Neural substrates underlying stress susceptibility in virgin female mice confer stress-coping in mother mice

Disruptions in caregiving can lead to profound impacts on emotional and physical development in young across species, including humans. Here, we examine the divergent impact of stress on mouse caregiving neural circuitry in alloparental and maternal females.
Published in Neuroscience
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Parents, grandparents, aunts, uncles, cousins, teachers, babysitters, nannies, and other caregivers, professional or not, participate in the care of children.  However, we know that parents, particularly, undergo physiological changes that adapt them for care of their own children.  The physical, financial, emotional, and mental demands of parenting can be stressful.  Stress during pregnancy, childbirth, or in the early postnatal period is a risk factor for psychiatric disorders including Postpartum Depression, Postpartum Anxiety, and other disorders.  Around 20% of mothers and 10% of fathers in the United States are diagnosed with these disorders annually.  Motivated by this profound impact of stress on parents, our lab set out to study how stress affects neural circuits underlying infant care.

In mice, we can observe alloparental care, or infant caregiving by a non-parent, as well as enhanced infant caregiving in parents.  Using this animal model, we asked how stress may affect alloparental or maternal care in females and the underlying neurobiological substrates.  We focused on a specific class of neurons in the hypothalamus that genetically expresses the neuropeptide urocortin-3 (Ucn3).  In a previous study, we found that this neuronal population is involved in infant-directed neglect and aggression (Autry et al., eLife, 2021) and these cells have also been associated with the stress response. 

First, we assessed the activity of Ucn3 neurons in virgin females or mothers after interacting with pups.  We found that both virgin females and mothers with litters that interacted with a newborn showed more activity in Ucn3 neurons than females that interacted with a control stimulus.  We next blocked activity in these cells using a chemogenetic approach to uncover the impact on infant-directed behavior.  Virgin females with inhibited Ucn3 neurons were faster to retrieve newborn pups compared to control females.

Using chronic restraint stress, we found that virgin female mice displayed reduced infant caregiving as well as reduced exploratory behavior.  This deficit in alloparental care was associated with increased activity of Ucn3 neurons.  To determine if Ucn3 cells were necessary for stress-induced deficits in alloparental behavior, we used the chemogenetic strategy to inhibit Ucn3 neurons in chronically stressed virgin females.  We were able to reverse deficits in retrieval as well as other infant-directed behaviors due to stress by blocking activity of Ucn3 neurons.

When we applied the same chronic restraint stress to mothers, however, we observed no effect on caregiving behavior.  In fact, we tried additional stressors including intruder stress and chronic variable stress, and never observed a decrease in maternal behavior.  Surprisingly, these various maternal stresses led to differential impacts on indirect parental behavior (nest building), exploratory behavior, and circulating stress hormones.  These parameters correlated with alterations in the activity of Ucn3 neurons.  For example, in chronically restrained mothers, the activity in Ucn3 neurons goes down, potentially to protect infant caregiving behavior in animals experiencing repeated stress.  On the other hand, Ucn3 neural activity is higher in mothers that experienced chronic variable stress, and this activity correlates with enhanced nest-building behavior.

Our interpretation is that Ucn3 neurons undergo changes during pregnancy and lactation.  When we examined single-cell sequencing and spatial sequencing data on this population of cells, we find that they express the oxytocin receptor, estrogen receptor, prolactin receptor, and the progesterone receptor, which may explain how these cells are sensitive to hormonal changes in the peripartum period.

Based on these findings, we concluded that Ucn3 neurons are a critical mediator of stress-induced deficits in infant caregiving behavior in virgin females.  However, in mothers, these cells may be involved in the preservation of maternal care by regulating stress-coping behaviors.  In the future, we are excited to further explore the neurobiology underlying the resilience of parenting to stress and study what factors confer stress-susceptibility in parents.

Link to original article at Molecular Psychiatry:

https://rdcu.be/c1aWX

About the authors:  Brenda Abdelmesih is a fifth-year graduate student at Albert Einstein College of Medicine and awardee of the Tishman Fellowship and a diversity supplement from NIH.  Dr. Anita Autry is an assistant professor at the Albert Einstein College of Medicine and an awardee of the Whitehall Award, the NARSAD Young Investigator Award, the ACNP Travel Award, and an R00 from NICHD.  See our website at autrylab.org.

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