1. Context
Aerobic exercise (AE) has important physiological effects on the cardiovascular, respiratory, musculoskeletal, and nervous systems (1). AE increases myelin regeneration, axonal regeneration, brain angiogenesis, myelin sheath thickness, Schwann cell core area, and neurogenesis. These effects may improve sensory and motor function, enhance the survival and differentiation of transplanted stem cells, relieve pain, and improve cognitive function (2-4). With population aging and the increasing number of patients with Alzheimer disease, several studies have investigated the effects of AE on neurogenesis, particularly in the hippocampus. AE can increase neurogenesis and improve cognitive function, especially memory (5-7). Evidence also indicates that neurogenesis occurs in brain regions other than the hippocampus (8-10), including the cerebellum (11).
Brain-derived neurotrophic factor (BDNF) is highly expressed in the hippocampus and cerebellum, regions in which substantial neurogenesis has been reported (12). The cerebellum contributes to movement coordination as well as cognitive, emotional, and reward-related processes (13). Consistent with its role in cognitive function, cerebellar involvement has also been described in nonmotor disorders, including autism spectrum disorder and attention-deficit/hyperactivity disorder (14). Neurogenesis is one mechanism through which AE may affect brain function, and AE is an important stimulus for neurogenesis (15, 16). Aerobic training can promote neurogenesis by increasing the gene and protein expression of neurotrophic factors, particularly BDNF (17, 18). BDNF is among the primary neurodevelopmental factors investigated in relation to physical activity (PA) (18). Exercise-related changes have been reported in BDNF expression in the rodent hippocampus (19, 20), in circulating BDNF levels, and in hippocampal volume (21, 22).
BDNF promotes neurogenesis, neuronal plasticity, neuronal and microglial growth and survival, signal transmission, and the induction and maintenance of synaptic potentiation (23). Its neurotrophic effects may improve cognitive and emotional processes and may reduce the risk of mood disorders, depression, and cognitive impairment (24, 25). Although the effects of AE on hippocampal BDNF and neurogenesis have been widely examined, the cerebellum is also an important target. Therefore, this review focuses on the effects of AE on cerebellar BDNF and the molecular mechanisms that may mediate these effects.
2. Evidence Acquisition
A comprehensive PubMed search was conducted to identify studies examining the effects of AE on BDNF and cerebellar neurogenesis. The literature search was performed between November and December 2024 and included publications from 2000 through 2024. Only original experimental studies conducted in rats or mice and published in English were included; letters and reviews were excluded. Studies that did not evaluate the effects of AE or aerobic training on BDNF gene or protein expression, or on cerebellar neurogenesis, were excluded. Search terms included aerobic exercise, aerobic training, endurance exercise, endurance training, cerebellum, the cerebellum, neurogenesis, brain-derived neurotrophic factor, and BDNF.
3. Results
According to the inclusion and exclusion criteria, 19 PubMed articles investigated the effects of AE on BDNF and neurogenesis. These articles were published between 2002 and 2022. Thirteen studies used rats, 5 used mice, and 1 used BALB/c mice. Eight studies investigated treadmill running, 7 investigated wheel running, 2 used swimming training, 1 used gait training, and 1 examined running on a flat track. No articles meeting the inclusion criteria were published in 2000, 2001, 2023, or 2024.
3.1. Effects of Aerobic Exercise on Cerebellar BDNF
Aerobic exercise alters brain morphology, biochemistry, and behavior (17). Neurogenesis is among the most prominent changes associated with AE and is largely related to increased gene and protein expression of neurotrophic factors, particularly BDNF (26). Most studies reviewed here reported increased cerebellar BDNF after AE; however, findings were not uniform.
Risedal et al. (27) reported no change in cerebellar BDNF expression after wheel running, exposure to an enriched environment, or social housing in rats with cortical infarction, although behavioral performance improved across groups independently of BDNF expression. Johnson et al. (28) reported increased hippocampal BDNF protein expression after voluntary wheel running, but no increase in the spinal cord or cerebellum. In aged rats exposed to D-galactose, light- and moderate-intensity AE for 4 weeks did not change IGF-1 or BDNF levels (29). In a model of incomplete spinal cord injury, AE improved motor function and increased synaptophysin, MAP-2, and BDNF levels in the motor cortex, but not in the cerebellum or spinal cord (30).
