Chinese Journal of Physiology

: 2021  |  Volume : 64  |  Issue : 4  |  Page : 186--193

Exercise-induced increases of corticosterone contribute to exercise-enhanced adult hippocampal neurogenesis in mice

Tzu-Feng Wang1, Sheng-Feng Tsai2, Zi-Wei Zhao2, Monica Meng-Chun Shih3, Chia-Yih Wang2, Ting-Ting Yang4, Yu-Min Kuo2,  
1 Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University and Academia Sinica, Taipei; Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of Cell Biology and Anatomy, College of Medicine; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3 National Laboratory Animal Center, Taipei, Taiwan
4 Department of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan

Correspondence Address:
Dr. Ting-Ting Yang
Department of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung
Dr. Yu-Min Kuo
Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No. 1 University Road, Tainan 701


Adult hippocampal neurogenesis (AHN) is suppressed by chronic stress. The negative effect of stress is mainly attributed to increased levels of stress hormones (e.g. glucocorticoids, GCs). Exercise enhances AHN, yet it also stimulates GC secretion. To delineate the paradoxical role of GCs, we took the advantage of a unique mouse strain (L/L) which exhibits an inert response to stress-induced secretion of GCs to study the role of GCs in exercise-induced AHN. Our results showed that basal corticosterone (CORT), the main GCs in rodents, levels were similar between the L/L mice and wild-type (WT) mice. However, levels of CORT in the L/L mice were barely altered and significantly lower than those of the WT mice during treadmill running (TR). AHN was enhanced by 4 weeks of TR in the WT mice, but not L/L mice. WT mice that received daily injection of CORT to evoke serum CORT levels similar to those during exercise for 4 weeks did not affect AHN, whereas injection with large amount of CORT inhibited AHN. Taken together, our results indicated that exercise-related elevation of CORT participates in exercise-enhanced AHN. CORT alone is not sufficient to elicit AHN and may inhibit AHN if the levels are high.

How to cite this article:
Wang TF, Tsai SF, Zhao ZW, Shih MM, Wang CY, Yang TT, Kuo YM. Exercise-induced increases of corticosterone contribute to exercise-enhanced adult hippocampal neurogenesis in mice.Chin J Physiol 2021;64:186-193

How to cite this URL:
Wang TF, Tsai SF, Zhao ZW, Shih MM, Wang CY, Yang TT, Kuo YM. Exercise-induced increases of corticosterone contribute to exercise-enhanced adult hippocampal neurogenesis in mice. Chin J Physiol [serial online] 2021 [cited 2022 Jul 1 ];64:186-193
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Full Text


Adult neurogenesis occurs in two brain regions: the subventricular zone around the lateral ventricle and the subgranular zone of the dentate gyrus (DG) in the hippocampus.[1] Successful integration of the newborn DG neurons into the hippocampal circuitry plays important roles in formation, exhibition, and/or extinction of certain types of hippocampus-dependent memory.[2],[3] The productions of newborn neurons are regulated by at least four parameters: (1) number of the neural stem/precursor cells, (2) proliferation of the neural stem/precursor cells, (3) ratio of neuronal lineage specification of the proliferated cells, and (4) survival of the newborn neurons. Different stimuli may differentially affect one or more of these factors to regulate the neurogenic process.[4]

Stress is a well-known negative factor of adult hippocampal neurogenesis (AHN).[5],[6] By applying different types and durations of stressors to mammalians, most studies agree that stress hormones contributed to stress-related inhibition of AHN.[7],[8],[9],[10] Stress activates the hypothalamic-pituitary-adrenal axis and stimulates the release of stress hormones, such as glucocorticoids (GCs), from the adrenal cortex into circulation, which are capable of crossing the blood-brain barrier. Exogenous administration of corticosterone (CORT) decreases the number of proliferating cells in the rodent DG,[11],[12] while depletion of GCs by bilateral adrenalectomy (ADX) increases the number of newborn neurons in the DG.[13],[14],[15]

