Exercise training improves long-term memory in obese mice

Abstract

Obesity has been linked to a range of pathologies, including dementia. In contrast, regular physical activity is associated with the prevention or reduced progression of neurodegeneration. Specifically, physical activity can improve memory and spatial cognition, reduce age-related cognitive decline, and preserve brain volume, but the mechanisms are not fully understood. Accordingly, we investigated whether any detrimental effects of high-fat diet (HFD)-induced obesity on cognition, motor behavior, adult hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) could be mitigated by voluntary exercise training in male C57Bl/6 mice. HFD-induced impairment of motor function was not reversed by exercise. Importantly, voluntary wheel running improved long-term memory and increased hippocampal neurogenesis, suggesting that regular physical activity may prevent cognitive decline in obesity.

Keywords

obesity / exercise / cognition

References

[1] Livingston G, Huntley J, Sommerlad A et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet (London, England) 2020; 396: 413- 46.

[2] Van Gaal LF, Mertens IL, Christophe E. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444: 875- 80.

[3] Manson JE, Skerrett PJ, Greenland P et al. The escalating pandemics of obesity and sedentary lifestyle: a call to action for clinicians. Arch Intern Med 2004; 164: 249- 58.

[4] Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 2019; 15: 288- 98.

[5] Lewis AR, Singh S, Youssef FF. Cafeteria-diet induced obesity results in impaired cognitive functioning in a rodent model. Heliyon 2019; 5: e01412.

[6] Jurdak N, Lichtenstein AH, Kanarek RB. Diet-induced obesity and spatial cognition in young male rats. Nutr Neurosci 2008; 11: 48- 54.

[7] Elias MF, Elias PK, Sullivan LM et al. Obesity, diabetes and cognitive deficit: the Framingham Heart Study. Neurobiol Aging 2005; 26: 11- 6.

[8] Hassing LB, Dahl AK, Pedersen NL et al. Overweight in midlife is related to lower cognitive function 30 years later: a prospective study with longitudinal assessments. Dement Geriatr Cogn Disord 2010; 29: 543- 52.

[9] Francis HM, Stevenson RJ. Higher reported saturated fat and refined sugar intake is associated with reduced hippocampal-dependent memory and sensitivity to interoceptive signals. Behav Neurosci 2011; 125: 943- 55.

[10] Akbaraly T, Sexton C, Zsoldos E et al. Association of long-term diet quality with hippocampal volume: longitudinal cohort study. Am J Med 2018; 131: 1372- 81.e4.

[11] Jacka FN, Cherbuin N, Anstey KJ et al. Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med 2015; 13: 215.

[12] Stojakovic A, Mastronardi CA, Licinio J et al. Long-term consumption of high-fat diet impairs motor coordination without affecting the general motor activity. J Transl Sci 2018; 5: 1- 10.

[13] Li L, Wang Z, Zuo Z. Chronic intermittent fasting improves cognitive functions and brain structures in mice. PLoS One 2013; 8: e66069.

[14] Ronan L, Alexander-Bloch AF, Wagstyl K et al. Obesity associated with increased brain age from midlife. Neurobiol Aging 2016; 47: 63- 70.

[15] Sui SX, Ridding MC, Hordacre B. Obesity is associated with reduced plasticity of the human motor cortex. Brain Sci 2020; 10: 579.

[16] Boitard C, Cavaroc A, Sauvant J et al. Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav Immun 2014; 40: 9- 17.

[17] Erion JR, Wosiski-Kuhn M, Dey A et al. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci 2014; 34: 2618- 31.

[18] Nakandakari SCBR, Munoz VR, Kuga GK et al. Short-term highfat diet modulates several inflammatory, ER stress, and apoptosis markers in the hippocampus of young mice. Brain Behav Immun 2019; 79: 284- 93.

[19] Hou J, Jeon B, Baek J et al. High fat diet-induced brain damaging effects through autophagy-mediated senescence, inflammation and apoptosis mitigated by ginsenoside F1-enhanced mixture. J Ginseng Res 2022; 46: 79- 90.

[20] Whiteman AS, Young DE, Budson AE et al. Entorhinal volume, aerobic fitness, and recognition memory in healthy young adults: a voxel-based morphometry study. Neuroimage 2016; 126: 229- 38.

[21] Erickson KI, Voss MW, Prakash RS et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 2011; 108: 3017- 22.

[22] Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med 2009; 39: 3- 11.

[23] Eisinger BE, Zhao X. Identifying molecular mediators of environmentally enhanced neurogenesis. Cell Tissue Res 2018; 371: 7- 21.

[24] Sorrells SF, Paredes MF, Cebrian-Silla A et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 2018; 555: 377- 81.

[25] Llorens-Martín M. Adult-born neurons in brain circuitry. Science 2019; 364: 530.

[26] Franjic D, Skarica M, Ma S et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 2022; 110: 452- 69.

[27] Van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999; 2: 266- 70.

