Lifestyle‑dependent Microglial Plasticity: Training The Brain Guardians

Abstract

Lifestyle is one of the most powerful tools for shaping human beings; lifestyle encompasses many aspects of interaction with the environment, from nutrition and education to physical activity and sleep quality. All of these factors combine to influence neuroplasticity and determine brain performance and cognitive lifespan. In particular, physical activity, exposure to an enriched environment, and dieting transform lifestyle events into the remodeling of brain homeostasis and reshaping of neural networks through complex modifications of microglia altering their phenotype and regulating their functional activity, ultimately enhancing neuroprotection and cognitive longevity.

Keywords

Microglia, Neuroplasticity, Enriched environment, Physical exercise, Lifestyle modifications, Diet, Cistanche benefits.

Click here to get the effects of Cistanche on Improving memory

Introduction

Lifestyle, neural plasticity, and cognitive performance

Adaptive behavior is critical for survival: In complex multicellular organisms, environmental challenges stimulate lifelong morphofunctional reorganization of the nervous system, known as neuroplasticity. Lifestyle is one of the most powerful tools for shaping humans; lifestyle encompasses many aspects of interaction with the environment, from nutrition and education to physical activity and sleep quality. There is compelling evidence that exposure of animals to environmental stimuli, including environmental enrichment, social engagement, and physical activity, affects neuroplasticity, influencing synaptic connectivity and neuronal morphology; similarly, dieting not only affects the whole organism but also reshapes the structure and function of the nervous system.

In rodents engaged in physical activity (usually in the form of free-entry running wheels), increases in neuronal dendrites, dendritic length and complexity, spine morphology, and synaptic density have been documented; these morphological changes are paralleled by increased expression of glutamate receptors and amplification of long-temporal enhancement (LTP) in several brain regions. This plastic remodeling appears to be associated with increased production of brain-derived neurotrophic factor (BDNF). Such alterations in morphological function could improve cognitive performance, including learning and memory, extend cognitive lifespan, and reduce the risk of dementia.

Intellectual engagement represents another lifestyle factor that positively influences cognitive longevity by stimulating neuroplasticity and by increasing cognitive reserve. There is compelling evidence for the role of education, occupational activity, creative challenge, and social engagement in prolonging physiological cognitive aging and delaying dementia. Similarly, dieting affects brain metabolism, neuronal plasticity, and synaptic connectivity, which in turn affects cognitive performance and cognitive longevity.

The cellular mechanisms of lifestyle effects on the brain remain to be fully elucidated; a growing body of evidence highlights the role of glial cells. Neuroglia is the primary homeostatic and defense arms of the nervous system and is critical for neuroplasticity and cognitive performance. In particular, glial cells are responsible for the brain's ability to compensate for lifelong pathological challenges and thus maintain the cognitive reserve. Physical activity and an enriched environment have been shown to significantly increase astrocyte complexity, volume, and surface area, enhance astrocyte coverage of synapses and blood vessels, and positively modulate astrocyte-dependent neurogenesis in adult neurogenic niches. Dieting also affects astrocytes: For example, caloric restriction leads to a substantial increase in astrocyte complexity and an increase in astrocyte synaptic coverage, resulting in enhanced control of extracellular glutamate and K+, which enhances long-term enhancement of the mouse hippocampus. Astrocytes are thought to be a key factor in translating lifestyle factors into brain plasticity and cognitive performance. Finally, diet, physical exercise, and environmental enrichment act on oligodendrocytes, thereby promoting myelin formation physiologically and pathologically.

In this article, we will outline the effects of lifestyle factors on the plasticity of a third major type of neuroglia-microglia, which contributes to brain physiology and represents the main arm of the central nervous system (CNS) defense system.

