Skip to main content
Download PDF

Lifestyle-dependent microglial plasticity: training the brain guardians

Biology Direct volume 16, Article number: 12 (2021) Cite this article

Abstract

Lifestyle is one of the most powerful instruments shaping mankind; the lifestyle includes many aspects of interactions with the environment, from nourishment and education to physical activity and quality of sleep. All these factors taken in complex affect neuroplasticity and define brain performance and cognitive longevity. In particular, physical exercise, exposure to enriched environment and dieting act through complex modifications of microglial cells, which change their phenotype and modulate their functional activity thus translating lifestyle events into remodelling of brain homoeostasis and reshaping neural networks ultimately enhancing neuroprotection and cognitive longevity.

Introduction: lifestyle, neural plasticity and cognitive performance

Adaptive behaviours are paramount for survival: in complex multicellular organisms, environmental challenges instigate life-long morpho-functional restructuring of the nervous system, known as neural plasticity. Lifestyle is one of the most powerful instruments shaping mankind; the lifestyle includes many aspects of interactions with the environment, from nourishment and education to physical activity and quality of sleep. There is compelling evidence demonstrating that exposure of animals to environmental stimulation including enriched environment, social engagement and physical activity affects neural plasticity and impacts synaptic connectivity and neuronal morphology; similarly, dieting not only affects the organism as a whole but also reshapes structure and modifies functions of the nervous system.

In rodents engaged in physical activity (usually in a form of free access to the running wheel), an increase in the neuronal arborisation, length and complexity of dendrites, spine morphology and synaptic densities has been documented; these morphological changes develop in paralleled with an increased expression of glutamate receptors and amplification of long-term potentiation (LTP) in several brain regions [1,2,3,4]. This plastic remodelling seems to be associated with an increase in production of brain-derived neurotrophic factor (BDNF) [5]. The morpho-functional changes translate into improved cognitive performance including learning and memory [6, 7], prolong cognitive longevity [8,9,10] and reduce the risk of dementia [8, 11,12,13].

Intellectual engagement represents another lifestyle factor that, by instigating neural plasticity, positively impacts on cognitive longevity by increasing cognitive reserve. There is convincing evidence demonstrating the role of education, occupational activities, creativity challenges and social engagement in prolonging physiological cognitive ageing and delaying dementia [14,15,16,17,18]. Similarly, dieting has been shown to affect brain metabolism, neuronal plasticity, and synaptic connectivity [19,20,21,22] thus impacting of cognitive performance and cognitive longevity [23, 24].

Cellular mechanisms of lifestyle action on the brain remain to be fully elucidated; there is mounting evidence highlighting the role of neuroglia. Neuroglia are the principal homeostatic and defensive arm of the nervous system, which is critical for neural plasticity and cognitive performance. In particular, neuroglia are responsible for the ability of brain to compensate life-long pathological challenges thus preserving cognitive reserve [25]. Physical activity and enriched environment has been shown to significantly increase the complexity, volume and surface area of astrocytes, enhance astrocytic coverage of synapses and blood vessels and positively modulate astrocyte-dependent neurogenesis in adult neurogenic niches [25,26,27,28,29]. Dieting also affects astrocytes: for example, caloric restriction induces substantial increase in astrocytic complexity and increase in astrocytic synaptic coverage, which enhances control over extracellular glutamate and K+ thus augmenting long-term potentiation in the hippocampus of mice [30]. Astrocytes have been proposed to be a critical element in translating lifestyle factors into brain plasticity and cognitive capabilities [31]. Finally, diet, physical exercise, and environmental enrichment act on oligodendrocytes thus promoting myelination in physiology and pathology [32,33,34,35].

In this paper we shall overview the effects of lifestyle factors on the plasticity of the third major type of neuroglia— microglial cells, which contribute to brain physiology and represent the principal arm of the defence system of the central nervous system (CNS).

Plasticity of microglia

Microglia are the neural cells of the non-neural origin [36]: microglial precursors in the form of foetal macrophages invade the neural tube early in development [37, 38]. These precursors disseminate throughout the brain and the spinal cord and undergo the most remarkable metamorphosis. Mature microglial cells are as different from macrophages as they could be: the latter are spherical or amoeboid, while the former possess highly elaborated processes resembling, in their fundamental design, neural cells. The profound morphological transfiguration is accompanied by similarly profound physiological change: microglial cells acquire a multitude of receptors to neurotransmitters and neurohormones, while retaining "immune" receptors as a legacy from their myeloid ancestry, making microglia are, arguably, the most "sensitive" cells of the CNS. In the normal brain, microglia appear in the form of 'never resting' cells which constantly survey the nervous tissue by their highly ramified and moving processes; hence these cells are defined as 'surveilling microglia'. In addition, microglia perform numerous physiological functions related to regulation of synaptic behaviour, shaping synaptic contacts and regulating adult neurogenesis thus ultimately modulating cognitive processes (Fig. 1) [39,40,41,42,43,44]. Microglia are highly heterogeneous and plastic cells, which present numerous distinct morphological shapes and functional states depending on the brain region, age and context [45, 46].