Given the role of the cerebellum in movement control, Klintsova et al. (31) assessed the effects of 1 to 14 days of acrobatic training and moderate AE on BDNF and TrkB expression. Both interventions increased expression, and training duration influenced the magnitude of the changes. The effects persisted longer after acrobatic training than after moderate-intensity AE, suggesting that complex motor learning and moderate PA with lower learning demands may have different effects on BDNF and TrkB expression.
Because inflammation and oxidative stress can negatively affect neurogenesis, Toldy et al. (32) examined the combined effects of swimming training and Urtica dioica leaf supplementation, which contains antioxidant and anti-inflammatory compounds, on oxidative stress markers and neurotrophic factors in the cerebellum and frontal lobe. Urtica dioica reduced free-radical production, whereas swimming had no significant effect on oxidative damage. Neither swimming nor Urtica dioica significantly affected NGF or BDNF. Swimming and Urtica dioica increased nuclear factor kappa B DNA-binding activity, whereas activator protein-1 DNA-binding activity increased more markedly. C-Jun levels decreased with swimming. These findings suggest that the antioxidant effects of Urtica dioica may occur independently of neurogenesis and that swimming may contribute to antiapoptotic processes (32).
Consistent with these findings, treadmill running for 20 minutes per day for 2 weeks did not significantly change BDNF content in the hippocampus, cortex, striatum, or cerebellum (33). Because this exercise protocol had neuroprotective effects, BDNF may not be directly involved in all neuroprotective mechanisms induced by AE after ischemia. In rats fed a high-fat diet, combining AE with melatonin inhibited the reduction in cerebellar BDNF and TrkB expression and reduced inflammatory cytokines, whereas training alone and melatonin alone had no significant effect (34).
Intermittent individual housing affects behavior and neurotrophin levels. Zhu et al. (35) studied wheel running in BALB/c mice under different housing conditions and found that intermittent individual housing altered behavior and brain neurotrophin levels; some of these changes were modified by AE. In adolescent rats, voluntary wheel running increased global histone 3 acetylation and BDNF expression in the hippocampus and cerebellum, whereas the expression of DNA methyltransferases and histone deacetylases decreased (36), indicating an epigenetic contribution to exercise-related effects.
In rats exposed to vanadium during lactation, impaired motor coordination and reduced plasma and cerebellar BDNF levels were reported. Five weeks of treadmill running during childhood and adolescence normalized plasma and cerebellar BDNF levels and increased cerebellar TrkB phosphorylation, thereby preventing motor coordination impairment (37). Moderate-intensity AE also reduced Purkinje cell degeneration, delayed motor dysfunction, and increased lifespan in spastic Han Wistar rats, a model of ataxia, in association with increased BDNF and TrkB expression (38).
Chalimoniuk et al. (39) reported that moderate-intensity endurance running increased spontaneous locomotor activity and BDNF and TrkB mRNA in the hippocampus, midbrain, and striatum, but not in the cerebellum or cerebral cortex. In contrast, components of the nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate pathway were altered in several brain regions, including the cerebellum (39). Inoue et al. (40) reported that treadmill exercise 5 days per week increased BDNF protein in the motor cortex and improved motor coordination. The study also reported increased cerebellar BDNF expression, whereas long-term inhibition of GABA receptors reduced BDNF mRNA expression and impaired coordination, suggesting that the duration of GABA receptor inhibition should be considered in clinical studies (40).
BDNF expression is reduced in the dentate gyrus, medial prefrontal cortex, and cerebellum in depression models, and voluntary running increased BDNF expression in these regions (41). In ovariectomized rats, 6 weeks of moderate-intensity interval training increased the number of cerebellar Purkinje cells and downregulated Bax expression. Improvements in motor function were correlated with Bcl-2, Bax, BDNF, synaptophysin, and Pgc-1α mRNA expression and with the number of cerebellar Purkinje cells, suggesting enhanced neurotrophic and neuroprotective signaling (42). Maternal PA increased neurotrophin expression in the cerebellum, cortex, and placenta and was associated with changes related to neural plasticity and cognitive function (43). Forced AE improved motor learning and increased BDNF in a mouse model of early-onset cerebellar degeneration (44). AE also improved ataxia and deficits in cerebellar Purkinje cell firing in mice with spinocerebellar ataxia type 6 after 1 month, supporting a neuroprotective role for exercise in this model (45). Table 1 summarizes the studies examining AE and BDNF in cerebellar tissue.
