Skip to main content
SpringerLink
Log in

Neuronal-Glial Mechanisms of Exercise-Evoked Stress Robustness

  • Chapter
  • First Online:
Behavioral Neurobiology of Stress-related Disorders

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 18))

Abstract

Stress robustness by definition, incorporates both stress resistance (organisms endure greater stressor intensity or duration before suffering negative consequences) and stress resilience (organisms recover faster after suffering negative consequences). Factors that influence stress robustness include the nature of the stressor, (i.e., controllability, intensity, chronicity) and features of the organism (i.e., age, genetics, sex, and physical activity status). Here we present a novel hypothesis for how physically active versus sedentary living promotes stress robustness in the face of intense uncontrollable stress. Advances in neurobiology have established microglia as an active player in the regulation of synaptic activity, and recent work has revealed mechanisms for modulating glial function, including cross talk between neurons and glia. This chapter presents supporting evidence that the physical activity status of an organism may modulate stress-evoked neuronal-glial responses by changing the CX3CL1-CX3CR1 axis. Specifically, we propose that sedentary animals respond to an intense acute uncontrollable stressor with excessive serotonin (5-HT) and noradrenergic (NE) activity and/or prolonged down-regulation of the CX3CL1-CX3CR1 axis resulting in activation and proliferation of hippocampal microglia in the absence of pathogenic signals and consequent hippocampal-dependent memory deficits and reduced neurogenesis. In contrast, physically active animals respond to the same stressor with constrained 5-HT and NE activity and rapidly recovering CX3CL1-CX3CR1 axis responses resulting in the quieting of microglia, and protection from negative cognitive and neurobiological effects of stress.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADR:

Adrenergic

βADR:

Beta Adrenergic Receptor

BDNF:

Brain Derived Neurotrophic Factor

CX3CL1:

CX3C Chemokine or Fractalkine

CX3CR1:

CX3C Chemokine 1 Receptor or Fractalkine receptor

5-HT:

Serotonin

IL-1β:

Interleukin-1beta

NE:

Norepinephrine

TNFα:

Tumor Necrosis Factor Alpha

US:

Uncontrollable stressor

References

  • Alonso M, Vianna MR, Depino AM, Mello e Souza T, Pereira P, Szapiro G, Viola H, Pitossi F, Izquierdo I, Medina JH (2002a) BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus 12:551–560. doi:10.1002/hipo.10035

    Article  CAS  PubMed  Google Scholar 

  • Alonso M, Vianna MR, Izquierdo I, Medina JH (2002b) Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus. Cell Mol Neurobiol 22:663–674

    Article  CAS  PubMed  Google Scholar 

  • Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, Hudson CE, Cole MJ, Harrison JK, Bickford PC, Gemma C (2011) Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging 32:2030–2044. doi:10.1016/j.neurobiolaging.2009.11.022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barrientos RM, Frank MG, Crysdale NY, Chapman TR, Ahrendsen JT, Day HE, Campeau S, Watkins LR, Patterson SL, Maier SF (2011) Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J Neurosci Official J Soc Neurosci 31:11578–11586. doi:10.1523/JNEUROSCI.2266-11.2011

    Article  CAS  Google Scholar 

  • Bian Y, Pan Z, Hou Z, Huang C, Li W, Zhao B (2012) Learning, memory, and glial cell changes following recovery from chronic unpredictable stress. Brain Res Bull. doi:10.1016/j.brainresbull.2012.04.008

    PubMed  Google Scholar 

  • Bland ST, Schmid MJ, Greenwood BN, Watkins LR, Maier SF (2006) Behavioral control of the stressor modulates stress-induced changes in neurogenesis and fibroblast growth factor-2. NeuroReport 17:593–597

    Article  CAS  PubMed  Google Scholar 

  • Campeau S, Nyhuis TJ, Kryskow EM, Masini CV, Babb JA, Sasse SK, Greenwood BN, Fleshner M, Day HE (2010) Stress rapidly increases alpha 1d adrenergic receptor mRNA in the rat dentate gyrus. Brain Res 1323: 109–118. doi:10.1016/j.brainres.2010.01.084 (S0006-8993(10)00238-6[pii])

    Google Scholar 

  • Campisi J, Sharkey C, Johnson JD, Asea A, Maslanik T, Bernstein-Hanley I, Fleshner M (2012) Stress-induced facilitation of host response to bacterial challenge in F344 rats is dependent on extracellular heat shock protein 72 and independent of alpha beta T cells. Stress 15:637–646. doi:10.3109/10253890.2011.653596

    Article  CAS  PubMed  Google Scholar 

  • Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924. doi:10.1038/nn1715

    Article  CAS  PubMed  Google Scholar 

  • D’Haese JG, Friess H, Ceyhan GO (2012) Therapeutic potential of the chemokine-receptor duo fractalkine/CX3CR1: an update. Expert Opin Ther Targets 16:613–618. doi:10.1517/14728222.2012.682574

