Advertisement

Neuronal-Glial Mechanisms of Exercise-Evoked Stress Robustness

  • Monika Fleshner
  • Benjamin N. Greenwood
  • Raz Yirmiya
Part of the Current Topics in Behavioral Neurosciences book series (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.

Keywords

Stress resistance Microglia Fractalkine Exercise 

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

  1. 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 PubMedCrossRefGoogle Scholar
  2. 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 22:663–674PubMedCrossRefGoogle Scholar
  3. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  4. 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 CrossRefGoogle Scholar
  5. 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 PubMedGoogle Scholar
  6. 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 17:593–597PubMedCrossRefGoogle Scholar
  7. 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
  8. 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 PubMedCrossRefGoogle Scholar
  9. 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 PubMedCrossRefGoogle Scholar
  10. 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 PubMedCrossRefGoogle Scholar
  11. Duman RS (1998) Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 44:324–335PubMedCrossRefGoogle Scholar
  12. Ekdahl CT (2012) Microglial activation—tuning and pruning adult neurogenesis. Front Pharmacol 3:41. doi: 10.3389/fphar.2012.00041 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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 PubMedCrossRefGoogle Scholar
  14. Fleshner M (2005) Physical activity and stress resistance: sympathetic nervous system adaptations prevent stress-induced immunosuppression. Exerc Sport Sci Rev 33:120–126PubMedCrossRefGoogle Scholar
  15. 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 PubMedCrossRefGoogle Scholar
  16. Greenwood BN, Fleshner M (2008) Exercise, learned helplessness, and the stress-resistant brain. Neuromol Med 10:81–98CrossRefGoogle Scholar
  17. Greenwood BN, Fleshner M (2011) Exercise, stress resistance, and central serotonergic systems. Exerc Sport Sci Rev 39:140–149. doi: 10.1097/JES.0b013e31821f7e45 PubMedCrossRefGoogle Scholar
  18. 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 120:269–281PubMedCrossRefGoogle Scholar
  19. 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 144:1193–1208PubMedCentralPubMedCrossRefGoogle Scholar
  20. 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 PubMedCrossRefGoogle Scholar
  21. 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 135:1295–1307PubMedCrossRefGoogle Scholar
  22. 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 20:4106–4114PubMedCentralPubMedCrossRefGoogle Scholar
  23. Kempermann G, Neumann H (2003) Neuroscience. Microglia: the enemy within? Science 302:1689–1690. doi: 10.1126/science.1092864 PubMedCrossRefGoogle Scholar
  24. 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 PubMedCrossRefGoogle Scholar
  25. 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 CrossRefGoogle Scholar
  26. 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
  27. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  28. Maier SF, Nguyen KT, Deak T, Milligan ED, Watkins LR (1999) Stress, learned helplessness, and brain interleukin-1 beta. Adv Exp Med Biol 461:235–249PubMedCrossRefGoogle Scholar
  29. 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 PubMedCrossRefGoogle Scholar
  30. 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 PubMedCrossRefGoogle Scholar
  31. Mizuno T, Kawanokuchi J, Numata K, Suzumura A (2003) Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 979:65–70PubMedCrossRefGoogle Scholar
  32. 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 18:2239–2246PubMedGoogle Scholar
  33. 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 991:123–132PubMedCrossRefGoogle Scholar
  34. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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 PubMedCrossRefGoogle Scholar
  36. Pocock JM, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30:527–535. doi: 10.1016/j.tins.2007.07.007 PubMedCrossRefGoogle Scholar
  37. 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 CrossRefGoogle Scholar
  38. 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 CrossRefGoogle Scholar
  39. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 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 CrossRefGoogle Scholar
  41. 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 CrossRefGoogle Scholar
  42. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 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 17:2785–2795Google Scholar
  44. 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 262:1–4PubMedCrossRefGoogle Scholar
  45. 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 CrossRefGoogle Scholar
  46. 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 35:561–572PubMedCrossRefGoogle Scholar
  47. 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 CrossRefGoogle Scholar
  48. 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 PubMedCrossRefGoogle Scholar
  49. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 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 PubMedCrossRefGoogle Scholar
  51. 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 PubMedCrossRefGoogle Scholar
  52. 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 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Monika Fleshner
    • 1
  • Benjamin N. Greenwood
    • 1
  • Raz Yirmiya
    • 2
  1. 1.Department of Integrative Physiology and The Center for NeuroscienceUniversity of ColoradoBoulderUSA
  2. 2.Department of PsychologyThe Hebrew University of JerusalemJerusalemIsrael

Personalised recommendations