Mesolimbic transcriptional response to hedonic substitution of voluntary exercise and voluntary ethanol consumption

Darlington, Todd M.; McCarthy, Riley Delaney; Cox, Ryan J.; Ehringer, Marissa A.

doi:10.1016/j.bbr.2013.11.011

Cited by 28 publications

(31 citation statements)

References 51 publications

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“…In this work, we have focused on the effects of concurrent exercise, in the form of voluntary wheel running, on ethanol consumption in adolescent C57BL/6 female and male mice. Our results reproduce the effects of exercise decreasing ethanol consumption and preference previously seen in adult mice [27,29,30], and hamsters [31,32]. As previously reported in other studies [reviewed in 24], exercise increased hippocampal BDNF expression in both female and male mice, suggesting a potential role of this neurotrophin in the adaptive response to wheel running.…”

Section: Discussionsupporting

confidence: 91%

Voluntary exercise decreases ethanol preference and consumption in C57BL/6 adolescent mice: Sex differences and hippocampal BDNF expression

Gallego

Cox

Funk

et al. 2015

Physiology & Behavior

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Adolescence is a period of high vulnerability for alcohol use and abuse. Early alcohol use has been shown to increase the risk for alcohol-related problems later in life; therefore effective preventive treatments targeted toward adolescents would be very valuable. Many epidemiological and longitudinal studies in humans have revealed the beneficial effects of exercise for prevention and treatment of alcohol addiction. Pre-clinical studies have demonstrated that access to a running wheel leads to decreased voluntary alcohol consumption in adult mice, hamsters, and rats. However, age and sex may also influence the effects of exercise on alcohol use. Herein, we studied male and female C57BL/6 adolescent mice using a 24-h two bottle choice paradigm to evaluate 21 days of concurrent voluntary exercise on alcohol consumption and preference. Given previously known effects of exercise in increasing the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and its role in regulating the reward system, BDNF mRNA and protein levels were measured at the end of the behavioral experiment. Our results demonstrate sex differences in the efficacy of voluntary exercise and its effects on decreasing alcohol consumption and preference. We also report increased BDNF expression after 21 days of voluntary exercise in both male and female mice. Interestingly, the distance travelled played an important role in alcohol consumption and preference in female mice but not in male mice. Overall, this study demonstrates sex differences in the effects of voluntary exercise on alcohol consumption in adolescent mice and points out the importance of distance travelled as a limiting factor to the beneficial effects of wheel running in female mice.

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Section: Discussionsupporting

confidence: 91%

Voluntary exercise decreases ethanol preference and consumption in C57BL/6 adolescent mice: Sex differences and hippocampal BDNF expression

Gallego

Cox

Funk

et al. 2015

Physiology & Behavior

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“…This study validates and extends the findings from our laboratory (Darlington et al, 2014; Ehringer et al, 2009; Gallego et al, 2015) both behaviorally and at the level of gene expression. Previously, striatal Drd1a showed reduced expression due to access to a running wheel (Darlington et al, 2014).…”

Section: Discussionsupporting

confidence: 90%

“…The concept of hedonic substitution, replacement of one rewarding behavior with another, is a promising area of research. Exercise has been used in the past to help reduce ethanol intake in heavy drinkers (Correia et al, 2005; Murphy et al, 1986; Weinstock, 2010; Werch et al, 2011), and animal studies have shown consistent interaction effects with ethanol consumption (Darlington et al, 2014; Ehringer et al, 2009; Hammer et al, 2010; McMillan, 1978; McMillan et al, 1995; Ozburn et al, 2008; Werme et al, 2002). However, little is known about the neurobiology of this interaction.…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known about the neurobiology of this interaction. Our laboratory first attempted to identify transcriptional changes underlying hedonic substitution, and the candidate genes Slc18a2 in the midbrain and Bdnf in the hippocampus were both found to respond differently to ethanol consumption and voluntary wheel running (Darlington et al, 2014; Gallego et al, 2015). The striatum plays an important role in the mesolimbic dopaminergic pathway, processing and integrating input from a number of other brain regions.…”

Section: Introductionmentioning

confidence: 99%

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Voluntary wheel running reduces voluntary consumption of ethanol in mice: identification of candidate genes through striatal gene expression profiling