Cistanche supplements

Plasticity of microglia

Microglia are neuronal cells of non-neural origin: Microglial precursors in the form of fetal macrophages invade the neural tube early in development. These precursors spread throughout the brain and spinal cord and undergo the most remarkable metamorphosis. Mature microglia are very different from macrophages: whereas macrophages are spherical or amoeboid, mature microglia have a highly complex process in their basic design, similar to neuronal cells. This profound morphological transformation is accompanied by equally profound physiological changes: microglia acquire a large number of neurotransmitter and neurohormone receptors while retaining "immune" receptors from their myeloid ancestors, making microglia arguably the most "sensitive" cells in the central nervous system. This makes microglia the most "sensitive" cells in the CNS. In the normal brain, microglia appear in a "never resting" form, and they are constantly observing the neural tissue through a highly branching and mobile process; therefore, these cells are defined as "surveillance microglia". In addition, microglia perform many physiological functions related to the regulation of synaptic behavior, the formation of synaptic contacts, and the regulation of adult neurogenesis, which ultimately regulates cognitive processes (Figure 1). Microglia are highly heterogeneous plastic cells that exhibit many different morphological shapes and functional states depending on brain region, age, and environment.

Lifestyle effects on microglia Physical exercise

Physical exercise can alter the density, morphological appearance, and molecular characteristics of microglia (Table 1). Ten days of physical exercise on a running wheel stimulates microglia proliferation in the superficial mouse cortex [47] and facilitates branching monitoring of microglia status in the mouse hippocampus. Microglia appear to translate many lifestyle changes into changes in adult neurogenesis within the neurogenic niches. Physical exercise is known to stimulate neurogenesis, enhance the survival of new neurons and improve memory. Physical exercise induces quite profound changes in microglia phenotype as these changes persist even after cell isolation and maintenance culture. Addition of purified microglia isolated from the brain of transgenic Csf1r-GFP mice expressing GFP under the control of the Csf1r gene (sorted by flow cytometry) to hippocampal neuronal cultures obtained from sedentary mice activated neuronal cells and increased neurogenesis. These effects were mediated through colony-stimulating factor 1 (CSF-1) and its receptor signaling axis. In contrast, microglia from older animals or young sedentary animals have no effect in recruiting and stimulating neuronal precursors. The same CSF-1 signaling cascade underlies the ability to recover from stress after physical exercise. The positive regulation of neurogenesis may also be mediated by increased microglia production of BDNF, a well-known enhancer of neurogenesis. In aged (but not adult) mouse microglia, voluntary physical activity increased the proportion of BDNF-expressing microglia, and microglia levels of BDNF were found to correlate with the density of newly generated neurons. Physical activity also increased the production of pre-neurogenic insulin-like growth factor (IGF1) in microglia, and IGF1 may mediate local microglial cell communication with neural precursor cells.

Although the precise description of the effects of physical exercise on microglia and its physiological mechanisms requires more research, there is substantial evidence that physical exercise promotes microglia-dependent neuroprotection in many pathological situations. For example, physical exercise protects against lipopolysaccharide (LPS)-induced neuroinflammation and associated cognitive deficits. This protective effect was associated with the inhibition of IL-1β, TNFα, and IL-10 mRNA expression in the hippocampus, suggesting that reduction of the pro-inflammatory response of microglia is a potential mechanism by which physical exercise may protect the central nervous system. Similar mechanisms may play a role in the aging process. For example, physical exercise reduces the proportion of pro- (IL-1β, IL-6, and TNFα) and anti-inflammatory (IL-10) cytokines in the hippocampus of aging rats. Microglia are a major source of cytokines in the aging brain and therefore may be the cause. Voluntary running on a running wheel for 8 weeks resulted in the diminished proliferation of hippocampal microglia in aged mice while running for 10 weeks resulted in diminished reactivity of microglia in the hippocampus and other brain regions in aged rats. Expression of the responsiveness markers CD68 and MHCII was increased in aged mice; exposure to physical activity decreased the density of CD68+ and MHCII+ microglia in the hippocampus in aged females, whereas CD68+ microglia were reduced and MHCII+ microglia were increased in the hippocampus in males. These data suggest that the effect of physical exercise on microglia immune profiles varies with age, sex, and brain region, which may reflect microglia heterogeneity. Exercise on a treadmill for 10 days attenuated cognitive decline and reduced glycolysis, glycolytic capacity, and PFKB3 enzymes in aged mice; similarly, aging markers such as β-galactosidase and P16INK4A were reduced, suggesting that exercise-related cognitive improvements are carefully orchestrated by normalization of microglia metabolic profiles and functions.

