Antidepressant responsiveness in adulthood is permanently impaired after neonatal destruction of the neurogenic pool

S Yu,P S Costa,R Stoffel,A Patchev,O F X Almeida,N Sousa,A P Ventura-Silva,J Zhang,I Zutshi,F Holsboer

doi:10.1038/tp.2016.255

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.

Highlights

The dynamic acquisition and loss of hippocampal neurons is implicated in the regulation of mood, cognition and the neuroendocrine response to stress.[1,2,3] The subgranular zone (SGZ) of the hippocampal dentate gyrus is endowed with a pool of neural precursor cells (NPC) that proliferate and differentiate into neurons or glial cells.[4]
Persistent, fluoxetine-irreversible depletion of the NPC pool by ND The efficacy of the DEX and FLX treatments are shown in Supplementary Figure S1
Confirming that ND retards the volumetric growth of the SGZ and granule cell layer (GCL),[30] stereological analysis showed that ND exerts inhibitory effects on hippocampal growth and the SGZ (P = 0.03, Supplementary Figure S2A) and GCL volume (P = 0.03; Supplementary Figure S2B), effects that persist through to adulthood

Summary

Introduction

The dynamic acquisition and loss of hippocampal neurons is implicated in the regulation of mood, cognition and the neuroendocrine response to stress.[1,2,3] The subgranular zone (SGZ) of the hippocampal dentate gyrus is endowed with a pool of neural precursor cells (NPC) that proliferate and differentiate into neurons or glial cells.[4]. The GC receptor agonist dexamethasone (DEX) is often used to treat life-threatening conditions in perinatal medicine despite concerns regarding optimal dosage and potential adverse effects.[18,19] The latter concerns arise from preclinical and clinical reports that perinatal DEX treatment can severely retard psychomotor, emotional and cognitive development.[20,21,22,23] As high levels of GC are encountered during stressful events, it is pertinent to note that clinical studies have shown that early life experiences have a critical role in shaping an individual’s mental health span trajectory.[24,25,26,27]

Methods

Results

Conclusion