Fig. 1
figure 1

Microglial functions in physiology and pathophysiology

Full size image

Lifestyle effects on microglia

Physical exercise

Physical exercise modifies density, morphological appearance, and molecular profile of microglia (Table 1). Ten days of physical exercise in the running wheel stimulates microglia proliferation in the superficial cortical layers [47], and favours ramified surveilling microglial state in the mouse hippocampus [48]. Microglia seem to translate numerous lifestyle modifications into changes in adult neurogenesis within neurogenic niches [49]. Physical exercises are known to stimulate neurogenesis, potentate survival of newborn neurones and improve memory [50,51,52,53]. Physical exercise induced rather profound changes in microglial phenotype, as these changes persisted even after cell isolation and maintenance in culture. Addition of purified (by FACS sorting of microglia isolated from transgenic Csf1r-GFP mice expressing GFP under control of Csf1r gene) microglia isolated from the brains of animals subjected to 3 weeks of voluntary running to the culture of hippocampal neurones obtained from sedentary mice activated neural cells and increased neurogenesis. These effects of microglia were mediated through colony-stimulating factor 1 (CSF-1) and its receptor signalling axis. Conversely, microglia from aged animals or young sedentary animals were not effective in recruiting and stimulating neuronal precursors [54]. The same CSF-1 signalling cascade underlies emergence of stress resilience following physical exercise [55]. Positive regulation of neurogenesis may also be mediated by an increase in microglial production of BDNF, which is well known enhancer of neurogenesis [56]. Voluntary physical activity increases the proportion of BDNF-expressing microglia in aged (but not in adult) mice microglia [57], while microglial levels of BDNF were found to correlate with the density of newly generated neurones. Physical activity also increases microglial production of pro-neurogenic insulin-like growth factor (IGF1), which may mediate local microglia-neural precursor cells communications [58]

Table 1 Effects of physical exercise on microglia
Full size table

Although precise description of effects of physical exercise on microglia and mechanisms involved in physiological conditions needs more investigations, there is a large body of evidence indicating that physical exercise promotes microglia-dependent neuroprotection in numerous pathological contexts. For instance, physical exercise protects against lipopolysaccharide (LPS)-induced neuroinflammation and associated cognitive impairment. This protection is associated with suppressed expression of IL-1β, TNFα and IL-10 mRNA in the hippocampus, indicating reduced microglial pro-inflammatory response as an underlying mechanism by which physical exercise might protect CNS [59]. Similar mechanisms may be operational in ageing. Physical exercise, for example, reduces the ratio between pro- (IL-1β, IL-6 and TNFα) and anti-inflammatory (IL-10) cytokines in the hippocampus of aged rats [60]. Microglia are the main source of cytokines in the ageing brain [61], hence are likely to be responsible. Voluntary exposure to the running wheel for 8 weeks attenuated microglial proliferation in the hippocampus of aged mice [62], whereas running for 10 weeks reduced microglial reactivity in the hippocampus and other brain regions of aged rats [63]. Aged mice show greater expression of reactivity markers CD68 and MHCII; exposure of aged females to physical activity decreased densities of CD68 + and MHCII + microglia in the hippocampus, whereas in males CD68 + microglia decreased and MHCII + microglia increased in hippocampus [63]. These data suggest that the effects of physical exercise on microglial immunological profiles vary with age, sex and brain region, probably reflecting microglial heterogeneity. Treadmill exercise for 10 days attenuated cognitive decline and reduced glycolysis, glycolytic capacity, and PFKB3 enzyme in aged mice; similarly, senescent markers such as β-galactosidase and P16INK4A, were also reduced suggesting the exercise-related improved cognition is orchestrated by a normalisation of the metabolic profile and functionality of microglia [64].

Physical exercise-induced microglial plasticity contributes to neuroprotection in neurodegenerative diseases. In the APP/PS1 mice Alzheimer`s disease (AD) model, twelve weeks of treadmill exercise decreased β-amyloid deposits and improved cognitive processes possibly through hippocampal microglia modulation [65]. Treadmill exercise improved cognitive performance including spatial learning and exploratory activity, and reduced β-amyloid deposits and microglial reactivity [66]. In the Tg2576 mice AD model, three weeks of voluntary wheel running significantly reduced hippocampal levels of IL-1β and TNF-α and decreased soluble β-amyloid40 as well as soluble fibrillar β-amyloid [67]. These results indicate that physical exercise can shift the immune response in the brain of an AD mouse model by transforming microglia to an antigen presenting phenotype, thus reducing β-amyloid burden, alleviating AD pathology and improving cognition [67].

In a Parkinson`s disease (PD) MPTP mouse model, treadmill exercise for 4 weeks ameliorated dopaminergic neuronal loss by suppressing microglial reactivity, preventing loss of nigrostriatal neurones and improving motor balance and coordination dysfunction [68]. In 6-hydroxydopamine PD rat model running wheel exercise for four weeks suppressed microglia reactivity and partially prevented neuronal damage and cognitive decline [69]. This potent modulation of microglia, which have a significant neuroprotective role in the PD brain [70], highlights microglia as a key cellular element translating beneficial effects of physical exercise in PD.

Physical exercise and related microglial changes seem to protect the CNS in the experimental autoimmune encephalomyelitis model induced by transfer of encephalitogenic T-cells. High-intensity six-week continuous treadmill training reduced microglia reactive oxygen species formation, neurotoxicity and pro-inflammatory response, which are all involved in the propagation of autoimmune neuroinflammation [71].

Environmental enrichment

Environmental enrichment is defined as a brain stimulating environment composed by physical (such as puzzle boxes, toys, numerous feeders, ropes and running wheels) and social (relationships with peers) elements [72]. In humans, environmental enrichment corresponds to intellectual, social and physical engagement, which contributes to cognitive longevity [73]. Exposure to enriched environment results in well characterised beneficial effects on the CNS including boosting adult neurogenesis, synaptic plasticity, cellular physiology, and remodelling of neuroglia resulting in cognitive improvements and acceleration of neurological recovery following insults of various aetiology (Table 2) [31, 72, 74,75,76,77].

