title: 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.
authors.affiliation: U930 Imaging and Brain, Inserm, Tours, France. alexandre.surget@ntnu.no
authors.forename: A
authors.initials: A
authors.lastname: Surget
authors.forename: A
authors.initials: A
authors.lastname: Tanti
authors.forename: E D
authors.initials: ED
authors.lastname: Leonardo
authors.forename: A
authors.initials: A
authors.lastname: Laugeray
authors.forename: Q
authors.initials: Q
authors.lastname: Rainer
authors.forename: C
authors.initials: C
authors.lastname: Touma
authors.forename: R
authors.initials: R
authors.lastname: Palme
authors.forename: G
authors.initials: G
authors.lastname: Griebel
authors.forename: Y
authors.initials: Y
authors.lastname: Ibarguen-Vargas
authors.forename: R
authors.initials: R
authors.lastname: Hen
authors.forename: C
authors.initials: C
authors.lastname: Belzung
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count / Q000379:methods / Q000706:statistics & numerical data; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D003907:Dexamethasone; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology / Q000627:therapeutic use; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D010912:Pituitary-Adrenal Function Tests / Q000379:methods; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011859:Radiography; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D013843:Thiazines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D006846:Hydrocarbons, Halogenated; C502407:SSR125543; D013843:Thiazines; D005473:Fluoxetine; D003907:Dexamethasone; D003345:Corticosterone