Elsevier

Neuroscience

Volume 102, Issue 2, 15 January 2001, Pages 369-379
Neuroscience

Reproductive status influences cell proliferation and cell survival in the dentate gyrus of adult female meadow voles: a possible regulatory role for estradiol

https://doi.org/10.1016/S0306-4522(00)00474-7Get rights and content

Abstract

Galea and McEwen [Galea and McEwan (1999) Neuroscience 89, 955–964] found that cell proliferation was suppressed in female meadow voles trapped during the breeding season relative to females trapped during the non-breeding season. We investigated the effect of reproductive status and estradiol level on cell proliferation and cell survival in adult laboratory-reared female meadow voles to control for the variables of age, experience and pregnancy that could confound the results derived from a wild sample. Voles were housed in either a long- or short-photoperiod to simulate season and a male or female cage partner was introduced to influence reproductive status. Because females are reflex ovulators, exposure to a male rapidly induces behavioural estrous and high levels of estradiol. Forty-eight hours after introducing a cage partner, we injected either bromodeoxyuridine or [3H]thymidine to mark cell synthesis and then examined labelled cells 2 h (cell proliferation) or five weeks (cell survival) later, respectively. To determine whether estradiol mimicked the effect of reproductive status, groups of reproductively inactive females were given a single injection of estradiol benzoate (10 μg) either four or 48 h prior to bromodeoxyuridine labelling. The density of proliferating cells in the granule cell layer and the hilus was elevated in reproductively inactive females compared to reproductively active females and was correlated negatively with serum estradiol level. Exposure to estradiol benzoate initially increased cell proliferation (within 4 h) but subsequently suppressed cell proliferation (within 48 h). In addition, the density of surviving cells was greater in reproductively inactive females relative to reproductively active females but reproductively active females had a greater rate of cell survival than did reproductively inactive females. Reproductive status did not influence the number of pyknotic cells in the dentate gyrus (at either 2 h or five weeks).

We conclude that reproductive status regulates cell proliferation in adult female meadow voles, possibly via an estradiol-regulated mechanism. The results from the present study showed that reproductively active female meadow voles have suppressed rates of cell proliferation in the dentate gyrus relative compared with reproductively inactive female meadow voles. Administering estradiol initially (within 4 h) elevates the cell proliferation within the dentate gyrus of adult females but subsequently (within 48 h) suppresses cell proliferation. However, more new cells survived in females with high endogenous levels of estradiol (reproductively active females). In conclusion, reproductive status regulates the level of cell proliferation and survival through a complex estradiol regulated mechanism(s).

Section snippets

Experimental procedures

All animals were treated in accordance with the guidelines set forth by the Canadian Council on Animal Care and with the policies on animal care established by The University of British Columbia. Every effort was made to minimise the number of animals used per group and to minimise the suffering of animals used throughout all experimental procedures.

Density of bromodeoxyuridine-labelled cells and pyknotic cells in the granular cell layer and hilus

A BrdU-labelled cell found in the subgranular zone of an adult female meadow vole is shown in Fig. 1A. BrdU-labelled cells were observed to occur primarily in clumps located in the subgranular zone. The density of BrdU-labelled cells in the granule cell layer was significantly greater in RI and EB4 females compared to RA females (P ≤ 0.0007) and EB48 females (P ≤ 0.0013, see Table 1). Similarly, the density of BrdU-labelled cells in the hilus (see Table 1) of RI females was greater compared

Discussion

The density of proliferating cells in the dentate gyrus was elevated in RI relative to RA females and was negatively correlated with serum estradiol level. These findings indicate that reproductive status regulates cell proliferation in female meadow voles. The degree of suppression in cell proliferation observed in RA versus RI females could be reproduced by exposing female meadow voles to EB for 48 h, but not 4 h. In fact, exposure to EB for 4 h tended to elevate the number of proliferating

Conclusions

Reproductive status, possibly through estradiol, regulates cell proliferation and survival in the dentate gyrus of adult female meadow voles. Initially, estradiol tends to increase cell proliferation in the dentate gyrus of rodents but subsequently induces a mechanism (perhaps CORT mediated) that suppresses cell proliferation. Although the density of labelled cells remains elevated in RI females relative to RA females, five weeks later, the rate of survival of newly formed granule cells in the

Acknowledgements

We wish to thank Wayne Yu and Joanne Weinberg for their assistance with the corticosterone radioimmunoassays and Catharine Rankin for her helpful comments regarding this manuscript. This research was funded by an Alzheimers Society of British Columbia grant to LAMG and an NSERC postgraduate scholarship to BKO. A portion of these data was presented at the 1999 Society for Neuroscience Meeting in Miami.

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