The potential contribution of light-intensity exercise-induced miR-486a-3p secretion on enhancing empathic behavior in mice

doi:10.21203/rs.3.rs-4859054/v1

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The potential contribution of light-intensity exercise-induced miR-486a-3p secretion on enhancing empathic behavior in mice

https://doi.org/10.21203/rs.3.rs-4859054/v1

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Empathy plays a crucial role in the maintenance of interpersonal relationships among mammals. Remarkably, engaging in light-intensity exercise has been identified as a facilitator of empathic behavior, a phenomenon associated with the upregulation of miR-486a-3p in the insular cortex. However, it remains to cover the contribution of miR-486a-3p and the mechanisms of changing levels of that in the insular cortex with light-intensity exercise. We initially assessed the impact of light-intensity exercise (7.0 m/min, 30 min/day, five days/week for four weeks) on helping behavior, mRNA in their insular cortex, and the secretion of exosomal miR-486a-3p from their gastrocnemius muscle. Subsequently, we explored the effects of a daily intraperitoneal injection of miR-486a-3p mimic over a two-week period on helping behavior. The intervention of light-intensity exercise, which enhanced helping behavior, resulted in elevated levels of miR-486a-3p in the insular cortex and exosomal miR-486a-3p in the plasma. Interestingly, there was no significant change observed in the levels of gastrocnemius muscle-derived exosomal miR-486a-3p. Moreover, the administration of mmu-miR-486a-3p mimic exhibited a similar enhancement of helping behavior in mice. Notably, both the exercise intervention and miR-486a-3p mimic treatment led to the downregulation of Pten mRNA and upregulation of Bdnf mRNA in the insular cortex. Our findings suggest that the increase in exosomal miR-486a-3p, originating from a source other than the gastrocnemius muscle, contributes to the empathy enhancement induced by light-intensity exercise. Furthermore, it is proposed that miR-486a-3p mimics the effects of light-intensity exercise, presenting a potential avenue for treating empathy-related behaviors.

Helping behavior

Exercise

Exosome

miR-486a-3p

Bdnf

Empathy, intricately tied to perspective-taking and emotional contagion [1], denotes the capacity to discern and engage with the emotions of others, fostering interpersonal connections [2, 3]. The decline in empathy is not only a catalyst for diminished prosocial behavior [4] but also constitutes a significant pathophysiological factor in individuals with autism spectrum disorder [5], emphasizing the pivotal role of human empathy as a crucial clinical focus. Notably, empathic behavior extends beyond the human domain, manifesting in other mammals, exemplified by rodents' helping behavior [6]. Consequently, employing behavioral tests in animal experiments proves valuable for devising innovative strategies aimed at augmenting empathy.

Exercise emerges as a prospective approach for empathy treatment, as prior research has indicated its potential to amplify both empathic behavior and the neuronal systems associated with empathy [7, 8]. Our investigation unveils a correlation between regular physical activity levels and heightened empathy in healthy young adults [9–12], suggesting the susceptibility of empathy to exercise. Notably, brain-derived neurotrophic factor (BDNF), a neuropeptide implicated in neuroplasticity enhancement, has been linked to empathic behavior as well as oxytocin [13, 14]. The upregulation of BDNF expressions in the insular cortex, a brain region intricately tied to empathy, is posited as a catalyst for the augmentation of empathic behavior [15]. Recent studies propose that light-intensity exercise intervention fosters empathic behavior through increased BDNF expressions in the insular cortex [16, 17]. This exercise regimen would hold promise as an optimal therapeutic strategy for enhancing empathy, not only in healthy individuals but also in autism spectrum disorders patients with motor impairments [18]. However, the precise mechanisms underlying the effects of exercise remain inadequately understood, necessitating further exploration to devise efficient strategies for empathy treatment.

