Circadian pattern of total and free corticosterone concentrations, corticosteroid-binding globulin, and physical activity in mice selectively bred for high voluntary wheel-running behavior
Introduction
Adrenal glucocorticoid hormones have highly integrated effects on both energy balance (Dallman et al., 1993, Pecoraro et al., 2005, Pecoraro et al., 2006, Dallman et al., 2007) and behavior (Breuner and Wingfield, 2000, Pecoraro et al., 2005, Pecoraro et al., 2006, Dallman et al., 2007). Under baseline conditions, plasma glucocorticoid (GC) levels vary predictably across a 24 h period (circadian variation) and, in some species, across the year in a seasonal pattern (for a review see Romero, 2002). Both circadian and seasonal patterns in GC secretion may have evolved to meet predictable rises in energy requirements (Romero, 2002, Pecoraro et al., 2006). For example, GC concentrations are highest around the time of arousal on a daily basis (morning for diurnal species and evening for nocturnal species), whereas seasonal peaks in baseline GC levels occur around the time of reproduction in several species of vertebrates, when energetic needs are often highest (Romero, 2002).
Acute elevations of circulating corticosterone (CORT) levels are superimposed on daily and seasonal fluctuations. In mammals (Lin et al., 1988, Lin et al., 1989, Coleman et al., 1998, Girard and Garland, 2002) and birds (Breuner et al., 1998, Lynn et al., 2003), CORT increases acutely in association with increases in locomotor activity. For example, in laboratory mice housed with access to wheels, plasma CORT concentration is significantly correlated with the number of wheel revolutions in the 20 min prior to blood sampling (Girard and Garland, 2002). Sparrows fed mealworms enriched with CORT display increased perch-hopping behavior (Breuner and Wingfield, 2000). Furthermore, ablation and replacement studies in rats have shown that CORT is necessary for rats to display schedule-induced wheel-running (Lin et al., 1988, Lin et al., 1989).
In a recent study, we reported that baseline plasma CORT levels of mice from lines that had been selectively bred for high levels of voluntary wheel-running are elevated twofold above those of their non-selected control lines (Malisch et al., 2007). Because of the known physiological effects of CORT that may support aerobically sustained exercise, such as increased lipolysis, proteolysis, and gluconeogenesis, with a simultaneous glycogen-sparing effect (Tharp, 1975, Coderre et al., 1992), we hypothesized that the increase in baseline CORT is an evolved (i.e., cross-generational) adaptation to support the high levels of wheel-running (nearly threefold higher than control mice). In addition, increased circulating CORT may promote wheel-running by increasing motivation to run. Running is a rewarding behavior (Belke and Garland, 2007, Brené et al., 2007) and elevation in plasma CORT increases the reward value of some behaviors. For example, increases in plasma CORT have been associated with increased self-administration of drugs, increased ingestions of saccharine, sucrose, and fats, and even increased self-administration of glucocorticoids (Piazza et al., 1993, Piazza and Le Moal, 1996, Piazza and Le Moal, 1997, Piazza and Le Moal, 1998, Bhatnagar et al., 2000, la Fleur et al., 2004, Pecoraro et al., 2004, Pecoraro et al., 2005).
Increased circulating CORT levels as a correlated response to selective breeding for high locomotor activity (Girard and Garland, 2002, Malisch et al., 2007) are an important finding from the perspective of evolutionary endocrinology (e.g., see Garland and Carter, 1994, Finch and Rose, 1995, Goymann et al., 2004, Ketterson et al., 2005, John-Alder and Cox, 2007, Zera et al., 2007), but downstream modulators could negate or amplify any effects of CORT on target tissues. For example, corticosteroid-binding globulin (CBG) circulates in the plasma and binds CORT with high affinity (Hammond, 1995). Although the exact function of CBG is unknown, one hypothesis is that CORT bound to CBG is biologically inactive (Mendel, 1989, Breuner and Orchinik, 2002). Like CORT, CBG levels are not static, and in mammals they can vary seasonally (Tinnikov, 1999), daily (Friaria et al., 1988, Hsu and Kuhn, 1988), and in response to stress (Tinnikov and Oskina, 1994, Fleshner et al., 1995, Spencer et al., 1996, Deak et al., 1999).
Here, we examine baseline total CORT, CBG levels, and calculated free CORT (the putatively biologically active fraction) at multiple points across the daily cycle. A finding that CBG is increased in HR mice would suggest that it might be buffering elevated CORT, and hence that elevated CORT may be a maladaptive byproduct of the selection regimen. In contrast, a decrease or no change in CBG levels would be consistent with the hypothesis that elevated CORT in HR mice may be an adaptation to promote wheel-running. We also compared the circadian pattern of total CORT, free CORT, and bound CORT with the circadian pattern of two measures of activity, home-cage and wheel-running.
Section snippets
Study animals
Adult (8- to 10-week-old) male Mus domesticus were obtained from an ongoing experiment in which four replicate lines of house mice are bred for high levels of voluntary running on days 5 + 6 of a 6-day exposure to wheels attached to standard housing cages (Swallow et al., 1998). Four replicate non-selected lines are maintained as controls (Swallow et al., 1998, Garland, 2003). Progenitors of these mice were from the outbred Hsd:ICR strain.
At weaning (21 days old), mice were toe-clipped for
Diel pattern of total CORT, CBG binding, and free CORT
For both high-runner and control lines, total CORT levels followed the expected diel pattern, with highest levels at 19:00 h, just prior to lights out (Fig. 1). Thus, time of day was a highly significant predictor of total CORT (Ptime < 0.0001). Linetype was also a significant predictor of total CORT (Plinetype = 0.0125), but the time ∗ linetype interaction was not significant (P = 0.560), indicating that the daily pattern of CORT secretion does not statistically differ between HR and C males. In this
Discussion
Values measured for circulating CORT levels (see also Malisch, 2007) are similar to those from previous studies (Coleman et al., 1998, Malisch et al., 2007). Although the study of Malisch et al. (2007) on both sexes and that of Girard and Garland (2002) on females both indicated that HR mice have elevated baseline CORT relative to C mice, they examined only a few times. In addition, a recent study of HR males (at 10 and 18 months of age) indicated plasma CORT levels during the middle of the
Acknowledgments
We thank Leslie Karpinski and Jim Sinclair for their help maintaining the mouse colony, Glennis Julian and Haruka Wada for their generous help during CORT and CBG sample analysis, Kevin Middleton for writing the R script that was used to process wheel-running and home-cage activity data, Andrea Radtke and Shana Van Cleave for their assistance during data collection, and Wendy Saltzman and Henry B. John-Alder for comments on earlier versions of the manuscript. This work was supported by National
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Present address: Departamento de Fisiologia, Instituto de Biociencias, UNESP-Botucatu CEP: 18618-000, Brazil.