Naturalistic rodent models of chronic early‐life stress

Abstract

A close association between early-life experience and cognitive and emotional outcomes is found in humans. In experimental models, early-life experience can directly influence a number of brain functions long-term. Specifically, and often in concert with genetic background, experience regulates structural and functional maturation of brain circuits and alters individual neuronal function via large-scale changes in gene expression. Because adverse experience during sensitive developmental periods is often associated with neuropsychiatric disease, there is an impetus to create realistic models of distinct early-life experiences. These can then be used to study causality between early-life experiential factors and cognitive and emotional outcomes, and to probe the underlying mechanisms. Although chronic early-life stress has been linked to the emergence of emotional and cognitive disorders later in life, most commonly used rodent models of involve daily maternal separation and hence intermittent early-life stress. We describe here a naturalistic and robust chronic early-life stress model that potently influences cognitive and emotional outcomes. Mice and rats undergoing this stress develop structural and functional deficits in a number of limbic-cortical circuits. Whereas overt pathological memory impairments appear during adulthood, emotional and cognitive vulnerabilities emerge already during adolescence. This naturalistic paradigm, widely adopted around the world, significantly enriches the repertoire of experimental tools available for the study of normal brain maturation and of cognitive and stress-related disorders including depression, autism, post-traumatic stress disorder, and dementia.

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

“…Simply removing the dam for extended periods of time would lead to hypothermia and starvation, so that many models have used intermittent maternal deprivation, resulting in intermittent stress, with sometimes variable outcomes (Lehmann and Feldon, 2000;Milstein and Holmes, 2007). An alternative approach has been to provoke chronic, persistent changes in maternal nurturing behaviors by the use of cages with limited nesting and bedding material (Gilles et al, 1996;Molet et al, 2014;Naninck et al, 2015). This 'simulated poverty' induces stress in the dams (Ivy et al, 2008), and alters their behaviors (Ivy et al, 2008;Rice et al, 2008;Rincón-Cortés and Sullivan, 2014).…”

“…In mammals, including humans, monkeys, and rodents, maternal input has perhaps the most significant influence on the type of environment experienced during development (Bowlby, 1950;Seay, 1962;Baram et al, 2012;Rincón-Cortés and Sullivan, 2014;Kundakovic and Champagne, 2015). In accordance, most animal models of early-life stress have targeted maternal interaction, disturbing either the quantity or quality of maternal care early in life (for recent reviews, see Molet et al, 2014;Nishi et al, 2014). Such models have become widely adopted, and from this vast literature it is clear that the ultimate outcome of early-life stress depends on several aspects of the 'stressful' experience: its timing, quality, severity, and duration.…”

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

“…[3][4][5][6] Another model of early-life adverse events is the rearing of pups by dams subjected postpartum to conditions of limited bedding and nesting stress. 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.…”

“…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. Indeed, Sprague-Dawley pups showed either no change 7,12 or increased 13 levels at PND9, whereas PND10 Wistar pups exhibited a delayed maturation of the adrenal glands with significant reduction in plasma corticosterone.…”

Stress during a Critical Postnatal Period Induces Region-Specific Structural Abnormalities and Dysfunction of the Prefrontal Cortex via CRF1

“…Here we applied a naturalistic mouse model of early-life stress, where an impoverished early environment is created by providing the dams with reduced nesting and bedding material from postnatal day 2 (P2) to P9 of their litter (Rice et al, 2008). This limited nesting and bedding material procedure has been shown to reduce the quality of maternal care and provoke prominent and lasting molecular, morphological, and behavioral alterations in the offspring (Molet et al, 2014), and has been used to uncover the involvement of CRF 1 in early-life stressinduced anxiety-related behavior and hippocampal dysfunction (Ivy et al, 2010;Wang et al, 2012;Wang et al, 2011). Using this model and thus restricting the time window of stress exposure to the first postnatal week, the short-and long-term effects of stress during this critical period on the morphological development of layers II/III and V pyramidal neurons in the mPFC were characterized.…”