Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice.

Sanghee Yun,Dieter Riethmacher,Devon R Richardson,Howard K Gershenfeld,Michele N Ross,Michael H Donovan,Amelia J Eisch,Robin Reister,Laure A Farnbauch,Diane C Lagace,Stephanie J Fischer

doi:10.1371/journal.pone.0147256

Abstract

Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors.

Highlights

Depression and anxiety are devastating, prevalent psychiatric disorders diagnosed in a great number of people during their lifetime [1]
As stress can influence neurogenesis, steps were taken to minimize potential stress differences among mice in the same cage: each cage was gently removed from the housing room and brought to the adjacent procedure room immediately prior to anesthesia; mouse cage transfer was performed by a researcher with clean personal protective equipment; and all mice in a cage were anesthetized within 3 min, and began exsanguination within 5 min, of being brought into the procedure room. With these and other steps, we have found neurogenesis levels in the Nestin-CreERT2 mouse line can be reliably and accurately evaluated with ~4 mice/treatment group, similar to N published in other neurogenesis studies [52,53,54], even when DG neurogenesis is quantified in only 1 hemisphere
Nestin-CreERT2/diphtheria toxin fragment A (DTA) transgenic mice have a transient reduction in DCX + neuroblasts/immature neurons and YFP+ cells, but a long-lasting reduction in Ki67+ progenitors

Summary

Introduction

Depression and anxiety are devastating, prevalent psychiatric disorders diagnosed in a great number of people during their lifetime [1]. A potential explanation for these DG changes is that depression and anxiety may interfere with the process of DG neurogenesis, where local progenitors and neuroblasts give rise to new DG GC neurons throughout life [10,11,12,13], or that treatment for these disorders may stabilize or even increase DG neurogenesis [14,15,16,17] Support for this “neurogenesis hypothesis” of affective and anxiety disorders comes from many studies, including human post-mortem studies showing that treatment with certain antidepressants increases the number of GCs and progenitors relative to non-treated MDD subjects [9, 18]. While it has long been postulated that adult DG neurogenesis contributes to the behavioral improvement seen after antidepressant administration, and reduced adult DG neurogenesis contributes to depressive- and anxiety-like behavior, as detailed below data from preclinical studies are conflicting, and more work is needed to test the proposed causal relationship

Results

Discussion

Conclusion