Table 1.
Summary of Studies Investigating the Effects of Aerobic Exercise on Cerebellar Tissue BDNF a
| Studies | Exercise Protocol | Subjects | Sample | Biomarkers | Findings |
|---|---|---|---|---|---|
| Risedal et al. (2002) (27) | 4 weeks running on the running wheel | cortical infarct rats | contralateral cortex, thalamus, hippocampus and cerebellum | BDNF gene expression | ↔ BDNF gene expression |
| Johnson et al. (2003) (28) | 7 days running on the running wheel | Mice | hippocampal Spinal and cerebellar | BDNF level | ↑ hippocampal BDNF level and ↔ spinal and cerebellar BDNF |
| Partadiredja et al. (2019) (29) | Four weeks, four sessions per week of light- (45% VO2max) and moderate- (55% VO2max) intensity exercise, by running on a treadmill. | Aged rats with D-galactose | cerebellar and serum | BDNF expression | ↔ cerebellar and serum BDNF |
| Ilha et al. (2019) (30) | 4-week overground gait training program | Spinal cord injury rat model | Motor cortex, cerebellum and spinal cord | BDNF expression | ↑ motor cortex and ↔ cerebellum and spinal cord |
| Klintsova et al. (2004) (31) | Fourteen days of moderately paced running on flat track | Rat | Cerebellar molecular layer and upper motor cortical layers | BDNF and TrkB expression | ↑ BDNF and TrkB expression in cerebellar molecular layer; ↑ BDNF and ↔ TrkB in upper motor cortical layers |
| Toldy et al. (2005) (32) | 1.5 h of swimming per day, 5 times/week, for 6 weeks, with Urtica dioica supplementation | Rat | cerebellum | protein BDNF | ↔ cerebellar BDNF protein |
| Cechetti et al. (2008) (33) | 2 weeks of 20 min/day of treadmill training | Rat | Hippocampus, cortex, striatum, and the cerebellum | BDNF levels | ↔ BDNF levels in hippocampus, cortex, striatum, and cerebellum |
| Sugiyama et al. (2020) (34) | 9 weeks of treadmill running, 5 sessions per week | high-fat diet-fed rat | cerebellum | BDNF and TrkB expression | ↑ cerebellar BDNF and TrkB expression with combined aerobic training and melatonin |
| Zhu et al. (2006) (35) | 6 weeks running on a running wheel | BALB/c mice | hippocampus, amygdala and cerebellum | BDNF and NGF levels | Regulating BDNF and NGF levels in hippocampus, amygdala and cerebellum |
| Abel et al. (2013) (36) | 1 week running on a running wheel | Mice (male, female) | Hippocampus cerebellum | BDNF expression | ↑ hippocampal and cerebellar BDNF expression |
| Wang et al. (2015) (37) | 5 weeks running on the treadmill | Rat | cerebellar and serum | BDNF level | Normalization of plasma and cerebellar BDNF levels |
| Van Kummer et al. (2015) (38) | 4 weeks of treadmill running (30 min/day, 5 days/week) | spastic Han Wistar rat | cerebellum Purkinje cell | BDNF and TrkB level | ↑ cerebellar Purkinje cell BDNF and TrkB |
| Chalimoniuk et al. (2015) (39) | 6-week endurance training (running) of moderate intensity on a treadmill | Rat | hippocampus, midbrain, striatum, cerebellum, and cerebral cortex | BDNF and TrkB expression | ↑ BDNF and TrkB mRNA in hippocampus, midbrain, and striatum; ↔ in cerebellum and cerebral cortex |
| Inoue et al. (2018) (40) | Running on a treadmill 5 days/week for 4 weeks | Mice | cerebellum | mRNA expression of BDNF | ↑ cerebellar BDNF mRNA expression |
| Algaidi et al. (2019) (41) | Voluntary running for 3 weeks on a running wheel | Depressed rat | Dentate gyrus, medial prefrontal cortex and cerebellum | BDNF expression | ↑ dentate gyrus, medial prefrontal cortex, and cerebellum |
| Rauf et al. (2020) (42) | 5 days a week running on a treadmill for 6 weeks | Ovariectomized rats | cerebellum | mRNA expressions of BDNF | ↑ cerebellar BDNF mRNA expression |
