Signalling of the corticotropin-releasing factor system in the nucleus accumbens impacts maternal aggression in lactating rats

Females undergo profound peripheral and central adaptations to prepare for motherhood, including complex alterations in neuroendocrine function and neurotransmitter signalling. These essential changes ensure that mothers can adequately respond to their offsprings’ needs. Among others, a finely tuned corticotropin-releasing factor (CRF) system has been identified as a prerequisite for the proper display of maternal behaviours, including maternal care, maternal motivation, and maternal aggression. Consequently, dysregulations of CRF adaptations can have detrimental effects on both the mother and the child and can even lead to maternal neglect, highlighting the need to understand the involvement of the CRF system in behavioural maladaptations. The nucleus accumbens (NAc), a heterogenous brain region at the interface of reward, motivation, and maternal circuits, plays a key role in these processes. In the present study, we investigated the involvement of the NAc CRF system in maternal behaviour in early lactating rats. On lactation day 9, maternal aggression was monitored during the maternal defence test (MDT), a well-established paradigm in which a lactating dam is confronted with an unfamiliar virgin female intruder in her home cage in the presence of her pups. Prior to the MDT, dams received bilateral, local injections of vehicle or CRF (1µg/0.5µL/side) in the NAc shell. In addition, for 60 minutes before and after the MDT, maternal care was monitored. Acute CRF infusion reduced the number of attacks and total nursing, indicating that activation of CRF subtype 1 receptors (CRFR1) in the NAc shell disrupts both maternal aggression and maternal care. To identify the neural circuits underlying these behavioural effects, whole‑brain c‑Fos mapping was performed. The analysis revealed differential activation patterns across several brain regions in response to CRF infusion with/without MDT exposure. Interestingly, pharmacological activation of CRFR1 in the NAc shell increased neuronal activation in the medial prefrontal cortex, suggesting the recruitment of a cortico-accumbal pathway in the modulation of maternal aggression. To further investigate this pathway, CRF+ projections from the medial prefrontal cortex to the NAc shell were chemogenetically activated. In addition, we examined CRF‑expressing projections to the NAc shell via unilateral microinfusion of a retrograde transported virus in this brain region of virgin female rats. This viral approach revealed CRF+ projections descending from the basolateral amygdala, entorhinal cortex, medial prefrontal cortex, paraventricular thalamus, and ventral subiculum. Using in situ hybridisation, we further characterised the nature of CRFR-expressing neurons in the NAc, with Crhr1 being predominantly expressed in the medial NAc on medium-sized spiny neurons. Crhr2 were primarily expressed in the rostral NAc and their expression on gamma aminobutyric acid (GABA)ergic interneurons increased towards the caudal pole. By combining behavioural pharmacology, whole-brain activity mapping, chemogenetics, viral tracing, and in situ hybridization, these findings highlight the critical role of NAc CRF signalling in regulating maternal aggression and provide novel insights into the NAc’s neuronal underpinnings.

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