Exercise induction at expression immediate early gene (c-Fos, ARC, EGR-1) in the hippocampus: a systematic review

Rahmi, Upik; Goenawan, Hanna; Sylviana, Nova; Setiawan, Iwan; Putri, Suci Tuty; Andriyani, Septian; Fitriana, Lisna Anisa

doi:10.1590/1980-5764-DN-2023-0015

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Dementia & Neuropsychologia

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View & Review • Dement. neuropsychol. 18 • 2024 • https://doi.org/10.1590/1980-5764-DN-2023-0015 copy

Exercise induction at expression immediate early gene (c-Fos, ARC, EGR-1) in the hippocampus: a systematic review

Indução de exercício físico na expressão do gene precoce imediato (c-Fos, ARC, EGR-1) no hipocampo: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT.

The immediate early gene exhibits activation markers in the nervous system consisting of ARC, EGR-1, and c-Fos and is related to synaptic plasticity, especially in the hippocampus. Immediate early gene expression is affected by physical exercise, which induces direct ARC, EGR-1, and c-Fos expression.

Objective:

To assess the impact of exercise, we conducted a literature study to determine the expression levels of immediate early genes (ARC, c-Fos, and EGR-1).

Methods:

The databases accessed for online literature included PubMed-Medline, Scopus, and ScienceDirect. The original English articles were selected using the following keywords in the title: (Exercise OR physical activity) AND (c-Fos) AND (Hippocampus), (Exercise OR physical activity) AND (ARC) AND (Hippocampus), (Exercise OR physical activity) AND (EGR-1 OR zif268) AND (Hippocampus).

Results:

Physical exercise can affect the expression of EGR-1, c-Fos, and ARC in the hippocampus, an important part of the brain involved in learning and memory. High-intensity physical exercise can increase c-Fos expression, indicating neural activation. Furthermore, the expression of the ARC gene also increases due to physical exercise. ARC is a gene that plays a role in synaptic plasticity and regulation of learning and memory, changes in synaptic structure and increased synaptic connections, while EGR-1 also plays a role in synaptic plasticity, a genetic change that affects learning and memory. Overall, exercise or regular physical exercise can increase the expression of ARC, c-Fos, and EGR-1 in the hippocampus. This reflects the changes in neuroplasticity and synaptic plasticity that occur in response to physical activity. These changes can improve cognitive function, learning, and memory.

Conclusion:

c-Fos, EGR-1, and ARC expression increases in hippocampal neurons after exercise, enhancing synaptic plasticity and neurogenesis associated with learning and memory.

