Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats

Abstract

Regular physical exercise is beneficial for both physical and mental health. By contrast, stress is associated with deleterious effects on health and there is growing evidence that regular physical exercise counteracts some of the effects of stress. However, most previous studies have suggested that prior exercise does not alter the acute hypothalamic pituitary adrenal (HPA) axis responses to stress. The present series of studies provides evidence that in rats, 6 weeks (but not 1 or 3 weeks) of voluntary wheel running reduces the HPA axis responses to lower-intensity stressors such as an i.p. saline injection, exposure to a novel environment or exposure to moderate intensity noise, but not to more intense stressors such as predator odour exposure or restraint. Daily exercise does not appear to be necessary for the reduction in HPA axis responses, with intermittent access (24 h out of each 72-h period) to a running wheel for 6 weeks, resulting in similar decrements in adrenocorticotrophic hormone and corticosterone release in response to 85 dBA noise exposure. Data from in situ hybridisation for c-fos mRNA are consistent with the hypothesis that voluntary exercise results in a decrease in HPA axis responsiveness to a low-intensity stressor at a central level, with no changes in primary sensory processing. Together, these data suggest that 6 weeks of daily or intermittent exercise constrains the HPA axis response to mild, but not more intense stressors, and that this regulation may be mediated at a central level beyond the primary sensory input.

Fig. 1

(a, b) Experiment 1a: Graphs to show the effect of a 30-min exposure to a novel environment on plasma levels of adrenocorticotrophic hormone (ACTH) (1a) or corticosterone (1b) in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN) or rats housed under sedentary conditions for 6 weeks, in similar cages but without a running wheel (SED). (c) Experiment 1B: Graph to show the levels of plasma corticosterone in response to different lengths of time in a novel environment, in different groups of SED and RUN rats. Rats either remained in their home cage (time = 0), or were exposed to the novel environment for 15, 30 or 60 min, after which a blood sample was taken from a lateral tail vein. Values represent the group mean ± SEM. *P < 0.05 compared to SED group.

Fig. 2

Graphs to show (a) plasma adrenocorticotrophic hormone (ACTH); (b) plasma corticosterone and (c) relative levels of c-fos mRNA in the paraventricular nucleus of the hypothalamus (PVH), 30 min after an i.p. 0.9% saline injection (Experiment 2), in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN) or rats housed under sedentary conditions for 6 weeks, in similar cages but without a running wheel (SED). Values represent the group mean ± SEM. *P < 0.05 compared to SED group.

Fig. 3

Graphs to show the effect of exposure to 85 dBA noise (Experiment 3) on plasma levels of (a) adrenocorticotrophic hormone (ACTH) and (b) corticosterone, in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN) or rats housed under sedentary conditions for 6 weeks, in similar cages but without a running wheel (SED). Separate groups of rats were exposed to background noise conditions (approximately 60 dBA; 0-min group) or 85 dBA white noise for 15 or 30 min. The 60-min group was exposed to 85 dBA noise for 30 min, followed by 30 min under background noise conditions. The solid black bar represents the noise exposure. Values represent the group mean ± SEM. *P < 0.05 compared to SED group (main effect of exercise)

Fig. 4

Graphs to show the effect of exposure to 30 min of 85 dBA noise (Experiment 4) on plasma levels of (a) adrenocorticotrophic hormone (ACTH) and (b) corticosterone, in separate groups of rats that had continuous access to a running wheel in their home cage for either 1, 3 or 6 weeks (RUN) or rats housed under sedentary conditions for the same time periods, in similar cages but without a running wheel (SED). Values represent the group mean ± SEM. *P < 0.001 compared to the 6-week SED group.

Fig. 5

Graphs to show the effect of exposure to 30 min of 85 dBA noise (Experiment 5) on plasma levels of (a) adrenocorticotrophic hormone (ACTH) and (b) corticosterone, in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN) or rats housed under sedentary conditions for the same time period, in similar cages but without a running wheel (SED). Half the RUN rats had access to running wheel during noise exposure (RUN) while the other half had the running wheel locked during noise exposure (RUN + Lock). Values represent the group mean ± SEM *P < 0.01 compared to the SED 60 dBA group. †P < 0.01 compared to the SED 85 dBA group.

