Circulating Insulin-Like Growth Factor I Mediates Exercise-Induced Increases in the Number of New Neurons in the Adult Hippocampus
Open accessAbstract
Although the physiological significance of continued formation of new neurons in the adult mammalian brain is still uncertain, therapeutic strategies aimed to potentiate this process show great promise. Several external factors, including physical exercise, increase the number of new neurons in the adult hippocampus, but underlying mechanisms are not yet known. We recently found that exercise stimulates uptake of the neurotrophic factor insulin-like growth factor I (IGF-I) from the bloodstream into specific brain areas, including the hippocampus. In addition, IGF-I participates in the effects of exercise on hippocampal c-fos expression and mimics several other effects of exercise on brain function. Because subcutaneous administration of IGF-I to sedentary adult rats markedly increases the number of new neurons in the hippocampus, we hypothesized that exercise-induced brain uptake of blood-borne IGF-I could mediate the stimulatory effects of exercise on the adult hippocampus. Thus, we blocked the entrance of circulating IGF-I into the brain by subcutaneous infusion of a blocking IGF-I antiserum to rats undergoing exercise training. The resulting inhibition of brain uptake of IGF-I was paralleled by complete inhibition of exercise-induced increases in the number of new neurons in the hippocampus. Exercising rats receiving an infusion of nonblocking serum showed normal increases in the number of new hippocampal neurons after exercise. Thus, increased uptake of blood-borne IGF-I is necessary for the stimulatory effects of exercise on the number of new granule cells in the adult hippocampus. Taken together with previous results, we conclude that circulating IGF-I is an important determinant of exercise-induced changes in the adult brain.
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Exercise increases production of IGF-1 and VEGF, which are linked to angiogenesis and neurogenesis.
“Other researchers have reported exercise-related increased productions of other neurotrophic factors such as insulin-like growth factor 1 and vascular endothelial growth factor, which have been linked with angiogenesis (the growth of new vasculature) and neurogenesis”
From Enrichment Effects on Adult Cognitive Development: Can the Functional Capacity of Older Adults Be Preserved and Enhanced? (2008) · cites this paper as Trejo, Carro, & Torres-Aleman, 2001
The paper reports that exercise increases uptake of circulating IGF-I into the brain and that IGF-I is necessary for exercise-induced increases in new hippocampal neurons (opening section and Discussion; page numbers unavailable). It does not report increased production of IGF-I, or address VEGF or angiogenesis. Thus it supports the IGF-I–neurogenesis link, but not the full claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIGF-1, VEGF and PF4 raise hippocampal neurogenesis in young mice.
“Factors including IGF-1 (ref. 9), VEGF10 and PF4 (ref.11) increase hippocampal neurogenesis in young mice”
From Exercise plasma boosts memory and dampens brain inflammation via clusterin (2021) · cites this paper as [9]
Levels of IGF-1 increase in the circulation in response to physical activity.
“Like BDNF, the levels of IGF-1 increase in the circulation in response to physical activity (521)”
From Lack of Exercise Is a Major Cause of Chronic Diseases (2012) · cites this paper as [521]
Both exercise and systemic infusion of IGF-1 increase new and survivability of BrdU+ cells in the hippocampus, likely signaling through IGF receptors on the luminal side of the brain.
“and both exercise and systemic infusion of IGF-1 increases new and survivability of BrdU+ cells in the hippocampus (323, 521), likely signaling through IGF-receptors located on the luminal side of the brain (323).”
From Lack of Exercise Is a Major Cause of Chronic Diseases (2012) · cites this paper as [521]
Treadmill exercise in rats increases cell proliferation via IGF-1 and cell proliferation and survival in the dentate gyrus.
“Specifically, treadmill exercises in rats increase cell proliferation via insulin-like growth factor-1 (Trejo et al., 2001) and cell proliferation and survival in the dentate gyrus (van Praag, Kempermann, & Gage, 1999b).”
From The influences of environmental enrichment, cognitive enhancement, and physical exercise on brain development: Can we alter the developmental trajectory of ADHD? (2011) · cites this paper as Trejo et al., 2001
Aerobic exercise stimulates the sprouting of new capillaries (angiogenesis) and improves vasculature within the hippocampus in animal models.
“It has been demonstrated in animal models that AE stimulates the sprouting of new capillaries (angiogenesis) and improves vasculature within the hippocampus (Trejo et al., 2001; van Praag et al., 2005).”
From Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment (2016) · cites this paper as Trejo et al., 2001
Inhibition of VEGF or IGF-1 impairs the promotional impact of AE on the rate of neurogenesis and spatial memory performance.
“Indeed, the inhibition of VEGF or IGF-1 has been demonstrated to impair the promotional impact of AE on the rate of neurogenesis (Trejo et al., 2001; Fabel et al., 2003; Ding et al., 2006) and spatial memory performance (Ding et al., 2006).”
From Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment (2016) · cites this paper as Trejo et al., 2001
Up-regulating either VEGF or IGF-1 can stimulate neurogenesis independently of AE.
“Conversely, up-regulating either VEGF or IGF-1 can stimulate neurogenesis independently of AE (Aberg et al., 2000; Carro et al., 2000; Trejo et al., 2001; Cao et al., 2004).”
From Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment (2016) · cites this paper as Trejo et al., 2001
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- Authors
- Trejo, J. L., Carro, E., & Torres-Alemán, I.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- ORCID
- Carro, Eva
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-03-01
- Volume
- 21
- Issue
- 5
- Pages
- 1628-1634
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762955
- OpenAlex
- W2136855986
- Cited by
- 1,017
- References
- 47
- Citations by year
- 2026: 27 · 2025: 29 · 2024: 25 · 2023: 30 · 2022: 34 · 2021: 40 · 2020: 42 · 2019: 48 · 2018: 34 · 2017: 48 · 2016: 50 · 2015: 52 · 2014: 54 · 2013: 45 · 2012: 57
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- insulin-like growth factor I, physical activity, adult hippocampus, adult neurogenesis, granule cells, Fos expression, neurotrophic factors
- MeSH terms
- Animals, Blood-Brain Barrier, Bromodeoxyuridine, Cell Count, Cell Division, Physical Exertion, Hippocampus, Immune Sera, Immunohistochemistry, Insulin-Like Growth Factor I, Male, Neurons, Phenotype, Rats, Wistar, Rats
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