Running at mild-to-moderate intensities increases AHN,[16],[17],[18] even though the activity of the hypothalamic-pituitary-adrenal axis and the levels of plasma GCs are increased during exercise.[19],[20] Such an exercise-GC paradox may be explained by bigger AHN positive effects (e.g. insulin-like growth factor-1 and brain-derived neurotrophic factor) than negative effects (e.g. GCs and oxidative stress) elicited by exercise. Another possible explanation is an inverted-U shape relationship between the GC level and AHN, similar to that described for GC levels and spatial memory.[21] It is possible that the elevated GC levels induced by exercise fall in an optimal range of the inverted-U shaped curve. This latter hypothesis is supported by the observation that depletion of GCs by ADX decreased the mild/moderate running-enhanced AHN.[22] Nonetheless, these premises are mainly derived from the ADX model, which abolishes the circulating GCs to abnormally low levels. Mice with normal physiological levels of GCs at basal state and during exercise will be an ideal model to dissect the role of GCs in exercise-enhanced AHN.

A mouse strain (Cyp11a1L/L, termed L/L hereafter), which has normal basal level of CORT without substantial fluctuation after stress stimulation, has been generated.[23] We took the advantage of the relatively inert response of the L/L mice to stress-induced secretion of CORT to investigate the role of GCs in exercise-enhanced AHN. The effects of long-term treadmill running (TR) on AHN were compared between the L/L and wild-type (WT) mice. We used bromodeoxyuridine (BrdU), a thymidine analog, to label dividing cells and doublecortin (DCX) immunoreactivity to label neuronal precursor cells in the DG of mice. To test the hypothesis of the inverted-U shaped relationship of GCs, we administrated exogenous CORT to WT mice in a manner mimicking the daily elevation of CORT during exercise to determine the effect of exercise-induced elevation of CORT on AHN.

 Materials and Methods


All animal experiments were performed in accordance with the National Institutes of Health Guideline for Animal Research (Guide for the Care and Use of Laboratory Animals) and were approved by the National Cheng Kung University Institutional Animal Care and Use Committee (approval no.: 104243). The mice were bred and housed 4%–5% in a humidity- (55% ± 10%) and temperature-controlled (24°C ± 1°C) specific-pathogen-free breeding unit of National Cheng Kung University Laboratory Animal Center under a 13-h light/11-h dark cycle (light-on period: 7 a.m.–8 p.m.) with unrestricted access to food and water.

The L/L strain of mice was a generous gift from Dr. Bon-chu Chung (Institute of Molecular Biology, Academia Sinica, Taiwan). The details of the generation of L/L transgenic mice were described elsewhere.[23] Briefly, a 2-bp mutation (from TAGCCTTGA to TAGaaTTGA) in the steroidogenic factor-1 (SF-1) response element of the Cyp11a1 promoter region was generated by site-directed in vitro mutagenesis. The mutant genes were sent into the embryonic stem cells by homologous recombination followed by blastocyst injection. The mutation-carrying heterozygous mice were selected and mated with EIIa-Cre mice containing universal Cre recombinase. The resulting mutant mouse line has a mutation in the proximal SF-1 binding site and an insertion of one and a half loxP sites in the intron 1 of Cyp11a1.[23] This allele was named mtP-L (abbreviated as L). All the mice were backcrossed to WT C57BL/6 mice for more than 15 generations as described.[23]

The SF-1 is a key regulator of the hypothalamic-pituitary-adrenal axis[24] and transcriptionally regulates the expression of CYP11A1, the first and rate-limiting enzyme in steroidogenesis.[25],[26] Mutation in the SF-1 response element of the Cyp11a1 promoter region results in a lower expression of CYP11A1 in the adrenal gland but does not affect basal secretion of CORT.[23] However, stress-induced increases in levels of circulating CORT are diminished.[23] Moreover, this mutation also downregulates the CYP11A1 expression in the testis and affects the synthesis of testosterone[23],[25] but does not affect the expressions of CYP11A1 in the ovary or placenta, the major organs governing the production of estradiol.[23] Accordingly, to avoid testosterone-related confounds, only female mice were used in this study.

