title: Exercise reverses the effects of early life stress on orexin cell reactivity in male but not female rats.
abstract: Early life stress (ELS) is a known antecedent for the development of mood disorders such as depression. Orexin neurons drive arousal and motivated behaviors in response to stress. We tested the hypothesis that ELS alters orexin system function and leads to an altered stress-induced behavioral phenotype in adulthood. We also investigated if voluntary exercise during adolescent development could reverse the ELS-induced changes. Male and female Wistar rats were subjected to maternal separation stress on postnatal days (PND) 2-14. A subset of animals was given access to running wheels in late adolescence (1hr/day, PND40-70). In adulthood, rats were exposed to restraint stress and then tested on the open field (OF) and elevated plus maze (EPM). Brains were processed for Fos-protein and orexin or tyrosine hydroxylase immunohistochemistry. Restraint stress stimulated Fos-protein expression in perifornical area orexin cells, the paraventricular hypothalamic nucleus, and paraventricular thalamic nuclei, but this neuronal response was dampened in male and female rats exposed to ELS. ELS also reduced exploration in the OF, without affecting EPM behavior. These neural and behavioral changes are consistent with a depressive-like phenotype. Adolescent exercise reversed the orexin and behavioral deficits in ELS males. Exercise was not protective in females, although this may be due to sex differences in running behavior. Our findings highlight the inherent plasticity of the orexin system-a trait that may lead to a state of pathological rewiring but could also be treated using non-pharmacological approaches. We also highlight a need to better understand the sex-specific changes in orexin circuits and stress-related pathology.
authors.affiliation: Neurobiology of Addiction Laboratory, The Centre for Brain and Mental Health Research, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle Newcastle, NSW, Australia.
authors.forename: Morgan H
authors.initials: MH
authors.lastname: James
authors.affiliation: Neurobiology of Addiction Laboratory, The Centre for Brain and Mental Health Research, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle Newcastle, NSW, Australia.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Campbell
authors.affiliation: Neurobiology of Addiction Laboratory, The Centre for Brain and Mental Health Research, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle Newcastle, NSW, Australia.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Walker
authors.affiliation: Neurobiology of Addiction Laboratory, The Centre for Brain and Mental Health Research, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle Newcastle, NSW, Australia.
authors.forename: Doug W
authors.initials: DW
authors.lastname: Smith
authors.affiliation: Neurobiology of Stress and Addiction Laboratory, Department of Psychology, University of Massachusetts Amherst, MA, USA.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Richardson
authors.affiliation: Neurobiology of Addiction Laboratory, The Centre for Brain and Mental Health Research, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle Newcastle, NSW, Australia.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Hodgson
authors.affiliation: Neurobiology of Addiction Laboratory, The Centre for Brain and Mental Health Research, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle Newcastle, NSW, Australia.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Dayas
keywords: exercise; hypocretin; hypothalamus; maternal separation; orexin; plasticity; sex-differences; stress
references.citation: Stress. 2010 Nov;13(6):506-15
references.pmid: 20666652
references.citation: J Pain. 2007 Dec;8(12):962-9
references.pmid: 17686657
references.citation: Alcohol. 2009 Sep;43(6):443-52
references.pmid: 19801274
references.citation: Endocrinology. 2006 May;147(5):2506-17
references.pmid: 16455779
references.citation: J Comp Neurol. 2001 Jun 18;435(1):6-25
references.pmid: 11370008