Keywords:
Genes, c-Fos; Hippocampus; Neurons; Exercise

No	Author	Animal population	Type of exercise	Techniques used	Results	Importance
1	Sable et al.¹¹11 Sable HJ, MacDonnchadh JJ, Lee HW, Butawan M, Simpson RN, Krueger KM, et al. Working memory and hippocampal expression of BDNF, ARC, and P-STAT3 in rats : effects of diet and exercise. Nutr Neurosci. 2022;25(8):1609-22. https://doi.org/10.1080/1028415X.2021.1885230 https://doi.org/10.1080/1028415X.2021.18...	Long-Evans Rat (n=28), Two groups (Exercise, Sedentary) DF-Exercise (n=7) DF-Sedentary (n=7) WD-Exercise (n=7) WD-Sedentary (n=7)	Treadmill: 25 m/min, three times/week for 30 min, six weeks	Tissue extraction and Western blotting	↑Protein BDNF, ARC, P-STAT3 in hippocampal	Exercise on Daniel Fast (DF) rats on spatial and neuroprotective working memory (WM) is more effective than on rats fed with the Western diet (WD)
2	O’Leary et al.¹²12 O’Leary JD, Hoban AE, Cryan JF, O’Leary OF, Nolan YM. Differential effects of adolescent and adult-initiated voluntary exercise on context and cued fear conditioning. Neuropharmacology. 2019;145(Pt A):49-58. https://doi.org/10.1016/j.neuropharm.2018.05.007 https://doi.org/10.1016/j.neuropharm.201...	Male Sprague Dawley Rat; Adult (8 weeks-old) and adolescent (4 weeks-old). n=41 (adolescent=20, adult=21) Two groups (Exercise) and (Sedentary control)	Running wheel Open field arena, diameter (90 cm) for seven weeks. Adult running; 3.96 km/day Adolescence running 3.43 km/day	qRT-PCR	↑Ekspresi mRNA ARC, Synaptophysin, BDNF, PSD-95, CREB, TLX, and DCX	Exercise initiated by adolescent rats (4 weeks) can increase mRNA expression as a marker of neural plasticity in the Hippocampus, whereas Exercise in adults does not increase gene expression. However, synaptophysin gene expression in the amygdala increased in adult rats (aged 8 weeks).
3	Sun et al.¹³13 Sun GC, Lee YJ, Lee YC, Yu HF, Wang DC. Exercise prevents the impairment of learning and memory in prenatally phthalate-exposed male rats by improving the expression of plasticity-related proteins. Behav Brain Res. 2021;413:113444. https://doi.org/10.1016/j.bbr.2021.113444 https://doi.org/10.1016/j.bbr.2021.11344...	Sprague Dawley Rat; N=40 Pregnant Rat Disruptor di-(2-ethylhexyl)-phthalate (DEHP), Postnatal (days 22–56) Two groups (Sedentary, Exercise), Postnatal (days 57–65) (open field test, test, Morris Water Maze).	Treadmill. 8 m/min, 30 min/day, seven days/week for four weeks	Western Blott Ellisa	↑BDNF, NMDAR, ARC, and synaptophysin Protein Expression at Hippocampus.	Exercise on rats exposed to Disruptor di-(2-ethylhexyl)-phthalate (DEHP) postnatal days 22–56 and days 57–65 can restore learning and memory disorders.
4	Tsuchida et al.¹⁴14 Tsuchida R, Yamaguchi T, Funabashi D, Koumi Y, Kita I, Nishijima T. Exercise type influences the effect of an acute bout of exercise on hippocampal neuronal activation in mice. Neurosci Lett. 2022;783:136707. https://doi.org/10.1016/j.neulet.2022.136707 https://doi.org/10.1016/j.neulet.2022.13...	Adult male C57BL/6J Mice (4 weeks-old) n=56. At 8 weeks of age, mice; Two groups: Treadmill (n=16) and Rotarod (n=40).	Treadmill (15 m/min (T15) 30 min/day and Rotarod 30 rpm (R30)); diameter of the rod 3.2 cm for five days.	Immunohistochemistry	↑Protein c-Fos.	At an exercise intensity of 15 m/min (T15), it is more effective in increasing hippocampal nerve activation than in rotarod exercise at 30 rpm (R30).
