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An inaugural workshop supported by “The Leo and Anne Albert Charitable Trust,” was held October 4–7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimer’s and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain.

Physical inactivity is the fourth leading global cause of death and is a major contributor to metabolic and endocrine diseases. In this review we provide a current update of the past 5 years in the field as it pertains to the most prevalent and deadly chronic diseases. Despite the prevalence of physical inactivity in modern society, it remains largely overlooked relative to other comparable risk factors such as obesity, and our molecular understanding of how physical inactivity impacts metabolism is still partially unknown. Therefore, we discuss current clinical inactivity models along with their most recent findings regarding health outcomes along with any discrepancies that are present in the field. Lastly, we discuss future directions and the need for translatable animal models of physical inactivity to discover novel molecular targets for the prevention of chronic disease.

Neuroinflammation is an early detectable marker of mild cognitive impairment, the transition state between normal cognition and dementia. Resistance-exercise training can attenuate the cognitive decline observed in patients with mild cognitive impairment. However, the underlying mechanisms of resistance training effects are largely unknown. To further elucidate mechanisms of the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training could ameliorate lipopolysaccharide-induced neuroinflammation. Five-week-old female Wistar rats received intracerebroventricular injections of lipopolysaccharides to induce neuroinflammation and cognitive impairment. Rats then underwent 3 wk of progressive ladder climbing to recapitulate resistance-exercise training in humans. Cognition was assessed toward the end of the training period by novelty object recognition testing. Neuroinflammation was measured one and 24 h after the last resistance-exercise training workout. Resistance-exercise training ameliorated cognitive impairment, diminished lipopolysaccharide-induced neuroinflammatory cytokine expression, and attenuated astrocyte remodeling in the dentate gyrus 24 h post exercise. Here, we provide evidence that the ladder-climbing model of resistance-exercise training in rats can improve cognition as early as 3 wk. In addition, these data support the hypothesis that resistance exercise can reduce lipopolysaccharide-induced neuroinflammation in the dentate gyrus.

Understanding the neuro-molecular mechanisms that mediate the quantity of daily physical activity (PA) level is of medical significance, given the tremendous health benefits associated with greater physical activity. Here, we examined the effects of intra-nucleus accumbens (NAc) inhibition of activator protein-1 (AP-1), an important transcriptional factor downstream of cAMP response element binding protein (CREB; a reward-related transcriptional regulator), on voluntary wheel running behavior in wild-type (WT) and low voluntary running (LVR) female rats. Transcriptome analysis of the nucleus accumbens (NAc; a brain region critical for PA reward and motivation) was performed to further determine molecular responses to intra-NAc AP-1 inhibition in these rat lines. Within WT rats, intra-NAc AP-1 inhibition caused a significant decrease in overnight running distance in comparison to control rats (p = 0.009). Transcriptomic and bioinformatic analysis in WT rats identified involvement of gene products that regulate cellular proliferation and development, which were cellular processes regulated by AP-1. In contrast to above decreased WT distances, intra-NAc AP-1 inhibition in LVR rats increased nightly running distance in comparison to LVR control rats (p = 0.0008). Further analysis identified gene products that are associated with regulating intracellular Ca

Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p &lt, 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.

Palatability driven feeding and voluntary physical activity are mediated by and influence similar neural mechanisms, notably through the actions of opioids within the nucleus accumbens. Recent studies suggest that access to a voluntary running wheel results in sex dependent behavioral and physiological adaptations related to opioid mediated palatability-driven feeding. To explore this relationship, male and female Wistar rats were given either access to a voluntary running wheel (RUN group) or no access (SED group) for one week prior to being stereotaxically implanted with bilateral cannulae targeting the nucleus accumbens. Following 7 days of recovery, with RUN or SED conditions continuing the duration of the experiment, all rats were assessed daily (2 h/day) for feeding behavior of concurrently accessible high-carbohydrate and high-fat diet for one week. Following this week, all rats were administered the μ-opioid receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) (0.0025 μg, 0.025 μg, or 0.25 μg/0.5 μl/side) or the opioid antagonist naloxone (20 μg/0.5 μl/side) into the nucleus accumbens and given concurrent access (2 h) to both diets. All groups expressed a significant baseline preference for the high-carbohydrate diet. DAMGO administration, compared to saline treatment, led to significant increased consumption of the high-carbohydrate diet in all treatment groups. While high-fat diet consumption also increased following DAMGO administration, the influence of DAMGO was much more robust for the preferred high-carbohydrate diet in all groups. Compared to males, females consumed significantly more of both diets at baseline and following DAMGO treatment. Both male and female rats in the RUN condition consumed more high-carbohydrate diet compared to rats in the SED condition. While males exhibited similar increased consumption of both diets regardless of RUN or SED condition, females in the RUN condition displayed a greater sensitivity to DAMGO-driven consumption of the preferred high-carbohydrate, compared to SED females.

Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNF-α (~400%) and IL-1β (~1,500%) mRNA ( P < 0.0001) after 6 wk. Five days after LPS injections, half of LPS-injected rats performed RT by ladder climbing for 6 wk, 3 days/wk, whereas half remained without ladders. RT for 6 wk increased lean body mass percentage ( P < 0.05), individual muscle masses (gastrocnemius and tibialis anterior) ( P < 0.05), and maximum lifting capacity ( P < 0.001). The RT group, compared with sedentary controls, had 1) ameliorated spatial learning deficits ( P < 0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, protein kinase B, and GSK-3β proteins ( P < 0.05), components of downstream IGF-1 signaling, and 3) increased dentate gyrus synaptic plasticity marker synapsin protein ( P < 0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-wk training duration, phosphorylation of ERK1/2 and GSK-3β proteins, as well as proliferation marker protein, PCNA, were significantly increased ( P < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus.NEW & NOTEWORTHY The data suggest that resistance-exercise training restores cognitive deficits induced by lipopolysaccharides and can activate associated IGF-1 signaling in the dentate gyrus. Our data show, for the first time, that as few as three resistance-exercise workouts (spread over 1 wk) can activate IGF-1 downstream signaling and increase proliferation marker PCNA in the dentate gyrus.

Considering the current obesity epidemic is due in large part to an energy imbalance, it is crucial to explore biological mechanisms that mediate palatable high energy food intake and physical activity behavior levels. Previous research demonstrates a unique sex dependent influence of physical activity on diet preference, specifically changes in palatable high-fat diet intake. Therefore, factors of motivation may be underlying the differential effect of physical activity in male and female rats on their diet preference. The present study extends this hypothesis by assessing diet preference in male and female Wistar rats selectively bred for high (HVR) and low (LVR) levels of voluntary wheel running distances. HVR and LVR rats were housed under either sedentary (SED) or voluntary wheel running access (RUN) conditions for the duration of the study. Following a 1 week acclimation period to these conditions, standard chow was replaced with concurrent ad libitum access to a choice of 3 pelleted diets (high-fat, high-sucrose, and high-corn starch); all 3 were provided in the home cage. Body weight, running distance, and intake of each diet was measured daily. At the conclusion of the 4 week diet preference test, animals were sacrificed and ventral striatum tissue was collected for later analysis. Results demonstrated intake patterns of diets were uniquely influenced by physical activity dependent on both the sex and the selectively bred line of rat. In addition, reward related ventral striatal mRNA expression was also dependent on both the sex and the selectively bred line of rat. Overall, the pattern of both behavioral and mRNA results suggest that voluntary wheel running behavior differentially mediates palatable diet consumption in males and females. Considering the pervasive abundance of both physical inactivity, combined with over-consumption of energy dense palatable diets, it is vital to understand the nature of these behavioral interactions.

The habenula is a small, diencephalic structure comprised of distinct subnuclei which receives inputs from the limbic forebrain and sends projections to various regions in the midbrain, making this region well positioned to influence reward and motivation. Genetic ablation of the dorsal medial habenula is known to decrease voluntary wheel-running in mice. However, the extent to which the medial habenula (MHb) mediates wheel-running motivation in the context of high or low motivation for voluntary physical activity remains to be determined. In so, we utilized 5-week-old female rats selectively bred to voluntarily run high (HVR) or low (LVR) distances in order to determine if inherent differences in medial habenula maturation accompany inherent differences in wheel-running motivation. We report a significantly higher expression of genes associated with MHb development (Brn3a, Nurr1, Tac1, and Kcnip) in HVR versus LVR rats. Furthermore, there was a positive correlation between Brn3a and Nurr1 expression and run distance in HVR, but not LVR rats. Similarly, NeuN and Synapsin 1, markers of neuronal maturation, were higher in HVR compared to LVR rats. Lastly, dendritic density was determined to be higher in the MHb of HVR versus LVR rats, while LVR rats showed a higher percentage of thin spines, suggesting a higher prevalence of immature dendrites in LVR rats. Taken together, the above findings highlight the involvement of MHb in driving the motivation to be physically active. Given pandemic levels of global physical inactivity, the role of the MHb offers a novel potential to improve our global health.

Physical inactivity is positively associated with anxiety and depression. Considering physical inactivity, anxiety, and depression each have a genetic basis for inheritance, our lab used artificial selectively bred low-voluntary running (LVR) and wild type (WT) female Wistar rats to test if physical inactivity genes selected over multiple generations would lead to an anxiety or depressive-like phenotype. We performed next generation RNA sequencing and immunoblotting on the dentate gyrus to reveal key biological functions from heritable physical inactivity. LVR rats did not display depressive-like behavior. However, LVR rats did display anxiogenic behavior with gene networks associated with reduced neuronal development, proliferation, and function compared to WT counterparts. Additionally, immunoblotting revealed LVR deficits in neuronal development and function. To our knowledge, this is the first study to show that by selectively breeding for physical inactivity genes, anxiety-like genes were co-selected. The study also reveals molecular insights to the genetic influences that physical inactivity has on anxiety-like behavior.