Fig. 6

Graphs to show the effect of exposure to 30 min of 85 dBA noise (Experiment 6) on (a) plasma adrenocorticotrophic hormone (ACTH); (b) plasma corticosterone and (c) relative levels of c-fos mRNA in the paraventricular nucleus of the hypothalamus (PVH), in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN), intermittent access (24 h out of 72 h) to a running wheel in their home cage for 6 weeks (RUN-INT) or were housed under sedentary conditions for the same time period, in similar cages but without a running wheel (SED). Values represent the group mean ± SEM *P < 0.01 compared to the SED and RUN 60 dBA groups. †P < 0.001 compared to the SED 85 dBA group. #P < 0.05 compared to the RUN 85 dBA group.

Fig. 7

Photomicrographs showing c-fos mRNA expression after 30 min exposure to 85 dBA noise (Experiment 6), in a rat housed under sedentary conditions for 6 weeks. Templates used for semi-quantitative analysis are shown for (a) prelimbic cortex (PL) and ventrolateral orbitofrontal cortex (ORBvl); (b) infralimbic cortex (IL); (c) dorsomedial caudate putamen (CPdm) and rostral lateral septum (LSr); (d) anteroventral area of the anterior bed nucleus of the stria terminalis (BSTav); (e) ventral lateral septum (LSv), oval nucleus of the bed nucleus of the stria terminalis (BSTov) and medial preoptic area (MPO); (f) paraventricular nucleus of the hypothalamus (PVH) and agranular insular cortex (AI); (g) CA1 region of the hippocampus (CA1), medial blade of the anterior dentate gyrus (DGmb), ventral posterior thalamus (VPT), central nucleus of the amygdala (CEA), lateral nucleus of the amygdala (LA), medial nucleus of the amygdala (MEA) and dorsomedial nucleus of the hypothalamus (DMH); (h) ventral subiculum (SUBv); (i) auditory cortex (AUD) and medial division of the medial geniculate complex with subparafascicular nucleus of the thalamus, parvocellular part (MGm/SPF). The insert is taken at a more rostral region of the medial geniculate complex to show the dorsal/ventral region analysed (MGd/v); (j) inferior colliculus (IC), dorsal raphe nucleus (DR) and cuneiform nucleus (CUN); (k) nucleus of the trapezoid body (NTB) and superior olivary complex (SOC); (l) ventral cochlear nucleus (VCO).

Fig. 8

Graphs to show the effect of exposure to 30 min of 85 dBA noise (Experiment 6) on c-fos mRNA expression in (a) auditory brain regions, or regions that responded to noise with increased c-fos mRNA expression, but did not show an interaction with exercise status and (b) brain regions previously associated with stress, that responded to noise with increased c-fos mRNA expression AND showed an interaction with exercise status, in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN), intermittent access (24 h out of 72 h) to a running wheel in their home cage for 6 weeks (RUN-I) or were housed under sedentary conditions for the same time period, in similar cages but without a running wheel (SED). To show patterns of expression on the same graph, levels of c-fos mRNA are expressed as mean standard score + 1.1. The mean standard score was calculated as: (group mean – ‘population’ mean)/‘population’ SD, with the ‘population’ referring to all animals in the experiment. All standard deviations for mean standard scores = 1 (and are not shown). For the regions analysed and abbreviations, see Fig. 7 and Table 5, respectively.

Fig. 9

Graphs to show the effect of exposure to 30 min of restraint or ferret odour (Experiment 7) on (a) plasma adrenocorticotrophic hormone (ACTH) and (b) plasma corticosterone, in rats that had continuous access to a running wheel in their home cage for 6 weeks (RUN) or were housed under sedentary conditions for the same time period, in similar cages but without a running wheel (SED). Values represent the group mean ± SEM. There were no significant differences between SED and RUN groups.