Cistanche pills

Microglia plasticity induced by physical exercise contributes to neuroprotection in neurodegenerative diseases. In the APP/PS1 mouse model of Alzheimer's disease (AD), 12 weeks of treadmill exercise may reduce β-amyloid deposition and improve cognitive processes through hippocampal microglia modulation. Treadmill exercise improves cognitive performance, including spatial learning and exploratory activities, and reduces β-amyloid deposition and microglial reactivity. In the Tg2576 mouse AD model, three weeks of autonomous treadmill exercise significantly reduced hippocampal IL-1β and TNF-α levels and decreased soluble β-amyloid40 and soluble fibrillar β-amyloid. These results suggest that physical exercise can alter immune responses in the brains of AD mouse models by converting microglia to an antigen-presenting phenotype, thereby reducing the β-amyloid burden, attenuating AD pathology, and improving cognition.

In the Parkinson's disease (PD) MPTP mouse model, treadmill exercise for 4 weeks improved dopaminergic neuron loss by inhibiting microglia reactivity, preventing loss of nigrostriatal neurons, and improving motor balance and coordination dysfunction. In a rat model of 6-hydroxydopamine PD, 4 weeks of roller exercise inhibited microglia reactivity and partially prevented neuronal damage and cognitive decline. This effective modulation of microglia has an important neuroprotective role in the PD brain, highlighting microglia as a key cellular component for the beneficial effects of physical exercise in PD.

In a model of experimental autoimmune encephalomyelitis induced by brain-derived t-cell transfer, physical exercise, and associated microglial cell changes appear to protect the central nervous system. Six consecutive weeks of intense treadmill training reduced microglia reactive oxygen species formation, neurotoxicity, and pro-inflammatory responses, all of which are associated with the propagation of autoimmune neuroinflammation.

Cistanche Tubulosa

How to improve your life by using Cistanche extract to improve your memory？

Memory is a fundamental cognitive function that allows us to store and recall information. However, as we age, our memory may decline, affecting daily activities and overall quality of life. Cistanche extract, a traditional Chinese medicine, has been suggested as a potential natural supplement to improve memory function. In this essay, we will explore how to use Cistanche extract to improve memory and enhance the overall quality of life.

Cistanche extract contains bioactive compounds such as phenylethanoid glycosides and echinacoside that have been shown to improve memory function in animal studies. Additionally, Cistanche extract has powerful antioxidant properties that protect the brain from oxidative damage, which can lead to cognitive impairment.

To use Cistanche extract to improve memory, individuals should take 1-2 grams of Cistanche powder per day, mixed with water or another liquid. This dosage may be adjusted by a healthcare provider based on individual needs and tolerances. Cistanche extract is safe for most people when used in appropriate amounts, but it's important to consult with a healthcare provider before starting any new supplements, especially if one has underlying health conditions or is taking medications.

Besides consuming Cistanche extract, there are various lifestyle interventions that can boost memory function. Regular physical exercise, a healthy diet, adequate sleep, stress management, and mental stimulation are all critical factors that help maintain brain health.

Physical exercise increases blood flow to the brain, which provides oxygen and nutrients that support nerve cell growth and survival. A moderate-intensity aerobic exercise regimen, such as brisk walking or cycling, has been shown to improve cognitive function, including memory.

A healthy diet rich in fruits, vegetables, whole grains, lean protein, and healthy fats provides essential nutrients that support brain health. Omega-3 fatty acids, found in oily fish like salmon, may improve memory function by enhancing communication between brain cells.

Getting enough sleep is essential for consolidating memories and allowing the brain to repair and rejuvenate. Adults need 7-9 hours of quality sleep per night, and sleep deprivation has been linked to cognitive impairment and memory loss.

Stress management techniques such as meditation, deep breathing, or yoga can improve memory by reducing cortisol, a hormone that impairs memory formation. Mental stimulation, such as reading, doing crossword puzzles, or learning a new skill, keeps the brain active and encourages the growth of new neurons.

In conclusion, memory decline is a natural part of aging, but there are ways to improve and maintain it. Cistanche extract is a promising natural supplement that can help enhance memory function and protect against cognitive impairments. However, it's essential to incorporate other lifestyle interventions such as exercise, a healthy diet, adequate sleep, stress management, and mental stimulation to optimize brain health and improve the overall quality of life.

References

1. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999;96:13427–31.

2. Yu Q, Li X, Wang J, Li Y. Effect of exercise training on long-term potentiation and NMDA receptor channels in rats with cerebral infarction. Exp Ther Med. 2013;6:1431–6.