    Article  PubMed  Google Scholar 

  • Duman RS (1998) Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 44:324–335

    Article  CAS  PubMed  Google Scholar 

  • Ekdahl CT (2012) Microglial activation—tuning and pruning adult neurogenesis. Front Pharmacol 3:41. doi:10.3389/fphar.2012.00041

    Article  PubMed Central  PubMed  Google Scholar 

  • Ekdahl CT, Kokaia Z, Lindvall O (2009) Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 158:1021–1029. doi:10.1016/j.neuroscience.2008.06.052

    Article  CAS  PubMed  Google Scholar 

  • Fleshner M (2005) Physical activity and stress resistance: sympathetic nervous system adaptations prevent stress-induced immunosuppression. Exerc Sport Sci Rev 33:120–126

    Article  PubMed  Google Scholar 

  • Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF (2007) Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 21:47–59. doi:10.1016/j.bbi.2006.03.005

    Article  CAS  PubMed  Google Scholar 

  • Greenwood BN, Fleshner M (2008) Exercise, learned helplessness, and the stress-resistant brain. Neuromol Med 10:81–98

    Article  CAS  Google Scholar 

  • Greenwood BN, Fleshner M (2011) Exercise, stress resistance, and central serotonergic systems. Exerc Sport Sci Rev 39:140–149. doi:10.1097/JES.0b013e31821f7e45

    Article  PubMed  Google Scholar 

  • Greenwood BN, Kennedy S, Smith TP, Campeau S, Day HE, Fleshner M (2003) Voluntary freewheel running selectively modulates catecholamine content in peripheral tissue and c-Fos expression in the central sympathetic circuit following exposure to uncontrollable stress in rats. Neuroscience 120:269–281

    Article  CAS  PubMed  Google Scholar 

  • Greenwood BN, Strong PV, Foley TE, Thompson RS, Fleshner M (2007) Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus. Neuroscience 144:1193–1208

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hatori K, Nagai A, Heisel R, Ryu JK, Kim SU (2002) Fractalkine and fractalkine receptors in human neurons and glial cells. J Neurosci Res 69:418–426. doi:10.1002/jnr.10304

    Article  CAS  PubMed  Google Scholar 

  • Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN, Fleshner M (2005) Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135:1295–1307

    Article  CAS  PubMed  Google Scholar 

  • Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kempermann G, Neumann H (2003) Neuroscience. Microglia: the enemy within? Science 302:1689–1690. doi:10.1126/science.1092864

    Article  CAS  PubMed  Google Scholar 

  • Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke HW, Kettenmann H (2012) Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun 26:419–428. doi:10.1016/j.bbi.2011.12.002

    Article  CAS  PubMed  Google Scholar 

  • Lauro C, Cipriani R, Catalano M, Trettel F, Chece G, Brusadin V, Antonilli L, van Rooijen N, Eusebi F, Fredholm BB, Limatola C (2010) Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death. Neuropsychopharmacol Official Publ Am Coll Neuropsychopharmacol 35:1550–1559. doi:10.1038/npp.2010.26

    Article  CAS  Google Scholar 

  • Leuner B, Gould E (2010) Structural plasticity and hippocampal function. Annu Rev Psychol 61(111–40):C1–C3. doi:10.1146/annurev.psych.093008.100359

    Google Scholar 

  • Maggi L, Scianni M, Branchi I, D’Andrea I, Lauro C, Limatola C (2011) CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci 5:22. doi:10.3389/fncel.2011.00022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maier SF, Nguyen KT, Deak T, Milligan ED, Watkins LR (1999) Stress, learned helplessness, and brain interleukin-1 beta. Adv Exp Med Biol 461:235–249

    Article  CAS  PubMed  Google Scholar 

  • Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev 29:829–841. doi:10.1016/j.neubiorev.2005.03.021

    Article  CAS  PubMed  Google Scholar 

  • Maslanik T, Bernstein-Hanley I, Helwig B, Fleshner M (2012) The impact of acute-stressor exposure on splenic innate immunity: a gene expression analysis. Brain Behav Immun 26:142–149. doi:10.1016/j.bbi.2011.08.006

    Article  CAS  PubMed  Google Scholar 

  • Mizuno T, Kawanokuchi J, Numata K, Suzumura A (2003) Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 979:65–70

    Article  CAS  PubMed  Google Scholar 

  • Nguyen KT, Deak T, Owens SM, Kohno T, Fleshner M, Watkins LR, Maier SF (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 18:2239–2246