Darlington

McCarthy

Cox

et al. 2016

Genes Brain and Behavior

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Hedonic substitution, where wheel running reduces voluntary ethanol consumption has been observed in prior studies. Here we replicate and expand on previous work showing that mice decrease voluntary ethanol consumption and preference when given access to a running wheel. While earlier work has been limited mainly to behavioral studies, here we assess the underlying molecular mechanisms that may account for this interaction. From four groups of female C57BL/6J mice (control, access to two-bottle choice ethanol, access to a running wheel, and access to both two-bottle choice ethanol and a running wheel), mRNA-sequencing of the striatum identified differential gene expression. Many genes in ethanol preference quantitative trait loci were differentially expressed due to running. Furthermore, we conducted Weighted Gene Co-expression Network Analysis and identified gene networks corresponding to each effect behavioral group. Candidate genes for mediating the behavioral interaction between ethanol consumption and wheel running include multiple potassium channel genes, Oprm1, Prkcg, Stxbp1, Crhr1, Gabra3, Slc6a13, Stx1b, Pomc, Rassf5, Polr2a, and Camta2. After observing an overlap of many genes and functional groups previously identified in studies of initial sensitivity to ethanol, we hypothesized that wheel running may induce a change in sensitivity, thereby affecting ethanol consumption. A behavioral study examining Loss of Righting Reflex to ethanol following exercise trended toward supporting this hypothesis. These data provide a rich resource for future studies that may better characterize the observed transcriptional changes in gene networks in response to ethanol consumption and wheel running.

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“…Circulating BDNF is elevated in humans following acute exercise and exercise training (16, 18, 22, 64). In the rodent hippocampus, Bdnf protein and mRNA are elevated following brief exercise exposures (≤ 7 days) (4, 12, 28, 43–45, 53, 63) and longer exercise exposures (>7 days) (4, 5, 10, 12, 17, 33, 37, 41, 43, 53, 67). Importantly, most studies in rodents that attempt to address mechanisms mediating the cognitive enhancing effects of chronic exercise have focused on exercise training ranging from ~7 days to 3 months and how longer voluntary wheel exposures influence mRNA expression of plasticity-associated genes is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent and independent effects of long-term voluntary wheel running on Bdnf mRNA and protein expression

Venezia

Guth

Sapp

et al. 2016

Physiology & Behavior

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The beneficial effects of physical activity on brain health (synaptogenesis, neurogenesis, enhanced synaptic plasticity, improved learning and memory) appear to be mediated through changes in region-specific expression of neurotrophins, transcription factors, and postsynaptic receptors, though investigations of sex differences in response to long-term voluntary wheel running are limited. Purpose To examine the effect of five months of voluntary wheel running on hippocampal mRNA and protein expression of factors critical for exercise-induced structural and functional plasticity in male and female adult mice. Methods At 8 weeks of age, male and female C57BL/6 mice were individually housed with (PA; n=20; 10 male) or without (SED; n=20; 10 male) access to a computer monitored voluntary running wheel. At 28 weeks, all mice were sacrificed and hippocampi removed. Total RNA was isolated from the hippocampus and expression of total Bdnf, Bdnf transcript IV, tPA, Pgc-1a, GluR1, NR2A, and NR2B were assessed with quantitative RT-PCR and total and mature Bdnf protein were assessed with ELISA. Results We found significantly higher Bdnf IV mRNA expression in PA males (p=0.03) and females (p=0.03) compared to SED animals. Total Bdnf mRNA expression was significantly greater in PA males compared to SED males (p=0.01), but there was no difference in females. Similarly, we observed significantly higher mature Bdnf protein in PA males compared to SED males (p=0.04), but not in females. Conclusion These findings indicate that the impact of long-term voluntary wheel running on transcriptional and post-translational regulation of Bdnf may be sex-dependent, though the activity-dependent Bdnf IV transcript is sensitive to exercise independent of sex.

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Mesolimbic transcriptional response to hedonic substitution of voluntary exercise and voluntary ethanol consumption

Cited by 28 publications

References 51 publications

Voluntary exercise decreases ethanol preference and consumption in C57BL/6 adolescent mice: Sex differences and hippocampal BDNF expression

Voluntary exercise decreases ethanol preference and consumption in C57BL/6 adolescent mice: Sex differences and hippocampal BDNF expression

Voluntary wheel running reduces voluntary consumption of ethanol in mice: identification of candidate genes through striatal gene expression profiling

Sex-dependent and independent effects of long-term voluntary wheel running on Bdnf mRNA and protein expression

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