3. Eadie BD, Redila VA, Christie BR. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol. 2005;486:39–47.

4. Stranahan AM, Khalil D, Gould E. Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocam pus. 2007;17:1017–22.

5. Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front Cell Neurosci. 2014;8:170.

6. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30:464–72.

7. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295–301.

8. Chang M, Jonsson PV, Snaedal J, Bjornsson S, Saczynski JS, Aspelund T, Eiriksdottir G, Jonsdottir MK, Lopez OL, Harris TB, et al. The effect of midlife physical activity on cognitive function among older adults:

9. AGES–Reykjavik Study. J Gerontol A Biol Sci Med Sci. 2010;65:1369–74. Dik M, Deeg DJ, Visser M, Jonker C. Early life physical activity and cognition at old age. J Clin Exp Neuropsychol. 2003;25:643–53.

10. Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, Kukull W. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144:73–81.

11. Gronek P, Balko S, Gronek J, Zajac A, Maszczyk A, Celka R, Doberska A, Czarny W, Podstawski R, Clark CCT, et al. Physical activity and Alzheimer’s disease: a narrative review. Aging Dis. 2019;10:1282–92.

12. Meng Q, Lin MS, Tzeng IS. Relationship between exercise and Alzheimer’s disease: a narrative literature review. Front Neurosci. 2020;14:131.

13. Reas ET, Laughlin GA, Bergstrom J, Kritz-Silverstein D, Richard EL, BarrettConnor E, McEvoy LK. Lifetime physical activity and late-life cognitive function: the Rancho Bernardo study. Age Ageing. 2019;48:241–6.

14. Phillips C. Lifestyle modulators of neuroplasticity: how physical activity, mental engagement, and diet promote cognitive health during aging. Neural Plast. 2017;2017:3589271.

15. Ball K, Berch DB, Helmers KF, Jobe JB, Leveck MD, Marsiske M, Morris JN, Rebok GW, Smith DM, Tennstedt SL, et al. Effects of cognitive training interventions with older adults: a randomized controlled trial. JAMA. 2002;288:2271–81.

16. Curlik DM 2nd, Shors TJ. Training your brain: Do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus? Neuropharmacology. 2013;64:506–14.

17. Staf RT, Hogan MJ, Williams DS, Whalley LJ. Intellectual engagement and cognitive ability in later life (the “use it or lose it” conjecture): a longitudinal, prospective study. BMJ. 2018;363:k4925.

18. Krell-Roesch J, Vemuri P, Pink A, Roberts RO, Stokin GB, Mielke MM, Christianson TJ, Knopman DS, Petersen RC, Kremers WK, et al. Association between mentally stimulating activities in late life and the outcome of incident mild cognitive impairment, with an analysis of the APOE epsilon4 genotype. JAMA Neurol. 2017;74:332–8.

19. Agrawal R, Gomez-Pinilla F. “Metabolic syndrome” in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signaling and cognition. J Physiol. 2012;590:2485–99.

20. Gomez-Pinilla F, Tyagi E. Diet, and cognition: interplay between cell metabolism and neuronal plasticity. Curr Opin Clin Nutr Metab Care. 2013;16:726–33.

21. Murphy T, Dias GP, Thuret S. Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plast. 2014;2014:563160.

22. Yamada D, Wada K, Sekiguchi M. Modulation of long-term potentiation of cortico-amygdala synaptic responses and auditory fear memory by dietary polyunsaturated fatty acid. Front Behav Neurosci. 2016;10:164.

23. Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K, Smith AD. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr. 2009;139:120–7.

24. Devore EE, Kang JH, Breteler MM, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. 2012;72:135–43.

25. Verkhratsky A, Augusto-Oliveira M, Pivoriunas A, Popov A, Brazhe A, Semyanov A. Astroglial asthenia and loss of function, rather than reactivity, contribute to the aging of the brain. Pfugers Arch. 2021;473:753–74.

26. Leardini-Tristao M, Andrade G, Garcia C, Reis PA, Lourenco M, Moreira ETS, Lima FRS, Castro-Faria-Neto HC, Tibirica E, Estato V. Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion. J Neuroinflammation. 2020;17:117.

27. Uda M, Ishido M, Kami K, Masuhara M. Effects of chronic treadmill running on neurogenesis in the dentate gyrus of the hippocampus of the adult rat. Brain Res. 2006;1104:64–72.