A total of 82 L/L and WT littermates were included in this study. Among them, 13 mice consisting of 8 WT and 5 L/L mice were used to determine the effects of a single bout of TR on the circulating levels of CORT. Twenty-four mice consisting of 12 WT and 12 L/L mice (6 mice per group) were used to examine the effects of a 4-week treadmill training on AHN. Twenty-five WT mice were used to test the effects of a single administration of CORT on circulating CORT levels. Twenty WT mice (5 mice per group) were used to address the effects of a 4-week CORT administration on basal circulating CORT levels and AHN. The number of animals used in each experiment was also indicated in each figure.

Treadmill running exercise

At 7-week-old, all WT and L/L female mice were subjected to a 1-week low-speed running to familiar the treadmill training and reduce the handling-related stress. During this familiarization week, the mice ran on a leveled, motor-driven treadmill (Model #: T408E; Diagnostic and Research Instruments Co., Taoyuan, Taiwan, ROC) at a speed of 7 m/min, 10 min/day, and 5 days/week. The distal end of the runway was shielded from light to attract the mice to run forward, and the proximal end of the runway was filled with sponges to stop the mice. No electric shock was given. The formal TR training started on the subsequent week.

The mice of TR group ran at speed of 10 m/min for 20-60 min per day (an increment of 10 min per day), 5 days/week for the 1st week, followed by 60 min/day at the same speed, 5 days/week for the next 3 weeks. This speed is at the range of mild intensity.[27] The training time started from 7:00 p.m. to 8:00 p.m., the last hour of the light cycle to harmonize with the circadian activity of the mice. The sedentary (SED) control mice were placed on an immobile treadmill next to the running treadmill during the training period.

Administration of exogenous corticosterone

CORT (Cat. #: 27840, Sigma-Aldrich, St. Louis, MO, USA) at doses of 0.25, 0.5, and 2 mg/kg body weight was prepared in 2.5% ethanol-water solution. The mice treated with 2.5% ethanol served as vehicle controls. To assess the kinetics of circulating CORT, mice were injected (i.p.) with CORT and their blood specimens (30–50 μl each) were collected from tail before and after the CORT injection in a 30-min interval for a total of 90 min. To determine the effect of CORT on AHN, mice received daily injection (i.p.) of CORT or vehicle for 4 weeks.

Blood collection and serum corticosterone measurement

Blood specimens were collected for the determination of serum CORT concentrations in three different experiments. In the first experiment to determine the effect of TR on circulating levels of CORT, both WT and L/L mice were given a single bout of TR at a speed of 10 m/min for 60 min after a 1-week acclimation for TR. Blood specimens were collected before, during, and after the run in a 30-min interval for a total of 120 min. In the second experiment to identify a dose of exogenous CORT injection that would increase serum CORT concentrations to a level similar to that after treadmill exercise, WT mice were injected (i.p.) different doses of CORT, and their blood specimens were collected in a 30-min interval for a total of 90 min. In the third experiment to determine the effect of a 4-week CORT injection on the basal level of circulating CORT of WT mice, blood specimens were collected from these mice 1 day after the end of CORT administration.

Blood samples (3–5 μL each) were collected from a tiny incision made by a needle puncture to their tails and centrifuged at 1000 × g, 4°C for 10 min to obtain sera. To minimize the confounding effect of handling stress, blood specimens were obtained from the same incision at different time points and the whole procedure for each collection was finished within 15 s. The serum levels of CORT were measured using a commercial kit (Cat. #: 501320, Cayman Chemical, Ann Arbor, MI, USA) following the manufacturer's protocol.

Labeling of dividing cells

To label the dividing cells, BrdU (50 mg/kg/day in normal saline, Cat. #: B5002, Sigma-Aldrich) was injected (i.p.) to mice daily during the last 5 days of the 4-week TR training and 4-week CORT injection. The BrdU+ cells were visualized using immunostaining as described below.

