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Adult-born neurons from the dorsal, intermediate, and ventral regions of the longitudinal axis of the hippocampus exhibit differential sensitivity to glucocorticoids

Molecular Psychiatry volume 26, pages 3240–3252 (2021)Cite this article

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Abstract

Hippocampal neurogenesis has been shown to play roles in learning, memory, and stress responses. These diverse roles may be related to a functional segregation of the hippocampus along its longitudinal axis. Indeed, the dorsal hippocampus (dHi) plays a predominant role in spatial learning and memory, while the ventral hippocampus (vHi) is predominantly involved in the regulation of anxiety, a behaviour impacted by stress. Recent studies suggest that the area between them, the intermediate hippocampus (iHi) may also be functionally independent. In parallel, it has been reported that chronic stress reduces neurogenesis preferentially in the vHi rather the dHi. We thus aimed to determine whether such stress-induced changes in neurogenesis could be related to differential intrinsic sensitivity of neural progenitor cells (NPCs) from the dHi, iHi, or vHi to the stress hormone, corticosterone, or the glucocorticoid receptor (GR) agonist, dexamethasone. Long-term exposure of rat NPCs to corticosterone or dexamethasone decreased neuronal differentiation in the vHi but not the dHi, while iHi cultures showed an intermediate response. A similar gradient-like response on neuronal differentiation and maturation was observed with dexamethasone treatment. This gradient-like effect was also observed on GR nuclear translocation in response to corticosterone or dexamethasone. Long-term exposure to corticosterone or dexamethasone treatment also tended to induce a greater downregulation of GR-associated genes in vHi-derived neurons compared to those from the dHi and iHi. These data suggest that increased intrinsic sensitivity of vHi NPC-derived neurons to chronic glucocorticoid exposure may underlie the increased vulnerability of the vHi to chronic stress-induced reductions in neurogenesis.

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Fig. 1: Corticosterone reduced cell proliferation in NPC cultures irrespective of the hippocampal sub-region they are derived from.
Fig. 2: Effects of short-term corticosterone (4 DIV) exposure on NPC differentiation into immature neurons (DCX+) and their maturation.
Fig. 3: Effects of longer-term corticosterone (7 DIV) exposure on NPCs differentiation into neurons (βIII-tubulin+) and their maturation.
Fig. 4: Effects of long-term dexamethasone exposure on NPC differentiation into neurons (βIII-tubulin+) and their maturation.
Fig. 5: Effects of long-term dexamethasone exposure on nuclear GR expression.

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Acknowledgements

BRL was supported by the National Council for Scientific and Technological Development-CNPq of Brazil (Grant number 249007/2013-4). OFO and YMN are funded Investigators and JFC a principal investigator of the APC Microbiome Institute, which is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (Grant number 12/RC/2273). We thank Dr. Ciaran O’Leime, MSc Tara Foley, MSc Suzanne Crotty and the UCC Biological Services Unit staff for technical assistance.

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Authors and Affiliations

  1. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland

    Brunno Rocha Levone, Martin G. Codagnone, Gerard M. Moloney, Yvonne M. Nolan, John F. Cryan & Olivia F. O’ Leary

  2. APC Microbiome Ireland, University College Cork, Cork, Ireland

    Martin G. Codagnone, Gerard M. Moloney, Yvonne M. Nolan, John F. Cryan & Olivia F. O’ Leary

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  1. Brunno Rocha Levone
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Correspondence to Olivia F. O’ Leary.

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Levone, B.R., Codagnone, M.G., Moloney, G.M. et al. Adult-born neurons from the dorsal, intermediate, and ventral regions of the longitudinal axis of the hippocampus exhibit differential sensitivity to glucocorticoids. Mol Psychiatry 26, 3240–3252 (2021). https://doi.org/10.1038/s41380-020-0848-8

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