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.

Keywords: animal models; dementia; depression; early-life experience; fragmentation; hippocampus; maternal care; memory; post-traumatic stress disorder; stress.

FIGURE 1

Parameters indicative of chronic stress in 9-day-old pups experiencing a week of CES; (left column) and in adult male rats (12 months of age; right column). Elevated basal corticosterone levels, higher adrenal weights, and modestly lower body weight are found in chronically stressed 9-day old rats. These changes are no longer apparent in adult rats. ^*p <.05; Student’s t-test. (Modified from Brunson et al. (2005), with permission).

FIGURE 2

Photograph of a cage at the moment of onset of the limited bedding/nesting chronic early-life stress paradigm in rats. Note the fine, plastic-coated aluminium-mesh floor and the shredded paper towel. The cage is placed on a metal cart.

FIGURE 3

Dendritic atrophy of CA1 pyramidal cells from early-life stressed middle-aged rats. Golgi-impregnated CA1 pyramidal cells were reconstructed using camera Lucida. Representative neurons from control (left) and CES (right) illustrate the reduction in dendritic branching in a neuron from the early-life stressed group. (Modified from Ivy et al. (2010), with permission).