- Rodent models have been instrumental in deciphering how central, or brain related, mechanisms affect physical activity behavior.
- To date, we and others provide evidence from rodent models to suggest that dopaminergic signaling from the ventral tegmental area to the nucleus accumbens, in part, regulates physical activity behavior.
- Other literature suggests that peripheral signals (i.e., circulating tissue-kines and hormones) also may affect physical activity behavior.
- Future research using rodent models will be crucial in understanding mechanisms that influence physical activity behavior, and such research can be leveraged to increase widespread physical activity participation.
Editor's note: Go online to view the Video Abstract in the Supplemental Digital Content: seehttp://links.lww.com/ESSR/A38.
Habitual sedentary behavior is a catalyst for cardiometabolic diseases, as well as an accelerated loss in muscular strength and aerobic capacity (5). Inadequate daily physical activity also can be detrimental to psychological health and cognition (10) and can even contribute to the development of some types of cancers (46). It is therefore not surprising that individuals who engage in minimal daily levels of physical activity exhibit increased mortality rates compared with individuals who engage in higher daily levels of moderate to vigorous daily physical activity (5).
Recent figures estimate that 58% of children aged between 6 and 11 yr fail to obtain the recommended 60 min·d−1 of physical activity and that 92% and 95% of adolescents and adults, respectively, fail to achieve a minimum standard of 30 min·d−1 (43). Hence, we posit that voluntary sedentarism is a widespread epidemic and suggest that research efforts should be aimed at increasing physical activity. To date, our research group and others have used rodent models to elucidate mechanisms in the brain that, in part, regulate physical activity behavior. Moreover, others have used rodent models to suggest that peripheral mechanisms contribute to physical activity behavior. Importantly, we hypothesize that central and peripheral mechanisms that regulate brain centers are critical in affecting physical activity behavior, and this review discusses literature related to this hypothesis.
Brain Dopamine and Opioid Signaling Are Associated With Physical Activity Behavior
Brain reward centers (Fig.) are critical for survival given their role in regulating natural reward states that reinforce feeding, fluid intake, and mating behaviors. Because physical activity, via migration and food seeking, was essential for hunter-gatherer survival in the evolutionary sense, these same brain reward centers likely contribute to physical activity behavior. The striatum is a subcortical region of the forebrain that receives glutamatergic and dopaminergic signals from other brain regions and is thought to be a hub for behaviors associated with reward. The nucleus accumbens (NAcc) is an aggregate of predominantly medium spiny neurons (MSNs) located within the ventral striatum that express D1-type (DRD1, DRD5) and/or D2-type (DRD2, DRD3, DRD4) dopamine receptors (41). The characteristics of D1 versus D2 NAcc neurons are elaborate and beyond the scope of this review, albeit it is notable that 40% of NAcc MSNs can coexpress D1- and D2-type receptors. What is well known is that dopaminergic signaling in both neuronal cell types has been linked to the reward response to drug use. For instance, earlier research has reported that administering the neurotoxin kainic acid to ablate NAcc neurons significantly reduces morphine self-administration (11). Subsequent evidence suggests that the NAcc is activated through dopaminergic signaling when rodents are administered cocaine, amphetamines, alcohol, opiates, and nicotine (9).