| Fragoso et al. (2020) (43) | voluntary PA cages, containing a running wheel, for 4 weeks | Rat | cerebellum hypothalamus, hippocampus and cortex | mRNA expressions of BDNF | ↔ cerebellar, hypothalamic, hippocampal, and cortical BDNF |
| Salomova et al. (2021) (44) | 6 weeks of running on running wheels (voluntary running) or a treadmill (forced PA) | Lurcher mice | cerebellum | BDNF level | ↑ cerebellar BDNF level |
| Cook et al. (2022) (45) | 6 weeks of running on running wheels or a treadmill (20 minutes at an increasing speed) | Spinocerebellar ataxia type 6 mice | cerebellar | BDNF expression | ↑ cerebellar BDNF expression |
a ↑ denotes an increase; ↔ denotes no change. Abbreviations: BDNF, brain-derived neurotrophic factor; PA, physical activity.
3.2. Molecular Mechanisms of BDNF Increase Following Aerobic Exercise
Aerobic exercise increases BDNF synthesis in the brain through several molecular mechanisms. In addition to stimulating brain BDNF, AE also affects circulating BDNF (46). High-intensity interval training and moderate-intensity AE can produce transient increases in circulating BDNF (47, 48). Proposed mechanisms include lactate-mediated activation of sirtuin 1 deacetylase, fibronectin type III domain-containing protein 5 (FNDC5), beta-hydroxybutyrate production, and pro-BDNF cleavage by tissue plasminogen activator, all of which may contribute to BDNF synthesis and release after AE (49-52).
Evidence suggests that BDNF can cross the blood-brain barrier (BBB) bidirectionally, such that circulating BDNF levels may reflect brain BDNF levels (53). Proteins and metabolic derivatives released by active skeletal muscle, including cathepsin B, lactate, and FNDC5/irisin, can cross the BBB during AE and stimulate BDNF expression in different brain regions (54). Increased intracellular Ca²⁺ in neurons and activation of the MAPK/ERK signaling pathway may also contribute. Ca2+/calmodulin-dependent protein kinase phosphorylates cAMP response element-binding protein, which activates BDNF gene transcription (55). When the ATP/ADP ratio increases, AMP kinase is activated, triggering the PGC-1α/FNDC5/irisin pathway and stimulating BDNF secretion in the brain (56).
The intensity, duration, and training period of AE affect BDNF expression and neurogenesis. Schmolesky et al. (57) reported that high-intensity AE at 80% of heart rate reserve and a longer duration of 40 minutes increased BDNF expression. BDNF expression also increased with exercise duration (57). A meta-analysis showed that high-intensity AE increased BDNF expression (58), and other studies have reported that moderate- to high-intensity AE increases BDNF (59).
4. Conclusions
Overall, the available evidence indicates that AE increases BDNF expression in rodents. This effect may be mediated by the release of myokines and metabolites from skeletal muscle, including cathepsin B, lactate, and FNDC5/irisin, into the circulation. These factors can cross the blood–brain barrier and stimulate BDNF expression in the brain. Increased cerebellar BDNF has been reported in healthy rodents, vanadium-exposed lactating rodents, and models of depression, ataxia, menopause, early-onset cerebellar degeneration, and spinocerebellar ataxia type 6. In these studies, AE-induced increases in BDNF were associated with improved brain function. Given the important role of the cerebellum in the central nervous system, increasing BDNF in this region may improve cerebellar function and reduce associated functional impairments. Therefore, AE may be considered a nonpharmacological strategy to support cerebellar function and may have potential as an intervention for disorders associated with cerebellar dysfunction.
