Antidepressants recruit new neurons to improve stress response regulation

Abstract

Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

“…In addition, fluoxetine treatment in uCMS rats activated pathways related to cellular respiration and metabolism, a finding in line with the presence of long-lived transcripts (Korostynski et al, 2013;Schwanhausser et al, 2011). Further, consistent with the findings of other studies (Encinas et al, 2006;Mateus-Pinheiro et al, 2013b;Surget et al, 2011), the actions of fluoxetine were more pronounced in neurons than in astrocytes and oligodendrocytes.…”

“…In addition, alterations in dendritic plasticity and cytogenesis in the hippocampal dentate gyrus (DG) are observed in the brains of animal models of depression and depressed patients (Lucassen et al, 2014;Pittenger and Duman, 2008). Importantly, these changes have been implicated in the onset of depressivelike symptoms and in the actions of antidepressants (ADs) in animal models of depression (Bessa et al, 2009a;Mateus-Pinheiro et al, 2013a, b;Surget et al, 2011).…”

Neurogenic hypothesis and psychiatric disorders

“…In contrast, when the trkB expression was abolished in differentiated neurons but not neural progenitor cells in the dentate gyrus, the animals showed response to antidepressant treatment with increased neurogenesis and reduced depression-like behavior. The findings were further supported by other studies [28,33] which indicate the lack of antidepressant or anxiolytic effect of psychotropic drugs in the situation of neurogenesis blockage, and a slower recovery of hypothalamic-pituitary-adrenal-axis after stress was found in neurogenesis-deficient mice [34,35]. Collectively, although impaired neurogenesis alone did not cause depression-like behavior, it may abolish the therapeutic effect of antidepressants or sustain the state of depressive disorders.…”

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

“…Finally, we analyzed SGK1 mRNA expression in the hippocampus of adult rats exposed to two well established rodent models of depression, characterized by both increased corticosterone levels and reduced neurogenesis (13)(14)(15): unpredictable chronic mild stress (UCMS) and prenatal stress (PNS). UCMS has been shown to reduce hippocampal neurogenesis in the ventral and in the dorsal hippocampus (18).…”

“…Here we investigate the role of SGK1 in these effects of cortisol in vitro. Moreover, we analyze SGK1 gene expression in the peripheral blood of drug-free depressed patients, and in the hippocampus of rats exposed to unpredictable chronic mild stress (UCMS) or prenatal stress (PNS), two in vivo stress models known to precipitate depressive behavior and to decrease hippocampal neurogenesis (13)(14)(15). Our findings identify SGK1 as a key enzyme involved in the downstream mechanisms by which glucocorticoids reduce neurogenesis and in the upstream potentiation and maintenance of GR function, even after glucocorticoid withdrawal.…”