A gene was sought that could reverse low voluntary running distances in a model of low voluntary wheel-running behavior. In order to confirm the low motivation to wheel-run in our model does not result from defects in reward valuation, we employed sucrose preference and conditioned place preference for voluntary wheel-access. We observed no differences between our model and wild-type rats regarding the aforementioned behavioral testing. Instead, low voluntary runners seemed to require less running to obtain similar rewards for low voluntary running levels compared to wild-type rats. Previous work in our lab identified protein kinase inhibitor alpha as being lower in low voluntary running than wild-type rats. Next, nucleus accumbens injections of an adenoviral-associated virus that overexpressed the protein kinase inhibitor alpha gene increased running distance in low voluntary running, but not wild-type rats. Endogenous mRNA levels for protein kinase inhibitor alpha, dopamine receptor D1, dopamine receptor D2, and Fos were all only lower in wild-type rats following overexpression compared to low voluntary runners, suggesting a potential molecular and behavioral resistance in wild-type rats. Utilizing a nucleus accumbens preparation, three intermediate early gene mRNAs increased in low voluntary running slices after dopamine receptor agonist SKF-38393 exposure, while wild-type had no response. In summary, the results suggest that protein kinase inhibitor alpha is a promising gene candidate to partially rescue physical activity in the polygenic model of low voluntary running. Importantly, there were divergent molecular responses to protein kinase inhibitor alpha overexpression in low voluntary runners compared to wild-type rats.

Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high-cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.

This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk.

NEW FINDINGS What is the central question of this study? We investigated whether 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) could prevent acute increases in body fat and changes in omental and subcutaneous adipose tissue following the sudden transition from physical activity to physical inactivity. What is the main finding and its importance? AICAR prevented fat gains following the transition from physical activity to inactivity to levels comparable to rats that remained physically active. AICAR and continuous physical activity produced depot-specific changes in cyclin A1 mRNA and protein that were associated with the prevention of fat gain. These findings suggest that targeting AMP-activated protein kinase signalling could oppose rapid adipose mass growth. The transition from physical activity to inactivity is associated with drastic increases in 'catch-up' fat that in turn foster the development of many obesity-associated maladies. We tested whether 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) treatment would prevent gains in body fat following the sudden transition from a physically active state to an inactive state by locking a voluntary running wheel. Male Wistar rats were either sedentary (SED) or given wheel access for 4 weeks, at which time rats with wheels continued running (RUN), had their wheel locked (WL) or had WL with daily AICAR injection (WL + AICAR) for 1 week. RUN and WL + AICAR prevented gains in body fat compared with SED and WL (P

Previous studies suggest an interaction between the level of physical activity and diet preference. However, this relationship has not been well characterized for sex differences that may exist. The present study examined the influence of sex on diet preference in male and female Wistar rats that were housed under either sedentary (no wheel access) (SED) or voluntary wheel running access (RUN) conditions. Following a 1 week acclimation period to these conditions, standard chow was replaced with concurrent ad libitum access to a choice of 3 pelleted diets (high-fat, high-sucrose, and high-corn starch) in the home cage. SED and RUN conditions remained throughout the next 4 week diet preference assessment period. Body weight, running distance, and intake of each diet were measured daily. At the conclusion of the 4 week diet preference test, animals were sacrificed and brains were collected for mRNA analysis. Fecal samples were also collected before and after the 4 week diet preference phase to characterize microbiota composition. Results indicate sex dependent interactions between physical activity and both behavioral and physiological measures. Females in both RUN and SED conditions preferred the high-fat diet, consuming significantly more high-fat diet than either of the other two diets. While male SED rats also preferred the high-fat diet, male RUN rats consumed significantly less high-fat diet than the other groups, instead preferring all three diets equally. There was also a sex dependent influence of physical activity on both reward related opioid mRNA expression in the ventral striatum and the characterization of gut microbiota. The significant sex differences in response to physical activity observed through both behavioral and physiological measures suggest potential motivational or metabolic difference between males and females. The findings highlight the necessity for further exploration between male and female response to physical activity and feeding behavior.

Prenatal overnutrition affects development into adulthood and influences risk of obesity. We assessed the transgenerational effect of maternal Western diet (WD) consumption on offspring physical activity. Voluntary wheel running was increased in juvenile (4-7 wk of age), but decreased in adult (16-19 wk of age), F1 female WD offspring In contrast, no wheel-running differences in F1 male offspring were observed. Increased wheel running in juvenile female WD offspring was associated with up-regulated dopamine receptor (DRD)-1 and -2 in the nucleus accumbens (NAc) and with down-regulated Lepr in the ventral tegmental area (VTA). Conversely, decreased wheel running by adult female WD offspring was associated with down-regulated DRD1 in the NAc and with up-regulated Lepr in the VTA. Body fat, leptin, and insulin were increased in male, but not in female, F1 WD offspring. Recombinant virus (rAAV) leptin antagonism in the VTA decreased wheel running in standard diet but not in WD F1 female offspring. Analysis of F2 offspring found no differences in wheel running or adiposity in male or female offspring, suggesting that changes in the F1 generation were related to in utero somatic reprogramming. Our findings indicate prenatal WD exposure leads to age-specific changes in voluntary physical activity in female offspring that are differentially influenced by VTA leptin antagonism.-Ruegsegger, G. N., Grigsby, K. B., Kelty, T. J., Zidon, T. M., Childs, T. E., Vieira-Potter, V. J., Klinkebiel, D. L., Matheny, M., Scarpace, P. J., Booth, F. W. Maternal Western diet age-specifically alters female offspring voluntary physical activity and dopamine- and leptin-related gene expression.

