Behavioral and psychoendocrinological rodent studies on the consequences of disturbances in mother-infant bonding for adult emotional, social and cognitive functioning

The first 1001 days of life, from conception to the second birthday, are crucial for child development. Infancy constitutes a sensitive period for neurodevelopment when experiences can induce lasting consequences in brain function and behavior. Different kinds of early-life stress (ELS) exist and increase the risk of development of psychopathology in later life. However, the specific consequences of ELS into adulthood are unclear and so are the putative mechanisms connecting ELS with negative outcomes. An important reason why these questions are hard to answer are the inherent difficulties of research in human subjects. Mouse models are not only preferable from an ethical point of view, they allow us to investigate mechanistic questions using invasive methods while controlling for factors that complicate human studies. We can benefit from these models because of the similarities between our species in terms of our altricial and social nature, similar physiology as well as homology in brain and behavior relationships. Regarding outcomes, mouse models simplify longitudinal (and transgenerational) research. Using standardized protocols, behavioral performance can be extensively probed at different ages in rodents. Regarding potential mechanisms connecting ELS to certain outcomes, both the mother-infant attachment bond and (epi)genetic factors have come into consideration but few studies have integrated these before. Attachment formation is crucial for newborns in altricial species, not only for nutrition and warmth but for normal emotional and social development. We now know that environmental factors like maternal care can ‘program’ stress reactivity through increasing or decreasing stress receptors in different brain regions in offspring. Since social skills develop based on our first attachment bond, the possibility exists that our sociobehavioral repertoire develops similarly. The social deficits in different neurodevelopmental and neuropsychiatric disorders such as autism, depression and schizophrenia should be noted in this respect.

The current research project utilized mouse models to detail the consequences of developmental perturbations in early life. We focused on two conditions, psychiatric illness in the mother (PPD), and neurodevelopmental issues in the child (ASD). Our first study describes the spectrum of changes in adult social behavior in a mouse model of ASD (related to Nbea haploinsufficiency). The second study reports about the effects of PPD on maternal care, maternal preference in juvenile offspring and adult neurobehavioral proficiency in the offspring. It represents the most elaborate investigation of functional alterations in this PPD model to date. The last study addresses the question whether this PPD model affects the genome-wide transcriptome in the brain of young pups. The first study shows that Nbea haploinsufficiency impacts different aspects of social behavior in adulthood, reminiscent of ASD symptoms. The results of the second study indicate subtle changes in bonding and different aspects of adult behavioral repertoire in offspring despite finding no marked differences in maternal care. The last study shows how this PPD model influences the transcriptome early on, depending on the brain region studied. The differentially expressed genes are known to be involved in neuronal functioning, neurodevelopment, innate fear, learning and memory, and different neuropsychiatric disorders. Since sex differences are a recurring finding in this project, we conclude that both males and females should be included in further research on ELS and that biological sex should be considered in diagnosis and counseling regarding attachment, related behavioral issues and psychological wellbeing. We hope that this work complements the growing field of early life stress by 1) focusing on sex differences, 2) focusing on social and emotional functioning in addition to cognitive performance, and 3) adding to the validation of the mouse models used to aid in further research on PPD and ASD.