Abstract
Pregnancy and lactation are periods of significant physiological adaptation to ensure a mother can meet the demands of a growing foetus and new-born offspring. One important adaptation is attenuation of the stress response, with pregnancy and lactation being periods of stress hypo-responsiveness. Stress hyporesponsiveness is important in pregnancy/lactation to allow for the energy normally used solely by the mother to be redistributed to care for the offspring to ensure their survival. The mechanism underlying the attenuation of the stress response is unclear. Corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), govern the stress response through regulating corticosteroid release. Elsewhere in the hypothalamus, we have previously shown that prolactin acting through the prolactin receptor (Prlr) in the medial preoptic area (MPOA) is required for maternal caregiving behaviour. We have recently found a GABAergic inhibitory neuronal current from MPOA Prlr-expressing neurons projecting to the PVN in female mice (MPOAPrlrPVN) (unpublished data). This project aimed to investigate whether the MPOAPrlrPVN neuronal pathway can regulate the stress response in female mice.
Firstly, we aimed to establish experimental paradigms that show suppression of the stress response in lactating compared to virgin mice (n=8/group). In a white-noise test, lactating mice showed a significantly attenuated corticosterone response post-white noise compared to the virgin mice (p < 0.0001). In a modified pup retrieval test, the mouse is exposed on testing day to a novel anxiogenic environment and three pups. In this test, virgin female mice took approximately 10x longer to enter a novel environment (p = 0.0148) and approach pups (p = 0.0047) than lactating mice, indicating an attenuated stress response in lactating mice.
Secondly, we tested whether optogenetic stimulation of MPOAPrlrPVN in virgin mice can induce lactation-like stress responses and maternal behaviour in virgin female mice compared to control mice (n=6/group). Prlr-Cre mice received unilateral injections of an AAV encoding a Cre-dependent light-activated receptor channel Chrimson (AAV-Syn-FLEX-rc[ChrimsonR-tdTomato]) into the MPOA and a fibre optic implanted above the PVN. One group of mice received light stimulation and the control group received no light. Stimulated animals showed no significant difference in corticosterone levels post-white noise stressor (p = 0.7610), compared to control animals, despite both of them having increases in corticosterone post stressor. Optogenetically stimulated mice showed no significantly decreased latencies to enter the novel environment (p = 0.9372) and to approach pups (p = 0.9372), indicating that the optogenetic stimulation did not attenuate the stress response.
In summary, these results demonstrated that the stress response is attenuated in lactating compared to virgin mice. However, stimulation of MPOAPrlrPVN neurons in virgin mice was not sufficient to induce lactation-like attenuation of the stress response. The neurological pathway underlying the maternal adaptation of a hyporesponsive HPA axis is still unknown, however, this study provides a preliminary basis for future pathways to be studied and explored.