Ovariectomy and high-fat diet (HFD) worsen obesity and metabolic dysfunction associated with low aerobic fitness. Exercise training mitigates metabolic abnormalities induced by low aerobic fitness, but whether the protective effect is maintained after ovariectomy and HFD is unknown.This study determined whether, after ovariectomy and HFD, exercise training improves metabolic function in rats bred for low intrinsic aerobic capacity.Female rats selectively bred for low (LCR) and high (HCR) intrinsic aerobic capacity (n = 30) were ovariectomized, fed HFD, and randomized to either a sedentary (SED) or voluntary wheel running (EX) group. Resting energy expenditure, glucose tolerance, and spontaneous physical activity were determined midway through the experiment, whereas body weight, wheel running volume, and food intake were assessed throughout the study. Body composition, circulating metabolic markers, and skeletal muscle gene and protein expression were measured at sacrifice.EX reduced body weight and adiposity in LCR rats (-10% and -50%, respectively; P0.05) and, unexpectedly, increased these variables in HCR rats (+7% and +37%, respectively; P0.05) compared with their respective SED controls, likely because of dietary overcompensation. Wheel running volume was approximately fivefold greater in HCR than LCR rats, yet EX enhanced insulin sensitivity equally in LCR and HCR rats (P0.05). This EX-mediated improvement in metabolic function was associated with thee gene upregulation of skeletal muscle interleukin-6 and interleukin-10. EX also increased resting energy expenditure, skeletal muscle mitochondrial content (oxidative phosphorylation complexes and citrate synthase activity), and adenosine monophosphate-activated protein kinase activation similarly in both lines (all P0.05).Despite a fivefold difference in running volume between rat lines, EX similarly improved systemic insulin sensitivity, resting energy expenditure, and skeletal muscle mitochondrial content and adenosine monophosphate-activated protein kinase activation in ovariectomized LCR and HCR rats fed HFD compared with their respective SED controls.

The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake.

Given the integral role of nucleus accumbens (NAc) cAMP response element binding protein (CREB) activity in motivational processes, the goal of the current study was to determine whether blunting chronic NAc CREB activity could rescue the low physical activity motivation of female, low voluntary running (LVR) rats. NAc CREB phosphorylation is elevated in these rats, a state previously attributed to deficits in reward valuation. It was recently shown that overexpression of the upstream CREB inhibitor, protein kinase inhibitor alpha (PKIα), increased LVR nightly running by ~threefold. Therefore, the current study addresses the extent to which NAc CREB attenuation influences female LVR and wild-type (WT) wheel-running behavior. Inducible reductions in NAc neuronal activity using Gi-coupled hM4Di DREADDs increased running behavior in LVR, but not in WT, rats. Similarly, site-directed pharmacological inhibition of NAc CREB activity significantly increased LVR nightly running distance and time by ~twofold, with no effect in WT rats. Finally, environmentally enriched LVR rats exhibit higher levels of running compared to socially isolated rats in what appeared to be a CREB-related manner. Considering the positive outcomes of upstream CREB modulation and environmental enrichment on LVR behavior, we believe that blunting NAc CREB activity has the neuromolecular potential to partially reverse low physical activity motivation, as exemplified by the LVR model. The positive physical activity outcome of early life enrichment adds translatable value to human childhood enrichment and highlights its importance on motivational processes later in life.

Estrogens are believed to enhance rodent voluntary wheel-running through medial preoptic (mPOA) estrogen receptor α (ERα) signaling, with little role attributed to estrogen receptor β (ERβ). Systemic ERβ activation has been shown to mitigate ERα driven increases in wheel-running. Therefore, the present goal was to determine whether ERβ signaling in the mPOA plays a similar modulatory role over ERα. We utilized outbred wild-type (WT) and rats selectively bred for low voluntary running (LVR) behavior to address whether mPOA ERβ signaling blunts ERα driven wheel-running behavior and immediate-early gene (Fos, Zif268, and Homer1) mRNA induction. Further, we addressed baseline mPOA mRNA expressions and circulating 17β-estradiol levels between female WT and LVR rats. Following ovariectomy, WT rats reduced running behavior ∼40 %, with no effect in LVR rats. Intra-medial preoptic injection of the ERα-agonist propylpyrazoletriol (PPT) increased wheel-running ∼3.5-fold in WT rats, while injections of the ERβ-agonist diarylpropionitrile (DPN) or a combination of the two agonists had no effect. Similarly, ERα-agonism (PPT) increased Fos and Homer1 induction ∼3-fold in WT and LVR isolated mPOA neurons, with no effect of the ERβ-agonist DPN alone or in combination with PPT, suggesting medial-preoptic ERβ activity may blunt ERα signaling. LVR rats exhibited higher mPOA mRNA expressions of Esr1, Esr2 and Cyp19a1, lower normalized uterine wet weights and lower 17β-estradiol plasma levels compared to WT, suggesting their low running may be due to low circulating estrogen levels. Collectively, these findings highlight mPOA ERβ as a potential neuro-molecular modulator of the estrogenic control of wheel-running behavior.