The impact of exercise on the brain is influenced not only by intrinsic brain mechanisms but also by the biochemical factors secreted from peripheral organs, such as “exerkines” [19, 20]. A number of studies proposed that the release of exosomes constitutes a key mechanism underlying the effects of exercise. Exosomes, small extracellular vesicles ranging from 40 to 160 nm, are secreted by various organs and contain microRNAs (miRNAs). These miRNAs, short non-coding RNAs approximately 21–25 nucleotides in length, bind to complementary regions of messenger RNAs (mRNAs), leading to mRNA degradation or the inhibition of translation [21]. Notably, some indications suggest that exercise-induced exosomal miRNAs released from muscles enhance biological and physiological functions not only in peripheral organs but also in the brain [22–24]. Additionally, previous studies have suggested that miRNAs derived from adipocytes and mesenchymal stromal cells contribute to the enhancement of brain function and neuroplasticity [25, 26]. Therefore, it is crucial to investigate peripheral organs-to-brain crosstalk to understand the detailed mechanisms underlying the effects of exercise.

A previous study has documented that light-intensity exercise intervention, known to augment empathy, results in an increase of miR-486a-3p along with the upregulation of Bdnf mRNA levels in the insular cortex [16]. The miR-486a-3p is recognized for its involvement in the growth of various cells and its suppression of mRNA levels in phosphatase and tensin homolog (Pten) [27, 28], a major tumor suppressor gene. PTEN serves as a down-regulator of the PI3K/AKT signaling pathway and influences BDNF expressions [29, 30]; thus, the elevation of miR-486a-3p levels in the insular cortex constitutes an underlying mechanism for the light-intensity exercise-induced enhancement in empathic behavior. However, it remains unclear whether miR-486a-3p derived from peripheral organs contributes to the effects of light-intensity exercise on empathy.

Here, our initial examination focused on evaluating the impact of light-intensity exercise intervention on the helping behavior, indicative of empathy, in mice, along with the secretion of exosomal miR-486a-3p from muscles. Subsequently, we delved into an investigation of the effects of daily intraperitoneal injections of mmu-miR-486a-3p mimic on empathic behavior in mice.

Animals

Male C57BL/6J mice, eight weeks of age, were procured from SLC Inc. (Japan) and were accommodated in a controlled environment with temperatures maintained between 21–23℃, operating on a 12-hour light/dark cycle (lights on from 8 AM to 8 PM). These mice had access to a standard pellet diet (Rodent Diet CE-2, CLEA Japan Inc., Japan) and water ad libitum. The experiments were reviewed and approved by the Gunma University Animal Care and Experimentation Committee (approval No. 22 − 012).

Exercise training

After a week of acclimatization to the housing environment, the mice were divided into exercise groups and non-exercise (sedentary) groups. Mice in the exercise group underwent running habituation on a forced exercise wheel bed without electric stimulation, ranging from 3.0 to 7.0 m/min for 30 min/day, five days/week, with two consecutive days of training followed by three consecutive days of training next to a rest day, spanning one week. Subsequently, they engaged in light-intensity exercise at 7.0 m/min on the same equipment for 30 min/day, five days/week, over a period of three weeks [16]. All sessions were conducted during the light period (from 8 AM to 10 AM). Helping behavior tests were administered to both exercise and sedentary groups for five days, concurrently with the exercise regimen during the fourth week.

Intraperitoneal injection of mmu-miR-486a-3p mimic

Following one week of acclimatization to the housing environment, the mice were divided into miR-486a-3p mimic-treated and non-treated (vehicle) groups. The mice in miR-486a-3p mimic-treated groups received daily intraperitoneal injections of mmu-miR-486a-3p mimic for 2 weeks. An 80 nmol/l solution of mmu-miR-486a-3p mimic was prepared by diluting it in 0.9% saline with 0.02% TE buffer. Mice received an injection of 10 µl/g body weight of the solution during the light period (0.8 nmol/kg body weight, once a day from 8 AM to 9 AM). Saline (Otsuka Pharmaceutical Factory, Japan) with 0.02% TE buffer was used as the vehicle. These mice did not undergo exercise training. The empathic behavior test was conducted for five days following a two-week treatment period.

