Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury

Authors: Xingrui Gong, Yongmei Chen, Jing Chang, Yue Huang, Meihau Cai, Mazhong Zhang

Published in: Journal of Neuroinflammation | Issue 1/2018

Login to get access

Abstract

Background

Infant nerve injury causes delayed adolescent neuropathic pain, but whether it also leads to psychiatric illness is unknown. Environmental enrichment (EE) increases social communication and activity. Thus, our goal was to test anxiety- and depression-like behaviors after infant peripheral nerve injury and evaluate the effect of environmental enrichment on these models of affective disorders.

Methods

Open field, elevated plus maze, sucrose preference, and pain behaviors (paw withdrawal threshold, spontaneous guarding score, and cold response to acetone) were measured in rats that received infant spared nerve injury (SNI). Enzyme-linked immune absorbent assay of cytokines was performed to evaluate the inflammatory response in the brain. Then, the ability of intracerebroventricular (ICV) injection of a microglia inhibitor, minocycline (MIN), and EE (a free-running wheel, a staircase, a plastic tunnel, a raised platform, and various colored balls) to reverse the infant SNI effects on behaviors and cytokines was examined.

Results

Infant nerve injury resulted in adolescent anxiety- and depression-like behaviors. The medial prefrontal cortex, basolateral amygdala, and ventral hippocampus were skewed to a pro-inflammatory profile. ICV injection of MIN reduced anxiety- and depression-like behaviors without affecting pain behaviors. In addition, ICV MIN skewed the brain towards an anti-inflammatory profile. Finally, environmental enrichment improved anxiety- and depression-like behaviors, as well as pain behaviors. EE increased brain IL-10 and decreased IL-1β and TNF-α.