Ketogenic diets (KDs) are shown to benefit hepatic metabolism; however, their effect on the liver when combined with exercise is unknown. We investigated the effects of a KD versus a “western” diet (WD) on markers of hepatic lipid metabolism and oxidative stress in exercising rats. Male and female Wistar rats with access to voluntary running wheels were randomized to 3 groups (n = 8–14 per group): standard chow (SC; 17% fat), WD (42% fat), or KD (90.5% fat) for 7 weeks. Body fat percentage (BF%) was increased in WD and KD versus SC, although KD females displayed lower BF% versus WD (p ≤ 0.05). Liver triglycerides were higher in KD and WD versus SC but were attenuated in KD females versus WD (p ≤ 0.05). KD suppressed hepatic markers of de novo lipogenesis (fatty acid synthase, acetyl coenzyme A carboxylase) and increased markers of mitochondrial biogenesis/content (peroxisome proliferator activated receptor-1α, mitochondrial transcription factor A (TFAM), and citrate synthase activity). KD also increased hepatic glutathione peroxidase 1 and lowered oxidized glutathione. Female rats exhibited elevated hepatic markers of mitochondrial biogenesis (TFAM), mitophagy (light chain 3 II/I ratio, autophagy-related protein 12:5), and cellular energy homeostasis (phosphorylated 5′AMP-activated protein kinase/5′AMP-activated protein kinase) versus males. These data highlight that KD and exercise beneficially impacts hepatic metabolism and oxidative stress and merits further investigation. Novelty KD feeding combined with exercise improved hepatic oxidative stress, suppressed markers of de novo lipogenesis, and increased markers of mitochondrial content versus WD feeding. Males and females responded similarly to combined KD feeding and exercise. Female rats exhibited elevated hepatic markers of autophagy/mitophagy and energy homeostasis compared with male rats.

The present study examined the influence of physical activity vs. sedentary home cage conditions on baseline and opioid-driven high-fat feeding behaviors in two common strains of laboratory rats. Sprague-Dawley and Wistar rats were singly housed with either access to a voluntary running wheel (RUN) or locked-wheel (SED) for 5 weeks, before being stereotaxically implanted with bilateral cannulae targeting the nucleus accumbens. Following recovery, with RUN or SED conditions continuing the duration of the experiment, all rats were given 2 h daily access to a high-fat diet for 6 consecutive days to establish a stable baseline intake. Over the next 2 weeks, all subjects were administered the μ-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) (multiple dose range) or saline into the nucleus accumbens, immediately followed by 2 h access to a high-fat diet. Drug treatments were separated by at least 1 day and treatment order was counterbalanced. Baseline consumption of the high-fat diet during the 1-week baseline acclimation period did not differ between RUN and SED groups in either rat strain. Higher doses of DAMGO produced increased fat consumption in both strains of rats, yet no differences were observed between RUN vs. SED treated groups. However, SED treatment produced a greater locomotor response following intra-accumbens DAMGO administration, compared to the RUN condition, during the 2 h feeding session. The data suggest that the animals housed in sedentary versus voluntary wheel running conditions may differ in behavioral tolerance to the locomotor but not the orexigenic activating properties of intra-accumbens DAMGO treatment.

Rats selectively bred for high (HCR) and low (LCR) aerobic capacity show a stark divergence in wheel running behavior, which may be associated with the dopamine (DA) system in the brain. HCR possess greater motivation for voluntary running along with greater brain DA activity compared to LCR. We recently demonstrated that HCR are not immune to ovariectomy (OVX)-associated reductions in spontaneous cage (i.e. locomotor) activity. Whether HCR and LCR rats differ in their OVX-mediated voluntary wheel running response is unknown.To determine whether HCR are protected from OVX-associated reduction in voluntary wheel running.Forty female HCR and LCR rats (age ~27weeks) had either SHM or OVX operations, and given access to a running wheel for 11weeks. Weekly wheel running distance was monitored throughout the intervention. Nucleus accumbens (NAc) was assessed for mRNA expression of DA receptors at sacrifice.Compared to LCR, HCR ran greater distance and had greater ratio of excitatory/inhibitory DA mRNA expression (both line main effects, P