Empathic behavior test

Experimental equipment previously described was used to test empathic behavior [16, 31]. Empathy-like behavior was defined as the act of door-opening to help a cage mate. The behavioral test took place from 7 AM to 8 AM, with all mice undergoing a four-day training period to learn the door-opening behavior using the empathy test equipment. On the fifth day, the mice were tested. Both learning and testing sessions lasting 3 min per mouse. During the test, a mouse was positioned in the ground area, while its cage mate was situated in the water pool area. The helping behavior of the mouse in the ground area was recorded for 3 min. Earlier instances of door opening indicated higher empathy in mice. It is crucial to note that cage mates in the water pool area were not subjected to an evaluation of helping behavior.

Tissue preparation

Two days after the testing session of the empathic behavior test, mice were anesthetized using isoflurane (Dainippon Sumitomo Pharma Co., Japan), and the blood samples were obtained from cardiac puncture. Subsequently, the insular cortex was collected and preserved in RNAlater™ Stabilization Solution (Invitrogen™, USA). The collected blood samples were put into microtubes with EDTA-2K (MHT-02; Health Wave Japan Inc., Japan), and then plasma was separated by centrifugation at 3,000 rpm. These samples were stored at -20℃ for subsequent biochemical analysis. Additionally, gastrocnemius muscle and plasma were collected and utilized for the extraction of exosomes.

Extraction of RNAs and exosomal miRNAs

According to the manufacturer's instructions, total RNAs and miRNAs were extracted from the tissue of the insular cortex utilizing the RNeasy Mini Kit and the miRNeasy Micro Kit (Qiagen Inc., USA), respectively. Gastrocnemius muscle tissues obtained from mice were immediately incubated in DMEM (Gibco-Thermo Fisher Scientific Inc., USA) supplemented with 10% of exosome-depleted FBS (EXO-FBSHI-50A-1; SBI LLC., USA) and 1% of Pen-Strep-Glutamine (Gibco-Thermo Fisher Scientific Inc., USA) for 24 hours in a humidified incubator at 37°C and 5% CO₂. The medium was then collected and filtered through 22 µm filters. Gastrocnemius muscle-derived exosomes in the medium were then precipitated using Exo-Prep (HBM-EXP-C25; HansaBioMed Life Sciences, Estonia). On the other hand, exosomes in plasma samples were precipitated using Exo-Prep (HBM-EXP-B5; HansaBioMed Life Sciences, Estonia). Subsequent to precipitation, miRNAs were extracted from the isolated exosomes using the miRNeasy Micro Kit (Qiagen Inc., USA).

Real-time PCR

Following the extraction of RNAs from the insular cortex, DNase I treatment was performed, and RNA quantification was conducted using the Qubit 4.0 (Invitrogen™, USA). For detection of the mRNA levels in the insular cortex, 1000 ng of RNA underwent reverse transcription to cDNA using the GeneAce cDNA Synthesis Kit (Nippon Gene, Japan). Subsequently, the mRNA levels of target genes were measured using 5.0 ng of cDNA, primers for each target gene, and the PowerTrack™ SYBR™ Green Master Mix in the StepOne Plus Real-Time PCR 96-well system (Thermo Fisher Scientific Inc., USA). The sequences of primers (forward and reverse) used in the current study are as follows: Pten, TGGCGGAACTTGCAATCCTCAGT, and TCCCGTCGTGTGGGTCCTGA; Bdnf, GATGAGGACCAGAAGGTTCG, and GATTGGGTAGTTCGGCATTG; Trkb, TGACGAGTTTGTCCAGGAGA, and TTGCTGCTCTCATTGAGGC; Creb1, TCAGCCGGGTACTACCATTC, and TCTCTTGCTGCTTCCCTGTT; β-actin, TATGCCAACACAGTGCTGTCTGG, and TACTCCTGCTTGCTGATCCACAT. The relative levels of each mRNA were calculated using the ΔΔCT method and normalized by β-actin mRNA levels.