Select rodent studies also have demonstrated that, similar to drugs of abuse, increased physical activity through voluntary or forced exercise initiates dopaminergic signaling in the NAcc. For instance, a single bout of treadmill exercise increases NAcc dopamine concentrations (15) as well as NAcc D1 receptor-mediated signaling (i.e., Fos transcription factor expression) (22). Voluntary wheel running over 30 d also has been shown to increase the NAcc expression of the ΔFosB transcription factor in rats (45), which also is observed after multiple bouts of cocaine and amphetamine use. Whether increased dopaminergic signaling in the NAcc is a consequence of exercise or acts to reinforce physical activity participation is debatable. However, a compelling argument for the latter is evidence demonstrating that the overexpression of ΔFosB in the NAcc neurons, which is induced by dopaminergic signaling, doubled voluntary running distance in mice over a 21-d period (45). Furthermore, more recent studies have used selective knockout models to demonstrate that dopaminergic signaling in the NAcc regulates physical activity behavior. For instance, Zhu et al. (47) used D1- and D2-Cre mice together with designer receptors exclusively activated by designer drugs (DREADD). When an adeno-associated virus-expressing Gq (hM3Dq)- or Gi (hM4Di)-coupled Cre-inducible DREADD was injected into the NAcc of D1- or D2-Cre mice, activation or inhibition of each population of NAcc neurons could be achieved. Interestingly, the authors reported that the activation of D1 NAcc neurons increased voluntary wheel running by ~20%, whereas activation of D2 neurons drastically reduced voluntary wheel running (~80%). Beeler et al. (3) subsequently reported D2 receptor-knockout mice exhibited greater than 10-fold reduction in voluntary wheel running over a 14-d period. Although the results of these two studies report opposite effects with regard to D2 receptor activation increasing and decreasing voluntary wheel running, respectively, both studies implementing selective dopamine receptor knockout models demonstrate that dopaminergic signaling in the NAcc, in part, dictates physical activity behavior.
The recent use of selective breeding models for physical activity behavior has provided additional evidence that NAcc dopaminergic signaling is associated with physical activity participation. Theodore Garland's laboratory was the first group to selectively breed mice that ran high voluntary distances (HR mice). We subsequently developed a line of high voluntary runner rats (HVRs) which will be discussed in greater detail below. Although their methodology of selection is beyond this review and described elsewhere (40), a brief synopsis is that it involved housing four lines of mice (10 families per line) in cages with access to activity wheels for a period of 6 d, and selection was based on the mean number of revolutions run on days 5 and 6. The 10 most active male and female mice per line were mated to create 10 families of HR, and offspring from these families were tested in a similar fashion to identify breeders for the next generation. Select studies that used Garland’s HR mice reported that a) intraperitoneal injections of Ritalin (methylphenidate; a dopamine reuptake inhibitor) and apomorphine (a nonselective dopamine agonist) decrease voluntary wheel running in HR mice versus control mice (28) and b) HR mice present significantly greater NAcc dopamine levels compared with control and obesity-prone mice in one study (24), albeit dopamine and dihydroxyphenylacetic acid levels were lower in other brain areas (i.e., the dorsal raphe nucleus and substantia nigra, respectively) in HR versus control lines in a different study (44).
Subsequent to the advent of Garland’s HR mouse line, our group established a selective breeding paradigm that generated HVR Wistar rats as well as rats that exhibited a low motivation to voluntarily run (i.e., LVR rats). Although we were interested in examining the molecular phenomena that contribute to the high running participation in HVR rats, our rationale for generating LVR rats was to examine the polygenic or polymolecular phenomena that promulgates sedentary behavior. Our selective breeding protocol was similar to Garland’s and is described in greater detail elsewhere (30), with exceptions being that a) we generated only one HVR and LVR line (13 families per line) and b) Garland did not generate LR mice, whereas we did not generate control lines. In our first publication describing the phenotypic differences between these lines, we reported that the 34-d-old generation 9 (G9) male and female HVR rats voluntarily run ~6.2 km per night, whereas LVR rats run ~0.6 km per night when given running wheel access for 6 d (30). It should be noted, however, that when wheel running access is provided for longer durations (i.e., 9 wk), G13 female HVR rats averaged more than 20 km per night, whereas female LVR rats averaged less than 3 km per night (36).
