Table 1.
Examples of positive, lack of positive, and negative effects of different forced training intensities on stress, behavior, and neurogenesis.
| Animal model | Treadmill protocol | Stress biomarkers | Effects on cognition | Histological and molecular procedures | References |
|---|---|---|---|---|---|
| Brain ischemia rat model: Adult Sprague-Dawley (SD) rats | - Sedentary (SED) group: 0 m/min - Low-intensity exercise (LI) group: 8 m/min - High-intensity exercise (HI) group: 20 m/min Duration in each group: 30 min/day for 14 days. |
Serum corticosterone (CORT) Only HI group presented higher serum CORT concentration (levels around 200 μg/ml) than SED group. |
Morris Water Maze (MWM) task LI but not HI group demonstrated a better spatial memory performance than SED group by spending more time in the target (platform) quadrant. | BDNF, Synapsin-I, PSD-95 Only the LI but not HI group presented increased levels of BDNF, Synapsin-I and PSD-95 in the contralesional hippocampus compared to the SED group. | Shih et al., 2013 |
| Adult male Sprague-Dawley (SD) with severe cortical impact | - Sedentary (Control) group: 0 m/min - Low-intensity (LI) group: Progressive speed until reaching a maximum of 8 m/min from day 8 to day 14 (end of the protocol). - High-intensity (HI) group: Progressive speed until reaching 12 m/min from day 4 to the end of the running protocol. Duration: 30 min/day for 14 days. |
No stress biomarkers were assessed | MWM task LI group had a shorter latency to locate the platform and a better performance in spatial memory compared to the control group. The HI exercise group showed a longer latency and a mild improvement in spatial memory compared to the control group. | BDNF LI group had increased levels of BDNF in the contralateral hippocampus respect de control group. p-CREB LI group had increased levels of p-CREB in the contralateral hippocampus respect de control group. | Shen et al., 2013 |
| Adult rats | Treadmill with speed paradigm based on the lactate threshold (LT being around 20 m/min) - Sedentary control (CONT) group: Duration: 6 weeks - Stress free mild exercise (ME, < LT) group: Duration: 6 weeks. - Intense exercise (IE, >LT) group: Duration: 6 weeks. |
Only IE causes general adaptive syndrome (GAS): hypercorticosteronemia, adrenal hypertrophy, thymic atrophy. | MWM task ME led to enhanced memory, but not learning, compared with CONT. IE produced no changes in either learning capacities, probably due to GAS. | Adult Hippocampal Neurogenesis (AHN) 2 weeks of training with stress-free mild exercise (ME), but not intense exercise (IE), comprising exercise stress, promotes adult hippocampal neurogenesis. | Inoue et al., 2015a |
| Adult male Wistar rats | Treadmill with speed paradigm based on the lactate threshold - Sedentary control (CONT) group: 0 m/min - Supra-lactate threshold (Middle speed) group: 25 m/min. - Sub-lactate-threshold (Low speed) group: 15 m/min. Duration: 30 min/day for 2 weeks. |
Serum ACTH levels Significant increases in plasma ACTH were observed during supra-LT running. | No behavioral tasks were performed | cFos induction Only supra-LT running significantly increased c-Fos induction in various hypothalamic regions. | Soya et al., 2007 |
| Male albino Sprague-Dawley rats (4–6 weeks old) | For 4 weeks: intensity of 70% of maximal oxygen consumption, for 1 h/day, 5 day/week. | No stress biomarkers were assessed | One-trial step-through passive avoidance test: ↑ learning and memory. | No histological or molecular procedures were performed | Chen et al., 2008 |
| Adult Wistar Rats | Treadmill with speed paradigm based on the lactate threshold - Sedentary control (CONT) group: 0 m/min |
Plasma CORT Only IE had the higher CORT concentration than CONT group. |