28. de Senna PN, Bagatini PB, Galland F, Bobermin L, do Nascimento PS, Nardin P, Tramontina AC, Goncalves CA, Achaval M, Xavier LL. Physical exercise reverses spatial memory deficit and induces hippocampal astrocyte plasticity in diabetic rats. Brain Res. 2017;1655:242–251.

29. Sirevaag AM, Greenough WT. Plasticity of GFAP-immunoreactive astrocyte size and number in the visual cortex of rats reared in complex environments. Brain Res. 1991;540:273–8.

30. Popov A, Denisov P, Bychkov M, Brazhe A, Lyukmanova E, Shenkarev Z, Lazareva N, Verkhratsky A, Semyanov A. Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus. Cell Death Dis. 2020;11:208.

31. Augusto-Oliveira M, Verkhratsky A. Mens sana in corporeal: lifestyle changes modify astrocytes to contain Alzheimer’s disease. Neural Regen Res. 2021;16:1548–9.

32. Zheng J, Sun X, Ma C, Li BM, Luo F. Voluntary wheel running promotes myelination in the motor cortex through Wnt signaling in mice. Mol Brain. 2019;12:85.

33. Yoon H, Kleven A, Paulsen A, Kleppe L, Wu J, Ying Z, Gomez-Pinilla F, Scarisbrick IA. The interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system. Biochim Biophys Acta. 2016;1862:545–55.

34. Chaddock-Heyman L, Erickson KI, Kienzler C, Drollette ES, Raine LB, Kao SC, Bensken J, Weisshappel R, Castelli DM, Hillman CH, et al. Physical activity increases white matter microstructure in children. Front Neuro sci. 2018;12:950.

35. Svatkova A, Mandl RC, Scheewe TW, Cahn W, Kahn RS, Hulshof Pol HE. Physical exercise keeps the brain connected: biking increases white matter integrity in patients with schizophrenia and healthy controls. Schizophr Bull. 2015;41:869–78.

36. Garaschuk O, Verkhratsky A. Microglia: the neural cells of nonneural origin. Methods Mol Biol. 2019;2034:3–11.

37. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330:841–5.

38. Ginhoux F, Lim S, Hoefel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45.

39. Augusto-Oliveira M, Arrifano GP, Lopes-Araujo A, Santos-Sacramento L, Takeda PY, Anthony DC, Malva JO, Crespo-Lopez ME. What do microglia really do in healthy adult brains? Cells. 2019;8.

40. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013;77:10–8.

41. Tay TL, Carrier M, Tremblay ME. Physiology of microglia. Adv Exp Med Biol. 2019;1175:129–48.

42. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci. 2011;31:16064–9.

43. Cserep C, Posfai B, Denes A. Shaping neuronal fate: functional heterogeneity of direct microglia-neuron interactions. Neuron.2020.

44. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.

45. Tan YL, Yuan Y, Tian L. Microglial regional heterogeneity and its role in the brain. Mol Psychiatry.2019.

46. Stratoulias V, Venero JL, Tremblay ME, Joseph B. Microglial subtypes: diversity within the microglial community. EMBO J. 2019;38:e101997.

47. Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex. 2003;13:845–51.

48. Olah M, Ping G, De Haas AH, Brouwer N, Meerlo P, Van Der Zee EA, Biber K, Boddeke HW. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia. 2009;57:1046–61.

49. Valero J, Paris I, Sierra A. Lifestyle shapes the dialogue between environment, microglia, and adult neurogenesis. ACS Chem Neurosci. 2016;7:442–53.

50. Opendak M, Gould E. Adult neurogenesis: a substrate for experience-dependent change. Trends Cogn Sci. 2015;19:151–61.

51. Farioli-Vecchioli S, Mattera A, Micheli L, Ceccarelli M, Leonardi L, Saraulli D, Costanzi M, Cestari V, Rouault JP, Tirone F. Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells. Stem Cells. 2014;32:1968–82.

52. Kempermann G, Fabel K, Ehninger D, Babu H, Leal-Galicia P, Garthe A, Wolf SA. Why and how physical activity promotes experience-induced brain plasticity. Front Neurosci. 2010;4:189.

