Our data show that EE can ameliorate submissive and depressive-like behaviors adopted by male mice in response to chronic psychosocial stress. Exposing subordinate wild-type animals to EE after SC (SC → EE) results in increased aggressive displays towards the dominant animal. Compared with SC → IE, SC → EE mice display normal hedonic drive, decreased anxiety-like behaviors and increased interaction with the SC partner, essentially restoring the animals' behavior to their pre-stress patterns. Importantly, our data show that EE's restorative effects depend on intact adult neurogenesis. Induction of the SC-induced submissive phenotype is similar between Ctrl and NG- mice. However, NG- animals neither reap the benefit of EE in extinguishing the SC-induced submissive phenotype nor realize EE's anti-depressive and anxiolytic effects.
We used daily social defeat in combination with chronic non-tactile exposure to induce a subordinate, depressive-like phenotype. Numerous models, including chronic unpredictable mild stress and chronic restraint stress, have been developed to induce depressive-like behaviors in rodents. However, these paradigms lack important psychosocial components inherent to human depression. Because stressful life events are often social in nature, ethologically relevant SC animal models may be particularly useful in understanding how differential social experiences lead to neurobiological changes that can influence behavior. Although both participants in an agonistic encounter experience social stress, its consequence is different for winners versus losers, with the social stress experienced by subordinates leading to increases in social withdrawal as well as depressive- and anxiety-like behaviors. In rodents, chronic antidepressant treatment increases aggression, resulting in elevated hierarchical status.28
In our study, SC → IE mice retain their submissive behavior upon SC re-exposure, suggesting an inability to cope with the previous adverse experience. In contrast, SC → EE mice showed an increase in aggressive behavior upon SC re-exposure, suggesting that EE promotes the acquisition of adaptive coping strategies.
In humans, physical exercise and positive psychosocial activities can improve cognitive function, reduce depressive symptoms and increase stress resiliency.29
In animals, exercise and complex environments exert profound influences on brain structure and chemistry as well as on cognitive and emotionally relevant behavioral measures.30, 31, 32
It has been suggested that EE insulates the individual from the adverse effects of uncontrollable stress exposure, tempering its emotional reactivity.14, 21
Animals living in EE show upregulation of hippocampal glucocorticoid receptor (GR) mRNA expression and increased glucocorticoid sensitivity.23, 33
Accordingly, enriched animals show blunted hypothalamic–pituitary–adrenal (HPA) axis responses to mild stressors.34
Moreover, exercise has been shown to enhance habituation of the HPA axis to repeated stressor exposure.35
These reports suggest that EE renders the HPA axis more adaptive, resulting in decreased emotional reactivity and increased emotional stability.
The hippocampus provides powerful inhibitory control over the HPA axis, and the DG in particular has been shown to strongly coordinate release of corticotropin-releasing hormone in the hypothalamic paraventricular nucleus.36
We recently reported that loss of adult neurogenesis alters the HPA-axis response to mild stress,37
suggesting a role for adult neurogenesis in mediation of HPA-axis activity by the hippocampus. The significance of HPA-axis modulation in depression is underscored by reports that successful antidepressant treatment is associated with resolution of impairment in HPA-axis negative feedback.38, 39
Our data show that the ability of animals to recover from the SC-induced submissive phenotype is critically dependent on intact neurogenesis. Given previous evidence that the HPA-axis is altered by EE exposure and that neurogenesis modulates the HPA-axis stress response, it is plausible that the antidepressant effects of EE in behavioral recovery from SC are mediated via regulation of the HPA axis by neurogenesis.