Table 2 Effects of enriched environment on microglia
Full size table

Environmental enrichment affects microglial densities. When 3-, 8- and 13-month-old C57BL/6 wild-type mice have been subjected to seven weeks of enriched environment, running wheel or combination of both, the density of Iba1 positive microglia in hippocampus increased. Enriched environment alone appeared to be more effective in increasing Iba1-labelled microglia; physical exercise on its own or in combination with environmental enrichment affected microglial density only in older animals. [78]. A longer environmental enrichment for 32–48 weeks promotes healthy ageing by reducing microglial expression of pro-inflammatory cytokines and MHCII. At the morphological level, environmental enrichment leads to microglial hypertrophy and increased ramification in hippocampus, hypothalamus and amygdala without changing microglial density [79]. In LPS-injection model of neuroinflammation, subjecting rats to enriched environment for 12 h/day for 7 weeks caused significant reduction of microglial reactivity with decreased expression of chemokines including Ccl2, Ccl3, Cxcl2, and cytokines including TNF-α and IL-1β [80].

Similarly, in the context of AD model, animals` exposure to the enriched environment boosts neuroprotection, which is, at least in part, associated with changes in microglia. In particular, exposure to enriched environment protected against direct β-amyloid toxicity through alleviating microglial reactivity, increasing microglial morphological complexity and decreasing expression of inflammatory cytokines such as IL-1β and TNF-α [81]. The underlying mechanism connecting environmental stimulation to the status of microglia is represented by an increased noradrenergic stimulation of the brain. This effect is mediated through activation of β-adrenoceptors: feeding mice with β-adrenergic agonist isoproterenol mimicked effects of environmental enrichment, whereas treating mice undergoing enriched environment with the β-adrenergic antagonist propranolol inhibited positive effect of environmental stimulation. This effect was also absent in transgenic animals lacking β1,2 adrenoceptors [82].

In the APP/PS1 mice AD model, environment enrichment for six weeks starting from 12 months of age, improved short-term memory, reduced microglial reactivity while increasing microglia phagocytic activity; the β-amyloid burden however remained unaffected [83]. Similarly, increased microglial phagocytic activity has been observed in 5xFAD AD mouse model subjected to six weeks of enriched environment as compared with animals in standard environment. In addition, exposure to environmental stimulation rescued adult neurogenesis and memory deficits simultaneously preventing β-amyloid dissemination [84]. An increase in microglial phagocytosis activity following exposure to enriched environment may also improve physiological ageing, known to suppress microglial phagocytic machinery [85].

Exposure to enriched environment does not always enhance microglial profiles. Systemic non-neurotropic dengue virus infection, for example, results in an increased size and complexity of microglia; exposure to the enriched environment reduced microglial diversity in lateral septum, with significant correlation between morphological complexity and the levels of TNF-α in the circulation [86]. At the same time, sedentary lifestyle negatively impacted on microglial reactivity, thus diminishing microglial neuroprotection [87]. Similar loss of morphological diversity occurs in the molecular layer of dentate gyrus in mice housed in long-term enriched environment, suggesting different microglial morphotypes may have different physiological roles in various environments, and that long-term enriched environment may be associated with adaptive microglial response to cognitive stimuli [88]. In Piry rhabdovirus model of encephalitis, mice exposed to enriched environment presented less CNS infection and substantially faster virus clearance, less microgliosis and less damage to the extracellular matrix than animals housed in standard environment [89]. In cocal virus infection, mice dwelling in standard environment demonstrated significant weight loss and higher mortality as compared with animals exposed to environmental stimulation. Additionally, enriched environment led to better locomotor and exploratory activity associated with less neuroinvasion and reduced microglial reactivity, revealing that enriched environment drives a more effective immune response in a mouse model of virus encephalitis [90].

In type 1 diabetic rats, enriched environment reduced microglial reactivity, improved memory and ameliorated cognitive comorbidities associated with diabetes [91]. Environmental stimulation also shapes microglial plasticity in glioma: glioma-bearing mice exposed to environmental stimulation have increased branching and patrolling activity of microglia, besides increased phagocytic activity [92].

Diet

Healthy diet, especially being applied in combination with other modifiable lifestyle factors discussed above, emerges as a promising strategy for preventing cognitive decline and promoting brain health [93, 94]. The adoption of a friendly diet or caloric restriction is positively associated with cognitive performance throughout lifespan, leading to cognitive improvements during infancy, adolescence and adulthood [95,96,97] and preserving cognitive functions in elderly [98]. The mechanisms by which diet affects the brain include modulation of synaptic plasticity, neuroglial support and adult neurogenesis [99]. On the other hand, high-fat diet is associated with obesity and cognitive impairments [100], which induces poor lifestyle choices leading to weight gain in a self-accelerating cycle [101].

Obesity is a world-wide concern which affects millions of people and represents an important risk factor for neurological disorders [102]. It is often caused by high-fat intake [103] and it is associated with impaired cognitive functions, neurodegenerative pathologies and atrophy in many brain areas including frontal lobe, anterior cingulate gyrus, hippocampus and hypothalamus [104]. Detrimental effects of high-fat diet on the brain include synaptic loss and microglial reactivity [105], the latter playing multiple roles in damaging the brain and affecting cognition [106,107,108]. On the other hand, the adoption of friendly low-fat diet rich in plant foods, moderate intake of fish, poultry and wine, and low intake of fat and red and processed meat promotes microglia-dependent neuroprotection through mitigating microglia-mediated brain disturbance [109].

Microglial appearance and functional activities are strongly affected by diet (Table 3); microglial changes contribute to brain response to both high-fat detrimental and low-fat friendly dieting. In Yucatan minipigs, for example, maternal high-fat diet during gestation and lactation modifies offspring's microglial density and morphology. These alterations occurred differently in hippocampus and prefrontal cortex; in the prefrontal cortex microglial density increased whereas in the hippocampus it remained unchanged compared to standard diet group; at a morphological level, anterior prefrontal cortex, dorsolateral prefrontal cortex and hippocampus presented higher number of unipolar microglia whereas orbitofrontal cortex presented higher number of multipolar microglia, both compared to standard diet group in hippocampus [110]. This brain region-dependent microglial response induced by high-fat diet is also observed in humans. Post-mortem analysis of the brain tissue obtained from obese individuals (body mass index, BMI, > 30) revealed increased microglial proliferation and morphological changes indicative of microglial reactivity (enlarged cell bodies and shortened processes) in the hypothalamus as compared with normal individuals (BMI < 25). At the same time in the cortex microglia kept physiological morphology (small cell bodies and ramified processes) in both obese and non-obese individuals [111].

