Maternal stress and the MPOA: Activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats

Stefanie M Klampfl,Milena M Schramm,Barbara M Gaßner,Katharina Hübner,Audrey F Seasholtz,Paula J Brunton,Doris S Bayerl,Oliver J Bosch

doi:10.1016/j.neuropharm.2018.02.019

Abstract

Maternal behavior and anxiety are potently modulated by the brain corticotropin-releasing factor (CRF) system postpartum. Downregulation of CRF in limbic brain regions is essential for appropriate maternal behavior and an adaptive anxiety response. Here, we focus our attention on arguably the most important brain region for maternal behavior, the hypothalamic medial preoptic area (MPOA).Within the MPOA, mRNA for CRF receptor subtype 1 (protein: CRFR1, gene: Crhr1) was more abundantly expressed than for subtype 2 (protein: CRFR2, gene: Crhr2), however expression of Crhr1, Crhr2 and CRF-binding protein (protein: CRFBP, gene: Crhbp) mRNA was similar between virgin and lactating rats. Subtype-specific activation of CRFR, predominantly CRFR1, in the MPOA decreased arched back nursing and total nursing under non-stress conditions. Following acute stressor exposure, only CRFR1 inhibition rescued the stress-induced reduction in arched back nursing while CRFR1 activation prolonged the decline in nursing. Furthermore, inhibition of CRFR1 strongly increased maternal aggression in the maternal defense test. CRFR1 activation had anxiogenic actions and reduced locomotion on the elevated plus-maze, however neither CRFR1 nor R2 manipulation affected maternal motivation. In addition, activation of CRFR1, either centrally or locally in the MPOA, increased local oxytocin release. Finally, inhibition of CRFBP (a potent regulator of CRFR activity) in the MPOA did not affect any of the maternal parameters investigated.In conclusion, activity of CRFR in the MPOA, particularly of subtype 1, needs to be dampened during lactation to ensure appropriate maternal behavior. Furthermore, oxytocin release in the MPOA may provide a regulatory mechanism to counteract the negative impact of CRFR activation on maternal behavior.

Highlights

The display of appropriate maternal behavior is the result of a variety of peripartum adaptations, including activation and inhibition of specific neurotransmitter systems in the brain
Crhr1 and Crhr2 mRNA expression in the medial preoptic area (MPOA) did not differ between virgin and lactating rats (Fig. 1 left); levels of Crhr1 mRNA expression were significantly greater than Crhr2 mRNA, independent of reproductive status
In brain areas such as the lateral septum (D'Anna and Gammie, 2009; Gammie et al, 2004) and the bed nucleus of the stria terminalis (BNST) (Klampfl et al, 2014, 2016a, b) corticotropin-releasing factor (CRF) plays a prominent role in impeding maternal behavior by reducing maternal care and maternal aggression while increasing anxiety

Summary

Introduction

The display of appropriate maternal behavior is the result of a variety of peripartum adaptations, including activation and inhibition of specific neurotransmitter systems in the brain. Bosch and Neumann, 2008, 2012; Pedersen et al, 1994; van Leengoed et al, 1987), the corticotropin-releasing factor (CRF) system impedes maternal behavior and needs to be down-regulated (Gammie et al, 2004; Klampfl et al, 2013, 2014, 2016a, b). CRF is the major stress neuropeptide involved in cellular, neuroendocrine, and behavioral responses to stress (Bale and Vale, 2004; Vale et al, 1981). It is released upon stressor exposure and triggers the central and peripheral stress response. CRF has anxiogenic and pro-depressive actions, amongst others (Reul and Holsboer, 2002a, b), which makes the CRF system one of the most promising candidate systems for treating mood disorders such as anxiety and depression

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