No behavioral tasks were performed | AHN ME was better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. | Inoue et al., 2015a |
| - Mild-exercise (ME, < LT) group: 15 m/min, 60 min/day. - Intense-exercise (IE, >LT) group: 40 m/min, 60 min/day. Duration: 6 weeks in total including the habituation period. Running took place during the dark phase (19:00 and 22:00). |
DNA microarray - ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN - IE-influenced genes linked to an excessive inflammatory immune response, known to be negative regulator of hippocampal neuroadaptation, were identified. |
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| Sprague-Dawley rats (5-weeks-old) | Treadmill: initial speed of 9 m/min for 20–60 min per day, 5 days per week for the first week, followed by 60 min/day at the same speed, 5 days/week. Increasing speed about 3 m/min per week reaching 16 m/min at the end of the training period. Running Wheel: singly placed in cages. | No stress biomarkers were assessed | Fear conditioning: No changes in the acquisition of fear-evoked conditional responses and ↑ context-conditioned freezing responses in treadmill and running wheel. Only treadmill improved the cue-conditioned performance. | No histological or molecular procedures were performed | Lin et al., 2012 |
| Male juvenile Sprague-Dawley rats (5 weeks old) | For 1 week: 30 min/day. Three groups: - low intensity (LI) group: ran at 5 m/min for the first 5 min, 8 m/min for the next 5 min and 11 m/min for the remaining 20 min; - moderate intensity (MI) group ran at 8 m/min for the first 5 min, 11 m/min for the next 5 min and 14 m/min for the remaining 20 min; - high intensity (HI) group ran at 8 m/min for the first 5 min, 11 m/min for the next 5 min and 22 m/min for the remaining 20 min. |
No stress biomarkers were assessed | No behavioral tasks perfomed | AHN ↑↑↑↑ BrdU+ and BrdU+/NeuN+ cells in the LI group; ↑↑↑ BrdU+ and BrdU+/NeuN+ cells in the MI group; ↑↑ BrdU+ cells in HI group; ↑ BrdU+ and BrdU+/NeuN+ cells in the control group. |
Lou et al., 2008 |
| Male Sprague-Dawley rats (2 weeks of age): induction of autism-like with valproic acid injections. | 30 min/day, five times a week for 4 weeks, starting postnatal day 28. Speed of 2 m/min for the first 5 min, at a speed of 5 m/min for the next 5 min, and then at a speed of 8 m/min for the last 20 min, with the 0° inclination. | No stress biomarkers were assessed | Open field and social interaction test: ↑ spatial learning memory in the autistic rats; Radial 8-arm maze test: ↑ working memory in the VPA-injected rats with exercise. |
AHN ↑ number of BrdU+ cells |
Seo et al., 2013 |
| Male Wistar rats subjected to surgery | For 1 week: 1h/day, 5-10 m/min. | No stress biomarkers were assessed | Object displacement task: ↑ spatial learning; Object substitution task: ↑ object recognition learning. |
No histological or molecular procedures were performed | Griffin et al., 2009 |
| C57BL/J6 mice | - Controls (CON): 0 m/min - Regular Runners (RR): 10 m/min, at the same time of the day until 28 days - Irregular Duration Runners (IDR): 10 m/min. Same time of the day but variable duration. - Irregular time-of-day runners (ITR): 10 m/min. Same duration but at different time of day. |
Serum CORT levels Day 4: No differences were found among runners. Day 29: RR group had significantly lower levels of serum CORT (110-150ng/ml at 10:00 am). |
MWM task The RR group had a lower escape latency in the acquisition compared to the CON or IDR group. Regarding memory consolidation, RR spent more time in the target quadrant compared to the other three groups. | RR group presented higher levels of BrdU+ cells compared to the other groups. | Li et al., 2013 |
| C57BL/J6 mice | Forced Walking Wheel System - Sedentary: 0m/min - Low impact runners (LIR): 10 m/min. 45 min/day. Duration: 10 weeks. - High impact runners (HIR): 21m/min, 45 min/day. Duration: 5 weeks. |