Preparation of brain sections

One day after the end of the 4-week TR training and the CORT administration, mice were deeply anesthetized with Zoletil (75 mg/kg, intraperitoneally; Virbac, Carros, France) and transcardially perfused with ice-cold normal saline followed by buffered 4% paraformaldehyde. The mouse brains were removed, postfixed in 4% paraformaldehyde at room temperature for 24 h, dehydrated with graded sucrose solutions (10%, 20%, 30%, and 35% in 0.1 M phosphate buffer), embedded, and sliced at 25-μm thickness coronal sections using a cryomicrotome.


The 25-μm brain sections containing dorsal DG (dDG, stereotaxic coordinates: bregma −1.0 mm to −2.0 mm) were washed with phosphate-buffered saline containing 0.3% Triton X-100 (PBS-T) to remove the embedding compounds, incubated in 2N HCl at 37°C for 30 min to denature the DNA, and washed by PBS-T to neutralize the pH. Brain sections were blocked with 3% normal goat serum (Cat. #: S-1000, Vector Laboratories, Burlingame, CA, USA) for 1 h at room temperature, probed with primary antibodies against BrdU (Cat. #: MAB4072, Millipore, Burlington, MA, USA) and DCX (Cat. #: 4604S, Cell Signaling Technology, Danvers, MA, USA) for 16 h at 4°C, incubated with Alexa-Fluor® 546 conjugated goat anti-mouse immunoglobulin G (IgG) (Cat. #: A11081, Thermo Fisher Scientific, Waltham, MA, USA) and Alexa-Fluor® 488 conjugated goat anti-rabbit IgG (Cat. #: A11070, Thermo Fisher Scientific) for 2 h at room temperature, and sealed with fluorescence mounting medium containing 4′,6-diamidino-2-phenylindole (DAPI) dye (Cat. #: ab104139, Abcam, Cambridge, UK). Primary antibodies were omitted for the detection of nonspecific bindings.

Cell counting

Immunofluorescence imaging was conducted with an optical fluorescence microscope (Model: Axio Imager A1, Carl Zeiss, Oberkochen, Germany) equipped with a digital camera (Model: Axiocam 305 Color, Carl Zeiss) which was driven by AxioVision SE64 software (version: 4.9.1, Carl Zeiss). Images containing dDG were captured and analyzed with ImageJ software (v2.0.0-rc-69/1.52p, U. S. National Institutes of Health). We used ImageJ to merge the multiple color channels and its “cell counter” tool to assist in counting the BrdU-immunoreactive (BrdU+), DCX-immunoreactive (DCX+), and BrdU and DCX dual-immunoreactive (BrdU+/DCX+) cells. The BrdU+ cells were determined by colocalization of BrdU and DAPI signals, while the BrdU+/DCX+ cells were determined by immunolabeling of BrdU and DCX. An unbiased stereology protocol was used to quantify labeled cells as previously described.[28] The number of BrdU+, DCX+, and BrdU+/DCX+ cells was counted in every sixth section throughout the dorsal hippocampus. The number of labeled cells per section was divided by the slide selection ratio to obtain the total number of labeled cells per dDG.

Statistical analysis

Results are presented as mean ± scanning electron microscope. Significance was set at P < 0.05. The effects of TR on the circulating CORT levels were analyzed by repeated-measures two-way (time and exercise) ANOVA followed by Sidak's multiple comparisons test. Two-way ANOVA followed by Tukey's multiple comparisons was used to analyze the effects of exercise and L/L mutation on neurogenesis. One-way ANOVA followed by Tukey's multiple comparisons was used to analyze the dose effects of CORT on neurogenesis.


Treadmill running increases levels of serum corticosterone

The effect of TR on serum CORT level was determined in the WT and L/L mice. Results showed that there was a significant interaction between the exercise time and the mouse strains [F (4, 11) =2.807, P = 0.037] [Figure 1]. Post hoc analyses revealed that WT and L/L mice had similar basal levels of CORT. However, TR-induced increases in the levels of serum CORT were only evident in the WT mice (30 vs. 0 min: P < 0.001; 60 vs. 0 min: P < 0.001), but not the L/L mice [Figure 1]. Furthermore, the levels of serum CORT in the L/L mice were lower than those of the WT mice at 30 and 60 min during the run and 30 min after the run (30 min: P = 0.001; 60 min: P < 0.001; 90 min: P = 0.016) [Figure 1]. These results showed that the L/L mice have a normal basal level of CORT but exhibited a blunted CORT response to exercise.{Figure 1}