Table 3 Effects of diet on microglia
Full size table

Distinct microglial response depends on the length of dieting. Hypothalamic microglia from mice fed with high-fat diet for 3 days upregulated expression of pro-inflammatory mediators including IL-1β, Cd74, Irf8 and IL-6. However, keeping the same mice on high-fat diet for eight weeks reduced expression of pro-inflammatory mediators and increased expression of anti-inflammatory molecules such as IL-10 and Pparg [111]. Early exposure (at postnatal days 21–60) of mice to a high-fat diet, triggered reactive microgliosis with increased expression of IL-1β and TNF-α, reduced neurogenesis and promoted immature morphology of dendritic spines along with reduced levels of scaffold protein Shank2 suggesting defective connectivity. In addition, these animals demonstrated cognitive impairment with spatial memory alterations [112]. Incubation of primary cultured microglia with palmitate, a saturated fatty acid present in high fat diet led to a secretion of exosomes which induced immature dendritic spine phenotype [112].

Similar changes were observed in mice fed with high-fat diet for eight weeks: animals showed reduced presence of synaptic markers, altered microglial morphology and cognitive disruption [105]. Recently, the mechanisms underlying obesity-associated cognitive decline were found to be influenced by reactive microglia. High-fat diet for 18 weeks made mice obese, which was associated with decreased dendritic spine density, increased microglial reactivity, increased microglial phagocytosis of synapses, which ultimately provoked cognitive impairment [106]. Reducing microglial reactivity with: (i) partial knockdown of fractalkine receptor CX3CR1; (ii) minocycline treatment, or (iii) annexin-V treatment prevented obesity-associated cognitive impairment. These data highlight microglial contribution to the synaptic loss and cognitive impairment associated with obesity [106].

In ageing, exposure to high-fat diet triggers reactive microgliosis in mice and in an APP/PS1 mouse model of amyloidosis [113]. Certain evidence indicates that even short-term consumption of high-fat diet may trigger cognitive deficits [114], although it remains doubtful whether this may be translated to humans. It has been suggested that the detrimental diet disrupts the ageing process by worsening the impact of ageing on microglial function and morphology, priming microglia in brain areas important for cognitive functions including hippocampus and amygdala [115, 116].

Appropriate diet therefore is critical for the brain performance and cognitive capabilities. In this context, diet-dependent modulation of microglia emerges as a non-pharmacological and non-invasive strategy to improve cognition and prolong cognitive longevity (Table 3) [117, 118]. Caloric restriction, in particular, protects the brain from age-dependent diseases and prolongs cognitive longevity [119,120,121,122]. Caloric restriction in combination with low-fat diet abolished age-dependent increase in Iba1 immunoreactivity, microglial density and expression of phagocytic marker Mac-2 in the white matter tract of hippocampus, the fimbria [123]. Caloric restriction for 6–12 months at 70% of ad libitum food intake has been shown to alleviate age-dependent dystrophic changes in microglia, manifested by decreased Ca2+ signalling and disorganised motility of microglial processes [124]. Combining the low-fat diet with caloric restriction reduced white matter microglial reactivity during ageing, modulating their morphology and reducing phagocytic markers [123]. Since microglial dystrophy is critical for ageing-induced brain dysfunction and cognitive decline, caloric restriction emerges as a non-pharmacological, cost-effective, and clinically relevant microglial modulator for rejuvenation of microglia.

Healthy diet with high content of flavonoids and phenolic compounds, present in plants, vegetables, and wine, protects cognition in subjects aged 65 or older. After 10 year`s follow up, individuals with highest flavonoids intake presented better cognitive performance compared with individuals with lowest intake: on average Mini-Mental State Examination score loss was 2.1 points in the latter, whereas in the former the score loss was only 1.2 points [125]. Polyphenol-rich diet is similarly associated with cognitive improvements in elderly [126]. Flavonoids and phenolic compounds are well known for their ability to affect microglial status, in particular by reducing microglial reactivity and restoring microglial homeostatic functions with beneficial influence on cognitive functions with consequent reduction in microglia-derived neuroinflammation and cognitive improvements [127,128,129,130]. Luteolin, a plant derived flavonoid, suppressed expression of pro-inflammatory genes in BV-2 microglia; whereas luteolin consumption significantly improved spatial working memory and reduced expression of inflammatory markers in hippocampi of aged (22–24 months old) mice [131]. Luteolin interacts with several signalling cascades modulating microglial transcriptomic profile and promoting anti-inflammatory and anti-oxidative phenotype, thus strengthening neuroprotection [132]. Similar outcomes were observed in ageing (19–21) months old rats fed with polyphenol rich açaí palm tree pulps; dietary supplementation with pulps of Euterpe oleracea (EO) and Euterpe precatoria (EP) for eight weeks improved working memory as tested by Morris water maze; the EO-supplemented diet, but not an EP one also improved reference memory. Treatment of BV-2 microglial cell line with serum obtained from rats receiving EO or EP rich diet reduced production of nitric oxide (NO) and expression of TNF-α [133].

Blueberries represent another source of polyphenols and anthocyanins well known to improve cognition especially in ageing [134,135,136], reduce microglial reactivity [137, 138], and counterbalance brain dysfunctions induced by high-fat diet [139]. In particular, mice exposed to the diet supplemented with blueberry showed significantly less Iba1 immunoreactivity and lower microglial density, together with higher levels of BDNF and larger number of newborn neurones. The BV-2 microglial cell lines treated with serum collected from mice fed with blueberry produced less NO [139].