5	Meireles et al.¹⁵15 Meireles LCF, Galvão Jr F, Walker DM, Cechinel LR, Grefenhagen AIS, Andrade G, et al. Exercise modalities improve aversive memory and survival rate in aged rats : role of hippocampal epigenetic modifications. Mol Neurobiol. 2019;56(12):8408-19. https://doi.org/10.1007/s12035-019-01675-w https://doi.org/10.1007/s12035-019-01675...	Male Wistar Rat (n=76); aged 2 and 22 months. Divided into five groups (Sedentary, Aerobic, Acrobatic, Resistance, and Combined)	Treadmill; Low intensity 5 m/min. Resistance training climbing (height 1 m, inclination of 85°) Acrobatic horizontal ladder (100 cm in diameter, 3 cm spaced rungs) Combined exercise modalities; 20-min exercise sessions, three times a week on alternate days, for 12 weeks	Chip	↑mRNA Promoter BDNF, c-Fos, and DNA methyltransferase 3a (Dnmt3a)	Exercise starting at the age of 22 months (aging) has an impact on cognitive decline. Resistance, acrobatic, aerobic, and combined modalities were able to enhance epigenetic (H3K9ac, H3K4me3, H4K8ac) and repressive (H3K9me2) marker mechanisms and aversive memory performance in aged mice
6	Schoenfeld et al.¹⁶16 Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E. Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. J Neurosci. 2013;33(18):7770-7. https://doi.org/10.1523/JNEUROSCI.5352-12.2013 https://doi.org/10.1523/JNEUROSCI.5352-1...	Adult male C57BL/6 Mice (n=24) (6 weeks of age) Divided in two groups (Exercise=12 and Sedentary=12)	Running wheel (swimming) 5 min, six weeks	Immunohistochemistry	Exercise ↑ protein c-Fos, ARC	In central dentate gyrus, exercise increased the number of new neurons and reduced anxiety behavior. In contrast, in the dorsal dentate gyrus, sedentary and exercised rats showed increased gene expression (c-Fos, ARC). (Interventioh rats experiencing stress while swimming in cold water
7	Keloglan et al.¹⁷17 Keloglan S, Sahin L, Cevik OS. Long-term treadmill exercise upregulated hippocampal learning-related genes without improving cognitive behaviour in socially isolated rats. Folia Morphol (Warsz). 2019;78(4):668-75. https://doi.org/10.5603/FM.a2019.0018 https://doi.org/10.5603/FM.a2019.0018...	Male Wistar Rat; 3 weeks-old; Postnatal days (PNDs) 21–34. n=32 Control (C) n=8; Social Isolation (SI) n=8; Exercised (E) n=8; Social isolation + Exercise (SE) n=8.	Treadmill: direct current shock (0.1–0.15 mA), 20-60 min/days, five days per week, four weeks	RT-PCR	Exercise ↑NMDAR, mRNA Cdk5r, ASCL1. BDNF, Cdk5r, ARC, c-Fos	Long-term treadmill training enhances learning-related genes and neurogenesis without increasing cognitive behavior in socially isolated mice. Exercise can alter brain development, function, and development due to neuropsychiatric disorders.
8	Zielinski et al.¹⁸18 Zielinski MR, Davis JM, Fadel JR, Youngstedt SD. Influence of chronic moderate sleep restriction and exercise training on anxiety, spatial memory, and associated neurobiological measures in mice. Behav Brain Res. 2013;250:74-80. https://doi.org/10.1016/j.bbr.2013.04.038 https://doi.org/10.1016/j.bbr.2013.04.03...	Male C57BL/6J Mice; n=40 Normal sleep + Sedentary, Normal sleep + Exercise, Sleep restriction + Sedentary, and Sleep restriction + Exercise	Treadmill 18–21 m/min, 60 min/day, six days/week, 11 weeks and 5% grade.	Immunohistochemistry.	↑Protein c-Fos, BDNF	Exercise increased memory recall with increased c-Fos positive cells
9	Ransome and Hannan¹⁹19 Ransome MI, Hannan AJ. Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice. Mol Cell Neurosci. 2013;54:93-107. https://doi.org/10.1016/j.mcn.2013.01.005 https://doi.org/10.1016/j.mcn.2013.01.00...	Female and male R6/1 HD transgenic mice, (12 weeks-old); Female wildtype (n=18) and R6/1 HD (n=18) 7 weeks of age control littermates; (n=9 wildtypes; n=9 R6/1 HD), run/enriched littermates (n=9 wildtypes; n=9 R6/1 HD)	Voluntary running 90 min, 7 days, 4 weeks	Immunofluorescence Immunohistochemistry	↑Protein c-Fos	Running induced Akt phosphorylation in the hippocampus of female wildtype mice, which was not reflected in R6/1 HD mice. Running in adult rats caused neurogenesis in the hippocampus
