Research reportHypothalamic and amygdaloid corticotropin-releasing hormone (CRH) and CRH receptor-1 mRNA expression in the stress-hyporesponsive late pregnant and early lactating rat
Introduction
Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), synthesized by parvocellular neurones of the paraventricular nucleus (PVN), are the principal regulators of pituitary adrenocorticotropic hormone (ACTH) secretion, particularly in response to stress. CRH and AVP also have central effects at hypothalamic and extrahypothalamic sites to integrate autonomic, neuroendocrine, and behavioural responses to stress [4], [16], [21]. In this respect, centrally-administered CRH can partially mimic the responses to stress, including increased arousal, grooming behaviour and locomotor activity, anxiogenesis, and autonomic and neuroendocrine activation [5], [16], [21], [35].
CRH mediates its actions through high-affinity membrane receptors located in the brain and pituitary [1], [13], [37], [41], [57]. CRH binding sites are present in areas of the neocortex, and several nuclei of the brainstem, limbic system and hypothalamus [13]. Most of these areas have direct and indirect connections with the PVN, which is both the main source of CRH peptide and an important relay area for neuroendocrine and autonomic regulation. The expression of CRH receptor type 1 (CRHR-1) mRNA in the PVN is very low or absent in resting conditions [31]. However, mRNA levels increase markedly with stress in a stimulus-specific manner, with an increase in parvocellular neurons following physical/psychological stress, and in the magnocellular PVN and SON following osmotic stimulation [31], [42], [45]. The function of CRH receptors in these nuclei is not clear, but in the PVN they may be part of positive autoregulatory mechanism [26], [31], [32]. This is suggested by the fact that i.c.v. infusion of CRH enhances the expression both of the immediate-early gene c-fos, indicating neuronal activation [24], [39], and of CRH gene [39] in the PVN.
While it is not possible to determine the site(s) of action of i.c.v. administered CRH, it is likely that at least some effects are mediated by receptors in the PVN, since in vitro electrophysiological studies have shown direct excitatory and indirect inhibitory actions of CRH on PVN neurons [59]. On the other hand, some of the behavioural effects appear to be mediated via CRH receptors at other sites, as indicated by the ability of chronic infusion of a CRHR-1 antisense oligodeoxynucleotide into the central nucleus of amygdala (ACe) to reduce anxiety-related behaviour in socially defeated rats [27].
Although it is clear that CRH and AVP mediate both neuroendocrine and behavioural responses to stress, with the latter being more involved in the response to chronic stress, the relative roles of these two peptides during states of stress hyporesponsiveness are not well understood. The periods around birth and lactation in the female are physiological states during which there is a marked alteration of responses to stress [9], [28]. Lactating rats show a reduction in the stress-induced increase in CRH and pro-enkephalin mRNA transcription [29], a markedly reduced stress-induced release of oxytocin [7], [22] and prolactin [23], and severely attenuated hypothalamo-pituitary-adrenal (HPA) responses to a wide range of stressors [9], [53], [54], [56]. Furthermore, late pregnant and lactating females (especially in early lactation) show lower restraint-induced c-fos mRNA expression in the PVN, medial amygdala (AMe) and lateral septum (LS) [9]. The mechanisms by which these areas show less c-fos mRNA expression, and presumably less neuronal activation, during stress in lactating females, are not known.
In addition to displaying attenuated responses to stress, lactating rats lack the increase in c-fos mRNA expression which is observed in the PVN, LS, and AMe of virgin females in response to i.c.v. infusion of CRH [10]. Lactation also abolishes CRH-induced oxytocin secretion [40]. If CRH exerts positive autoregulatory feedback on PVN function, it is possible that an impaired CRH receptor up-regulation in the PVN could contribute to the hyporesponsiveness to stress during lactation. The altered behavioural and neuroendocrine responses to stress during lactation may be due to a decrease in CRH receptor expression and CRH levels in amygdaloid nuclei could account for the disinhibition of the fear responses and increase in aggression in threatening situations [43].
The aims of this study were to assess CRH, CRHR-1 and AVP gene expression in basal and stressed conditions during pregnancy and lactation when the behavioural and neuroendocrine responses to stress are reversibly suppressed.
Section snippets
Animals and restraint procedures
Female virgin (210–250 g), pregnant (17–19 days) and 3-day lactating rats of the Sprague–Dawley strain (Charles River, USA) were housed in a 12-h light, 12-h dark cycle with access to rat chow and water ad libitum. Virgin and pregnant animals were housed in groups of three (cage size: 50×32×18.5 cm) and lactating females were housed with their litters (cage size: 40×24×20 cm). All rats were handled three times a week. For the virgin rats vaginal smears were performed given that the sensitivity
Hypothalamic areas
There was a marked reduction of basal CRH mRNA levels in the PVN of late pregnant females compared with that of virgin control rats (Fig. 2, Fig. 4). In contrast, CRH mRNA was elevated on day 3 of lactation showing levels significantly greater than those of virgin females (P<0.001) (Fig. 2, Fig. 4). Following restraint stress, the expression of CRH mRNA increased in the virgin female group (Fig. 2B) (P<0.05) but not in late pregnant or early lactating females (Fig. 2D,F) (two-way ANOVA; stress
Discussion
These data show marked fluctuations in basal levels of CRH mRNA in the PVN between reproductive states, with a decrease during late pregnancy and an increase during early lactation, changes which do not appear to correlate with the stress hyporesponsiveness characteristic of these states. On the other hand, consistent with the blunted stress responses, CRH mRNA responses to stress were absent during both pregnancy and lactation. In marked contrast, CRHR-1 mRNA and AVP mRNA responses to stress
Acknowledgements
This work was partially supported by a Welcome Trust grant (#053417) to Dr. C. Ingram and Prof. S.L. Lightman and a Short Term Fellowship from the Human Frontier Science Program to Dr. Ana da Costa.
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2019, Frontiers in NeuroendocrinologyCitation Excerpt :However, the responsiveness of the hypothalamic-pituitaryadrenal axis is attenuated postpartum in the majority of species studied so far. Large numbers of studies, using various stressors, highlight the attenuation of ACTH secretion and corticosterone synthesis compared to control virgin animals (restraint: (da Costa et al., 2001); Noise: (Windle et al., 1997); Swimming: (Walker et al., 1995; Toufexis et al., 1998); Foot shock: (Stern et al., 1973); Ether evaporation: (Banky et al., 1994); LPS: (Shanks et al., 1999); Interleukin (Brunton et al., 2005)). Importantly, it should be noted that the presence of pups and relevance of the stressor for the safety of the pups modulates the maternal stress response (Deschamps et al., 2003).
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2016, Hormones and BehaviorCitation Excerpt :Hence, hypo-activation of CRF-R during this sensitive period is an indispensable prerequisite for the appearance of appropriate maternal behavior. In order to guarantee such a hypo-activation, the CRF system has to adapt to this unique and demanding period on cellular (da Costa et al., 2001; Deschamps et al., 2003; Klampfl et al., 2013, 2014; Lightman et al., 2001; Walker et al., 2001) and neuroendocrine levels (Brunton et al., 2008; Klampfl et al., 2014). The CRF-BP is an interesting yet poorly studied candidate for controlling such adaptations postpartum even though it is known to be a potent regulator of CRF and Ucn 1 and, thus, CRF-R activity (Behan et al., 1989; Cortright et al., 1995; Potter et al., 1991; Westphal and Seasholtz, 2006).
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Present address: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3401, USA.