Conclusion: mens sana in corpore sana—microglia translate friendly lifestyle into brain health and cognitive longevity

The brain is endowed with remarkable plastic capacity both in structure and cellular functioning, which allows life-long adaptation to the exposome. The adoption of healthy lifestyle including regular exercise, intellectual engagement and friendly diet significantly impacts the brain, affecting different areas at different levels of nervous tissue organisation modulating brain-wide homoeostatic systems such as blood–brain barrier and glymphatic clearance, remodelling cellular networks and modifying molecular cascades in neural and non-neural cells. As a holistic therapy, these lifestyle factors have been associated with improvements in cognitive performance, speedy recovery in the contexts of neurotrauma, stroke and neuroinfections, promoting healthy ageing and arresting or retarding neurodegenerative alterations, which as yet, cannot be managed pharmacologically. Lifestyle challenges, at least in part, are translated through changes in microglial phenotypes, that underlie multiple beneficial adjustments of the nervous tissue (Fig. 2).

Fig. 2
figure 2

Microglia translate lifestyle into the neuroprotection and cognitive longevity. The adoption of friendly lifestyle induces morphological and functional plasticity of microglia, these plastic changes translate, at least in part, intellectual engagement, physical exercise and healthy diets into the brain health through enhanced neuroprotection, neurogenesis, and synaptic plasticity. Images of microglia has been re-drawn from ref [86] with permission

Full size image

Availability of data and materials

Not applicable.

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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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: AGES–Reykjavik Study. J Gerontol A Biol Sci Med Sci. 2010;65:1369–74.

    Article  PubMed  Google Scholar 

  9. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 ageing of the brain. Pflugers Arch. 2021;473:753–74.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 visual cortex of rats reared in complex environments. Brain Res. 1991;540:273–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 Neurosci. 2018;12:950.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Svatkova A, Mandl RC, Scheewe TW, Cahn W, Kahn RS, Hulshoff 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.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  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 brain? Cells. 2019;8.

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 Naffah-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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 through suppressing microglial activation in Parkinson’s disease mice. Life Sci. 2012;91:1309–16.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

  72. McDonald MW, Hayward KS, Rosbergen ICM, Jeffers MS, Corbett D. Is environmental enrichment ready for clinical application in human post-stroke rehabilitation? Front Behav Neurosci. 2018;12:135.

  73. Neupert SD, Growney CM, Zhu X, Sorensen JK, Smith EL, Hannig J. BFF: bayesian, fiducial, and frequentist analysis of cognitive engagement among cognitively impaired older adults. Entropy. 2021;23:428.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Bekinschtein P, Oomen CA, Saksida LM, Bussey TJ. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin Cell Dev Biol. 2011;22:536–42.

    Article  CAS  PubMed  Google Scholar 

  75. Ohline SM, Abraham WC. Environmental enrichment effects on synaptic and cellular physiology of hippocampal neurons. Neuropharmacology. 2019;145:3–12.

    Article  CAS  PubMed  Google Scholar 

  76. Rodriguez JJ, Terzieva S, Olabarria M, Lanza RG, Verkhratsky A. Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice. Cell Death Dis. 2013;4:e678.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Rodriguez JJ, Noristani HN, Olabarria M, Fletcher J, Somerville TD, Yeh CY, Verkhratsky A. Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res. 2011;8:707–17.

    Article  CAS  PubMed  Google Scholar 

  78. Singhal G, Morgan J, Corrigan F, Toben C, Jawahar MC, Jaehne EJ, Manavis J, Hannan AJ, Baune BT. Short-Term Environmental enrichment is a stronger modulator of brain glial cells and cervical lymph node T cell subtypes than exercise or combined exercise and enrichment. Cell Mol Neurobiol. 2021;41:469–86.

    Article  CAS  PubMed  Google Scholar 

  79. Ali S, Liu X, Queen NJ, Patel RS, Wilkins RK, Mo X, Cao L. Long-term environmental enrichment affects microglial morphology in middle age mice. Aging (Albany NY). 2019;11:2388–402.

    Article  CAS  Google Scholar 

  80. Williamson LL, Chao A, Bilbo SD. Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus. Brain Behav Immun. 2012;26:500–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Xu H, Gelyana E, Rajsombath M, Yang T, Li S, Selkoe D. Environmental enrichment potently prevents microglia-mediated neuroinflammation by human amyloid beta-protein oligomers. J Neurosci. 2016;36:9041–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Xu H, Rajsombath MM, Weikop P, Selkoe DJ. Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloid-β. EMBO Mol Med. 2018;10:e8931.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Stuart KE, King AE, King NE, Collins JM, Vickers JC, Ziebell JM. Late-life environmental enrichment preserves short-term memory and may attenuate microglia in male APP/PS1 mice. Neuroscience. 2019;408:282–92.

    Article  CAS  PubMed  Google Scholar 

  84. Ziegler-Waldkirch S, d’Errico P, Sauer J-F, Erny D, Savanthrapadian S, Loreth D, Katzmarski N, Blank T, Bartos M, Prinz M, et al. Seed-induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer’s disease. EMBO J. 2018;37:167–82.

    Article  CAS  PubMed  Google Scholar 

  85. Koellhoffer EC, McCullough LD, Ritzel RM. Old maids: aging and its impact on microglia function. Int J Mol Sci. 2017;18:769.