Similar to Garland’s approach, we embarked on a series of studies to examine NAcc features that differed between the HVR and LVR lines. In the first study, we reported that D1 receptor agonist and antagonist injections into the NAcc reduced nightly wheel running distance in G4 HVR rats, whereas these drugs did not affect nightly running in G4 LVR rats (31). From these data, we hypothesized that NAcc dopamine signaling sensitivity may be higher in the HVR line, and dopamine-related drug infusions in the HVR rats may have promulgated a reward signal to the NAcc, which reduced running. A follow-up study by our group (32) reported the transcriptome-wide differences that existed in the NAcc of G8-10 HVR versus LVR rats that were a) housed in standard rat cages without running wheels and b) housed in rat cages with voluntary running wheels for 6 d. Main findings from this study were a) NAcc “cell cycle”-related mRNA transcripts and Darpp-32-positive neurons (i.e., MSNs) were inherently lower in 28-d-old LVR versus HVR rats before the initiation of running, implying that neuronal maturation in the NAcc (and potentially other reward circuitry–related brain areas) is impaired in the LVR line, and b) the plasticity of select dopamine-related transcripts was lower after 6 d of voluntary wheel running in 34-d-old LVR versus HVR rats, suggesting that the development or reinforcement of reward in response to voluntary running may be impaired in the LVR line. As a side note, when comparing our NAcc transcriptomic profiles with striatal transcriptomic profiles of Garland’s HR and control lines, Saul et al. (37) reported that serotonin neurotransmission (Htr1b), glutamate signaling (Slc38a2), and G-protein–coupled receptor signaling (Gpr3) also may influence physical activity behavior given the high correlation between the expression of these genes in the striatum and wheel running levels.
Brown et al. (6) subsequently examined the effects of intraperitoneal cocaine administration on locomotor behavior in our G9-10 HVR and LVR rats housed without running wheels. Interestingly, cocaine administration was effective at increasing locomotor activity in LVR rats in a dose-dependent manner, whereas HVR rats presented an increased but blunted response in locomotion. This finding, again, suggests that HVR rats may inherently possess a heightened sensitivity to NAcc dopamine signaling relative to LVR rats and, because of this trait, cocaine administration or dopamine receptor agonist/antagonist injections reduce locomotor activity and voluntary wheel running behavior. As an interesting side note, the HVR rats exhibited 20% to 30% more ambulatory activity than LVR rats over a 3-d (20 min·d−1) monitoring period before the cocaine administration experiments. Thus, not only are our LVR rats less motivated to voluntarily exercise, but they also are more sedentary in standard housing conditions. Whether this phenomena is partially due to HVR versus LVR differences in factors that dictate exercise ability (i.e., maximal aerobic capacity or biomechanical differences) remains to be determined, albeit it also should be noted that our report is in agreement with Garland’s model in that HR mice also exhibit more home-cage activity versus control line mice (23).
Beyond studying NAcc dopamine-related gene expression and signaling differences between the HVR and LVR rats, we also were interested in studying the effects of NAcc opioid signaling between these lines given that there is ample evidence that opioid administration to rodents rapidly and robustly increases dopamine levels in the NAcc through stimulation of upstream ventral tegmental area (VTA) dopaminergic neurons (20,38). Ruegsegger et al. (36) reported that mu opioid receptor (Oprm1) mRNA was intrinsically threefold greater in the NAcc of HVR compared with LVR rats. Moreover, and similar to D1 agonism and antagonism, Oprm1 agonism and antagonism in the NAcc significantly decreased running in the HVR rats but did not alter running in the LVR rats. In a follow-up study (35), we reported that ablating NAcc neurons with the neurotoxin 6-hydroxydopamine in HVR rats attenuated reductions in wheel running after injection of the opioid receptor antagonist naltrexone. Together, these two studies suggest that higher levels of running observed in HVR versus LVR rats may, in part, also be mediated by increased NAcc opioidergic signaling, which, in turn, may amplify NAcc dopaminergic signaling. Collectively, the aforementioned rodent experiments from our group (summarized in the Table) provide several lines of evidence to suggest that the physical activity behavior is associated with increased dopaminergic and opioidergic signaling in the NAcc.
Peripheral Physiological Mechanisms That Also May Contribute to Physical Activity Behavior
Beyond central mechanisms, there also is evidence that peripheral mechanisms may contribute to physical activity behavior. For instance, the aforementioned study by our group (30) examined the body composition and skeletal muscle phenotypes between G8 HVR and LVR lines with the intent of examining potential peripheral phenotypes that differed between these lines. Interestingly, we observed that 28-d-old LVR rats were 7% to 8% heavier than HVR rats before the initiation of voluntary wheel running, although body fat percentage (assessed via small animal dual x-ray absorptiometry) was similar between lines. We also reported that HVR rats presented ~15% greater oxidative plantaris muscle fibers compared with LVR rats before the initiation of voluntary wheel running, although 6 d of wheel running significantly increased the proportion of oxidative fibers in this muscle in both lines. These findings led us to hypothesize that, although physical activity behavior is associated with the brain’s reward circuitry, other peripheral phenotypes (in this case, muscle fiber type makeup) also may contribute to this behavior.
