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. 2010 Aug 17;107(33):14823-7.
doi: 10.1073/pnas.0914568107. Epub 2010 Jul 30.

Stress coping stimulates hippocampal neurogenesis in adult monkeys

David M Lyons  1 , Paul S Buckmaster, Alex G Lee, Christine Wu, Rupshi Mitra, Lauren M Duffey, Christine L Buckmaster, Song Her, Paresh D Patel, Alan F Schatzberg
Affiliations

Stress coping stimulates hippocampal neurogenesis in adult monkeys

David M Lyons et al. Proc Natl Acad Sci U S A. .

Abstract

Coping with intermittent social stress is an essential aspect of living in complex social environments. Coping tends to counteract the deleterious effects of stress and is thought to induce neuroadaptations in corticolimbic brain systems. Here we test this hypothesis in adult squirrel monkey males exposed to intermittent social separations and new pair formations. These manipulations simulate conditions that typically occur in male social associations because of competition for limited access to residency in mixed-sex groups. As evidence of coping, we previously confirmed that cortisol levels initially increase and then are restored to prestress levels within several days of each separation and new pair formation. Follow-up studies with exogenous cortisol further established that feedback regulation of the hypothalamic-pituitary-adrenal axis is not impaired. Now we report that exposure to intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey males. Hippocampal neurogenesis in rodents contributes to spatial learning performance, and in monkeys we found that spatial learning was enhanced in conditions that increased hippocampal neurogenesis. Corresponding changes were discerned in the expression of genes involved in survival and integration of adult-born granule cells into hippocampal neural circuits. These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression.

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Conflict of interest statement

Conflict of interest statement: A.F.S. consults to and has equity in BrainCells, Inc. All other authors declare no potential conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Coping with intermittent social stress improves learning over repeated test sessions administered at 3-mo intervals. Correct test response rates are presented for monkeys intermittently housed alone and in new pairs (●) compared with control monkeys (○) housed continuously with a familiar companion (mean± SEM, n = 6 per condition, *P < 0.05).
Fig. 2.
Fig. 2.
Coping with intermittent social stress enhances hippocampal neurogenesis with no net gain in granule cell counts or granule cell layer volumes. (A) Representative granule cell double-labeled with NeuN (green) and BrdU (red). Total number of (B) BrdU/NeuN-labeled granule cells, (C) thionin-stained granule cells, and (D) granule cell layer volumes from monkeys intermittently housed alone and in new pairs (solid bars) compared with control monkeys (open bars) housed continuously with a familiar companion (mean ± SEM, n = 6 per condition, *P = 0.047). All measures were collected 12 wk after the last of five i.v. injections of BrdU to provide ample time for maturation of adult-born neurons.
Fig. 3.
Fig. 3.
Localization of mRNA for gene correlates of learning and hippocampal neurogenesis. Radiographs of mRNA from the left cerebral hemisphere (Upper) and corresponding hippocampus (Lower) are presented for five genes identified by microarray. Abbreviations: DG, dentate gyrus; H, hilus; CA1, hippocampal CA1 field; CA2/3, hippocampal CA2 and CA3 fields; ARL6IP5, ADP ribosylation-like factor 6 interacting protein 5; IGF1, insulin-like growth factor 1; PRG-3, plasticity-related gene 3; PHLPP, PH domain and leucine-rich repeat protein phosphatase; GRM7, metabotropic glutamate receptor 7.
Fig. 4.
Fig. 4.
Coping with intermittent social stress down-regulates PRG-3 expression in subregions of hippocampus. Gray level measures of PRG-3 gene expression in monkeys intermittently housed alone and in new pairs (solid bars) compared with control monkeys (open bars) housed continuously with a familiar companion (mean ± SEM, n = 5–6 per condition, *P < 0.05). Abbreviations: DG, dentate gyrus; H, hilus; CA1, hippocampal CA1 field; CA2/3, hippocampal CA2 and CA3 fields.
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