    Article  PubMed Central  CAS  Google Scholar 

  86. Gomes GF, Peixoto R, Maciel BG, Santos KFD, Bayma LR, Feitoza Neto PA, Fernandes TN, de Abreu CC, Casseb SMM, de Lima CM, et al. Differential microglial morphological response, TNFalpha, and viral load in sedentary-like and active murine models after systemic non-neurotropic dengue virus infection. J Histochem Cytochem. 2019;67:419–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Carvalho-Paulo D, Bento Torres Neto J, Filho CS, de Oliveira TCG, de Sousa AA, dos Reis RR, dos Santos ZA, de Lima CM, de Oliveira MA, Said NM et al. Microglial morphology across distantly related species: phylogenetic, environmental and age influences on microglia reactivity and surveillance states. Front Immunol. 2021;12.

  88. de Oliveira TCG, Carvalho-Paulo D, de Lima CM, de Oliveira RB, Santos Filho C, Diniz DG, Bento Torres Neto J, Picanço-Diniz CW. Long-term environmental enrichment reduces microglia morphological diversity of the molecular layer of dentate gyrus. Eur J Neurosc. 2020.

  89. de Sousa AA, Reis R, Bento-Torres J, Trévia N, Lins NAdA, Passos A, Santos Z, Diniz JAP, Vasconcelos PFdC, Cunningham C et al. Influence of enriched environment on viral encephalitis outcomes: behavioral and neuropathological changes in albino swiss mice. PLOS ONE. 2011;6:e15597.

  90. Freitas P, Lima AVL, Carvalho KGB, Cabral TDS, Farias AM, Rodrigues APD, Diniz DG, Picanco Diniz CW, Diniz Junior JAP. Limbic encephalitis brain damage induced by cocal virus in adult mice is reduced by environmental enrichment: neuropathological and behavioral studies. Viruses. 2020;13.

  91. Piazza FV, Segabinazi E, Centenaro LA, do Nascimento PS, Achaval M, Marcuzzo S. Enriched environment induces beneficial effects on memory deficits and microglial activation in the hippocampus of type 1 diabetic rats. Metabolic Brain Dis. 2014;29:93–104.

  92. Garofalo S, Porzia A, Mainiero F, Di Angelantonio S, Cortese B, Basilico B, Pagani F, Cignitti G, Chece G, Maggio R et al. Environmental stimuli shape microglial plasticity in glioma. Elife. 2017: 6

  93. Rakesh G, Szabo ST, Alexopoulos GS, Zannas AS. Strategies for dementia prevention: latest evidence and implications. Ther Adv Chronic Dis. 2017;8:121–36.

    Article  PubMed Central  PubMed  Google Scholar 

  94. Baranowski BJ, Marko DM, Fenech RK, Yang AJT, MacPherson REK. Healthy brain, healthy life: a review of diet and exercise interventions to promote brain health and reduce Alzheimer’s disease risk. Appl Physiol Nutr Metab. 2020;45:1055–65.

    Article  PubMed  Google Scholar 

  95. Nyaradi A, Oddy WH, Hickling S, Li J, Foster JK. The relationship between nutrition in infancy and cognitive performance during adolescence. Front Nutr. 2015;2:2.

    Article  PubMed Central  PubMed  Google Scholar 

  96. Isaacs EB, Morley R, Lucas A. Early diet and general cognitive outcome at adolescence in children born at or below 30 weeks gestation. J Pediatr. 2009;155:229–34.

    Article  PubMed  Google Scholar 

  97. McEvoy CT, Hoang T, Sidney S, Steffen LM, Jacobs DR Jr, Shikany JM, Wilkins JT, Yaffe K. Dietary patterns during adulthood and cognitive performance in midlife: the CARDIA study. Neurology. 2019;92:e1589–99.

    Article  PubMed Central  PubMed  Google Scholar 

  98. Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, Aggarwal NT. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015;11:1015–22.

    Article  PubMed Central  PubMed  Google Scholar 

  99. Pani G. Neuroprotective effects of dietary restriction: Evidence and mechanisms. Semin Cell Dev Biol. 2015;40:106–14.

    Article  CAS  PubMed  Google Scholar 

  100. Martin AA, Davidson TL. Human cognitive function and the obesogenic environment. Physiol Behav. 2014;136:185–93.

    Article  CAS  PubMed  Google Scholar 

  101. Spyridaki EC, Avgoustinaki PD, Margioris AN. Obesity, inflammation and cognition. Cur Opin Behav Sci. 2016;9:169–75.

    Article  Google Scholar 

  102. Bhat ZF, Morton JD, Mason S, Bekhit AEA, Bhat HF. Obesity and neurological disorders: dietary perspective of a global menace. Crit Rev Food Sci Nutr. 2019;59:1294–310.

    Article  PubMed  Google Scholar 

  103. Hu S, Wang L, Yang D, Li L, Togo J, Wu Y, Liu Q, Li B, Li M, Wang G, et al. Dietary fat, but not protein or carbohydrate, regulates energy intake and causes adiposity in mice. Cell Metab. 2018;28:415-431e414.

    Article  CAS  PubMed  Google Scholar 

  104. Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, Hua X, Leow AD, Toga AW, Thompson PM. Brain structure and obesity. Hum Brain Mapp. 2010;31:353–64.

    PubMed  Google Scholar 

  105. Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN, McEwen BS, Gould E. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA. 2015;112:15731–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Cope EC, LaMarca EA, Monari PK, Olson LB, Martinez S, Zych AD, Katchur NJ, Gould E. Microglia play an active role in obesity-associated cognitive decline. J Neurosci. 2018;38:8889–904.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Miller AA, Spencer SJ. Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav Immun. 2014;42:10–21.

    Article  CAS  PubMed  Google Scholar 

  108. Garcia-Caceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, Horvath TL, Yi CX, Chowen JA, Verkhratsky A, et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019;22:7–14.