Key points Physical inactivity, which drastically increases with advancing age, is associated with numerous chronic diseases. The nucleus accumbens (the pleasure and reward ‘hub’ in the brain) influences wheel running behaviour in rodents. RNA-sequencing and subsequent bioinformatics analysis led us to hypothesize a potential relationship between the regulation of dendritic spine density, the molecules involved in synaptic transmission, and age-related reductions in wheel running. Upon completion of follow-up studies, we developed the working model that synaptic plasticity in the nucleus accumbens is central to age-related changes in voluntary running. Testing this hypothesis, inhibition of Cdk5 (comprising a molecule central to the processes described above) in the nucleus accumbens reduced wheel running. The results of the present study show that reductions in synaptic transmission and Cdk5 function are related to decreases in voluntary running behaviour and provide guidance for understanding the neural mechanisms that underlie age-dependent reductions in the motivation to be physically active. Abstract Increases in age are often associated with reduced levels of physical activity, which, in turn, associates with the development of numerous chronic diseases. We aimed to assess molecular differences in the nucleus accumbens (NAc) (a specific brain nucleus postulated to influence rewarding behaviour) with respect to wheel running and sedentary female Wistar rats at 8 and 14 weeks of age. RNA-sequencing was used to interrogate transcriptomic changes between 8- and 14-week-old wheel running rats, and select transcripts were later analysed by quantitative RT-PCR in age-matched sedentary rats. Voluntary wheel running was greatest at 8 weeks and had significantly decreased by 12 weeks. From 619 differentially expressed mRNAs, bioinformatics suggested that cAMP-mediated signalling, dopamine- and cAMP-regulated neuronal phosphoprotein of 32 kDa feedback, and synaptic plasticity were greater in 8- vs. 14-week-old rats. In depth analysis of these networks showed significant (∼20–30%; P

AB Introduction: In the absence of exercise training, rats selectively bred for high intrinsic aerobic capacity (high-capacity running (HCR)) are protected against ovariectomy (OVX)-induced insulin resistance (IR) and obesity compared with those bred for low intrinsic aerobic capacity (low-capacity running (LCR)). Purpose: This study determined whether OVX HCR rats remain protected with exposure to high-fat diet (HFD) compared with OVX LCR rats. Methods: Female HCR and LCR rats (n = 36; age, 27-33 wk) underwent OVX and were randomized to a standard chow diet (NC, 5% kcal fat) or HFD (45% kcal fat) ad libitum for 11 wk. Total energy expenditure, resting energy expenditure, spontaneous physical activity (SPA), and glucose tolerance were assessed midway, whereas fasting circulating metabolic markers, body composition, adipose tissue distribution, and skeletal muscle adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial markers were assessed at sacrifice. Results: Both HCR and LCR rats experienced HFD-induced increases in total and visceral adiposity after OVX. Despite similar gains in adiposity, HCR rats were protected from HFD-induced IR and reduced total energy expenditure observed in LCR rats (P < 0.05). This metabolic protection was likely attributed to a compensatory increase in SPA and associated preservation of skeletal muscle AMPK activity in HCR; however, HFD significantly reduced SPA and AMPK activity in LCR (P < 0.05). In both lines, HFD reduced citrate synthase activity, gene expression of markers of mitochondrial biogenesis (tFAM, NRF1, and PGC-1[alpha]), and protein levels of mitochondrial oxidative phosphorylation complexes I, II, IV, and V in skeletal muscle (all P < 0.05). Conclusion: After OVX, HCR and LCR rats differentially respond to HFD such that HCR increase while LCR decrease SPA. This "physical activity compensation" likely confers protection from HFD-induced IR and reduced energy expenditure in HCR rats. (C) 2016 American College of Sports Medicine

Key points Physiologically relevant rodent models of non-alcoholic steatohepatitis (NASH) that resemble the human condition are limited. Exercise training and energy restriction are first-line recommendations for the treatment of NASH. Hyperphagic Otsuka Long–Evans Tokushima fatty rats fed a western diet high in fat, sucrose and cholesterol for 24 weeks developed a severe NASH with fibrosis phenotype. Moderate intensity exercise training and modest energy restriction provided some improvement in the histological features of NASH that coincided with alterations in markers of hepatic stellate cell activation and extracellular matrix remodelling. The present study highlights the importance of lifestyle modification, including exercise training and energy restriction, in the regulation of advanced liver disease. Abstract The incidence of non-alcoholic steatohepatitis (NASH) is rising but the efficacy of lifestyle modifications to improve NASH-related outcomes remain unclear. We hypothesized that a western diet (WD) would induce NASH in the Otsuka Long–Evans Tokushima Fatty (OLETF) rat and that lifestyle modification would improve this condition. Eight-week-old Long–Evans Tokushima Otsuka (L) and OLETF (O) rats consumed a control diet (10% kcal fat, 3.5% sucrose) or a WD (45% kcal fat, 17% sucrose, 1% cholesterol) for 24 weeks. At 20 weeks of age, additional WD-fed OLETFs were randomized to sedentary (O-SED), food restriction (O-FR; ∼25% kcal reduction vs. O-SED) or exercise training (O-EX; treadmill running 20 m min–1 with a 15% incline, 60 min day–1, 5 days week–1) conditions for 12 weeks. WD induced a NASH phenotype in OLETFs characterized by hepatic fibrosis (collagen 1α1 mRNA and hydroxyproline content), as well as elevated inflammation and non-alcoholic fatty liver disease activity scores, and hepatic stellate cell activation (α-smooth muscle actin) compared to Long–Evans Tokushima Otsuka rats. FR and EX modestly improved NASH-related fibrosis markers (FR: hydroxyproline content, P 0.05). Although neither EX nor FR led to complete resolution of the WD-induced NASH phenotype, both independently benefitted liver fibrosis via altered hepatic stellate cell activation and extracellular matrix remodelling.