53. Speisman RB, Kumar A, Rani A, Foster TC, Ormerod BK. Daily exercise improves memory, stimulates hippocampal neurogenesis, and modulates immune and neuroimmune cytokines in aging rats. Brain Behav Immun. 2013;28:25–43.

54. Vukovic J, Colditz MJ, Blackmore DG, Ruitenberg MJ, Bartlett PF. Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J Neurosci. 2012;32:6435–43.

55. Fleshner M, Greenwood BN, Yirmiya R. Neuronal-glial mechanisms of exercise-evoked stress robustness. In: Pariante CM, Lapiz-Bluhm MD, editors Behavioral neurobiology of stress-related disorders. Berlin: Springer; 2014. pp. 1–12.

56. Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev. 2014;94:991–1026.

57. Littlefeld AM, Setti SE, Priester C, Kohman RA. Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a pro-neurogenic phenotype in aged mice. J Neuroinflammation. 2015;12:138.

58. Llorens-Martin M, Torres-Aleman I, Trejo JL. Mechanisms mediating brain plasticity: IGF1 and adult hippocampal neurogenesis. Neuroscientist. 2009;15:134–48.

59. Mota BC, Kelly AM. Exercise alters LPS-induced glial activation in the mouse brain. Neuronal Signal. 2020;4:NS20200003.

60. Gomes da Silva S, Simoes PS, Mortara RA, Scorza FA, Cavalheiro EA, da Graca Nafah-Mazzacoratti M, Arida RM. Exercise-induced hippocampal anti-inflammatory response in aged rats. J Neuroinflammation. 2013;0:61.

61. Barrientos RM, Kitt MM, Watkins LR, Maier SF. Neuroinflammation in the normal aging hippocampus. Neuroscience. 2015;309:84–99.

62. Kohman RA, DeYoung EK, Bhattacharya TK, Peterson LN, Rhodes JS. Wheel running attenuates microglia proliferation and increases the expression of a pro-neurogenic phenotype in the hippocampus of aged mice. Brain Behav Immun. 2012;26:803–10.

63. Kohman RA, Bhattacharya TK, Wojcik E, Rhodes JS. Exercise reduces the activation of microglia isolated from the hippocampus and brain of aged mice. J Neuroinflammation. 2013;10:885.

64. Mela V, Mota BC, Milner M, McGinley A, Mills KHG, Kelly ÁM, Lynch MA. Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells. Brain Behav Immun. 2020;87:413–28.

65. Zhang X, He Q, Huang T, Zhao N, Liang F, Xu B, Chen X, Li T, Bi J. Treadmill exercise decreases Aβ deposition and counteracts cognitive decline in APP/PS1 mice, possibly via hippocampal microglia modifications. Front Aging Neurosci. 2019;11:78.

66. Ke HC, Huang HJ, Liang KC, Hsieh-Li HM. Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise. Brain Res. 2011;1403:1–11.

67. Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008;5:13–13.

68. Sung YH, Kim SC, Hong HP, Park CY, Shin MS, Kim CJ, Seo JH, Kim DY, Kim DJ, Cho HJ. Treadmill exercise ameliorates dopaminergic neuronal loss by suppressing microglial activation in Parkinson’s disease mice. Life Sci. 2012;91:1309–16.

69. Real CC, Doorduin J, Kopschina F, García PV, de Paula FD, Britto D, Luiz R, de Vries EFJ. Evaluation of exercise-induced modulation of glial activation and dopaminergic damage in a rat model of Parkinson’s disease using [11C]PBR28 and [18F]FDOPA PET. J Cereb Blood Flow Metab. 2017;39:989–1004.

70. Badanjak K, Fixemer S, Smajić S, Skupin A, Grünewald A. The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease. Int J Mol Sci. 2021; 22.

71. Zaychik Y, Fainstein N, Touloumi O, Goldberg Y, Hamdi L, Segal S, Nabat H, Zoidou S, Grigoriadis N, Katz A et al. High-intensity exercise training protects the brain against autoimmune neuroinflammation: regulation of microglial redox and pro-inflammatory functions. Front Cell Neurosci. 2021;15.

1. Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém 66075‑110, Brazil.

2. Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester M13 9PT, UK.

3. Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, 01102 Vilnius, Lithuania.

4. Achucarro Center for Neurosci‑ ence, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.

5. Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain.