The central corticotropin-releasing factor system mediates maternal neglect in lactating rats
Final Report Abstract
Peripartum adaptations on physiological, emotional and behavioral levels entail complex alterations of the female’s brain, including dampened and enhanced signaling of the brain corticotropin‐releasing factor (CRF) and oxytoxin (OT) systems, respectively. Hence, their failed peripartum adaptations have detrimental behavioral and psychological outcome, as we have shown for the medial preoptic area and the bed nucleus of the stria terminalis. We now dissected the neurobiological basis of maternal neglect and postpartum mood disorders with focus on the paraventricular nucleus (PVN; part of the stress axis, contains CRF‐ and OT‐positive neurons) in interaction with the nucleus accumbens (NAc; central region of reward system and maternal circuits). We revealed that the CRF binding protein (CRF‐BP; binds free CRF and Urocortin (UCN) 1 making it no longer available to bind to CRF receptors) in the PVN triggers the lactation‐specific blunted stress response. Not only were the mRNA expression of Crh‐bp increased and of Crh‐r1 decreased in the PVN of lactating rats. Plasma corticosterone secretion in lactating rats increased after intra‐PVN infusion of CRF‐BP inhibitor CRF(6–33) followed by CRF, but not by vehicle (VEH). This demonstrates that CRF‐BP buffers increasing CRF levels in lactation. In addition, lactating rats treated with acute and chronic CRF(6–33) displayed increased and decreased maternal aggression, respectively. The PVN sends OT and CRF projections to the NAc shell (NAcSh), and we found that CRF‐positive neurons further origin from the prelimbic cortex, amygdala, and paraventricular thalamus, among others. Within the NAc, CRF‐R1 were predominantly expressed in the medial NAc on medium‐sized spiny neurons, but also in the rostral part on GABAergic interneurons. CRF‐R2 were mainly expressed in the rostral NAc and its expression on GABAergic interneurons increased towards the caudal pole. When CRF‐R1 were activated in the NAcSh by local CRF infusion, mainly the display of nursing postures was negatively affected along with a strong decrease of maternal motivation to retrieve displaced pups back into the nest. In addition, increased signaling of CRF‐R1, but also of CRF‐R2 (via UCN3) infusion, significantly reduced maternal defensive behavior against an intruder. During maternal defense, OT release within the NAc increased; the same effect was seen with intra‐NAc retrodialysis of CRF, but not of UCN3. Interestingly, UCN3, but not CRF, increased anxiety‐related behavior in lactating and virgin females, whereas in males CRF, but not UCN3, facilitated anxiety‐related behavior thereby unraveling a so far unknown sex‐difference. Since the NAc is part of the reward system, we measured local dopamine release in response to CRF‐R activation; CRF caused a more tonic whereas UCN3 resulted in a more phasic dopamine release suggesting different functions in the interactions with the specific CRF family members. To study the origin of maternal neglect, we applied established pregnancy stress paradigms, i.e., repeated non‐social (daily restraint stress of alternating durations; pregnancy days (PD) 7 to PD20) versus social stress (daily alternating overcrowding and restraint stress; PD5 to PD17). Non‐social stress impaired whereas social stress improved maternal motivation and nursing. At the same time, social stress impaired the lactation‐specific basal hypercortisolism. Analysis of the CRF system is still ongoing. In addition, we studied the effects of daily brief (15min) versus long (180min) maternal separation. Long maternal separation had stronger effects on the mothers, with decreased maternal motivation, increased licking/grooming the pups, and increased OT‐R binding in the medial preoptic area, a central hub for maternal behavior. Finally, we studied how the total loss of offspring after one day of mothering experience alters physiological and behavioral parameters after one, three, or six days. One day of loss increased the neuronal activity in the limbic system, which positively correlated between the prelimbic cortex and basolateral amygdala like in human mothers grieving over child loss. Up to 3 days of loss, OT‐R binding was decreased in the central amygdala. Regarding the stress response, we did not detect any differences between the groups either under basal conditions or following stressor exposure (forced swimming; FST). On the sixth day of offspring loss, mothers displayed significantly increased passive stress‐coping behavior in the FST. In conclusion, this project resulted in numerous significant results of translational value. It was highly successful with respect to scientific publications, the promotion and support of young scientists, and subsequent collaborations with distinguished international neuroscientists.