The skeletal muscle acts as an endocrine organ to secrete hormones or “myokines,” and several of these myokines acutely increase in circulation in response to exercise (26). It is possible that exercise-induced myokines could traverse the blood-brain barrier to initiate a “muscle-brain communication” axis, which affects physical activity behavior. In this regard, it has been posited that the exercise-induced expression and secretion of opioids from the skeletal muscle during exercise may initiate an endurance athlete’s “runner’s high” that operates through opioid-mediated signaling in brain reward centers and reinforces exercise behavior (4). Furthermore, the exercise-induced expression and secretion of interleukin 6 from the skeletal muscle has been extensively documented, and this has led some to posit that this myokine can cross the blood-brain barrier to affect brain metabolism via ligand binding (27). The latter phenomena may not directly relate to peripheral mechanisms contributing to physical activity behavior, albeit it does provide a proof-of-concept model whereby exercise-induced myokine secretion may affect reward signaling cascades in certain brain regions to modulate this behavior.
Akin to the skeletal muscle, adipose tissue acts as an endocrine organ and secretes adipokine hormones that have systematic physiological effects. Leptin has historically been a well-studied adipokine because of its role in regulating appetite and thermogenesis. Notably, there is a rise in leptin secretion with an increase in adiposity, and it has been documented that leptin can cross the blood-brain barrier to affect hypothalamic signaling (2). In the context of peripheral signals that affect physical activity behavior, leptin is a compelling candidate to consider given that a) dopaminergic VTA neurons express leptin receptors (13), b) the direct administration of leptin into the VTA reduces neuronal firing rates and, thus, dopamine output to efferent synapses (16), and c) the long-term RNAi-mediated knockdown of the leptin receptor in the VTA has been shown to increase locomotor activity (16). Moreover, within Garland’s HR mice line, higher circulating leptin levels were negatively correlated with the amount and speed of voluntary wheel running (14). These data collectively form a hypothetical model subject to future research that links obesity, high circulating leptin levels, and a decrease in VTA-NAcc signaling with a decrease in physical activity participation. Adiponectin, an adipokine associated with positive health benefits (i.e., increased insulin sensitivity and reduced inflammation), also is an attractive candidate as a modulator of physical activity behavior. For instance, circulating adiponectin is 60% greater in Garland’s HR versus control mouse lines, suggesting that higher blood levels may be linked to higher physical activity participation levels (18). However, others have reported that the intracerebroventricular injection of adiponectin transiently reduces locomotor activity in rats (25). Moreover, unlike leptin, adiponectin likely does not cross the blood-brain barrier (39), making the link between this adipokine and reward signaling in the brain difficult to rationalize. Notwithstanding, and given the interesting links that exist between myokines/adipokines and potential brain signaling phenomena, future research should examine the roles that these molecules have in contributing toward physical activity behavior.
The potential hormonal influence on physical activity behavior also should be noted. In this regard, Timothy Lightfoot (21) authored an excellent review citing his and others’ original research, which demonstrates that estrogen, progesterone, and testosterone levels, in part, regulate daily physical activity levels. Specific highlights of this review were as follows: a) in rodents, females present 20% to 55% greater physical activity compared with male counterparts, and this may be due to the effects that estrogen (or ovarian function) has on physical activity motivation, b) one study of 17β-estradiol implantation into the medial preoptic area and anterior hypothalamus increased wheel running activity in ovariectomized female rats (12), and c) testosterone propionate (100 μg·d−1) and estradiol (10 μg·d−1) injections increased running wheel activity in castrated male rats, whereas dihydrotestosterone propionate injections did not (34); these results implicate that the effects of testosterone on increasing physical activity may be due to its aromatizing into estrogen. What also is noted by Lightfoot in his review is research illustrating that estrogen can enhance dopaminergic signaling in the NAcc within minutes of exposure (42), which links the peripheral action of estrogens to physical activity behavior through dopaminergic signaling in the NAcc.
