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

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.

Keywords: Anxiety; Corticotropin-releasing factor; Corticotropin-releasing factor-binding protein; Maternal behavior; Medial preoptic area; Oxytocin.

Fig. 1

Crhr1, Crhr2 (left) and Crhbp (right) mRNA expression in the MPOA in virgin and lactating rats. Data are presented as mean grain area + SEM. n = 5–10 per group. *p < 0.05 versus Crhr1 (two-way ANOVA; factors: reproductive status, brain site).

Fig. 2

Effect of pharmacological manipulation of MPOA CRFR1 or CRFR2 on maternal care under (A) non-stress conditions on LD 1 or (B) stress conditions on LD 7. Arched back nursing (ABN), total nursing, and licking/grooming (LG) were scored for 60 min before (basal) and (A) for 90 min after infusion (t 0 to t +90) as well as for 60 min in the afternoon (t +300 to t +330) or (B) for 60 min after infusion combined with the maternal defense test (t 0 to t +30). Dams received an acute bilateral infusion of either (i) vehicle (VEH), (ii) CRFR1 agonist (ago; h/rCRF), (iii) CRFR1 antagonist (ant; CP-154,526), (iv) CRFR2 ago (hUcn3/stresscopin), or (v) CRFR2 ant (astressin-2B) into the MPOA. Data are presented as group means + SEM. n = 6–8 rats per group. **p ≤ 0.01, *p ≤ 0.05 versus VEH-treated group; ++ p ≤ 0.01, + p ≤ 0.05 versus basal levels in the same group (two-way RM ANOVA).

Fig. 3

Effect of pharmacological manipulation of MPOA CRFR1 or CRFR2 on maternal aggression in lactating rats. Maternal aggression against a virgin female intruder was scored during a 10-min maternal defense test. The number of attacks (left) and sum of aggressive behaviors (right) exhibited by the resident are shown. For details on treatments, see the Fig. 2 legend. Data are presented as mean + SEM. n = 6 per group. **p < 0.01 versus VEH (one-way ANOVA; factor: treatment).

Fig. 4

Effect of pharmacological manipulation of MPOA CRFR1 or CRFR2 on anxiety-related behavior in lactating rats. The percent time spent on the open arms, the number of full open arm entries and closed arm entries during the 5-min test are shown. For details on treatments, see the Fig. 2 legend. Data are presented as group means + SEM. n = 6 per group. *p < 0.05 versus VEH (one-way ANOVA; factor: treatment); #p < 0.05 versus VEH (independent t-test).

Fig. 5

Effect of ICV or intra-MPOA CRFR activation on maternal care and oxytocin release in the MPOA of lactating rats. Arched back nursing (ABN) and licking/grooming (LG) (A) as well as oxytocin release in the MPOA (B) were assessed for 60 min before (t −60 to t −30) and 90 min after ICV drug infusion (t 0 to t +60) under non-stress conditions. (C) Oxytocin release in the MPOA was measured for 60 min before (t −60 to t −30), 30 min during (t 0), and 60 min after (t +30 to t +60) retrodialysis. For (A) and (B), dams received an acute ICV infusion of either (i) vehicle (VEH), (ii) CRFR1 agonist (ago; h/rCRF), or (iii) CRFR2 ago (hUcn3/stresscopin). For (C), dams received chronic CRFR1 agonist retrodialysis into the MPOA. Data are presented as group means + SEM. n = 6–8 rats per group. **p ≤ 0.01, *p ≤ 0.05 versus VEH-treated group (two-way RM ANOVA).