10	Zhong et al.²⁰20 Zhong T, Ren F, Huang CS, Zou WY, Yang Y, Pan YD, et al. Swimming exercise ameliorates neurocognitive impairment induced by neonatal exposure to isoflurane and enhances hippocampal histone acetylation in mice. Neuroscience. 2016;316:378-88. https://doi.org/10.1016/j.neuroscience.2015.12.049 https://doi.org/10.1016/j.neuroscience.2...	Male C57BL/6 Mice; n=294, groups of 12–20 mice	Swimming, water depth 5–15 cm. 5 min, four times/session, every session 30 min, five days/week, four weeks	Immunohistochemistry	↑Protein c-Fos, histone acetylation, CREB) - binding protein (CBP)	There was increased hippocampal acetylation of H3K9, H4K5, and H4K12, an increased number of c-Fos-positive cells one hour after CFC training, and less memory impairment and increased histone acetylation and (CREB)-binding protein (CBP) in rats that underwent exercise regular swimming
11	Cefis et al.²¹21 Cefis M, Prigent-Tessier A, Quirié A, Pernet N, Marie C, Garnier P. The effect of exercise on memory and BDNF signaling is dependent on intensity. Brain Struct Funct. 2019;224(6):1975-85. https://doi.org/10.1007/s00429-019-01889-7 https://doi.org/10.1007/s00429-019-01889...	Wistar Rat, 10-week-old; n=69 Two groups: SED (sedentary), Exercise (EX12, EX18)	Treadmill Low-intensity exercise (12 m/min, EX12), High-intensity (18 m/min, EX18), 30 min/day, one week	Western Blotting	↑Protein c-Fos, BDNF, Synaptophysin	High-intensity exercise (E18) improves memory performance compared to low intensity (EX12) and sedentary.
12	Tsai et al.²²22 Tsai SF, Wen YW, Kuo YM. Acute and long-term treadmill running differentially induce c-Fos expression in region- and time- dependent manners in mouse brain. Brain Struct Funct. 2019;224(8):2677-89. https://doi.org/10.1007/s00429-019-01926-5 https://doi.org/10.1007/s00429-019-01926...	6-week-old Mice; n=30 Four groups: 1-day single-bout (Acute Exercise); Without Exercise (Basal); Exercise for one hour (E1h); and Exercise for one hour and rest at the home cage for two hours (E1hR2h)	Treadmill - Acute exercise; 10 m/min, 60 min - Long-time exercise: 10 m/min for 20–60 min/day, five days/week, four weeks	Immunohistochemistry Western Blott	↑Protein c-Fos	Acute exercise caused increased c-Fos+ cell density in the ventral hip hippocampal CA1 region, primary somatosensory cortex, other hippocampal subregions, and striatum Long-term exercise increased c-Fos+ cell density in the striatum, primary somatosensory, primary and secondary motor cortex, hippocampal subregion, hypothalamic nucleus, and lateral periaqueductal gray
13	Belviranlı and Okunda²³23 Belviranlı M, Okudan N. Exercise training protects against aging-induced cognitive dysfunction via activation of the hippocampal PGC-1α/FNDC5/BDNF pathway. Neuromolecular Med. 2018;20(3):386-400. https://doi.org/10.1007/s12017-018-8500-3 https://doi.org/10.1007/s12017-018-8500-...	Female Wistar rats (aged 3 months) and (aged 20 months); n= 30 Four groups: Control (Yc, n=8); Young Exercise (Yt, n=8); Aged control (AC, n=7); and Aged Exercise (AT, n=7).	Running wheel, 90 days	Western Blott	↑mRNA BDNF, FNDC5, PGC-1α, mTOR, ARC, c-Fos, ERK, SIRT, dan FOXO	Exercise training improved spatial learning and memory in aged rats

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E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[1] Correspondence: Upik Rahmi; Email: upikrahmi@upi.edu.