    CAS  PubMed  Google Scholar 

  • O’Connor KA, Johnson JD, Hansen MK, Wieseler Frank JL, Maksimova E, Watkins LR, Maier SF (2003) Peripheral and central proinflammatory cytokine response to a severe acute stressor. Brain Res 991:123–132

    Article  PubMed  Google Scholar 

  • Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC (2011) CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J Neuroinflammation 8:9. doi:10.1186/1742-2094-8-9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458. doi:10.1126/science.1202529

    Article  CAS  PubMed  Google Scholar 

  • Pocock JM, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30:527–535. doi:10.1016/j.tins.2007.07.007

    Article  CAS  PubMed  Google Scholar 

  • Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci Official J Soc Neurosci 31:16241–16250. doi:10.1523/JNEUROSCI.3667-11.2011

    Article  CAS  Google Scholar 

  • Rozeske RR, Evans AK, Frank MG, Watkins LR, Lowry CA, Maier SF (2011) Uncontrollable, but not controllable, stress desensitizes 5-HT1A receptors in the dorsal raphe nucleus. J Neurosci Official J Soc Neurosci 31:14107–14115. doi:10.1523/JNEUROSCI.3095-11.2011

    Article  CAS  Google Scholar 

  • Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705. doi:10.1016/j.neuron.2012.03.026

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tremblay ME, Majewska AK (2011) A role for microglia in synaptic plasticity? Communicative Integr Biol 4:220–222. doi:10.4161/cib.4.2.14506

    Article  Google Scholar 

  • Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci Official J Soc Neurosci 31:16064–16069. doi:10.1523/JNEUROSCI.4158-11.2011

    Article  CAS  Google Scholar 

  • Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237. doi:10.1101/lm.51202

    Article  PubMed Central  PubMed  Google Scholar 

  • Vaidya VA, Marek GJ, Aghajanian GK, Duman RS (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci Official J Soc Neurosci 17:2785–2795

    CAS  Google Scholar 

  • Vaidya VA, Terwilliger RM, Duman RS (1999) Role of 5-HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 262:1–4

    Article  CAS  PubMed  Google Scholar 

  • Vukovic J, Colditz MJ, Blackmore DG, Ruitenberg MJ, Bartlett PF (2012) Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J Neurosci Official J Soc Neurosci 32:6435–6443. doi:10.1523/JNEUROSCI.5925-11.2012

    Article  CAS  Google Scholar 

  • Weiss JM, Stout JC, Aaron MF, Quan N, Owens MJ, Butler PD, Nemeroff CB (1994) Depression and anxiety: role of the locus coeruleus and corticotropin-releasing factor. Brain Res Bull 35:561–572

    Article  CAS  PubMed  Google Scholar 

  • Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD (2011) Microglia and memory: modulation by early-life infection. J Neurosci Official J Soc Neurosci 31:15511–15521. doi:10.1523/JNEUROSCI.3688-11.2011

    Article  CAS  Google Scholar 

  • Wynne AM, Henry CJ, Godbout JP (2009) Immune and behavioral consequences of microglial reactivity in the aged brain. Integr Comp Biol 49:254–266. doi:10.1093/icb/icp009

    Article  CAS  PubMed  Google Scholar 

  • Wynne AM, Henry CJ, Huang Y, Cleland A, Godbout JP (2010) Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav Immun 24:1190–1201. doi:10.1016/j.bbi.2010.05.011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213. doi:10.1016/j.bbi.2010.10.015

    Article  CAS  PubMed  Google Scholar 

  • Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275. doi:10.1038/nn1629

    Article  CAS  PubMed  Google Scholar 

  • Zoladz PR, Park CR, Halonen JD, Salim S, Alzoubi KH, Srivareerat M, Fleshner M, Alkadhi KA, Diamond DM (2011) Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia. Hippocampus. doi:10.1002/hipo.20922

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Integrative Physiology and The Center for Neuroscience, University of Colorado, Boulder, CO, 80309, USA

    Monika Fleshner & Benjamin N. Greenwood

  2. Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel

    Raz Yirmiya

Authors
  1. Monika Fleshner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjamin N. Greenwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raz Yirmiya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Fleshner .

Editor information

Editors and Affiliations

  1. Department of Psychological Medicine, Institute of Psychiatry Kings College London, London, United Kingdom

    Carmine M. Pariante

  2. Family and Community Health Systems, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

    M. Danet Lapiz-Bluhm

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Fleshner, M., Greenwood, B.N., Yirmiya, R. (2014). Neuronal-Glial Mechanisms of Exercise-Evoked Stress Robustness. In: Pariante, C., Lapiz-Bluhm, M. (eds) Behavioral Neurobiology of Stress-related Disorders. Current Topics in Behavioral Neurosciences, vol 18. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2014_277

Download citation

Publish with us

Policies and ethics

Search

Navigation