Following the extraction of miRNAs from the insular cortex and exosomes, DNase I treatment was performed, and miRNA quantification was conducted using the Qubit 4.0 (Invitrogen™, USA). For the detection of miRNA levels in the insular cortex, gastrocnemius muscle- and plasma-derived exosomes, ten ng of miRNA was reverse transcribed to cDNA using the Taqman™ MicroRNA Reverse Transcription Kit and the Taqman™ MicroRNA Assay (miR-486a-3p: 002093, and U6 snRNA: 001973; Thermo Fisher Scientific Inc., USA). Then, miR-486a-3p and U6 levels were measured using 0.67 ng of cDNA, the Taqman™ MicroRNA Assay, and the Taqman™ Fast Advanced Master Mix in the StepOne Plus (Thermo Fisher Scientific Inc., USA). The relative levels of miR-486a-3p were calculated by ΔΔCT method and normalized by U6 snRNA levels.

Statistical analysis

Data are expressed as mean ± standard error (SEM) and were analyzed using Prism version 10 (MDF, Japan). Before analyzing comparisons between groups, we checked the normality of raw data distribution using histograms. When the data were normally distributed, parametric tests (unpaired t-test) were used for statistical analyses. If we could not confirm that data were distributed normally, non-parametric tests (Mann-Whitney test) were used for statistical analyses. On the other hand, before analyzing correlations, we checked the normality of raw data distribution by Kolmogorov-Smirnov test. When the data were normally distributed, Pearson correlation was used for statistical analyses. If the data were not distributed normally, Spearman correlation was used. Statistical significance was set at p < 0.05.

The effects of light-intensity exercise on empathic behavior and miR-486a-3p levels

The mice with light-intensity exercise intervention showed significant shorter duration until the door opening compared to the sedentary mice (Fig. 1A; p = 0.0247). While levels of gastrocnemius muscle-derived exosomal miR-486a-3p were no difference (Fig. 1B; p = 0.2823), there were significant higher levels of plasma exosomal miR-486a-3p in the mice with light-intensity exercise than that in the sedentary mice (Fig. 1C; p = 0.0485). Furthermore, miR-486a-3p levels in the insular cortex were significantly higher in the mice with light-intensity exercise than that in the sedentary mice (Fig. 1D; p = 0.0062), demonstrating a correlation trend with door opening (Fig. 1E; r = -0.5071, p = 0.0562). The plasma exosomal miR-486a-3p levels exhibited a correlation trend with the miR-486a-3p levels in the insular cortex (Fig. 1F; r = 0.4496, p = 0.0927), but did not show a correlation trend with the gastrocnemius muscle-derived exosomal miR-486a-3p levels (Fig. 1G; r = -0.2789, p = 0.3141).

The effects of light-intensity exercise on mRNA levels in the insular cortex

The mice with light-intensity exercise intervention showed significant lower levels of Pten mRNA in the insular cortex compared to the sedentary mice (Fig. 2A; p = 0.0306). Additionally, Bdnf mRNA levels in the insular cortex were significantly higher in the mice with light-intensity exercise than that in the sedentary mice (Fig. 2B; p = 0.0401). However, the insular cortical mRNA levels of Trkb and cAMP response element binding protein (Creb1), acting as the receptor and downstream factor for BDNF, respectively, were no difference between two groups (Fig. 2C and D; Trkb: p = 0.0661, Creb1: p = 0.0668). Furthermore, Fndc5, a BDNF modulator, did not show difference (Fig. 2E; p = 0.2290).

The changes of empathic behavior, miR-486a-3p levels, and mRNA levels with intraperitoneal injection of miR-486a-3p mimic

As well as the effects of light-intensity exercise intervention, the mice received daily intraperitoneal injection of miR-486a-3p mimic showed significant shorter duration until door opening compared to the non-treated mice (Fig. 3; p = 0.0097). There was a trend towards increased levels of plasma miR-486a-3p in the mice treated with miR-486a-3p mimic compared to the non-treated mice (Fig. 4A; p = 0.0658). Additionally, miR-486a-3p levels in the insular cortex were significant higher in the mice treated with miR-486a-3p mimic than that in the non-treated mice (Fig. 4B; p = 0.0131). The mice treated with miR-486a-3p mimic also showed significant lower Pten mRNA levels in the insular cortex than the non-treated mice (Fig. 4A; p = 0.0144). The mRNA levels of Bdnf, Trkb, and Creb1 in the insular cortex were significant higher in the mice treated with miR-486a-3p mimic than that in the non-treated mice (Fig. 4B; Bdnf: p = 0.0232, Trkb: p = 0.0001, Creb1: p = 0.0068). Conversely, Fndc5 mRNA levels did not show difference (Fig. 4E; p = 0.1051).