Two fundamental lines of research have pointed to a link between hippocampal neurogenesis and depression. First, stress, an important etiological factor in the pathogenesis of depression, decreases hippocampal neurogenesis. Second, many antidepressant therapies, including electroconvulsive therapy, exercise and antidepressant drugs, enhance hippocampal neurogenesis.40, 41, 42, 43
Moreover, pharmacological therapies have a delayed onset of efficacy that parallels the protracted time scale of increased neurogenesis. The functional significance of antidepressant-induced enhancement of neurogenesis was shown in rodents with the report that ablation of cell proliferation by hippocampal irradiation blocked specific behavioral effects of antidepressants.9, 24, 44
It remains unclear whether impaired neurogenesis and development of depression per se
are causally related. Adult neurogenesis and depression are not well correlated in several rodent models of depression, and ablating neurogenesis does not appear to affect baseline anxiety- and depressive-like behaviors10, 45
Our results support these data, showing that loss of neurogenesis does not directly lead to depressive- or anxiety-like behaviors (). We do, however, uncover a role for neurogenesis in mediating the beneficial effects of EE in recovery from a depressive-like state. In both Ctrl and NG- animals, SC induction led to a submissive phenotype, but only Ctrl animals were able to take advantage of EE for recovery. A recent report by Meshi et al.46
showed that hippocampal neurogenesis was not required for baseline EE-induced improvements in spatial learning and anxiety-like behavior. These previous results coupled with our data lend support to the idea that hippocampal neurogenesis does not mediate baseline improvements in behaviors, but it may be specifically important in the remediation of impaired behaviors.
In addition to the possible effects of EE and neurogenesis on stress responsiveness via the HPA axis, new neurons may be influencing context-specific memory formation, which could contribute to EE's ability to remediate behavioral impairments in our SC model. Hippocampal network models suggest that increased DG cell turnover can enhance encoding of new memories, whereas simultaneously degrading old memory recall.47, 48
Supporting this idea, it has been proposed that the DG and specifically its newly born neurons, may have a unique role in ‘pattern separation', enabling the animal to amplify differences between old and new representations of an experience.49, 50, 51
Their physiological properties render adult-born DG neurons more sensitive to successive exposures to the same environment,52
which could provide a neurobiological correlate for distinguishing between similar environments. The inability to detect and then respond to contextual changes results in a process that has been dubbed the ‘uncoupling of effect from external context',53
and the cognitive distortions produced by this uncoupling are thought to be associated with development of disturbed mood. Indeed, recent findings54, 55
show a causal relationship between reduced neurogenesis and an anxiogenic phenotype and thus provide further evidence for links between adult neurogenesis and the ability to both integrate novel information into existing memory and temporally separate novel events. This theory would predict that in our paradigm NG- mice exposed to EE would be unable to uncouple the SC-acquired negative experiences, leading to perpetuation of the submissive phenotype. In contrast, stimulation of neurogenesis in Ctrl mice exposed to EE would facilitate coupling of positive affect with the new environmental context. As a result, Ctrl/EE mice would be rendered better able to detect and then capitalize on improvements in the environment, thus facilitating amelioration of submissive and depressive behaviors. In our model, Ctrl/EE mice showed a robust recovery from the SC-induced submissive phenotype when compared with both Ctrl/IE and NG-/EE mice, suggesting a role for neurogenesis in the extinction of the submissive, depressive-like state.
The current results support the hypothesis that impaired neurogenesis results in inefficient integration of novel stimulation, rendering the animal unable to distinguish changes in contextual and temporal information. Thus, newborn cells in the DG may be important for the animal to perceive a similar negative environment (SC), and to then adopt new coping strategies to combat it. The ability of EE to accelerate and enhance neurogenesis may be critical for this process. Furthermore, newborn DG cells may also be necessary for the animal to take advantage of the new contextual experiences provided by EE. If neurogenesis is impaired, existing DG cells must represent features of both the old and new environments as well as their emotional contexts, compromising the animal's ability to adapt to the new context with appropriate affect.
In conclusion, our study makes several important contributions. First, exposure to chronic psychosocial stress results in an ethologically relevant behavioral phenotype that resembles hallmarks of clinical depression in humans. Second, EE rescues the submissive phenotype and depressive-like behaviors adopted in response to chronic psychosocial stress, suggesting that EE increases stress resiliency and promotes adaptive coping. Third, these beneficial effects of EE are dependent on intact adult neurogenesis. These findings suggest that maladaptive responses to adverse psychosocial situations can be ameliorated by behavioral therapies, and that these improvements may be aided by promoting neurogenesis.