Sustained remission from depressive-like behavior depends on hippocampal neurogenesis

Abstract

Impairment of hippocampal neurogenesis has been associated with the expression of depressive-like symptoms and some studies have suggested neurogenesis as a critical factor in the normalization of behavior by antidepressant (AD) drugs. This study provides robust evidence that ongoing neurogenesis is essential for the maintenance of behavioral homeostasis and that its pharmacological arrest precipitates symptoms commonly found in depressed patients. Further, the incorporation of newly born neurons and astrocytes into the preexisting hippocampal neurocircuitry is shown to be necessary for the spontaneous recovery from the adverse effects of stress and for long-term benefits of AD treatments.

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.…”

Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood

“…The resulting persistent HPA axis hyperactivity may set in motion a vicious cycle, in which glucocorticoid abnormalities continue to reduce neurogenesis, ultimately leading to long-term disturbances in stress reactivity and sustained anxiety-like and depressive-like behaviour. This is supported by a rodent study showing that neurogenesis is required for spontaneous recovery from anhedonia, anxiety and cognitive flexibility impairments 4–6 weeks after exposure to chronic stress 137 .…”

“…Non-pharmacological antidepressant strategies also potently increase neurogenesis and include interventions such as electroconvulsive shock therapy, environmental enrichment, physical exercise and calorific restriction 23,53,123,142,147,148 . Accordingly, neurogenesis is sufficient to confer antidepressant effects in chronically stressed mice 128,149 and to facilitate spontaneous remission from depression-like symptoms 137 . Enhancing neurogenesis through pharmacological or non-pharmacological means may thus be a promising strategy to confer stress resilience or antidepressant effects in patients.…”

“…During stressful experiences, neuroendocrine responses and anxiety-like and depressive-like behaviour are less increased in mice with high levels of neurogenesis (part a ) than in mice with low levels of neurogenesis 135,136 (part b ). Once the stressor has ended, neurogenesis facilitates reversal learning and cognitive flexibility 137 to promote positive adaptation to novel, non-threatening environments. Therefore, increasing neurogenesis may facilitate fast recovery from HPA axis hyperactivity and anxiety-like and depressive-like behaviours and may prevent the development of chronic stress-induced psychopathology (part a ).…”

Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment

“…9, 38–40 Chronic stress produces a decrease in hippocampal neurogenesis, 41–43 raising the possibility that ablation of neurogenesis may increase the susceptibility to the behavioral effects of stress. Some studies have observed such an increase in stress susceptibility, 44, 45 whereas others have reported that ablation of neurogenesis on its own does not produce an increased sensitivity to the behavioral effects of stress. 6, 46 Our results on the overexpression of BMP4 support the conclusion that stimulation of neurogenesis plays a key role in antidepressant efficacy, but that a reduction in adult hippocampal neurogenesis is not, by itself, sufficient to induce the onset of depressive symptoms.…”