In the current study, we investigated the involvement of muscle-derived exosomal miR-486a-3p in the light-intensity exercise-induced enhancement of empathic behavior in mice. Our findings indicated that the mice with light-intensity exercise intervention showed significant higher levels of exosomal miR-486a-3p in plasma than the sedentary mice, while there is no significant difference observed in gastrocnemius muscle-derived exosomal miR-486a-3p levels. Furthermore, the mice with exercise intervention showed significant higher levels of miR-486a-3p and Bdnf mRNA in the insular cortex compared to the sedentary mice, concomitant with the better helping behavior. Moreover, the mice received daily intraperitoneal injection of miR-486a-3p mimic showed significant better helping behavior in mice, mimicking the effects observed with light-intensity exercise intervention.

The current result (Fig. 1A) revealed an enhancement of helping behavior with light-intensity exercise, aligning with previous observations in young adults and rodents [10, 16, 17]. This suggests that light-intensity exercise intervention would hold promising potential for the treatment of empathy. Consistent with other reports [16], the current study also confirmed an increase of miR-486a-3p in the insular cortex with the light-intensity exercise regimen, which was associated with empathic behavior (Fig. 1D and E). Exercise-induced upregulation of circulating exosomal miR-486 levels has been previously reported [23], and the current exercise regimen significantly elevated exosomal miR-486a-3p levels in plasma (Fig. 1C). Additionally, the plasma exosomal miR-486a-3p levels showed a correlation trend with the miR-486a-3p levels in the insular cortex (Fig. 1F), suggesting that increased plasma exosomal miR-486a-3p may contribute to higher miR-486a-3p levels in the insular cortex. In contrast, the exosomal miR-486a-3p levels derived from the gastrocnemius muscle remained unchanged (Fig. 1B) and did not correlate with the plasma exosomal miR-486a-3p levels (Fig. 1G). Although it is essential to investigate exosome secretion from other types of muscles (e.g., plantaris, such a major fast-twitch muscle), our current results suggest that peripheral organs other than muscles may contribute to the elevation of exosomal miR-486a-3p levels in plasma. Exercise has the potential to alter the profiles of exosome secretion not only from muscles but also from various organs [32, 33]. Further, prior reports have proposed that exosomal miRNAs, such as miR-9-3p derived from adipocytes and miR-132-3p derived from mesenchymal stromal cells, play a role in promoting brain function and neuroplasticity [25, 26]. Future studies should explore the changes in the secretions of exosomal miR-486a-3p from organs and cell types other than muscles with the current exercise regimen.

The current exercise regimen resulted in the upregulation of miR-486a-3p levels and the downregulation of Pten mRNA levels in the insular cortex (Fig. 2A). Additionally, exercise intervention significantly increased Bdnf mRNA levels in the insular cortex (Fig. 2B). Notably, miR-486a-3p is recognized as a suppressor of Pten mRNA [27, 28], and the knockdown in PTEN expression contributes to an increase BDNF expression in the brain [30]. Consequently, the elevated levels of Bdnf mRNA with exercise in the current study would occur through the PTEN/BDNF pathway. The miR-486a-3p is also predicted as a potential modulator for Fndc5 on miRDB (http://www.mirdb.org); FNDC5 enhances BDNF expressions [34]. However, mRNA levels of Fndc5 remained unchanged in the insular cortex (Fig. 2E). These results imply that the current exercise regimen increases Bdnf mRNA levels through the PTEN/BDNF pathway but not the FNDC5/BDNF pathway in the insular cortex. To date, oxytocin has been considered a pivotal molecule in empathy [35], modulating neuronal plasticity in the insular cortex [36, 37]. Conversely, some prior studies have reported uncertain effects of oxytocin on empathy [38, 39]. Based on our findings, miR-486a-3p emerges as a novel molecule with the potential to treat empathy, offering an innovative approach to therapeutic strategies compared to oxytocin.

