Table 1.
Summary of the effects of increased physical activity on the rodent brain. The neuroprotective benefits of physical activity are noted in a variety of ages; ‘age at onset’ describes the age, if specified, at which the activity paradigm (whether it be acute or chronic) is commenced. (The specific effects on vasculature are not included in this table.) Please see abbreviation listed below the table
| System affected by increased activity | Age at onset, Species, Sex | ’Exercise’ duration and protocol | Details |
| Blood-brain barrier/Neurovascular unit | 7-8 weeks; 13 weeks, mice (male) | 5 weeks; 2 weeks (respectively), VWR | Reduced pro-inflammatory cytokines and methamphetamine-induced oxidative stress in cerebral vasculature; enhanced expression and/or co-localisation of tight junction proteins (e.g. claudin-5, occludin and ZO-1) [91, 93] |
| 12 weeks, mice (male) | 5 weeks, VWR | Maintained BBB integrity (enhanced expression and/or co-localisation of tight junction proteins claudin-5, occludin and ZO-1) in a mouse model of early brain metastasis; limited tumour extravasation [132] | |
| adult, rats (male) | 3 consecutive days, TR•30 min, speeds increasing from 5 m/min to 12 m/min, 0 incline | Reduced the expression of MMP, and mitigated BBB disruption (specifically, the reduction of occludin) following middle cerebral arterial occlusion in ischemia model of stroke (TR within 24 hrs) [130] | |
| 12 months, mice (female) | 6 months, VWR | VWR from middle to early old-age attenuated age-related deterioration of neurovascular structures and vascular leakage (shown by extravasation of fibrin[ogen]), microglial activation, and decline in astrocytic ApoE; the benefit to the NVU was not seen in exercised ApoE deficient mice [92] | |
| Glymphatic System | 9 weeks, mice (female) | 5 weeks, VWR (averaged 6.7 km per night) | Glymphatic influx (as measured by fluorescent tracer) increased in awake, exercised mice as compared to mice that had been sedentary; overall tracer influx was impaired during acute running (measured in awake running mice); history of daily running increased CSF flux in widespread brain regions (primarily in hypothalamus and ventral parts of the cortex) [145] |
| 14–16 months, mice (male) | 6 weeks, VWR | Increased expression of AQP4 on astrocytic endfeet; accelerated clearance of tracer and decreased Aβ accumulation; increased dendrites, dendritic spines and postsynaptic density protein (PSD95); improved spatial memory [94] | |
| Neurotrophins | |||
| BDNF | 8 weeks, mice (male) | Acute session, TR•120 min, at 15 m/min, with an incline of 5% •mice were acclimated to motorized TR running for 3 days (5 min/day,15 m/min, 5%); acute session began 72 hrs after acclimatisation | Obese, glucose-intolerant mice (fed high-fat diet) shown to have a reduction in BDNF levels, as well as reduction in TrkB phosphorylation and CREB activation in the prefrontal cortex; 2 hrs following an acute session of TR, levels of phosphorylated TrkB and CREB significantly elevated over sedentary mice fed the same high fat diet [347] |
| 2 – 5 months, mice and rats | 3 days – 4 weeks, VWR | BDNF consistently upregulated with VWR, along with proteins associated with BDNF signalling cascade; most notably increased in dentate gyrus, CA1, CA3, and CA4 of the hippocampus, and in the most caudal third of cortex (examples: [4, 5, 85, 86, 186, 190, 348, 349]) | |
| 2 months, rats (male) | 3 days, VWR (against 100 g resistance) | Positive correlation between exercise and hippocampal protein levels of [synaptic proteins] synapsin I and synaptophysin mRNA; synapsin I correlated with the amount of exercise (i.e. running distance); blocking TrkB (BDNF signalling) abolished the upregulation of both proteins [86] | |
| 3 months, rats (male) | 1 week, VWR (against 100 g resistance)•minimum of 100 m/day | Increased BDNF, concomitant with improved performance on MWM; inhibiting the action of BDNF blocked cognitive enhancement following exercise, as well as downstream proteins involved in synaptic plasticity (CREB and synapsin I); best performance (learning and recall) associated with highest expression of BDNF and CREB mRNA levels [5] | |