    Article  CAS  PubMed  Google Scholar 

  109. Hornedo-Ortega R, de Pablos RM, Cerezo AB, Richard T, Garcia-Parrilla MC, Troncoso AM, Microglia-mediated neuroinflammation and mediterranean diet. In: Preedy VR, Watson RR, editors The mediterranean diet. Elsevier: Amsterdam. 2020

  110. Val-Laillet D, Kanzari A, Guerin S, Randuineau G, Coquery N. A maternal Western diet during gestation and lactation modifies offspring’s microglial cell density and morphology in the hippocampus and prefrontal cortex in Yucatan minipigs. Neurosci Lett. 2020;739:135395.

    Article  CAS  PubMed  Google Scholar 

  111. Baufeld C, Osterloh A, Prokop S, Miller KR, Heppner FL. High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol. 2016;132:361–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Vinuesa A, Bentivegna M, Calfa G, Filipello F, Pomilio C, Bonaventura MM, Lux-Lantos V, Matzkin ME, Gregosa A, Presa J, et al. Early exposure to a high-fat diet impacts on hippocampal plasticity: implication of microglia-derived exosome-like extracellular vesicles. Mol Neurobiol. 2019;56:5075–94.

    Article  CAS  PubMed  Google Scholar 

  113. Graham LC, Harder JM, Soto I, de Vries WN, John SW, Howell GR. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease. Sci Rep. 2016;6:21568.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Spencer SJ, D’Angelo H, Soch A, Watkins LR, Maier SF, Barrientos RM. High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory. Neurobiol Aging. 2017;58:88–101.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Spencer SJ, Basri B, Sominsky L, Soch A, Ayala MT, Reineck P, Gibson BC, Barrientos RM. High-fat diet worsens the impact of aging on microglial function and morphology in a region-specific manner. Neurobiol Aging. 2019;74:121–34.

    Article  CAS  PubMed  Google Scholar 

  116. Butler MJ, Cole RM, Deems NP, Belury MA, Barrientos RM. Fatty food, fatty acids, and microglial priming in the adult and aged hippocampus and amygdala. Brain Behav Immun. 2020;89:145–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Johnson RW. Feeding the beast: can microglia in the senescent brain be regulated by diet? Brain Behav Immun. 2015;43:1–8.

    Article  CAS  PubMed  Google Scholar 

  118. Pena-Altamira E, Petralla S, Massenzio F, Virgili M, Bolognesi ML, Monti B. Nutritional and pharmacological strategies to regulate microglial polarization in cognitive aging and alzheimer’s disease. Front Aging Neurosci. 2017;9:175.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Witte AV, Fobker M, Gellner R, Knecht S, Floel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci USA. 2009;106:1255–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Leclerc E, Trevizol AP, Grigolon RB, Subramaniapillai M, McIntyre RS, Brietzke E, Mansur RB. The effect of caloric restriction on working memory in healthy non-obese adults. CNS Spectr. 2020;25:2–8.

    Article  PubMed  Google Scholar 

  121. Fontana L, Ghezzi L, Cross AH, Piccio L. Effects of dietary restriction on neuroinflammation in neurodegenerative diseases. J Exp Med.2021;218.

  122. Bok E, Jo M, Lee S, Lee BR, Kim J, Kim HJ. Dietary Restriction and Neuroinflammation: A Potential Mechanistic Link. Int J Mol Sci. 2019;20.

  123. Yin Z, Raj DD, Schaafsma W, van der Heijden RA, Kooistra SM, Reijne AC, Zhang X, Moser J, Brouwer N, Heeringa P, et al. Low-fat diet with caloric restriction reduces white matter microglia activation during aging. Front Mol Neurosci. 2018;11:65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Olmedillas Del Moral M, Frohlich N, Figarella K, Mojtahedi N, Garaschuk O. Effect of caloric restriction on the in vivo functional properties of aging microglia. Front Immunol. 2020;11:750.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, Barberger-Gateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol. 2007;165:1364–71.

    Article  CAS  PubMed  Google Scholar 

  126. Valls-Pedret C, Lamuela-Raventos RM, Medina-Remon A, Quintana M, Corella D, Pinto X, Martinez-Gonzalez MA, Estruch R, Ros E. Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J Alzheimers Dis. 2012;29:773–82.

    Article  CAS  PubMed  Google Scholar 

  127. Rangarajan P, Karthikeyan A, Dheen ST. Role of dietary phenols in mitigating microglia-mediated neuroinflammation. Neuromolecular Med. 2016;18:453–64.

    Article  CAS  PubMed  Google Scholar 

  128. Hornedo-Ortega R, Cerezo AB, de Pablos RM, Krisa S, Richard T, Garcia-Parrilla MC, Troncoso AM. Phenolic compounds characteristic of the mediterranean diet in mitigating microglia-mediated neuroinflammation. Front Cell Neurosci. 2018;12:373.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Jang S, Johnson RW. Can consuming flavonoids restore old microglia to their youthful state? Nutr Rev. 2010;68:719–28.

    Article  PubMed  Google Scholar 

  130. Flanagan E, Muller M, Hornberger M, Vauzour D. Impact of flavonoids on cellular and molecular mechanisms underlying age-related cognitive decline and neurodegeneration. Curr Nutr Rep. 2018;7:49–57.

    Article  PubMed Central  PubMed  Google Scholar 

  131. Jang S, Dilger RN, Johnson RW. Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr. 2010;140:1892–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Dirscherl K, Karlstetter M, Ebert S, Kraus D, Hlawatsch J, Walczak Y, Moehle C, Fuchshofer R, Langmann T. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation. 2010;7:3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Carey AN, Miller MG, Fisher DR, Bielinski DF, Gilman CK, Poulose SM, Shukitt-Hale B. Dietary supplementation with the polyphenol-rich acai pulps (Euterpe oleracea Mart and Euterpe precatoria Mart) improves cognition in aged rats and attenuates inflammatory signaling in BV-2 microglial cells. Nutr Neurosci. 2017;20:238–245.