The daily intraperitoneal injection of mmu-miR-486a-3p mimic enhanced empathic behavior in mice with upregulation of miR-486a-3p levels in their insular cortex (Figs. 3 and 4). Furthermore, miR-486a-3p mimic treatment resulted in reduced Pten mRNA levels and increased Bdnf mRNA levels in the insular cortex (Fig. 4A and B). These findings suggest that miR-486a-3p holds the potential to mimic the effects of light-intensity exercise in treating empathy. In the current study, we focused on the effects of intraperitoneal injection; thus, further investigation is necessary to elucidate the action mechanism using local injection of miR-486a-3p mimic into the insular cortex. While Trkb and Creb1 mRNA levels in the insular cortex remained unaltered with light-intensity exercise intervention (Fig. 2C and D), miR-486a-3p mimic treatment significantly increased these mRNA levels in the insular cortex (Fig. 4C and D). Exercise induces complex physiological alterations, and changes in TrkB levels with exercise are indeterminate [40, 41]. Given that PTEN is a down-regulator of the PI3K/AKT signaling pathway [29] and the activation of PI3K/AKT signaling contributes to enhancing BDNF and TrkB expressions in neuronal cells [42], a straightforward treatment, such as an injection of miR-486a-3p mimic, might be more effective in increasing Trkb mRNA compared to exercise intervention.

The current study has some limitations. Firstly, it's important to note that the current study demonstrated a restricted approach of analyzing only miR-486a-3p and evaluated its relative expressions but not absolute number of copies. Thus, further studies should address this aspect comprehensively. Second, our focus was limited to the insular cortex in the present study, neglecting other brain regions and their sub-regions associated with empathic behavior. Future investigations are warranted to explore these brain regions and their connections with the insular cortex. Finally, we exclusively measured mRNA levels, lacking information on protein levels and phosphorylation. It is imperative to delve into these aspects to elucidate the mechanism underlying the empathy-enhancing effect.

In conclusion, our current findings represent the first demonstration that light-intensity exercise intervention enhances empathic behavior with an increase in exosomal miR-486a-3p in the plasma, but not in gastrocnemius muscle-derived exosomal miR-486a-3p levels. Furthermore, the treatment of miR-486a-3p mimic enhanced empathic behavior in mice, suggesting that the secretion of exosomal miR-486a-3p, originating from a source other than the gastrocnemius muscle, contributes to the effects of light-intensity exercise in treating empathy. These findings have the potential to advance and develop innovative therapeutic strategies for the treatment of empathy.

Funding:

This research has been supported by the Uehara Memorial Foundation, and the Meiji Yasuda Life Foundation of Health and Welfare.

Data availability:

The datasets in the current study are available from the corresponding author on reasonable request.

Declaration of competing interest

The authors inform no conflicts of interest.

Author contribution

TS: Conceptualization, Methodology, Resources, Investigation, Writing–original draft, Writing–review & editing, Funding acquisition; KY, YY and CT: Investigation, Writing–review & editing.

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The potential contribution of light-intensity exercise-induced miR-486a-3p secretion on enhancing empathic behavior in mice

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Version 1

Abstract

Figures

Introduction

Materials and methods

Animals

Exercise training

Intraperitoneal injection of mmu-miR-486a-3p mimic

Empathic behavior test

Tissue preparation

Extraction of RNAs and exosomal miRNAs

Real-time PCR

Statistical analysis

Results

The effects of light-intensity exercise on empathic behavior and miR-486a-3p levels

The effects of light-intensity exercise on mRNA levels in the insular cortex

Discussion

Declarations

References

Additional Declarations

Status:

Version 1