Increased corticosterone contributes to treadmill running-enhanced adult hippocampal neurogenesis

Four weeks after TR training at mild intensity, AHN were analyzed by counting the number of BrdU+, DCX+, and BrdU+/DCX+ cells in the subgranular zone of the dDG [Figure 2]a. The results showed that SED L/L and WT mice had similar basal number of BrdU+/DCX+, BrdU+, and DCX+ cells [L/L-SED vs. WT-SED: [Figure 2]b, P = 0.994; [Figure 2]c, P = 0.697; [Figure 2]d, P = 0.783]. Four weeks of TR significantly increased the number of BrdU+/DCX+, BrdU+, and DCX+ cells in the WT mice [WT-TR vs. WT-SED: [Figure 2]b, P < 0.001; [Figure 2]c, P < 0.001; [Figure 2]d, P = 0.019], but not the L/L mice [L/L-TR vs. L/L-SED: [Figure 2]b, P = 0.252; [Figure 2]c, P = 0.646; [Figure 2]d, P = 0.893]. The TR-induced increases in number of BrdU+/DCX+, BrdU+, and DCX+ cells in the L/L mice were significantly lower than those of the WT mice [L/L-TR vs. WT-TR; [Figure 2]b, P = 0.033; [Figure 2]c, P = 0.005; [Figure 2]d, P = 0.032]. These results indicate that exercise-induced increases of the CORT are involved in the exercise-enhanced AHN.{Figure 2}

Mimicking the exercise-induced corticosterone response by administration of exogenous corticosterone fails to enhance adult hippocampal neurogenesis

To test the hypothesis of the inverted-U shaped relationship of GCs, we injected CORT to mice in a temporal and dose-dependent manner mimicking the exercise-evoked CORT response. Initially, we determined the kinetics of circulating CORT levels by exogenous injections of CORT at various doses. Results showed that serum levels of CORT elevated within 30 min and resumed to basal level 90 min after the injection [Figure 3]. At the 30-min time point, the average circulating level of CORT of mice that received 0.5 mg/kg CORT injection was around 200 ng/mL, similar to those of the TR mice [Figure 1]. After a 4-week daily administration of CORT at doses of 0.25, 0.5, and 2 mg/kg, the basal levels of circulating CORT in these mice were similar to those mice that received a daily injection of vehicle [P = 0.742, one-way ANOVA, [Figure 4]a. Furthermore, daily injection of CORT for 4 weeks at 0.5 mg/kg, inducing an increment of CORT comparable with that evoked by TR, or lower (0.25 mg/kg) did not alter the number of BrdU+/DCX+, BrdU+, or DCX+ cells in the dDG of mice [Figure 4]. On the other hand, mice that received daily injection of CORT at a relatively large amount (2 mg/kg) had reduced number of BrdU+/DCX+ and DCX+ cells in their dDG [[Figure 4]b, P = 0.033; [Figure 4]d, P = 0.027]. These results suggest that elevation of CORT alone is not sufficient to elicit AHN.{Figure 3}{Figure 4}


Excess GC signaling hampers AHN.[11],[12],[29] However, long-term regular exercise elevates circulating GCs and enhances AHN.[16],[17],[18] To explore the exercise-GC paradox, we adopted the unique phenotype of L/L transgenic mice which exhibit normal levels of CORT without a dramatic response after stress stimulation. Our results strongly suggest that the elevated CORT promotes long-term exercise-induced AHN. These results are in agreement with previous findings that eradicating GCs by ADX reduced treadmill exercise-enhanced AHN in mice.[22] Interestingly, exogenous administrations of CORT mimicking the temporal and dose responses of exercise-related elevation of CORT failed to enhance AHN; whereas, administrations of CORT at large amount suppressed AHN. Taken together, our results showed that exercise-elicited secretion of CORT enhanced exercise-induced AHN. Low levels of CORT were not sufficient to cause AHN, while high levels of CORT inhibited AHN.

