Early-Life Stress Paradigm Transiently Alters Maternal Behavior, Dam-Pup Interactions, and Offspring Vocalizations in Mice

Abstract

Animal models can help elucidate the mechanisms through which early-life stress (ELS) has pathophysiological effects on the developing brain. One model that has been developed for rodents consists of limiting the amount of bedding and nesting material during the first postnatal weeks of pup life. This ELS environment has been shown to induce “abusive” behaviors by rat dams towards pups, while mouse dams have been hypothesized to display “fragmented care”. Here, as part of an ongoing study of gene-environment interactions that impact brain development, we analyzed long observation periods of wild-type C57Bl/6J dams caring for wild-type and Met heterozygous pups. Met encodes for the MET receptor tyrosine kinase, which is involved in cortical and hippocampal synaptogenesis. Dams with limited resources from postnatal day (P)2 to P9 preserved regular long on-nest periods, and instead increased the number of discrete dam-pup interactions during regular off-nest periods. Immediately after dams entered the nest during off-nest periods in this ELS environment, pups responded to these qualitatively different interactions with an increased number of ultrasonic vocalizations (USV) and audible vocalizations (AV), communication signals that have been associated with aversive and painful stimuli. After returning to control conditions, nest entry behaviors normalized, and dams did not show altered anxiety-like or contextual fear learning behaviors after pup weaning. Furthermore, female mice that had undergone ELS as pups did not show atypical nest entry behaviors in control conditions in adulthood, suggesting that these specific maternal behaviors are not learned during the ELS period. The results suggest that atypical responses of both mother and pups during exposure to this ELS environment likely contribute to long-term negative outcomes in mice, and that these responses more closely resemble the effects of limited bedding on rat dams and pups than was previously suggested. Discerning how different early-life stressors mediate changes in maternal-pup interactions can help elucidate the mechanisms of ELS on brain development and behavior.

Emotional learning, stress, and development: An ever-changing landscape shaped by early-life experience

“…Furthermore, use of this paradigm allows for a sustained induction of ELS throughout a defined period during the first weeks of life, limits experimenter impact associated with handling and observation, and limits the introduction of additional variables that can impact neurodevelopment, including sustained effects on thermoregulation and malnutrition. This model has been well characterized, leads to reliable induction of stress in pup, and effects that have been replicated by more than a half a dozen labs (64, 66, 67, 72, 74–77). In addition, this form of manipulation appears to have potent effects on the development of circuits underlying both the fear response as well as regulation of the stress axis (78, 79).…”

“…In rodents, multiple paradigms exist to induce early life stress (ELS) through manipulation in maternal care, including maternal handling (58), maternal separation (59, 69), maternal deprivation (68, 70), natural variation in the quality of maternal care (71), and maternal bedding manipulation paradigms (61, 62, 64, 67, 72). The recent use of maternal bedding manipulation paradigms offers advantages over other approaches as (1) it mirrors loss of resources to care for the young, (2) induces stress in the dam resulting in reliable changes in the dynamic interactions between mother and pup (e.g.…”

Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential

“…Part of the elegance of this model is its simplicity, which leads to a robust and reproducible change in parental behavior across rodent species within as well as across laboratories and continents (Heun-Johnson & Levitt, 2016; Korosi et al, 2010; Rice, et al, 2008). In fact what appears from reviewing the data collected from the laboratories worldwide using this model, is that the main features of the paradigm that we seek to model (i.e.…”

Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex

“…7,8 This model has face validity in humans 7,8 where the mother is continuously present but provides an altered repertoire of maternal behaviors indicative of fragmented and erratic care 9 and altered dam-pup interactions. 10 It has also the advantage of minimizing variability linked to handling of the pups to perform daily maternal separation. 8,11 Disturbance of maternal behavior by limited nesting stress (LNS) exposure during the post-natal days (PND) 2 to 10 impacts significantly on the development of the hypothalamic-pituitary-adrenal (HPA) axis in offspring with contrasting effects on corticosteronemia according to the strain studied.…”