Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus

Abstract

Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.

Figure 1

Effect of prenatal stress on cell proliferation in 28-day-, 3-month-, 10-month-, and 22-month-old male rats. There was a significant decline of cell proliferation with increasing age in both control and prenatally stressed rats. Furthermore, for the four ages investigated, prenatal stress consistently decreased cell proliferation as compared with control. *, P < 0.05 in comparison to age-matched control group; **, P < 0.01. Notice the different ordinal scale between data for 28-day-old rats and the other ages studied.

Figure 2

Illustration of BrdUrd-labeled cells in the dentate gyrus. Photomicrographs of BrdUrd immunoreactivity in frontal section of the dentate gyrus in a control (a) and a prenatally stressed (b) rat . (Scale = 1.5 cm for 500 μm.) (c) Confocal illustration of BrdUrd-labeled cells in the dentate gyrus showing that newborn cells were mainly neurons. Indeed, BrdUrd-IR cells (red nuclear stain, Cy3) colocalized with the neuronal marker NeuN (green stain) as indicated by the yellow nuclear staining. (d) Newly born cells are rarely astrocytes because BrdUrd-IR cells (red nuclear stain) is not stained for the astroglial marker GFAP (green stain).

Figure 3

Effect of prenatal stress on total number of granule cells in 28-day-, 3-month-, 10-month-, and 22-month-old male rats. Although the total number of granule cells was not different among different ages in control rats, there was a progressive decline of total granule cell number with increasing age after prenatal stress. Interestingly, this decline in prenatally stressed rats was observable from 3 months of age continuing until 22 months of age. *, P < 0.05 in comparison to age-matched control group.

Figure 4

Effect of prenatal stress on number of pyknotic cells in 3-month-, 10-month-, and 22-month-old male rats. With increasing age, there was a progressive increase in the total number of pyknotic cells. There was no effect of prenatal stress.

Figure 5

Spatial learning in a water maze. The latency to find the platform by the control group was significantly less than that observed for the prenatally stressed group. (Inset) The means over the 5 days of testing. **, P < 0.01 in comparison to control group.

Figure 6

Effect of training in the water maze on cell proliferation in control and prenatally stressed rats. Acquisition of a spatial task increased the rate of hippocampal neurogenesis in control rats but not in prenatally stressed rats. Prenatal stress decreased the total number of BrdUrd-IR cells and, in this group, the number of newly born cells was identical for manipulated as well as for trained animals. (Inset) Correlation between cell proliferation and mean latency to reach the platform. *, P < 0.05 as compared with manipulated control group; °, P < 0.05 and °°, P < 0.01 as compared with control group.