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. 2013 Feb;25(2):158-67.
doi: 10.1111/j.1365-2826.2012.02377.x.

Developmental changes in desensitisation of c-Fos expression induced by repeated maternal separation in pre-weaned mice

N Horii-Hayashi  1 , T Sasagawa, W Matsunaga, Y Matsusue, C Azuma, M Nishi
Affiliations
Free PMC article

Developmental changes in desensitisation of c-Fos expression induced by repeated maternal separation in pre-weaned mice

N Horii-Hayashi et al. J Neuroendocrinol. 2013 Feb.
Free PMC article

Abstract

Early-life stress has long-lasting effects on neuroendocrine and behaviour in adulthood. Maternal separation (MS) is used as a model of early-life stress and daily repeated MS (RMS) for 3 h during the first two postnatal weeks is widely used in rodent studies. However, it is not fully understood whether early-life animals desensitise/habituate to repeated stress. In the present study, we investigated the effects of daily RMS for 3 h and acute/single time MS (SMS) for 3 h on the plasma corticosterone level and c-Fos expression in the brain in mice at different postnatal ages. Mice were subjected to: (i) RMS from postnatal day (PND) 1 to 14 (RMS14); (ii) RMS from PND14 to 21 (RMS21); (iii) SMS on PND14 (SMS14); and (iv) SMS on PND21 (SMS21). Plasma corticosterone and c-Fos expression were examined on the final day in each experiment. The basal corticosterone levels in RMS14 and RMS21 were equal to those in respective age-matched controls. After the final separation, the levels were significantly increased and were comparable with those after SMS14 and SMS21, respectively. Histological analysis indicated that c-Fos expression significantly increased in many brain regions, including the paraventricular nucleus, prefrontal cortex, hippocampus, and basolateral and medial amygdale in both SMS14 and SMS21 mice. However, c-Fos expression in RMS14 mice significantly increased in many regions, whereas such increases were hardly seen in RMS21 mice. These results indicate that repeated early-life stress neither increases basal corticosterone, nor decreases the magnitude of the corticosterone response during the first three postnatal weeks, although desensitisation of c-Fos expression induced by repeated stress is changed during postnatal development.

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Figures

Figure 1
Figure 1
Graphical representation of maternal separation (MS) procedures and brain regions analysed for c-Fos expression. (a) Repeated MS (RMS) was performed from postnatal day (PND) 1 to 14 (RMS14) or PND14 to 21 (RMS21). Acute/single time MS (SMS) was performed on PND14 (SMS14) or PND21 (SMS21). A triangle (▴) indicates a single trial of MS. (b) Shaded regions were subjected to c-Fos expression analysis. Values under the schematic diagrams indicate the distance from the bregma line. For abbreviations, see Table 1.
Figure 2
Figure 2
Plasma corticosterone levels of repeated MS (RMS) and acute/single time MS (SMS) mice on postnatal day (PND) 14 and PND21. The graphs show plasma corticosterone concentrations on PND14 (a) and PND21 (b) (n = 5-9 for each group). Blood samples were collected before (pre-RMS) and after (post-RMS) the final separation for RMS mice and after separation for SMS mice. *P < 0.05 versus control; #P < 0.05 versus Pre-RMS. For abbreviations, see Table 1.
Figure 3
Figure 3
Immunohistochemical images of c-Fos expression after maternal separation (MS) on postnatal day 14. (a–e) Representative immunohistochemical images of c-Fos expression in nonseparated control (left), repeated MS (RMS) 14 (centre) and acute/single time MS (SMS) 14 (right) mice in the paraventricular nucleus (PVN) (a), prelimbic cortex (PrL) (b), hippocampal CA1 (CA1), hippocampal CA3 (CA3) and dentate gyrus (DG) in the hippocampus (c), bed nucleus of stria terminalis (BST) (d), and basolatera region of the amygdala (BLA) and central amygdaloid nucleus (Ce) in the amygdala (e). ac, anterior commissure. Scale bars = 500 (a–c), 250 μm (d, e). For abbreviations, see Table 1.
Figure 4
Figure 4
Immunohistochemical images of c-Fos expression after maternal separation (MS) on postnatal day 21. (a–e) Representative immunohistochemical images of c-Fos expression in nonseparated control (left), repeated MS (RMS) 21 (centre) and acute/single time MS (SMS) 21 (right) mice in the paraventricular nucleus (PVN) (a), prelimbic cortex (PrL) (b), hippocampal CA1 (CA1), hippocampal CA3 (CA3) and dentate gyrus (DG) in the hippocampus (c), bed nucleus of stria terminalis (BST)(d), and basolatera region of the amygdala (BLA)and central amygdaloid nucleus (Ce) in the amygdala (e) . ac, anterior commissure. Scale bars = 500 (a–c, e), 250 μm (d). For abbreviations, see Table 1.
Figure 5
Figure 5
c-Fos expression in the hypothalamus and limbic forebrain after maternal separation (MS). The graphs show the numbers of c-Fos-positive cells on postnatal day (PND)14 (a) and PND21 (b) in nonseparated control (white bar), repeated MS (RMS) (grey bar) and acute/single time MS (SMS) (black bar) mice (n = 4-5 for each group). *P < 0.05 versus control; #P < 0.05 versus RMS.
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