Future Directions and Conclusions
Research regarding how brain reward circuitry affects physical activity behavior is novel, and several future endeavors remain to be pursued. Notably, although past research from our laboratory and others have focused on the relation between dopaminergic and opioidergic signaling in the NAcc and physical activity participation in rodents, there is evidence from Garland’s mice suggesting that different brain regions such as the dentate gyrus (29) and cerebellum (7) also may contribute to physical activity behavior. Other studies using Garland’s mice report that endocannabinoid antagonism reduces running in HR mice (19), caffeine increases running behavior in HR and control mice (8), and HR mice present lower concentrations of serotonin (or 5-hydroxyindoleacetic acid, a serotonin metabolite) in different brain regions (i.e., the dorsal striatum and substantia nigra) versus control mice (44). Hence, these data collectively suggest that nondopaminergic signaling phenomena in cannabinoid-, serotonin-, and/or caffeine-sensitive brain regions likely contribute to physical participation, and a future direction for exercise physiologists and neuroscientists alike would be to better define the complex brain circuitry that collectively regulates physical activity behavior. As a future direction specific to our LVR line, it would be enticing to identify a pharmaceutical drug that increases long-term physical activity participation. Indeed, the aforementioned article by Saul et al. (37) examining the striatal transcriptomic differences between Garland’s HR and control lines advanced bioinformatics suggests that rottlerin (a protein kinase C δ inhibitor), linifanib (a tyrosine kinase inhibitor), and/or 7-benzylidenenaltrexone (a delta-opioid receptor antagonist) may be candidates to increase running motivation in rodents. However, given our previous findings demonstrating that cocaine also increases locomotor activity in LVR rats (6), we posit that the pursuit of an “exercise motivation drug” could be tenuous given that this hypothetical drug would likely have to operate in a similar fashion to cocaine, opiates, and amphetamines to propagate dopaminergic signaling in the NAcc. Instead, a reasonable future aim in the LVR line would be to decipher how different environmental stimuli potentially affect physical activity participation in the LVR rats. In this regard, we recently published a study examining how daytime treadmill training (5 d·wk−1, 20 min·d−1) affected nightly wheel running in young LVR rats (28 d old before training, 63 d after training) (17). Interestingly, nighttime running increased from less than 0.5 km per night (baseline) to 1.5 km per night by week 5 in the treadmill-trained LVR rats, whereas untrained rats ran less than 0.5 km/night throughout the monitoring period. However, assays on the VTA or NAcc were not performed, and it remains unknown as to whether treadmill training altered molecular or structural features in these brain regions. Notably, similar data in Garland’s HR and control mice suggest that early-life wheel access (for 3 wk postweaning) significantly increased voluntary wheel running in both lines later in life when voluntary running wheels were reintroduced when compared with counterparts that did not have wheel access early in life (1). Thus, these data collectively lend interest in examining how early childhood exercise in humans affects longitudinal physical activity participation into adulthood. Moreover, future work with the LVR rodents could examine if a minimal exercise dose or threshold is needed to “hardwire” neural circuits at a young age and result in lifelong exercise adherence.
In closing, research using mechanistic rodent models has led to a better understanding and appreciation of how the molecular milieu in brain reward centers is related to physical activity behavior. Given the statistics of low physical activity participation along with the evidence that voluntary sedentarism is a major contributor to preventable diseases, future research in this arena can hopefully be translated to humans with the intent of increasing widespread physical activity participation.
The authors thank Tom Childs as well as Drs. Matthew Will, Joe Company, Ryan Toedebusch, and Kevin Wells and other past doctoral and undergraduate students involved with our HVR and LVR experiments. The authors also graciously thank Drs. Theodore Garland and Steve Britton and associated laboratory members for sharing insight into their respective selective breeding models throughout the years.
Partial funding for these projects was obtained from grants awarded to F.W.B. by the College of Veterinary Medicine at the University of Missouri as well as AHA 16PRE2715005 (G.N.R) and the University of Missouri Life Sciences Program (G.N.R. and J.D.B.). This project also was largely supported by anonymous funds donated through the College of Veterinary Medicine’s Development Office.
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