Conclusions

Infant nerve injury induces adolescent anxiety- and depression-like behaviors and central nervous inflammation. Environmental enrichment reduces these behaviors by normalizing the inflammation balance in the brain.
Literature
1.
Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:2433–45.CrossRefPubMed
2.
Epstein SA, Kay G, Clauw D, Heaton R, Klein D, Krupp L, Kuck J, Leslie V, Masur D, Wagner M, Waid R, Zisook S. Psychiatric disorders in patients with fibromyalgia. A multicenter investigation. Psychosomatics. 1999;40:57–63.CrossRefPubMed
3.
Argoff CE. The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach. Clin J Pain. 2007;23:15–22.CrossRefPubMed
4.
Eyre HA, Papps E, Baune BT. Treating depression and depression-like behavior with physical activity: an immune perspective. Front Psych. 2013;4:3.
5.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497–511.CrossRefPubMed
6.
Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci. 2015;38:637–58.CrossRefPubMed
7.
Wang YL, Han QQ, Gong WQ, Pan DH, Wang LZ, Hu W, Yang M, Li B, Yu J, Liu Q. Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats. J Neuroinflammation. 2018;15:21.CrossRefPubMedPubMedCentral
8.
Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010;10:167–84.CrossRefPubMed
9.
Anand P, Birch R. Restoration of sensory function and lack of long-term chronic pain syndromes after brachial plexus injury in human neonates. Brain. 2002;125:113–22.CrossRefPubMed
10.
Melzack R, Israel R, Lacroix R, Schultz G. Phantom limbs in people with congenital limb deficiency or amputation in early childhood. Brain. 1997;120(Pt 9):1603–20.CrossRefPubMed
11.
Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain. 2003;103:199–207.CrossRefPubMed
12.
ATHERTON DD, TAHERZADEH O, ELLIOT D, ANAND P. Age-dependent development of chronic neuropathic pain, allodynia and sensory recovery after upper limb nerve injury in children. J Hand Surg Eur Vol. 2008;33:186–91.CrossRefPubMed
13.
McKelvey R, Berta T, Old E, Ji RR, Fitzgerald M. Neuropathic pain is constitutively suppressed in early life by anti-inflammatory neuroimmune regulation. J Neurosci. 2015;35:457–66.CrossRefPubMedPubMedCentral
14.
Gong X, Chen Y, Fu B, Jiang J, Zhang M. Infant nerve injury induces delayed microglial polarization to the M1 phenotype, and exercise reduces delayed neuropathic pain by modulating microglial activity. Neuroscience. 2017;349:76–86.CrossRefPubMed
15.
Fasick V, Spengler RN, Samankan S, Nader ND, Ignatowski TA. The hippocampus and TNF: common links between chronic pain and depression. Neurosci Biobehav Rev. 2015;53:139–59.CrossRefPubMed
16.
Zhou F, Chen C, Huang Y, Hu H, Li L, Tan Y. The effects of enriched environmental intervention on the parturition outcome and filial health of pregnant mice with chronic pain. Biol Res Nurs. 2018;20:264–71.CrossRefPubMed
17.
Salam JN, Fox JH, Detroy EM, Guignon MH, Wohl DF, Falls WA. Voluntary exercise in C57 mice is anxiolytic across several measures of anxiety. Behav Brain Res. 2009;197:31–40.CrossRefPubMed
18.
Gong X, Jiang J, Zhang M. Exercise preconditioning reduces neonatal incision surgery-induced enhanced hyperalgesia via inhibition of P38 mitogen-activated protein kinase and IL-1β, TNF-α release. Int J Dev Neurosci. 2016;52:46–54.CrossRefPubMed
19.
Decosterd I, Clifford W. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000;87:149–58.CrossRefPubMed
20.
Xie W, Strong JA, Zhang JM. Active nerve regeneration with failed target reinnervation drives persistent neuropathic pain. eNeuro. 2017;4:e8–17.CrossRef
21.
Zhang JM, Tonelli L, Regenold WT, McCarthy MM. Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats. Neuroscience. 2010;169:544–54.CrossRefPubMedPubMedCentral
22.
Ahmadalipour A, Sadeghzadeh J, Vafaei AA, Bandegi AR, Mohammadkhani R, Rashidy-Pour A. Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats. Neuroscience. 2015;305:372–83.CrossRefPubMed
23.
Réus GZ, Abelaira HM, Maciel AL, Dos Santos MAB, Carlessi AS, Steckert AV, Ferreira GK, De Prá SD, Streck EL, Macêdo DS, Quevedo J. Minocycline protects against oxidative damage and alters energy metabolism parameters in the brain of rats subjected to chronic mild stress. Metab Brain Dis. 2015;30:545–53.CrossRefPubMed
24.
Porterfield VM, Gabella KM, Simmons MA, Johnson JD. Repeated stressor exposure regionally enhances beta-adrenergic receptor-mediated brain IL-1β production. Brain Behav Immun. 2012;26:1249–55.CrossRefPubMed
25.
Gerrits MM, Vogelzangs N, van Oppen P, van Marwijk HW, van der Horst H, Penninx BW. Impact of pain on the course of depressive and anxiety disorders. Pain. 2012;153:429–36.CrossRefPubMed
26.
Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry. 2012;83:495–502.CrossRefPubMed
27.
Lehmann ML, Cooper HA, Maric D, Herkenham M. Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages. J Neuroinflammation. 2016;13:224.CrossRefPubMedPubMedCentral
28.
Arakawa S, Shirayama Y, Fujita Y, Ishima T, Horio M, Muneoka K, Iyo M, Hashimoto K. Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline. Pharmacol Biochem Behav. 2012;100:601–6.CrossRefPubMed
29.
Yang Y, Salayandia VM, Thompson JF, Yang LY, Estrada EY, Yang Y. Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery. J Neuroinflammation. 2015;12:26.CrossRefPubMedPubMedCentral
30.
Ossola B, Lantto TA, Puttonen KA, Tuominen RK, Raasmaja A, Mannisto PT. Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and -independent programmed cell death. J Neurosci Res. 2012;90:682–90.CrossRefPubMed
31.
Padi SS, Kulkarni SK. Minocycline prevents the development of neuropathic pain, but not acute pain: possible anti-inflammatory and antioxidant mechanisms. Eur J Pharmacol. 2008;601:79–87.CrossRefPubMed