There has never been an outcome measure for human health more important than peak oxygen consumption (V̇o2 peak), yet little is known regarding the molecular triggers for its lifetime decline with aging. We examined the ability of physical activity or 5 wk of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) administration to delay the initial aging-induced decline in lifetime-apex V̇o2 peakand potential underlying molecular mechanisms. Experiment 1 consisted of female rats with (RUN) and without (NO RUN) running wheels, while experiment 2 consisted of female nonrunning rats getting the AMPK agonist AICAR (0.5 mg/g/day) subcutaneously for 5 wk beginning at 17 wk of age. All rats underwent frequent, weekly or biweekly V̇o2 peaktests beginning at 10 wk of age. In experiment 1, lifetime-apex V̇o2 peakoccurred at 19 wk of age in both RUN and NO RUN and decreased thereafter. V̇o2 peakmeasured across experiment 1 was ∼25% higher in RUN than in NO RUN. In experiment 2, AICAR delayed the chronological age observed in experiment 1 by 1 wk, from 19 wk to 20 wk of age. RUN and NO RUN showed different skeletal muscle transcriptomic profiles both pre- and postapex. Additionally, growth and development pathways are differentially regulated between RUN and NO RUN. Angiomotin mRNA was downregulated postapex in RUN and NO RUN. Furthermore, strong significant correlations to V̇o2 peakand trends for decreased protein concentration supports angiomotin's potential importance in our model. Contrary to our primary hypothesis, wheel running was not sufficient to delay the chronological age of lifetime-apex V̇o2 peakdecline, whereas AICAR delayed it 1 wk.

Objective Based upon a Booth lab goal of establishing molecular regulators of physical activity motivation, my current study focuses on the effects of short-term inhibition of protein kinase A (PKA) activity in the nucleus accumbens (NAc). The NAc is a brain region integral to motivated behaviors. Downstream immediate-early gene (IEG) expression from PKA has been shown to exhibit rapid responses to acute stimuli, such as voluntary wheel-running behavior. According to previous work in our lab, long-term NAc overexpression of the endogenous PKA inhibitor, Protein Kinase Inhibitor Alpha (PKIα), increased nightly running distance in rats selectively bred for low voluntary running (LVR) behavior (Mol Neurobiol 2018 Jun 21). However, paradoxically, the same PKIα overexpression failed to increase running distance in wild-type (WT) rats. It is known that chronic manipulation of the NAc PKA pathway produces different molecular (gene expression profiles) and behavioral outcomes from that of acute manipulations. Given the above, the goal of the current work is to determine how short-term inhibition of PKA in the NAc influences its downstream gene networks and the nightly voluntary running behavior in WT rats. Methods An ex vivo preparation of the NAc was utilized to determine the effects of Rp-cAMPS, a selective protein kinase A inhibitor, upon its stimulation of dopamine D1-like receptor agonist SKF 38393 on downstream gene expression level in sedentary WT female rats. Further, real-time PCR was implemented to analyze the transcriptional expression of IEGs (Homer-1, Arc, Zif268) following Rp-cAMPS administration. Results Data showed that there were no significant difference of mRNA level for Homer-1, Arc or Zif268 among the vehicle, 50uM, 100uM and 200uM Rp-cAMPS treatment groups upon the stimulation of 10uM SKF 38393. Conclusions In addition to the PKA, other protein kinases such as Ca++ activated and growth factor activated kinases have both been shown to phosphorylate CREB at Ser133, and thus, lead to activation of gene transcription. Given the above results of the ex vivo experiment, in which NAc slices were treated with multiple dosages of Rp-cAMPS concurrent with the stimulation of SKF 38393, it is possible that other protein kinase pathways could be compensating the effects of short-term inhibition of PKA and, in turn, lead to no difference of IEG expression. Further experiments will need to be performed in order to testify this hypothesis.

Purpose Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and nonhuman animal models. This consensus article, developed as a result of an American College of Sports Medicine-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity. Conclusions Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants.

AB Purpose: This article reports on the findings and recommendations of the "Physiology of Sedentary Behavior and Its Relationship to Health Outcomes" group, a part of a larger workshop entitled Sedentary Behavior: Identifying Research Priorities sponsored by the National Heart, Lung, and Blood Institute and by the National Institute on Aging, which aimed to establish sedentary behavior research priorities. Methods: The discussion within our workshop led to the formation of critical physiological research objectives related to sedentary behaviors, that is, if appropriately researched, would greatly affect our overall understanding of human health and longevity. Results and Conclusions: Primary questions are related to physiological "health outcomes" including the influence of physical activity versus sedentary behavior on the function of a number of critical physiological systems (aerobic capacity, skeletal muscle metabolism and function, telomeres/genetic stability, and cognitive function). The group also derived important recommendations related to the "central and peripheral mechanisms" that govern sedentary behavior and how energy balance has a role in mediating these processes. General recommendations for future sedentary physiology research efforts indicate that studies of sedentary behavior, including that of sitting time only, should focus on the physiological effect of a "lack of human movement" in contradistinction to the effects of physical movement and that new models or strategies for studying sedentary behavior-induced adaptations and links to disease development are needed to elucidate underlying mechanism(s)

