Topilko, T. et al. Neuron (2022) https://doi.org/10.1016/j.neuron.2022.01.012

A new study on nest building, a form of maternal behavior observed in pregnant animals including mice, reveals that this behavior is mediated by peptidergic neurons of a specific nucleus in the brain.

During pregnancy, female mammals go through numerous neurobehavioral changes that are necessary for the survival of the offspring. These changes are primarily mediated by the brain via a neuroendocrinological network that includes peptide signaling, progesterone and other hormones. In rodents, nesting preparation is a maternal adaptation to pregnancy aiming to provide a shelter and warmth to the litter after birth. However, the neuronal and endocrinological mechanisms underlying this maternal behavioral response are still unclear.

In a new study, Topilko and colleagues from the Universities of Sorbonne and Buenos Aires, implemented a multidisciplinary approach consisting of advanced whole-brain histology via iDISCO+ clearing, genetic manipulation, optogenetics, chemogenetics, in vivo fiber photometry and electrophysiology in C57BL6/NRj female mice and identified a brain region that is active during nest building in pregnancy. This nucleus, called Edinger-Westphal (EW), is located in the midbrain and contains peptidergic neurons that are critical for nest building behavior. The findings also suggest that a combination of three neuropeptides, urocortin 1, cholecystochinine (CCK), and cocaine- and amphetamine-regulated transcript, is necessary for nest building, with CCK possibly having a more predominant role. These neuropeptides are co-expressed in all peptidergic EW neurons in the “centrally projecting EW” (EWcp), a part of the EW that projects to other brain areas. In addition, the EWcp contains glutamatergic and GABAergic neurons that may also respond to nesting.

The researchers further demonstrate that progesterone, a critical hormone for pregnancy, enables nest building by modulating EWcp neuronal firing. In mice, nest building occurs mainly before the animal’s sleep. Here, the findings show that EWcp peptidergic neurons are activated during arousal before sleep, which specifically promotes nesting behavior.

The study also sheds light on EW-projecting targets and identifies a broad brain network underlying this maternal behavior. Brain targets include the brainstem, midbrain, hypothalamus, amygdala and the prefrontal cortex, which have been previously linked to sleep, arousal and parental behaviors.

In conclusion, this new study reveals that EWcp peptidergic neurons mediate hormonal control of nest building in pregnant mice, a behavioral adaptation vital for reproductive fitness.