[28] Van Praag H. Neurogenesis and exercise: past and future directions. Neuromolecular Med 2008; 10: 128- 40.

[29] Rauskolb S, Zagrebelsky M, Dreznjak A et al. Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth. J Neurosci 2010; 30: 1739- 49.

[30] Li Y, Yui D, Luikart BW et al. Conditional ablation of brain-derived neurotrophic factor-TrkB signaling impairs striatal neuron development. Proc Natl Acad Sci USA 2012; 109: 15491- 6.

[31] Neeper SA, Góauctemez-Pinilla F, Choi J et al. Exercise and brain neurotrophins. Nature 1995; 373: 109.

[32] Marlatt MW, Potter MC, Lucassen PJ et al. Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol 2012; 72: 943- 52.

[33] Zajac M, Pang T, Wong N et al. Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington’s disease mice. Hippocampus 2010; 20: 621- 36.

[34] Sleiman SF, Henry J, Al-Haddad R et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 2016; 5: e15092.

[35] Araya A, Orellana X, Godoy D et al. Effect of exercise on circulating levels of brain-derived neurotrophic factor (BDNF) in overweight and obese subjects. Horm Metab Res 2013; 45: 541- 4.

[36] Rodriguez AL, Whitehurst M, Fico BG et al. Acute high-intensity interval exercise induces greater levels of serum brain-derived neurotrophic factor in obese individuals. Exp Biol Med 2018; 243: 1153- 60.

[37] Chiazza F, Bondi H, Masante I et al. Short high fat diet triggers reversible and region specific effects in DCX⁺ hippocampal immature neurons of adolescent male mice. Sci Rep 2021; 11: 21499.

[38] Bernardino L, Agasse F, Silva B et al. Tumor necrosis factor-α modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures. Stem Cells 2008; 26: 2361- 71.

[39] Arnett HA, Mason J, Marino M et al. TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 2001; 4: 1116- 22.

[40] de Paula GC, Brunetta HS, Engel DF et al. Hippocampal function is impaired by a short-term high-fat diet in mice: increased blood-brain barrier permeability and neuroinflammation as triggering events. Front Neurosci 2021; 15: 734158.

[41] Dinel AL, Andre C, Aubert A et al. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome. PLoS One 2011; 6: e24325.

[42] Iosif RE, Ekdahl CT, Ahlenius H et al. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci 2006; 26: 9703- 12.

[43] Ohyagi Y, Asahara H, Chui DH et al. Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB J 2005; 19: 1- 29.

[44] Horvath TL, Sarman B, García-Cáceres C et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA 2010; 107: 14875- 80.

[45] Thaler JP, Yi CX, Schur EA et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012; 122: 153- 62.

[46] Kim JD, Yoon NA, Jin S et al. Microglial UCP2 mediates inflammation and obesity induced by high-fat feeding. Cell Metab 2019; 30: 952- 62.e5.

[47] Valdearcos M, Robblee MM, Benjamin DI et al. Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 2014; 9: 2124- 38.

[48] André C, Guzman-Quevedo O, Rey C et al. Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation. Diabetes 2017; 66: 908- 19.

[49] Lee MH, Kim H, Kim SS et al. Treadmill exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal dentate gyrus of gerbils. Life Sci 2003; 73: 2455- 65.

[50] Fang G, Zhao J, Li P et al. Long-term treadmill exercise inhibits neuronal cell apoptosis and reduces tau phosphorylation in the cerebral cortex and hippocampus of aged rats. Sci Bull 2017; 62: 755- 7.

[51] Do K, Laing BT, Landry T et al. The effects of exercise on hypothalamic neurodegeneration of Alzheimer’s disease mouse model. PLoS One 2018; 13: e0190205.

[52] Pitts MW. Barnes maze procedure for spatial learning and memory in mice. Bio Protoc 2018; 8: e2744.

[53] Yadang FSA, Nguezeye Y, Kom CW et al. Scopolamine-induced memory impairment in mice: neuroprotective effects of Carissa edulis (Forssk) Valh (Apocynaceae) aqueous extract. IJADR 2020; 2020: 6372059.

[54] Inoue T, Ikegami R, Takamatsu Y et al. Temporal dynamics of brain BDNF expression following a single bout of exercise: a bioluminescence imaging study. Neurosci Lett 2023; 799: 137120.

[55] Ito D, Imai Y, Ohsawa K et al. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 1998; 57: 1- 9.

[56] Robison LS, Albert NM, Camargo LA et al. High-fat diet-induced obesity causes sex-specific deficits in adult hippocampal neurogenesis in mice. eNeuro 2020; 7: ENEURO.0391- 19.2019.

[57] Dong J, Pan YB, Wu XR et al. A neuronal molecular switch through cell-cell contact that regulates quiescent neural stem cells. Sci Adv 2019; 5: eaav4416.

[58] Sah N, Peterson BD, Lubejko ST et al. Running reorganizes the circuitry of one-week-old adult-born hippocampal neurons. Sci Rep 2017; 7: 10903.

