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Antidepressants recruit new neurons to improve stress response regulation - PubMed

. 2011 Dec;16(12):1177-88.

doi: 10.1038/mp.2011.48. Epub 2011 May 3.

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Antidepressants recruit new neurons to improve stress response regulation

A Surget et al. Mol Psychiatry. 2011 Dec.

Free PMC article

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.

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Figures

Figure 1
Figure 1

Focal hippocampal X-irradiation ablates cell proliferation in the subgranular zone (SGZ). (a) Schematic representation of the experimental design. A first cohort of mice was used to assess SGZ cell proliferation, see (b) and (c). Two other cohorts of mice were used for behavioral measures, see Figure 2. (b) Representative images of BrdU+ cells (‘black cells') in the SGZ (scale bar, 50 μm). (c) The cell proliferation assessed by the number of BrdU-positive cells per mm3 of the granule cell layer (GCL), n=5–7 per group.#P<0.05 UCMS mice vs control-vehicle mice; *P<0.05 and **P<0.01 UCMS-fluoxetine mice vs UCMS-vehicle mice, or between line-connected groups. Data represent mean±s.e.m.

Figure 2
Figure 2

Hippocampal neurogenesis is required for the behavioral effects of fluoxetine but not of the corticotropin-releasing factor 1 antagonist SSR125543. (a) Schematic representation of the apparatus used for the Cookie test (CT). (b, c) The consumption of the cookie (number of bites) in the CT, n=13–14 per group for (b) and n=10 per group for (c). #P<0.05 and ##P<0.01 UCMS mice vs control-vehicle mice; *P<0.05 and **P<0.01 UCMS-fluoxetine/SSR125543 mice vs UCMS-vehicle mice. Data represent mean±s.e.m.

Figure 3
Figure 3

Chronic stress impairs hippocampal modulation of brain areas involved in the stress response, an effect reversed by fluoxetine. (a) Schematic representation of the neurocircuitry underlying hippocampal regulation of the hypothalamo-pituitary-adrenal (HPA) axis. Hippocampal CA1 and subiculum subregions send glutamatergic outputs (+) toward subcortical relay sites, such as medial preoptic area (mPOA) and ventrolateral preoptic area (vlPOA), anteromedial and posteromedial bed nucleus of stria terminalis (amBST and pmBST), lateral septum (LS), dorsomedial and lateral hypothalamic nuclei (DMH and LH). These sites contain GABAergic neuron population (–) underlying inhibitory influences on the paraventricular nucleus (PVN). (b) Schematic representation of the experimental design. Veh and dexamethasone (DEX) mean vehicle and DEX, respectively. (c) Schematic representation of the guide-cannula implantation (bar: bregma=−3.08, lateral=±2.3, vertical=−1.4) and of the DEX infusion sites, one millimeter lower (asterisk). The figure is adapted from Paxinos and Franklin (2001). (d) Representative images of Fos+ cells from the amBST (scale bar, 50 μm). (e) Changes induced by intrahippocampal DEX infusion on the number of Fos+ cells in LS amBST, pmBST, mPOA, vlPOA, DMH, LH, anteroventral BST (avBST) and PVN, n=4 per group. #P<0.05 UCMS-vehicle mice vs control-vehicle mice; †P<0.1 and *P<0.05 UCMS-fluoxetine mice vs UCMS-vehicle mice. Data represent mean±s.e.m.

Figure 4
Figure 4

Chronic stress and fluoxetine alters the sensitivity of newborn and older hippocampal granule cells to novelty/glucocorticoid effects. (a) Schematic representation of the experimental design. (b) Representative images of NeuN+ (blue), Fos+ (red), BrdU+ (green) cells and colocalization (merged) in the granular cell layer (GCL) of the dentate gyrus (scale bar, 50 μm). Arrowheads show NeuN+/BrdU+newborn neurons. NeuN+/Fos+ cells listed among cells belonging to the inner part of the GCL (including the SGZ) are indicated by white arrows (NeuN+/Fos+/BrdU− cells) or arrowhead (NeuN+/Fos+/BrdU+ cells). (c) The figure shows the effects of novelty and dexamethasone on the recruitment of granule cells (NeuN+/Fos+ cells per GCL mm3), n=4–5 per group. The dark part at the basis of each bar represents the proportion of NeuN+/Fos+ cells listed in the inner part of the GCL. (d) The figure shows the effects of novelty and DEX on the recruitment of newborn granule cells (NeuN+/Fos+/BrdU+ cells per GCL mm3), n=4–5 per group. (e) Proportion of Fos+ cells (%) in NeuN+/BrdU− cells and NeuN+/BrdU+ cells of the GCL, n=8–10 per group. (f) Proportion of the NeuN+/Fos+ cells listed in the inner part of the GCL, n=8–10 per group. #P<0.05 UCMS-vehicle mice vs control-vehicle mice; *P<0.05 UCMS-fluoxetine mice vs UCMS-vehicle mice. †P<0.1 Veh-treated mice vs DEX-treated mice or NeuN+/BrdU− cells vs NeuN+/BrdU+ cells. DEX-P, dexamethasone-phosphate; Flx, fluoxetine; Veh, vehicle. Data represent mean±s.e.m.

Figure 5
Figure 5

Fluoxetine-induced improvement of the HPA axis negative feedback under chronic stress conditions involves hippocampal neurogenesis. (a) Schematic representation of the experimental design. (b) Schedule of the fecal sample collection and of the dexamethasone-phosphate (DEX-P) administration. (c) The DEX suppression test allowed assessing the integrity of the HPA axis negative feedback. The figure shows the DEX-induced suppression of fecal corticosterone metabolites (CORT), n=8–11 per group. #P<0.05 UCMS-vehicle mice vs control-vehicle mice; *P<0.05 and **P<0.01 UCMS-fluoxetine mice vs UCMS-vehicle mice, or between line-connected groups. Data represent mean±s.e.m.

Figure 6
Figure 6

Adult-generated granule neurons are required to restore the hippocampal inhibition of the hypothalamo-pituitary-adrenal axis under chronic stress conditions. (a) Schematic representation of the experimental design. (b) Schematic representation of the guide-cannula implantation (bar: bregma=−3.08, lateral=±2.3, vertical=−1.4) and of the dexamethasone (DEX) infusion sites, one millimeter lower (asterisk). The figure is adapted from Paxinos and Franklin (2001). (c) An intrahippocampal DEX suppression test has been used to test the ability of hippocampus to inhibit the HPA axis. The figure shows the corticosterone (CORT) suppression induced by intrahippocampal DEX infusion, n=7–8 per group. #P<0.05 UCMS mice vs control-vehicle mice; *P<0.05 and **P<0.01 UCMS-fluoxetine mice vs UCMS-vehicle mice, or between line-connected groups. Veh, vehicle; DEX, dexamethasone. Data represent mean±s.e.m.

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