4449.

PMID: 39317446 PMC: 11458361. DOI: 10.1111/bph.17325.

Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance.

Mavanji V, Pomonis B, Shekels L, Kotz C Brain Sci. 2024; 14(5).

PMID: 38790443 PMC: 11117928. DOI: 10.3390/brainsci14050464.

Distinct lateral hypothalamic CaMKIIα neuronal populations regulate wakefulness and locomotor activity.

Heiss J, Zhong P, Lee S, Yamanaka A, Kilduff T Proc Natl Acad Sci U S A. 2024; 121(16):e2316150121.

PMID: 38593074 PMC: 11032496. DOI: 10.1073/pnas.2316150121.

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson's Disease.

Stanojlovic M, Pallais J, Kotz C Int J Mol Sci. 2021; 22(2).

PMID: 33466831 PMC: 7830608. DOI: 10.3390/ijms22020795.

References

Hara J, Beuckmann C, Nambu T, Willie J, Chemelli R, Sinton C . Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001; 30(2):345-54. DOI: 10.1016/s0896-6273(01)00293-8. View

Kiwaki K, Kotz C, Wang C, Lanningham-Foster L, Levine J . Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats. Am J Physiol Endocrinol Metab. 2003; 286(4):E551-9. DOI: 10.1152/ajpendo.00126.2003. View

Garland Jr T, Schutz H, Chappell M, Keeney B, Meek T, Copes L . The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J Exp Biol. 2010; 214(Pt 2):206-29. PMC: 3008631. DOI: 10.1242/jeb.048397. View

Schone C, Huang Cao Z, Apergis-Schoute J, Adamantidis A, Sakurai T, Burdakov D . Optogenetic probing of fast glutamatergic transmission from hypocretin/orexin to histamine neurons in situ. J Neurosci. 2012; 32(36):12437-43. PMC: 6621251. DOI: 10.1523/JNEUROSCI.0706-12.2012. View

Teske J, Billington C, Kotz C . Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neuroscience. 2013; 256:91-100. PMC: 3888868. DOI: 10.1016/j.neuroscience.2013.10.028. View

Kotz C, Wang C, Teske J, Thorpe A, Novak C, Kiwaki K . Orexin A mediation of time spent moving in rats: neural mechanisms. Neuroscience. 2006; 142(1):29-36. DOI: 10.1016/j.neuroscience.2006.05.028. View

Mieda M, Hasegawa E, Kisanuki Y, Sinton C, Yanagisawa M, Sakurai T . Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci. 2011; 31(17):6518-26. PMC: 3732784. DOI: 10.1523/JNEUROSCI.6506-10.2011. View

Baldo B, Gual-Bonilla L, Sijapati K, Daniel R, Landry C, Kelley A . Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur J Neurosci. 2004; 19(2):376-86. DOI: 10.1111/j.1460-9568.2004.03093.x. View

Perez-Leighton C, Butterick-Peterson T, Billington C, Kotz C . Role of orexin receptors in obesity: from cellular to behavioral evidence. Int J Obes (Lond). 2012; 37(2):167-74. PMC: 3759245. DOI: 10.1038/ijo.2012.30. View

10.

Funato H, Tsai A, Willie J, Kisanuki Y, Williams S, Sakurai T . Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. 2009; 9(1):64-76. PMC: 2630400. DOI: 10.1016/j.cmet.2008.10.010. View

11.

Teske J, Perez-Leighton C, Billington C, Kotz C . 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(11):R1337-45. PMC: 3882567. DOI: 10.1152/ajpregu.00229.2013. View

12.

Teske J, Billington C, Kuskowski M, Kotz C . Spontaneous physical activity protects against fat mass gain. Int J Obes (Lond). 2011; 36(4):603-13. PMC: 3163117. DOI: 10.1038/ijo.2011.108. View

13.

Levine J, Lanningham-Foster L, McCrady S, Krizan A, Olson L, Kane P . Interindividual variation in posture allocation: possible role in human obesity. Science. 2005; 307(5709):584-6. DOI: 10.1126/science.1106561. View

14.

Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y . Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron. 2005; 46(2):297-308. DOI: 10.1016/j.neuron.2005.03.010. View

15.

Ravussin E, Lillioja S, Anderson T, Christin L, Bogardus C . Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest. 1986; 78(6):1568-78. PMC: 423919. DOI: 10.1172/JCI112749. View

16.

Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli R, Tanaka H . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998; 92(4):573-85. DOI: 10.1016/s0092-8674(00)80949-6. View

17.

Muschamp J, Hollander J, Thompson J, Voren G, Hassinger L, Onvani S . Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A. 2014; 111(16):E1648-55. PMC: 4000785. DOI: 10.1073/pnas.1315542111. View

18.

Peyron C, Tighe D, van den Pol A, de Lecea L, Heller H, Sutcliffe J . Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998; 18(23):9996-10015. PMC: 6793310. View

19.

Espana R, Baldo B, Kelley A, Berridge C . Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience. 2001; 106(4):699-715. DOI: 10.1016/s0306-4522(01)00319-0. View

20.

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. PMC: 3464355. DOI: 10.1111/j.1749-6632.2012.06585.x. View