[59] Trinchero MF, Buttner KA, Cuevas JNS et al. High plasticity of new granule cells in the aging hippocampus. Cell Rep 2017; 21: 1129- 39.

[60] Snyder JS, Glover LR, Sanzone KM et al. The effects of exercise and stress on the survival and maturation of adult-generated granule cells. Hippocampus 2009; 19: 898- 906.

[61] Tapia-Rojas C, Aranguiz F, Varela-Nallar L et al. Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer’s disease. Brain Pathol 2016; 26: 62- 74.

[62] Kobilo T, Liu QR, Gandhi K et al. Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learn Mem 2011; 18: 605- 9.

[63] Ke HC, Huang HJ, Liang KC et al. 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.

[64] Wolf SA, Kronenberg G, Lehmann K et al. Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biol Psychiatry 2006; 60: 1314- 23.

[65] Maliszewska-Cyna E, Xhima K, Aubert I. A comparative study evaluating the impact of physical exercise on disease progression in a mouse model of Alzheimer’s disease. J Alzheimer's Dis 2016; 53: 243- 57.

[66] Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors (Chur, Switzerland) 2004; 22: 123- 31.

[67] Adlard PA, Perreau VM, Engesser-Cesar C et al. The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise. Neurosci Lett 2004; 363: 43- 8.

[68] Berchtold NC, Castello N, Cotman CW. Exercise and time-dependent benefits to learning and memory. Neuroscience 2010; 167: 588- 97.

[69] Matthews VB, Åström M-B, Chan M et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 2009; 52: 1409- 18.

[70] English JD, Sweatt JD. A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 1997; 272: 19103- 6.

[71] Atkins CM, Selcher JC, Petraitis JJ et al. The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1998; 1: 602- 9.

[72] Selcher JC, Atkins CM, Trzaskos JM et al. A necessity for MAP kinase activation in mammalian spatial learning. Learn Mem (Cold Spring Harbor, N.Y.) 1999; 6: 478- 90.

[73] Widegren U, Ryder J, Zierath J. Mitogen-activated protein kinase signal transduction in skeletal muscle: effects of exercise and muscle contraction. Acta Physiol Scand 2001; 172: 227- 38.

[74] Williamson D, Gallagher P, Harber M et al. Mitogen-activated protein kinase (MAPK) pathway activation: effects of age and acute exercise on human skeletal muscle. J Physiol 2003; 547: 977- 87.

[75] Liu W, Wu W, Lin G et al. Physical exercise promotes proliferation and differentiation of endogenous neural stem cells via ERK in rats with cerebral infarction. Mol Med Rep 2018; 18: 1455- 64.

[76] Chen MJ, Russo-Neustadt AA. Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 2009; 19: 962- 72.

[77] Lee SS, Kim CJ, , Shin MS et al. Treadmill exercise ameliorates memory impairment through ERK-Akt-CREB-BDNF signaling pathway in cerebral ischemia gerbils. J Exerc Rehabil 2020; 16: 49- 57.

[78] Wang BZ, Yang JJ, Zhang H et al. AMPK signaling regulates the age-related decline of hippocampal neurogenesis. Aging Dis 2019; 10: 1058- 74.

[79] Lin JY, Kuo WW, Baskaran R et al. Swimming exercise stimulates IGF1/PI3K/Akt and AMPK/SIRT1/PGC1α survival signaling to suppress apoptosis and inflammation in aging hippocampus. Aging (Albany NY) 2020; 12: 6852- 64.

[80] Alosco ML, Spitznagel MB, Raz N et al. Obesity interacts with cerebral hypoperfusion to exacerbate cognitive impairment in older adults with heart failure. Cerebrovasc Dis Extra 2012; 2: 88- 98.

[81] Selim M, Jones R, Novak P et al. The effects of body mass index on cerebral blood flow velocity. Clin Auton Res 2008; 18: 331- 8.

[82] Bourbeau K, Mermier C, Zuhl M et al. Mechanisms of aerobic exercise in attenuating obesity-induced cognitive impairment: a brief review. Obes Med 2023; 39: 100484.

[83] Ferrara PJ, Lang MJ, Johnson JM et al. Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice. Life Metab 2023; 2: load014.

[84] Chen H, Tao Y, Li MD et al. Temporal patterns of energy intake and cognitive function and its decline: a community-based cohort study in China. Life Metab 2022; 1: 94- 7.

[85] Pennington ZT, Dong Z, Feng Y et al. ezTrack: an open-source video analysis pipeline for the investigation of animal behavior. Sci Rep 2019; 9: 19979.

[86] Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protocols 2008; 3: 1101- 8.

[87] Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996; 16: 2027- 33.

[88] García-Moreno A, López-Domínguez R, Ramirez-Mena A et al. GeneCodis 4: expanding the modular enrichment analysis to regulatory elements. bioRxiv 2021.04.15.439962, 2021, preprint: not peer reviewed.

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2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.