| 9 months, mice (female) | 8 months, VWR (note: same animals underwent behavioural testing at 1 and 6-months) | VWR throughout middle-age (i.e. 8 months total) increased BDNF protein levels in the hippocampus of 15 month-old runners compared to age-matched controls; reduced age-related cognitive decline [48] | |
| 8 or 12 months, mice (male) | 5 or 8 weeks, TR•began at 10 m/min, 20 min for the first day and increased 10 min/day until 60 min/day reached; intensity increased to maintain 70% of animals’ VO2 max; speed increased to 11 m/min in final week | Increased proliferation and maturation in dentate gyrus, and restored age-dependent decline in BDNF and TrkB [350] | |
| 24 months, rats (female) | 1 week habituation + 4 weeks exercise regimen, TR (4 consecutive days/week)•daily regimen: warm-up (3 min, 2 m/min), two bouts of running (4–6 min, 10 m/min) with 1 min interval between | In aging rats, shorts bouts of mild-intensity exercise increased muscle oxygen consumption by soleus and heart; lactate levels remained stable throughout 4 weeks (levels indicative of mild-moderate intensity exercise); reversed age-related spatial learning and memory impairment; increased Bdnf mRNA and protein in hippocampus; increased levels of phosphorylated AKT and phosphorylated CREB protein in the hippocampus; results suggest even short bouts of exercise effective at facilitating hippocampal plasticity [82] | |
| 4 weeks, mice (male) | 4 weeks | Increased production of DBHB, a ketone body produced in the liver and capable of crossing the BBB, which in turn induced activity of BDNF promotors in the hippocampus via HDAC2/HDAC3 inhibition; increase in neurotransmitter release, dependent upon TrkB signalling [192] | |
| NGF | 3 – 4 months, rats (male) | 2, 4 or 7 days, VWR•mice acclimated to wheel for 3 days, then removed for 10 before testing [3, 190] | NGF is increased in the acute/short-term phase, reported in the hippocampus at 2 – 3 days and in the cortex, from 2 – 7 days [3, 85, 190] |
| 3 – 4 months, rats (male) | 4, 7 and 28 days, VWR•1 week acclimation•at least 5 km/day [85] | ||
| IGF-1 | adult, rats (male) | 5 days, VRW (against 100 g resistance) | 5 days VWR increased hippocampal levels of IGF-1, but not IGF-2; improved performance on MWMBlocking hippocampal IGF-1 receptors during 5-day exercise period blocked the uptake of circulating IGF-1 into the hippocampus and in turn, diminished the upregulation of BDNF and its precusor, pro-BDNF; diminished rate of acquisition and abolished preference for probe quadrant in MWM; eliminated exercise-facilitated upregulation of synapsin I mRNA and protein in the hippocampus [1] |
| adult, rats (male) | 2 weeks, TR•60 minutes, 17 m/min•rats assigned to both sedentary group and exercise familiarised to treadmill | In response to exercise, IGF-1 participates in neuronal stimulation and c-fos expression in hippocampus; subcutaneous administration of IGF-1 to sedentary animals increased number of new neurons in the hippocampus; infusion of IGF-1 anti-serum blocked uptake of circulating IGF-1 into hippocampus, which abolished increase in new neurons; infusion of IGF-1 anti-serum throughout exercise period abolished both short-term and long-term survival of new cells in hippocampus [89] | |
| Note: Physical activity produces increase in IGF-1 levels in circulation and hippocampus; uptake of circulating IGF-1 into hippocampus involved in both exercise-induced elevation in BDNF and neurogenesis; infusion of IGF-1 increases glutamate receptor subunits (particularly NR2A and NR2B) in aged mice; IGF-1 levels correlated with vascular density [1, 29, 43, 200, 215, 219, 220] | |||
| Neurotransmitters | |||
| DA | young, rats (male) | young rats: 6 months ‘endurance training’, TR•progressive treadmill test performed on an 18° incline, correlated to peak oxygen consumption [254] | Increased radioligand ([3H]SP) binding to D2 receptors in the striatum and increased “synaptic coupling ratio” (defined as the “specific DA binding/DOPAC concentration”) [254]; in aged rats, regular exercise attenuated age-associated increases in DA metabolites (which can be associated oxidative stress), and increased D2 receptor binding [351] |
| ►18 months, rats (male) ►aged rats: 12 weeks, TR [351] | |||