  134. Youdim KA, Shukitt-Hale B, Martin A, Wang H, Denisova NA, Bickford PC, Joseph JA. Short-term dietary supplementation of blueberry polyphenolics: beneficial effects on aging brain performance and peripheral tissue function. Nutr Neurosci. 2000;3:383–97.

    Article  CAS  Google Scholar 

  135. Goyarzu P, Malin DH, Lau FC, Taglialatela G, Moon WD, Jennings R, Moy E, Moy D, Lippold S, Shukitt-Hale B, et al. Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci. 2004;7:75–83.

    Article  PubMed  Google Scholar 

  136. Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ, Bickford PC. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci. 1999;19:8114–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Willis LM, Freeman L, Bickford PC, Quintero EM, Umphlet CD, Moore AB, Goetzl L, Granholm AC. Blueberry supplementation attenuates microglial activation in hippocampal intraocular grafts to aged hosts. Glia. 2010;58:679–90.

    PubMed Central  PubMed  Google Scholar 

  138. Lau FC, Bielinski DF, Joseph JA. Inhibitory effects of blueberry extract on the production of inflammatory mediators in lipopolysaccharide-activated BV2 microglia. J Neurosci Res. 2007;85:1010–7.

    Article  CAS  PubMed  Google Scholar 

  139. Carey AN, Gildawie KR, Rovnak A, Thangthaeng N, Fisher DR, Shukitt-Hale B. Blueberry supplementation attenuates microglia activation and increases neuroplasticity in mice consuming a high-fat diet. Nutr Neurosci. 2019;22:253–63.

    Article  PubMed  Google Scholar 

  140. Wang J, Yue B, Zhang X, Guo X, Sun Z, Niu R. Effect of exercise on microglial activation and transcriptome of hippocampus in fluorosis mice. Sci Total Environ. 2021;760:143376.

    Article  CAS  PubMed  Google Scholar 

  141. Giorgetti E, Panesar M, Zhang Y, Joller S, Ronco M, Obrecht M, Lambert C, Accart N, Beckmann N, Doelemeyer A, et al. Modulation of microglia by voluntary exercise or CSF1R inhibition prevents age-related loss of functional motor units. Cell Rep. 2019;29:1539-1554 e1537.

    Article  CAS  PubMed  Google Scholar 

  142. Lu Y, Dong Y, Tucker D, Wang R, Ahmed ME, Brann D, Zhang Q. Treadmill exercise exerts neuroprotection and regulates microglial polarization and oxidative stress in a streptozotocin-induced rat model of sporadic Alzheimer’s disease. J Alzheimers Dis. 2017;56:1469–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Chabry J, Nicolas S, Cazareth J, Murris E, Guyon A, Glaichenhaus N, Heurteaux C, Petit-Paitel A. Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior. Brain Behav Immun. 2015;50:275–87.

    Article  CAS  PubMed  Google Scholar 

  144. Ehninger D, Wang LP, Klempin F, Romer B, Kettenmann H, Kempermann G. Enriched environment and physical activity reduce microglia and influence the fate of NG2 cells in the amygdala of adult mice. Cell Tissue Res. 2011;345:69–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  145. Gomes GF, Peixoto R, Maciel BG, Santos KFD, Bayma LR, Feitoza Neto PA, Fernandes TN, de Abreu CC, Casseb SMM, de Lima CM, et al. Differential microglial morphological response, TNFα, and viral load in sedentary-like and active murine models after systemic non-neurotropic dengue virus infection. J Histochem Cytochem. 2019;67:419–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  146. Brown SM, Bush SJ, Summers KM, Hume DA, Lawrence AB. Environmentally enriched pigs have transcriptional profiles consistent with neuroprotective effects and reduced microglial activity. Behav Brain Res. 2018;350:6–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK. Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep. 2014;9:2124–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  148. Bosch-Queralt M, Cantuti-Castelvetri L, Damkou A, Schifferer M, Schlepckow K, Alexopoulos I, Lutjohann D, Klose C, Vaculciakova L, Masuda T, et al. Diet-dependent regulation of TGF. Nat Metab. 2021;3:211–27.

  149. Gutierrez-Martos M, Girard B, Mendonca-Netto S, Perroy J, Valjent E, Maldonado R, Martin M. Cafeteria diet induces neuroplastic modifications in the nucleus accumbens mediated by microglia activation. Addict Biol. 2018;23:735–49.

    Article  PubMed  Google Scholar 

  150. Milanova IV, Kalsbeek MJT, Wang XL, Korpel NL, Stenvers DJ, Wolff SEC, de Goede P, Heijboer AC, Fliers E, la Fleur SE, et al. Diet-induced obesity disturbs microglial immunometabolism in a time-of-day manner. Front Endocrinol (Lausanne). 2019;10:424.

    Article  Google Scholar 

Download references

Acknowledgements

No.

Funding

No funding.

Author information

Authors and Affiliations

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

    Marcus Augusto-Oliveira

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

    Alexei Verkhratsky

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

    Alexei Verkhratsky

  4. Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

    Alexei Verkhratsky

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

    Alexei Verkhratsky

Authors
  1. Marcus Augusto-Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexei Verkhratsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Authors contributed equally. Both authors read and approved the final manuscript.

Corresponding authors

Correspondence to Marcus Augusto-Oliveira or Alexei Verkhratsky.

Ethics declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

No completing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Augusto-Oliveira, M., Verkhratsky, A. Lifestyle-dependent microglial plasticity: training the brain guardians. Biol Direct 16, 12 (2021). https://doi.org/10.1186/s13062-021-00297-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13062-021-00297-4

Keywords

  • Microglia
  • Neuroplasticity
  • Enriched environment
  • Physical exercise
  • Lifestyle modifications
  • Diet

Biology Direct

ISSN: 1745-6150

Contact us