In the brain, GCs primarily bind to the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR); the latter has higher affinity for GCs than the former.[30] Although the granule cells in the DG express both GR and MR, relatively few newborn progenitor cells express GR.[31] It has been shown that long-term treadmill exercise reduces the expression of hippocampal MR and pharmacologically blocking MR by its antagonist spironolactone further increases the number of exercise-induced elevations of neuronal precursor cells in the DG.[22] Furthermore, although low level of cortisol (100 nM) has been found to increase the proliferation of immortalized human hippocampal progenitor cells, these proliferated neural progenitor cells differentiated more toward the astrocyte than the neuronal linage, resulting a net decrease in newborn neurons.[32] Such a phenomenon could also be abolished by the spironolactone.[32] We have determined the expression levels of MR in the dorsal hippocampi of L/L and WT mice and found no significant difference between them (P = 0.440, unpaired Student's t-test, 5 mice each). This piece of evidence further strengthens the notion that the decreased AHN in the L/L-TR mice is caused by low levels of CORT during TR.

In agreement with previous findings,[11],[12],[29] we also found that large dose of GCs inhibited AHN. It has been demonstrated that high concentrations of cortisol (100 μM) decrease the proliferation of immortalized hippocampal progenitor cells via a GR-dependent pathway.[32] Gene expression microarray and pathway analysis revealed that GCs at high concentrations activate serum/GC-inducible kinase (SGK) 1, which inhibits the neurogenic Hedgehog pathway.[33] SGK1 can also potentiate GR activation by increasing GR phosphorylation and GR nuclear translocation.[33] Additionally, autophagic cell death of hippocampal neural stem cells has also been linked to chronic stress and high levels of CORT-suppressed AHN.[34] It has been shown that the CORT-induced autophagic cell death of hippocampal neural stem cells is regulated by SGK3.[34] Albeit, we cannot ignore the possibility that GCs may affect the stem-cell niche neighboring cells or remote targets, which sends afferent projections and/or humoral signals to the subgranular zone of DG. It will be of interest to explore the role of GC signals in AHN in animal models with region- and cell type-specific deletion of GR/MR in future.

It is worthy to mention that CORT also modulates the antidepressant-induced AHN.[35] Fluoxetine, a selective serotonin reuptake inhibitor, is widely used in treating depression.[36] Long-term treatment of fluoxetine is known to increase AHN,[37] which has been linked to its therapeutic effectiveness.[38] Interestingly, fluoxetine-induced AHN is CORT dependent as ADX could eliminate such effect.[35] Restoring the CORT rhythm in the ADX rats resumes the fluoxetine-induced increases in AHN.[35] These results suggest that stimulation of AHN by fluoxetine requires rhythmic change in CORT, which further support that the concentrations and kinetics of GCs play critical roles in exercise-GC paradox of AHN.


We adopted a unique mouse model, which has normal basal level of CORT but a blunted CORT response to exercise, to delineate the role of CORT in exercise-enhanced AHN. We showed that exercise-related CORT release facilitates the exercise-enhanced AHN. Daily administration of CORT for 4 weeks at a frequency and dose evoking the circulating CORT levels similar to that fluctuated during exercise failed to increase AHN. Taken together, our results showed that the exercise-induced CORT contributes to the exercise-enhanced AHN. However, CORT alone is not sufficient to elicit AHN.

Ethical approval

All animal experiments were done in accordance with the National Institutes of Health Guideline for Animal Research (Guide for the Care and Use of Laboratory Animals) and approved by the National Cheng Kung University Institutional Animal Care and Use Committee (ethical approval reference number: 104243).


We thank Dr. Bon-chu Chung (Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan) for the restoration of L/L mouse line.

Financial support and sponsorship

This study was supported by the Ministry of Science and Technology, Taiwan (Grant #: MOST 107-2320-B-006-054-MY3).

Conflicts of interest

There are no conflicts of interest.


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