| 8 weeks, mice (males) | 2 or 4 weeks, TR•10 m/min for 20–60 min per day (increased at an increment of 10 min per day), 5 days/week the first week; 60 min/day at the same speed, 10 m/min, 5 days/week for additional 1 or 3 weeks•both mice assigned to exercise and sedentary groups underwent 1 week of habituation training on the treadmill (9 m/min, 10 min/day for 5 days) | TR regimen (meant to replicate moderate exercise in humans) completely protected against LPS-induced dopaminergic neuronal loss in the substantia nigra and attenuated motor impairment following 4 weeks of running; neuroprotection in the nigrostriatal pathway was dependent on the activation of the BDNF-TrkB signalling pathway rather than modulation of microglial activation or cytokine/chemokine levels; intrastriatal perfusion of BDNF alone was sufficient to counteract LPS-induced DA neuron loss; protection not observed after 2 weeks of running [246] | |
| 3 months vs 23 months, rats (female) | 9 weeks, TR•5 days/week, intensity adjusted to approximately 70% of their peak oxygen consumption (time, grade and speed increased as weeks progressed, and differed for each age group) | TH mRNA, TH immunoreactivity, and TH activity showed age-related decline in the hypothalamus; endurance training significantly elevated all TH parameters in the hypothalamus of old animals (p < 0.05), but there was no significant change in young animals following training [259] | |
| Note: DA neurotransmission has been shown to increase BDNF production, as well as surface expression and phosphorylation of TrkB (in vitro and in vivo); TrkB signalling shown to increase expression of D1 and D3 receptors (in vitro and in vivo) [246–248, 259] | |||
| NA | 3 months, rats (male) | 3 days, VWR | BDNF mRNA upregulated in CA1, CA2, CA3, CA4 and detate gyrus; modest increase in BDNF mRNA with antidepressant, tranylcypromine, CA3 and dentate gyrus only; β-adrenergic receptor blockade significantly blunted BDNF mRNA elevations in response to exercise, and inhibited modest elevations resulting from antidepressant treatment in CA3 [189] |
| young, rats (sex not specified)•age not specified, 146 + /–2 g at start of study | 5 days/week, 2 weeks (TR) (1 hour, 25 m/min, 3% slope)•workload corresponded to 70% VO2 max•4 day break, in which microdialysis probe implanted + recovery•Acute session of 1 or 2 hrs | Increased levels of NA centrally and peripherally following 1 and 2 hr exercise sessions; the peak of NA concentration in the cortex is higher with 2 hours of exercise, and levels remain elevated for longer periods as compared to a 1-hour session [266] (see also [265]) | |
| adult, rats (male)•age not specified, 220 g on arrival | 5 days, VWR (against 100 g resistance) | Blocking the β-adrenergic receptors with propranolol (β-blocker that crosses the BBB) but not nadolol (peripherally acting, does not cross the BBB) before each of five consecutive nights of exercise reversed the exercise-induced improvement in learning and memory in rat [271] (see also [270]) | |
| 5-HT | adult,rats (male)•age not specified, 300 +/–15 g at start of study | Acute session, 120 min, TR•trained 6 – 7 times prior to experiment day, gradually accustomed to run at 25 m/min; 2 days before experimentation, ran 30 min at a speed of 25 m/min | Hippocampal and cortical 5-HT levels significantly increased by 90 min of intense aerobic exercise (collected by microdialysis); maximal levels in the cortex, 30 min after exercise cessation and in the hippocampus, 60 min after cessation; hippocampal levels remained elevated at least 90 minutes after cessation; cortical 5-HT levels rapidly decrease when hippocampal levels still maximal [352] |
| 6 weeks vs 3 months vs 1 year, mice (female)•Tph2 -/- and controls | 6 days, VWR | Tph2-deficient mice have normal baseline hippocampal neurogenesis but impaired proliferation in response to increased physical activity; serotonergic deficits results in alterations in Sox2-positive precusor cells; serotonergic signalling required for proproliferative effect on physical activity, in young and aged animals [292] (see also: [293]) | |
| Glutamate | 28 – 40 days, mice (sex not specified) | 7 – 10 days, VWR averaged 4 km/day | Synaptic plasticity in dentate gyrus examined in vitro: LTP significantly greater in slices prepared from runners than control animals; LTP significantly reduced by NR2B subunit antagonists in both groups; LTP blocked by an antagonist with higher affinity for NR2A (NVP-AAM077) in running groups, with only slight depression in controls; NVP-AAM077 completely blocked LTD in runners but not controls [236] |