No stress biomarkers were assessed | MWM task In the acquisition phase, HIR had longer escape latencies compared to LIR group and sedentary controls. Regarding memory consolidation performance, LIR crossed the platform quadrant more than HIR. Rotorod test 5 weeks of HIR led to significant improvement in rotorod test performance. | No histological or molecular procedures were performed | Kennard and Woodruff-Pak, 2012 |
| Adult male C57BL/6 mice | For 2 weeks: 7 days/week, 40 min/day, speed 12 m/min. | No stress biomarkers were assessed | No behavioral tasks perfomed | AHN ↑ number of BrdU+ cell; ↑ density of spine of granule cells in the DG |
Glasper et al., 2010 |
| Adult male C57BL/6 mice | For 2 weeks: 5 days/week, 40 min/day, speed 12 m/min. | No stress biomarkers were assessed | No behavioral tasks perfomed | AHN No changes in the number of mature granule neurons; ↑ number of DCX+/CLR− cells; ↑ number of (DCX+/CLR+)/Granule neurons; ↑ total DCX+/Granule neurons; ↑ total CLR+/Granule neurons |
Llorens-Martín et al., 2006 |
| Adult male C57BL/6J mice (5-weeks-old) | 10 m/min, 20 min for the first day, with an increment of 10 min/day until reaching 60 min/day to fulfill the 70% of maximal oxygen consumption. The running duration was 60 min/day, and the running speed was increased gradually from 10 to 12 m/min. The speed was accelerated 1 m/min every 2 weeks. | No stress biomarkers were assessed | No behavioral tasks perfomed | AHN ↑ number of Nestin+ cells in the SGZ; ↑ number of Ki67+ cells; ↑ more DCX+ cells, with prominently developed dendrites; ↑ pCREB expression; ↑ BDNF expression |
Nam et al., 2014 |
| Male BALB/c mice (3-months old) | For 4 weeks: 10 m/min, for 20-60 min/day, 5 days/week. | No stress biomarkers were assessed | One-trial passive avoidance: ↑ retention latency. Multiple-trial passive avoidance: | No histological or molecular procedures were performed | Liu et al., 2008 |
| ↑ just the retention phase of memory (not the acquisition). | |||||
| C57BL/6 male mice (19 months) | For 8 weeks, 5 days/week, 2 sessions/day, 5° incline. For the first week, each session consisted of a 10-min warm-up at 15 m/min followed by 30 min at 18 m/min. During the following 7 weeks, treadmill speed was progressively increased every week. Specifically, for weeks 2, 3, 4, 5, 6, 7, and 8 the treadmill speed was set to 21 m/min, 22 m/min, 23 m/min, 24 m/min, 25 m/min, 25 m/min, and 26 m/min, respectively. | No stress biomarkers were assessed | No behavioral tasks perfomed | No changes in DCX mRNA levels; ↑ VEGF mRNA; No changes in BDNF mRNA levels |
Lezi et al., 2014 |
In general, the highest intensities lead to a higher concentration of stress biomarkers, and either to a lower improvement, no improvement or negative effects (compared to sedentary controls) in behavioral performance and neurogenesis. Most authors designate the different intensities according to the velocity of running, based on the assumption that a correlation exists between running speed and lactate threshold (LT) although most of them do not measure lactate in their studies, so we have used the different running velocity as a classification criterion. LT, lactate threshold. References included in the Table and not in the text are: (Van Praag et al., 1999; Griesbach et al., 2004; Adlard et al., 2005; Bjørnebekk et al., 2005; Eadie et al., 2005; Redila and Christie, 2006; Kohl et al., 2007; Soya et al., 2007; Stranahan et al., 2007; Naylor et al., 2008; Leasure and Decker, 2009; Berchtold et al., 2010; Creer et al., 2010; Falls et al., 2010; Lafenêtre et al., 2010; Kennard and Woodruff-Pak, 2012; Li et al., 2013; Shen et al., 2013; Shih et al., 2013; Fischer et al., 2014; Inoue et al., 2015a,b; Radahmadi et al., 2015).