Brain-wide neural mechanisms enhancing maternal behavioral response to infant cues

PROJECT SUMMARY/ABSTRACT From the moment of giving birth, a mother must quickly adapt to the new demands of motherhood, attending to signals from her offspring and using them to inform her behavior. The brain’s adaptability to motherhood is of the utmost importance: inappropriate responses to infant cues can negatively affect not only infant outcomes, but also the mother’s mental health. Maladaptive responses to infant cues have been associated with neurological changes impacting motherhood, such as those that lead to poor mother-infant bonding and postpartum depression (PPD). Paving the way for the development of novel predictors and therapeutics for such conditions, animal research has begun to disentangle innate and learned components of the neural circuitry underlying maternal responses to infant cues. For example, distress vocalizations emitted by mouse pups, termed pup calls, elicit maternal behavior and time-locked neural activity in left primary auditory cortex (A1) in both mothers and virgin females with prior pup exposure, but not pup-naïve virgin females. However, naïve virgins are primed with innate neuronal tuning to a narrow range of pup calls, which broadens with pup care experience to allow for more reliable caregiving and A1 responses. Prior findings, including those of sponsor Dr. Bianca Jones Marlin, have shown that this increase in pup call salience is facilitated, at least in part, by the neuropeptide oxytocin (OXT). However, it is still unknown whether other brain regions exhibit similar experience- dependent, OXT-mediated plasticity during motherhood. To address this research gap, this proposal aims to uncover the brain areas responsible for enhanced behavioral responses to pup calls in mice with maternal experience, both in the presence and absence of typical OXT signaling. This project will take advantage of cutting-edge techniques that allow for whole-brain imaging and genetic manipulation of neuromodulatory signaling, including activity mapping via immediate early genes (IEGs), genetic disruption of OXT signaling, and functional magnetic resonance imaging (fMRI) of awake mice, in which co-sponsor Dr. Itamar Kahn is an expert. Aim 1 will use whole-brain activity mapping via IEGs and fMRI in females with varying maternal care experience to characterize the experience-dependent representation of pup calls throughout the brain. Aim 2 will use daily maternal behavior assays and longitudinal fMRI to assess pup call responses as virgins learn to provide maternal care through observation of a mother. In order to model atypical OXT signaling, which has been associated with PPD, this learning process will be compared between oxytocinergic neuron-ablated versus control virgins. Together, these efforts will identify brain regions that are important for maternal responses to infant cues, including in cases of atypical OXT signaling. These brain regions will serve as a launching point for future research toward using fMRI to identify signatures of potential maladaptive caregiving and developing targeted treatment when maladaptive caregiving puts the child’s well-being and the mother’s mental health at risk.