| 3 months, rats (male) | 3, 7 or 28 days, VWR (against 100 g resistance)•VWR followed 1 week habituation at least 5 km/day•Similar results seen with TR, 3, 7, 15 or 30 days (40 minutes daily, 10 m/min) | Increased synaptic glutamate receptors (mRNA and/or protein levels) in several brain regions including, but not limited to, the hippocampus, motor cortex, sensory cortex, and striatum; mRNA expression of NMDAR subunits modulated in hippocampus after 3 days of VMR (NR2A and NR2B); AMPA receptors modulated after 10 days of VWR or 30 days of TR [85, 186, 353] | |
| 3 months, rats (male) | 3 or 7 days, VWR at least 5 km/day (against 100 g resistance) | Blocking NMDAR (MK-801, delivered unilaterally by microsphere into hippocampus) was sufficient to fully abrogate exercise-induced increases in Bdnf, TrkB, CREB, and Synapsin I, suggesting an interaction between BDNF and glutamate signalling may be necessary for increased transcription of genes modulating synaptic plasticity [4] | |
| GABA | 5–6 weeks, mice (male) | 10 days, VWR | GABAergic transmission excitatory in the first two weeks and becomes inhibitory as granule cells mature and integrate into networks; involved in initial integration of adult-born neurons [354]Young, 1-week old progenitor cells receive input from inhibitory GABAergic interneurons and cholinergic input from the septum, as well as multiple intra-hippocampal glutamatergic cells types, all of which have been implicated in the maturation and integration of new neurons [296]; exercise enhances new dentate granule cell number, arborization and morphological complexity but only NMDA-mediated glutamatergic inputs shown to be modified by running [296] Electrophysiological recordings from slices taken from exercised mice suggest that alternations to glutamatergic inputs, rather than GABAergic inputs, are predominately responsible for increased morphological complexity in new neurons [296] |
| 5–6 weeks, mice (male) | 40 days, VWR | In new neurons, ratio of interneuron inputs to new neurons was reduced, but GABAergic inhibitory synaptic transmission was not changed by running; in mature granular cells in the outer molecular layer, synaptic inhibition was strongly increased, (possibly due to interneuron sprouting of axonal collaterals onto these cells) [297] | |
| young, rats (males),•age not specified, 140 – 160 g on arrival | 4 weeks, VWR•ran 5 – 9 km per night•began running 1 week after arrival | Gene expression of various GABAA receptor subunits as well as the GABA-synthesising enzyme glutamic acid decarboxylase-67 (GAD67) altered in the forebrain of runners (in situ hybridisation histochemistry): region-specific decreases in mRNA expression of α2, β3 and γ2 GABAAR subunits and region-specific increases in β1 subunit; α5 and δ subunits showed differential increases in mRNA expression levels; GAD67 mRNA increased in many forebrain regions, including all hippocampal cell layers, peri-paraventricular nucleus, bed nucleus stria terminalis, nucleus accumbens core and motor cortex [241] | |
| 6 weeks, mice (male) | 6 weeks | During cold water swim stress, increased expression of the protein products of the immediate early genes c-fos and arc in granular neurons (new and mature) of sedentary mice but not runnersRunners showed enhanced local inhibitory mechanisms in the hippocampus during stress test: increased in stress-induced activation of hippocampal interneurons, expression of vesicular GABA transporter, and extracellular GABA release [355] | |
| ACh | adult, rats (male) | 5 minutes, walking on treadmill (2.3 m/min, 0 incline) | Increased ACh (as well as NA and 5-HT) levels in cerebral cortex, sampled from freely-behaving animals by microdialysis [226, 227, 356] |
| 3–4 months, rats (male) | 30 seconds or 3 minutes, walking on treadmill (4 cm/s, 0 incline) | Increased ACh in hippocampus; increased regional blood flow; abolished by AChR antagonists; various degrees of physical activity shown to elevate ACh levels in cortex and hippocampus [357] | |
