Glucocorticoids Orchestrate Divergent Effects on Mood through Adult Neurogenesis

Abstract

Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal role in the etiology of depression remains elusive. The antidepressant actions of environmental enrichment are neurogenesis-dependent, but the contribution of enrichment-elevated glucocorticoids is unexplored. Importantly, for both social defeat and environmental enrichment, how glucocorticoids interact with neurogenesis to alter mood is unknown. Here we investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment in mice. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesis—via HPA axis interactions —is directly involved in precipitating the depressive phenotype following social defeat. Mice adrenalectomized prior to social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared to sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrate that glucocorticoid-dependent declines in neurogenesis drive changes in mood following social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience.

Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors

“…A previous study showed that the effects of social defeat stress and environmental enrichment on both neurogenesis and stress-related behavior are dependent on modulation of the HPA axis, as adrenalectomized mice with clamped CORT levels were unaffected by these environmental manipulations (Lehmann et al, 2013). Data presented here further suggests that CORT-mediated changes in neurogenesis are required for behavioral effects, as mice with increased neurogenesis do not display CORT-induced behavioral effects.…”

Repeated social defeat stress induces neuroinflammation and impairs hippocampal neurogenesis that differentially regulate mood and cognition

“…In the current study, the number of newly formed astrocytes, as marked by GFAP/BrdU double-labeling, in the dentate gyrus did not vary with RSD when examined at The attenuation in the number of neurons was evident in the caudal hippocampus of RSD-exposed mice compared to the controls. This region-specific differential effect of social defeat stress on neurogenesis has also been demonstrated in previous studies [38]. Moreover, existing literature exploring the functional dichotomy of the hippocampus implicates the rostral and the caudal hippocampus in cognitive and affective processing respectively [39].…”

Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

“…Although depression was traditionally considered to have a neurochemical basis, structural connectivity and plasticity changes, including neurogenesis, may contribute to its etiology as well. Later studies have suggested that neurogenesis is implicated in antidepressant drug action (Perera et al 2011;Surget et al 2011), but it remains elusive how exactly newborn neurons contribute to mood and depression, besides their cognitive deficits, which are related, but not specific to mood disorders (Revest et al 2009;Snyder et al 2011;Anacker and Pariante 2012;Lehmann et al 2013;Lucassen et al 2013a,b).…”