The results of these experiments demonstrate that the social context in which an experience occurs can dramatically influence the central response to stress hormones. When experienced in a group setting, running stimulates adult neurogenesis. However, when running occurs in social isolation, these positive effects are suppressed. Although runners housed in either social condition experience elevations in corticosterone during one part of the active phase, only those that run alone are vulnerable to the negative influence of glucocorticoids on neurogenesis in the hippocampus. Preventing the elevation in glucocorticoid levels in socially isolated runners stimulates neurogenesis, while group housed animals respond to short-term running with enhanced neurogenesis regardless of their glucocorticoid status.
These paradoxical effects may be the result of a competitive interaction between glucocorticoids, which suppress neurogenesis16-21
and an unidentified factor(s), which positively regulates neurogenesis, and is altered by both running and social housing. Although several candidate mechanisms likely exist; one interesting possibility is the neurotransmitter serotonin which, through its 5HT1A receptor subtype, enhances neurogenesis.24
Levels of serotonin have been shown to increase in the hippocampus with exercise,25
while expression of the 5HT1A receptor has been shown to decrease with both social isolation,26
and with prolonged elevation of corticosterone.27
The extent to which serotonin participates in interactions among social housing, running, glucocorticoids and neurogenesis, however, remains to be determined.
Prolonged exercise ultimately enhanced neurogenesis in the dentate gyrus of animals living in social isolation. This change occurred some time between 24 and 48 days of running, and was accompanied by a significant increase in the volume of the brain region. The basis for these changes in adult neurogenesis and dentate gyrus volume are unknown, but may involve alterations in the vascular structure. Angiogenesis supports cell proliferation in the subgranular zone, possibly through increased expression of neurotrophic factors28, 29
and physical activity has been shown to promote extension of the vasculature.30
It is noteworthy that socially isolated runners in the social housing study, but not those of the time course study exhibited decreased levels of adult neurogenesis. This differential response of socially isolated runners to short-term physical activity may be related to the added stress of daily injections.23
Indeed, daily handling and injection was found to significantly elevate levels of circulating corticosterone. Moreover, replacing the injections with cold water stress resulted in virtually identical effects on cell proliferation. Thus, in the presence of additional stressors, socially isolated runners exhibit decreased neurogenesis compared to controls. In the absence of additional stressors, socially isolated runners have levels of adult neurogenesis that are similar to sedentary controls. These results are consistent with a study showing that footshock-induced decreases in neurogenesis can be eliminated by social housing.31
Our data suggest that social housing alters the HPA axis response to stress- while isolated runners experience robust elevations in corticosterone in response to stress, group housed runners show no such increase in corticosterone. Collectively, these results suggest that socially isolated runners may be exposed to higher levels of corticosterone under certain conditions and furthermore, that elevations in adrenal steroids are involved in both the negative effects and prevention of the positive effects on neurogenesis since preventing elevations in glucocorticoid levels not only eliminated the negative effects but enabled the positive effects on neurogenesis to emerge.
Numerous studies have reported enhanced neurogenesis following voluntary running in animals housed in groups.12-15,32
Similar results have been obtained using forced running paradigms33,34
. These latter studies also examined animals housed in groups (J. Trejo, personal communication; C-J Kim, personal communication). Some studies, however, have examined the effects of running on adult neurogenesis in individually-housed animals; most of these findings are consistent with our data, in that the duration of running used to enhance adult neurogenesis was relatively long.35-37
However, there are a few reports of increased cell proliferation in socially isolated adult rats following short bouts of running. Two of these studies examined individually-housed Spontaneously Hypertensive Rats (SHR).38,39
Since these experiments were conducted in female animals, which show estrous cycle dependent fluctuations in neurogenesis40
and running activity, and this rat strain differs from the Sprague-Dawley in the rate of hippocampal cell proliferation under basal conditions,41
it is not surprising that the physiological response to having access to a running wheel would also differ. In contrast to our results, Eadie et al42
have reported increased cell proliferation in the dentate gyrus of individually-housed adult male Sprague-Dawley rats following ~17 days of running, considerably earlier than we observed an increase in neurogenesis. This discrepancy raises the possibility that the duration of living in social isolation may be an important determinant of the effect, as these investigators housed their animals in isolation for 3 days, as opposed to the 7 day acclimation period we used, prior to the initiation of running. Our findings that the duration of individual housing alters the response of running on cell proliferation suggest this may be the case.
Running is a natural rodent behavior that appears to have a hedonic component. Naïve laboratory reared rodents will readily engage in wheel running, even without additional incentives, and can be trained to bar press for wheel access.43
Conversely, rodents accustomed to running will experience physiological and behavioral signs of withdrawal when suddenly denied access to a wheel.44,45
Our results suggest that engaging in an internally motivated, apparently pleasurable, activity can exert radically different influences on neural plasticity depending on the context in which it occurs. In a socially deprived environment, the enhancement of neurogenesis by running is delayed, and in the presence of additional stressors, neurogenesis is actually suppressed. By contrast, running in a group setting elevates neurogenesis – despite HPA axis activation, and in the context of additional stressors, such as injection or cold water stress. Although it is possible that different social contexts may alter the hedonic value of running, our behavioral data indicate no differences in the duration, frequency or distance run across social groups. Collectively, these results indicate that social isolation can both delay the enhancement of plasticity by physical exercise, and exacerbate the consequences of stressful stimuli. Structural plasticity and, in particular, adult neurogenesis in the hippocampus, have been linked to anxiety regulation and the therapeutic actions of antidepressants.46,47
Our findings present a potential mechanism whereby social isolation may predispose the organism to a negative outcome in the presence of physiologically ambiguous experiences.