| ►26–29 months, ‘healthy aged’ rats (male) | ► 30 seconds or 3 minutes, walking on treadmill (2, 4, or 8 cm/s, 0 incline) | ►Similarly, increased ACh release in hippocampus of aged rats (likely cholinergic fibres that originate in the septal complex of forebrain and project to hippocampus); increased regional blood flow [237]. | |
| adult, mice (male) | 15 consecutive days, TR (30 min, 5 m/min, 0 incline) | In scopolamine-treated mice, a pharmacological model of amnesia, treadmill exercise ameliorated short-term memory impairment, suppressed AChE expression, and enhanced angiogenesis [239] | |
| Note: An increased concentration of ACh in the hippocampus supports the generation of theta oscillations, which serves to facilitate synaptic plasticity, learning and memory [240, 324, 325]. | |||
| Neurogenesis | 3 weeks, mice (female) | 40 days in enriched environment (tunnels, toys and running wheel; 3 mice per cage)►second group survived 68 days total (after 40 days in enriched or control environments, tested on MWM for 5 consecutive days, then returned to assigned environments for an additional 23 days) | Housing in enriched environments, which included running wheels, induced neurogenesis: when mice were sacrificed 1 day after final BrdU injection (daily, 12 days), no significant difference between two groups suggesting little influence on proliferative activity of progenitor cells in dentate gyrus; when mice sacrificed 4 weeks after last injection, a significantly higher number of BrdU+ cells in the dentate gyrus of mice living in enriched environments, suggesting a survival-promoting effect on proliferating neuronal precursors; studies in mice of an alternative background (129/SvJ rather than C57BL/6) did show a significant increase in the number of progenitor cells under similar conditions [72, 73] |
| 3 months, mice (female) | 12 days, 40 days, VWR (vs other conditions in enriched environments) | Running is sufficient to increase hippocampal neurogenesis: an increase in both proliferating cells (measured 1 day after last BrdU injection, injected daily for 12 days) as well surviving neurons, after an additional 4 weeks of VWR, seen in running group and enriched environment groups only LTP and spatial learning in mice [56] | |
| 3 months, mice (female) | 2 months or 4 months, VWR 1+ months | Improved performance on MWM, increased cell proliferation (as measured by BrdU+ cells) and enhanced LTP in the dentate gyrus. | |
| 3 months vs 19 months, mice (male) | 45 days, VWR | Faster acquisition and better retention on MWM than sedentary age-matched controls; age-related decline in neurogenesis ameliorated (compared to young and aged controls); fine morphology of new neurons did not differ between young and aged runners; perimeter and surface area of blood vessel increased in young runners but not aged mice; angiogenesis was not a rate-limiting factor for neurogenesis (angiogenesis not increased in this study, although reported to be increase in motor cortex, cerebellum and hippocampus following running in other studies) [57] | |
| 3 months vs, 12 and24 months, mice (male) | 6 months VWR (young mice) vs 10 days VWR (aged) | Chronic (i.e. long-term) running starting at 3 months of age attenuated age-dependent decline in precursor cell proliferation measured at 9 months; short-term running reduced age-related decline in cell proliferation at 12 and 24 months, but did not return net neurogenesis to ‘young levels’ in this study [41] |
ACh – acetylcholine; AChE – acetylcholinesterase; AKT – Protein kinase B; BDNF – brain derived neurotrophic factor; BrdU – bromodeoxyuridine; CA – cornu Ammonis (i.e. hippocampal subfield); CREB – cAMP response element-binding protein; CSF – cerebrospinal fluid; DA – dopamine; DCX – doublecortin; DOPAC – 3,4-Dihydroxyphenylacetic acid (a dopamine metabolite); DRN – dorsal raphe nucleus; HDAC – histone deacetylase; 5-HT – serotonin; IGF-1 – insulin growth factor 1; LPS – Lipopolysaccharide; LTD – long-term depression; LTP – long-term potentiation; MMP – matrix metalloproteinases; MWM – Morris Water Maze; NA – noradrenaline; NMDAR – N-methyl-D-aspartate receptor; NR2A/2B – NMDAR subunits 2A and 2B; NGF – neurotrophic growth factor; TR – treadmill running (controlled for duration and speed); VWR – voluntary wheel running (animals are freely behaving); ZO-1 – zonula occludens 1.