32.
Kaster MP, Gadotti VM, Calixto JB, Santos ARS, Rodrigues ALS. Depressive-like behavior induced by tumor necrosis factor-α in mice. Neuropharmacology. 2012;62:419–26.CrossRefPubMed
33.
Pan Y, Chen X, Zhang Q, Kong L. Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun. 2014;41:90–100.CrossRefPubMed
34.
Pan Y, Lin W, Wang W, Qi X, Wang D, Tang M. The effects of central pro-and anti-inflammatory immune challenges on depressive-like behavior induced by chronic forced swim stress in rats. Behav Brain Res. 2013;247:232–40.CrossRefPubMed
35.
Maes M, Song C, Yirmiya R. Targeting IL-1 in depression. Expert Opin Ther Targets. 2012;16:1097–112.CrossRefPubMed
36.
Neis VB, Manosso LM, Moretti M, Freitas AE, Daufenbach J, Rodrigues ALS. Depressive-like behavior induced by tumor necrosis factor-α is abolished by agmatine administration. Behav Brain Res. 2014;261:336–44.CrossRefPubMed
37.
Mesquita AR, Correia-Neves M, Roque S, Castro AG, Vieira P, Pedrosa J, Palha JA, Sousa N. IL-10 modulates depressive-like behavior. J Psychiatr Res. 2008;43:89–97.CrossRefPubMed
38.
Blume J, Douglas SD, Evans DL. Immune suppression and immune activation in depression. Brain Behav Immun. 2011;25:221–9.CrossRefPubMed
39.
Vachon P, Millecamps M, Low L, Thompsosn SJ, Pailleux F, Beaudry F, Bushnell CM, Stone LS. Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain. Behav Brain Funct. 2013;9:22.CrossRefPubMedPubMedCentral
40.
Ross JL, Queme LF, Lamb JE, Green KJ, Ford ZK, Jankowski MP. Interleukin 1β inhibition contributes to the antinociceptive effects of voluntary exercise on ischemia/reperfusion-induced hypersensitivity. Pain. 2018;159:380–92.CrossRefPubMed
41.
Wegner M, Helmich I, Machado S, Nardi AE, Arias-Carrion O, Budde H. Effects of exercise on anxiety and depression disorders: review of meta-analyses and neurobiological mechanisms. CNS Neurol Disord Drug Targets. 2014;13:1002–14.CrossRefPubMed
42.
Carter T, Morres ID, Meade O, Callaghan P. The effect of exercise on depressive symptoms in adolescents: a systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2016;55:580–90.CrossRefPubMed
43.
Svensson M, Lexell J, Deierborg T. Effects of physical exercise on neuroinflammation, neuroplasticity, neurodegeneration, and behavior: what we can learn from animal models in clinical settings. Neurorehabil Neural Repair. 2015;29:577–89.CrossRefPubMed
44.
Jurgens HA, Johnson RW. Environmental enrichment attenuates hippocampal neuroinflammation and improves cognitive function during influenza infection. Brain Behav Immun. 2012;26:1006–16.CrossRefPubMedPubMedCentral
45.
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.CrossRefPubMedPubMedCentral
46.
Koss WA, Belden CE, Hristov AD, Juraska JM. Dendritic remodeling in the adolescent medial prefrontal cortex and the basolateral amygdala of male and female rats. Synapse. 2014;68:61–72.CrossRefPubMed
47.
Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, Fallon B, Mazei-Robison M, Ku SM, Harrigan E, Winstanley CA, Joshi T, Feng J, Berton O, Nestler EJ. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB. J Neurosci. 2014;34:3878–87.CrossRefPubMedPubMedCentral
48.
Chen J, Song Y, Yang J, Zhang Y, Zhao P, Zhu XJ, Su HC. The contribution of TNF-alpha in the amygdala to anxiety in mice with persistent inflammatory pain. Neurosci Lett. 2013;541:275–80.CrossRefPubMed
49.
O'Leary OF, Cryan JF. A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis. Trends Pharmacol Sci. 2014;35:675–87.CrossRefPubMed
50.
Pentkowski NS, Blanchard DC, Lever C, Litvin Y, Blanchard RJ. Effects of lesions to the dorsal and ventral hippocampus on defensive behaviors in rats. Eur J Neurosci. 2006;23:2185–96.CrossRefPubMed
51.
Kjelstrup KG, Tuvnes FA, Steffenach HA, Murison R, Moser EI, Moser MB. Reduced fear expression after lesions of the ventral hippocampus. Proc Natl Acad Sci U S A. 2002;99:10825–30.CrossRefPubMedPubMedCentral
52.
Sorge RE, Mapplebeck JCS, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin J, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji R, Zhang J, Salter MW, Mogil JS. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18:1081–3.CrossRefPubMedPubMedCentral
53.
Nemeth CL, Reddy R, Bekhbat M, Bailey J, Neigh GN. Microglial activation occurs in the absence of anxiety-like behavior following microembolic stroke in female, but not male, rats. J Neuroinflammation. 2014;11:174.CrossRefPubMedPubMedCentral
54.
Pyter LM, Kelly SD, Harrell CS, Neigh GN. Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats. Brain Behav Immun. 2013;30:88–94.CrossRefPubMedPubMedCentral
55.
Ramsey JM, Cooper JD, Bot M, Guest PC, Lamers F, Weickert CS, Penninx BW, Bahn S. Sex differences in serum markers of major depressive disorder in the Netherlands study of depression and anxiety (NESDA). PLoS One. 2016;11:e156624.
Metadata
Title
Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury
Authors
Xingrui Gong
Yongmei Chen
Jing Chang
Yue Huang
Meihau Cai
Mazhong Zhang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1301-7

Other articles of this Issue 1/2018

Journal of Neuroinflammation 1/2018 Go to the issue

Research

The role of HFE genotype in macrophage phenotype

Research

Histamine upregulates the expression of histamine receptors and increases the neuroprotective effect of astrocytes

Research

TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity

Research

Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration

Research

Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats

Research

Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors in hippocampus by enhancing activation of the IL-1 receptor: underlying mechanisms