references.citation: Front Neurosci. 2014 Feb 25;8:36
references.pmid: 24616658
references.citation: Stress. 2011 May;14(3):335-43
references.pmid: 21438770
references.citation: Pharmacol Biochem Behav. 2010 Mar;95(1):121-8
references.pmid: 20045021
references.citation: Behav Brain Res. 2010 Dec 20;215(1):77-82
references.pmid: 20615434
references.citation: Arch Gen Psychiatry. 2008 Apr;65(4):409-15
references.pmid: 18391129
references.citation: J Neurosci. 2003 Apr 1;23(7):2889-98
references.pmid: 12684476
references.citation: Neurochem Int. 1998 Oct;33(4):287-97
references.pmid: 9840219
references.citation: Science. 2006 Feb 10;311(5762):864-8
references.pmid: 16469931
references.citation: Trends Mol Med. 2007 Jul;13(7):269-77
references.pmid: 17544850
references.citation: J Neurosci Methods. 1993 Apr;47(1-2):73-83
references.pmid: 8100600
references.citation: Eur J Neurosci. 2013 Feb;37(3):469-78
references.pmid: 23121339
references.citation: J Physiol. 2012 Aug 15;590(16):3677-89
references.pmid: 22641785
references.citation: Exp Brain Res. 1989;76(3):572-80
references.pmid: 2676574
references.citation: PLoS One. 2012;7(5):e36871
references.pmid: 22590628
references.citation: Psychoneuroendocrinology. 2010 Nov;35(10):1553-64
references.pmid: 20594764
references.citation: Neuroscience. 2012 Aug 30;218:138-53
references.pmid: 22626650
references.citation: Eur J Neurosci. 1999 Jul;11(7):2312-22
references.pmid: 10383620
references.citation: Trends Neurosci. 2006 Oct;29(10):571-7
references.pmid: 16904760
references.citation: Endocrinology. 2005 Sep;146(9):3724-31
references.pmid: 15961555
references.citation: Behav Brain Res. 2013 Aug 1;250:316-25
references.pmid: 23707245
references.citation: Brain Res Bull. 2012 Dec 1;89(5-6):203-10
references.pmid: 22982687
references.citation: Int J Neuropsychopharmacol. 2011 Jun;14(5):684-90
references.pmid: 21447232
references.citation: Trends Pharmacol Sci. 1991 Nov;12(11):402-4
references.pmid: 1686685
references.citation: Prog Brain Res. 2000;122:81-103
references.pmid: 10737052
references.citation: J Affect Disord. 2009 Feb;113(1-2):179-82
references.pmid: 18533274
references.citation: Biochem Biophys Res Commun. 2000 Apr 2;270(1):318-23
references.pmid: 10733946
references.citation: Psychopharmacology (Berl). 2010 Oct;212(2):251-65
references.pmid: 20645079
references.citation: Neuroreport. 2000 Jun 26;11(9):1977-80
references.pmid: 10884055
references.citation: Brain Res Mol Brain Res. 1993 May;18(3):195-200
references.pmid: 8497182
references.citation: Biol Psychiatry. 2008 Jan 15;63(2):152-7
references.pmid: 17570346
references.citation: Nature. 2014 May 15;509(7500):282-3
references.pmid: 24834516
references.citation: Dev Neurosci. 1996;18(1-2):49-72
references.pmid: 8840086
references.citation: J Comp Neurol. 2007 Feb 20;500(6):1050-63
references.pmid: 17183538
references.citation: Metab Brain Dis. 2004 Jun;19(1-2):3-14
references.pmid: 15214501
references.citation: Front Behav Neurosci. 2013 Mar 06;7:18
references.pmid: 23509439
references.citation: Drug Alcohol Depend. 2008 Nov 1;98(1-2):129-35
references.pmid: 18585870
references.citation: Eur Neuropsychopharmacol. 2007 Sep;17(9):573-9
references.pmid: 17346943
references.citation: Neuropsychopharmacology. 2000 Mar;22(3):219-29
references.pmid: 10693149
references.citation: J Neurosci. 1998 Dec 1;18(23):9996-10015
references.pmid: 9822755
references.citation: Neuropharmacology. 2012 Mar;62(4):1607-18
references.pmid: 22019722
references.citation: Regul Pept. 2004 May 15;118(3):183-91
references.pmid: 15003835
references.citation: J Neurosci. 2008 Mar 19;28(12):3071-5
references.pmid: 18354010
references.citation: Prog Brain Res. 2012;198:133-61
references.pmid: 22813973
references.citation: Eur J Neurosci. 2001 Oct;14(7):1143-52
references.pmid: 11683906
references.citation: FEBS Lett. 1998 Oct 30;438(1-2):71-5
references.pmid: 9821961
references.citation: Eur J Neurosci. 2009 Oct;30(8):1603-14
references.pmid: 19811530
references.citation: Brain Res. 2005 Oct 19;1059(2):179-88
references.pmid: 16168969