title: Antidepressant responsiveness in adulthood is permanently impaired after neonatal destruction of the neurogenic pool.
abstract: The dynamic turnover of hippocampal neurons is implicated in the regulation of cognitive and affective behavior. Extending our previous demonstration that administration of dexamethasone (ND) to neonatal rats depletes the resident population of neural precursor cells (NPC) and restrains the size of the neurogenic regions, we now show that the adverse effects of ND persist into adulthood. Specifically, ND impairs repletion of the neurogenic pool and neurogenesis; ND also compromises cognitive performance, the ability to actively adapt to an acute stressor and, the efficacy of glucocorticoid (GC) negative feedback. Interestingly, although ND depletes the neurogenic pool, it does not permanently abolish the proliferative machinery of the residual NPC population; however, ND increases the susceptibility of hippocampal granule neurons to apoptosis. Although the antidepressant fluoxetine (FLX) reverses the latter phenomenon, it does not replenish the NPC pool. Treatment of ND-treated adult rats with FLX also improves GC negative feedback, albeit without rescuing the deleterious effects of ND on behavior. In summary, ND leads to protracted disruption of mental functions, some of which are resistant to antidepressant interventions. We conclude that manipulation of the NPC pool during early life may jeopardize the therapeutic potential of antidepressants in adulthood.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.|Brain Research Instrument Innovation Center, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Zutshi
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Stoffel
authors.affiliation: Max-Delbrück-Zentrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: A P
authors.initials: AP
authors.lastname: Ventura-Silva
authors.affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: N
authors.identifier: 0000-0002-8755-5126
authors.initials: N
authors.lastname: Sousa
authors.affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: P S
authors.initials: PS
authors.lastname: Costa
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.|HMNC Brain Health, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Patchev
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: O F X
authors.initials: OF
authors.lastname: Almeida
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000928:Antidepressive Agents; D005938:Glucocorticoids; D005473:Fluoxetine; D003907:Dexamethasone