By 2030 type 2 diabetes and associated complications will be the seventh leading cause of death globally. In this context, obesity and physical inactivity have emerged as major risk factors for several chronic metabolic disorders. While exercise training exerts numerous health-related benefits in terms of the prevention and treatment of many disease states, including type 2 diabetes, it is currently under-prescribed and under-valued. We contend that unless urgent action is taken to curb the tidal wave of inactivity-related metabolic diseases, the worldwide economic burden associated with the rise in the number of diagnosed cases of type 2 diabetes will trigger the start of an economic death march for both industrial and developing nations alike. In this commentary we look ahead to 2065 and consider the impact that lifestyle interventions and associated strategies are likely to have in curbing the epidemic tide of type 2 diabetes. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).

Abnormally elevated postprandial glucose and triacylglycerol (TAG) concentrations are risk factors for cardiovascular disease in type 2 diabetes. The most effective time to exercise to lower postprandial glucose and TAG concentrations is unknown. Thus the aim of this study was to determine what time is more effective, either pre- or postdinner resistance exercise (RE), at improving postprandial risk factors in patients with type 2 diabetes. Thirteen obese patients with type 2 diabetes completed three trials in a random order in which they consumed a dinner meal with 1) no RE (NoRE), 2) predinner RE (RE → M), and 3) postdinner RE beginning 45 min after dinner (M → RE). Clinical outcome measures included postprandial glucose and TAG concentrations. In addition, postprandial acetaminophen (gastric emptying), endocrine responses, free fatty acids, and β-cell function (mathematical modeling) were measured to determine whether these factors were related to changes in glucose and TAG. The TAG incremental area under the curve (iAUC) was ∼92% lower ( P ≤ 0.02) during M → RE compared with NoRE and RE → M, an effect due in part to lower very-low-density lipoprotein-1 TAG concentrations. The glucose iAUC was reduced ( P = 0.02) by ∼18 and 30% during the RE → M and M → RE trials, respectively, compared with NoRE, with no difference between RE trials. RE → M and M → RE reduced the insulin iAUC by 35 and 48%, respectively, compared with NoRE ( P < 0.01). The glucagon-like peptide-1 iAUC was ∼50% lower ( P ≤ 0.02) during M → RE compared with NoRE and RE → M. Given that predinner RE only improves postprandial glucose concentrations, whereas postdinner RE improves both postprandial glucose and TAG concentrations, postdinner RE may lower the risk of cardiovascular disease more effectively.

The United States is unfit for optimal health with its low level of cardiorespiratory fitness (CRF). Low CRF clinically translates to markedly higher rates of type 2 diabetes (T2D). While the percentages of obesity (13%) and type 2 diabetes (T2D) (1.6%) were too large in 1960, they have both increased manyfold in the past half century to 36% and 7%, respectively, in 2013 in the United States. Historically, type 2 diabetes (T2D) was rare in youth. In contrast, T2D was an adult disease, appearing after 30 years of age. Around 1990, T2D accounted for less than 3% of adolescent diabetes. Ten years later, it accounted for 45% of youth cases. Physical inactivity decreases CRF, and decreases in CRF increase mortality in T2D. This chapter considers (a) CRF’s association with morbidity and mortality, (b) factors determining CRF, and (c) clinical implications associated with low CRF. Also discussed are associations of low CRF with (a) glucose metabolism, (b) metabolic syndrome, (c) increased prevalence with cardiovascular diseases, and (d) increases in multiple risk factors for increased mortality. The relationship of changes in CRF on changes in the relative risk of death is presented. CRF’s inverse relationships are given with various pathological mechanisms (insulin resistance, hyperlipidemia, body composition, obesity, and inflammation). CRF is not fixed at an inheritable level but can be modulated up (by increased physical activity) or down (by physical inactivity, such as sedentary lifestyle). However, genes fix a decline in CRF beginning as early as adolescence.

Dopaminergic signaling differences in the nucleus accumbens (NAcc) seemingly predispose rats to adopt different physical activity behaviors. Physical activity behavior also may be regulated through peripheral mechanisms (i.e., muscle and fat derived as well as hormonal signals). We hypothesize that physical activity behavior is regulated by the convergence of central and peripheral mechanisms onto the NAcc.

Exercise physiology is an old profession that dates back to 1500 B.C.E., having rises and falls in intervening years. The author provides comments from firsthand observations he has experienced in the past six decades. Events in the 1950s and 1960s caused a rise in exercise physiology in the next decades, with a decline being initiated in the late 1990s by the Center for Scientific Review's decision to treat exercise by individual organs or individual diseases rather than as a preexisting vibrant translational science for human health. In the opinion of this author and of some National Institutes of Health (NIH) program officials, the decline of qualified individuals to wisely spend taxpayer's monies on exercise research has resulted in the December 13, 2013 publication of the NIH's “Request for Information (RFI): Identifying Gaps in Understanding the Mechanisms of Physical Activity-Induced Health Benefits.”

The original version of this article unfortunately contained mistake in Table 2 to where two directionality arrows were inverted.