Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity - PubMed (original) (raw)

Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity

Richard J Windle et al. J Neurosci. 2004.

Abstract

We reported previously that the neuropeptide oxytocin attenuates stress-induced hypothalamo-pituitary-adrenal (HPA) activity and anxiety behavior. This study sought to identify forebrain target sites through which oxytocin may mediate its anti-stress effects. Ovariectomized, estradiol-treated rats received intracerebroventricular infusions of oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr), and the patterns of neuronal activation after restraint stress were determined by semiquantitative mapping of c-fos mRNA expression. Oxytocin administration significantly attenuated the release of ACTH and corticosterone and the increase in corticotropin-releasing factor mRNA expression in the hypothalamic paraventricular nucleus (PVN) in response to 30 min restraint. Restraint also induced the expression of c-fos mRNA in selective regions of the forebrain, including the PVN, paraventricular thalamic nucleus, habenula, medial amygdala, ventrolateral septum (LSV), most subfields of the dorsal and ventral hippocampus, and piriform and endopiriform cortices. In most cases, this level of gene expression was unaffected by concomitant administration of oxytocin. However, in the PVN, LSV, and throughout all subfields of the dorsal hippocampus, restraint evoked no detectable increase in c-fos mRNA in animals treated with either dose of oxytocin. Vasopressin had no effects on either HPA axis responses or neuronal activation in response to restraint, indicating that the effects were highly peptide selective. These data show that central oxytocin attenuates both the stress-induced neuroendocrine and molecular responses of the HPA axis and that the dorsal hippocampus, LSV, and PVN constitute an oxytocin-sensitive forebrain stress circuit.

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Figures

Figure 1.

Figure 1.

The effect of central oxytocin and vasopressin administration on plasma ACTH (A) and corticosterone (B) concentrations in control animals (open bars) or after a 30 min period of restraint (filled bars). Groups of ovariectomized, estradiol-treated rats were infused centrally with either saline or saline containing 1 or 10 ng/hr oxytocin or 10 ng/hr vasopressin for a period of 5 d before restraint. Values represent the mean ±SE; n = 8–12.*p < 0.05, one-tailed t test versus nonrestrained controls infused with the same treatment; +p < 0.05, post hoc Tukey's test in ANOVA; a, b, bars labeled with different letters differ significantly by post hoc Tukey's test in which a significant interaction was detected in the ANOVA.

Figure 2.

Figure 2.

The effect of central infusion of oxytocin and vasopressin on restraint-induced CRF mRNA expression in the PVN. A–D, Images of autoradiograms demonstrating the distribution of hybridized CRF mRNA in the PVN of nonrestrained (A, C) and restrained (B, D) ovariectomized, estradiol-treated rats infused centrally with either saline (A, B) or 10 ng/hr oxytocin (C, D). Scale bar, 100 μm. Note that the marked expression of CRF mRNA induced by restraint in the saline-infused animal (B) is absent in the oxytocin-infused animal (D). E, CRF mRNA expression levels in control animals (open bars) or after a 30 min period of restraint (filled bars). Values shown are the mean ± SE of integrated optical density measurements in arbitrary units (n = 4–6). *p < 0.05, one-tailed t test versus nonrestrained controls infused with the same treatment.

Figure 3.

Figure 3.

Effect of central infusion of oxytocin and vasopressin on restraint-induced c-fos mRNA expression in the PVN. A–D, Images of representative autoradiograms showing the hybridized c-fos mRNA signal in the PVN of nonrestrained (A, C) and restrained (B, D) ovariectomized, estradiol-treated rats infused centrally with either saline (A, B) or 10 ng/hr oxytocin (C, D). The restraint-induced signal in the saline-infused animal (B) is absent in the oxytocin-infused animal (D). Scale bar, 100 μm. Note that, in all cases, the presence of the PVN was confirmed in adjacent sections. E, Values for mean ± SE (n = 6–8) integrated optical density measurements of c-fos mRNA expression in the PVN of control animals (open bars) and animals after a 30 min restraint (filled bars). *p < 0.05, one-tailed t test versus nonrestrained controls infused with the same treatment; a, b, bars labeled with different letters differ significantly by post hoc Tukey's test in which a significant interaction was detected in the ANOVA.

Figure 4.

Figure 4.

Effect of oxytocin and vasopressin on restraint-induced c-fos mRNA expression in dorsal hippocampus. A–D, Images of representative autoradiograms showing the distribution ofhybridizedc-_fos_mRNA in the dorsal hippocampus of nonrestrained (A,C) and restrained (B,D) ovariectomized, estradiol-treated rats infused centrally with saline (A, B) or 10 ng/hr oxytocin (C, D). The subfields indicated are CA1, CA2, and dentate gyrus (DG). Scale bar, 100 μm. c-fos mRNA expression is lower in restrained animals treated with oxytocin (D) than those infused with saline (B). E, F, Values of mean ± SE (n = 5–8) integrated optical density measurements of c-fos mRNA expression in the CA1 (E), CA2 (F), and dentate gyrus (G) of control animals (open bars) and animals after a 30 min restraint (filled bars). *p < 0.05, one-tailed t test versus nonrestrained controls infused with the same treatment; a, b, bars labeled with different letters differ significantly by post hoc Tukey's test in which a significant interaction was detected in the ANOVA.

Figure 5.

Figure 5.

Effect of oxytocin and vasopressin on restraint-induced c-fos mRNA expression in the LSV. A–D, Images of representative autoradiograms showing the distribution of hybridized c-fos mRNA in the LSV of nonrestrained (A, C) and restrained (B, D) ovariectomized, estradiol-treated rats infused centrally with saline (A, B) or 10 ng/hr oxytocin (C, D). Note the clear area of hybridized signal just above the anterior commissure (ac) of the saline-infused restrained animal. Scale bar, 100 μm. E, Mean ± SE (n = 6–8) integrated optical density measurements of c-fos mRNA expression in the LSV of control animals (open bars) or animals undergoing a 30 min period of restraint (filled bars). *p < 0.05, compared with nonrestrained controls infused with the same treatment. +p < 0.05, post hoc Tukey's test in ANOVA.

Figure 6.

Figure 6.

The effect of central oxytocin and vasopressin administration on c-fos mRNA expression within the piriform cortex (A) and medial amygdala (B) of control animals (open bars) or after a 30 min period of restraint (filled bars). Groups of ovariectomized, estradiol-treated rats were infused with saline or saline containing either oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr) for a period of 5 d before study. Values are the mean ± SE of integrated optical density measurements (n = 6–8). *p < 0.05, one-tailed t test versus nonrestrained controls infused with the same treatment; a, b, bars labeled with different letters differ significantly by post hoc Tukey's test in which a significant interaction was detected in the ANOVA.

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