Enduring Neurobiological Consequences of Early-Life Stress: Insights from Rodent Behavioral Paradigms

Abstract

Stress profoundly affects physical and mental health, particularly when experienced early in life. Early-life stress (ELS) encompasses adverse childhood experiences such as abuse, neglect, violence, or chronic poverty. These stressors can induce long-lasting changes in brain structure and function, impacting areas involved in emotion regulation, cognition, and stress response. Consequently, individuals exposed to high levels of ELS are at an increased risk for mental health disorders like depression, anxiety, and post-traumatic stress disorders, as well as physical health issues, including metabolic disorders, cardiovascular disease, and cancer. This review explores the biological and psychological consequences of early-life adversity paradigms in rodents, such as maternal separation or deprivation and limited bedding or nesting. The study of these experimental models have revealed that the organism's response to ELS is complex, involving genetic and epigenetic mechanisms, and is associated with the dysregulation of physiological systems like the nervous, neuroendocrine, and immune systems, in a sex-dependent fashion. Understanding the impact of ELS is crucial for developing effective interventions and preventive strategies in humans exposed to stressful or traumatic experiences in childhood.

Keywords: anxiety; cancer; depression; dopamine; glucocorticoids; neurodegenerative diseases; neuronal plasticity; neurotrophins.

Figure 1

Impact of early-life adversity on brain development and lifelong outcomes. Early-life adversities, including child abuse and neglect, exposure to violence, parental divorce, childhood physical illness, and family economic hardship, profoundly influence brain development. These adversities are strongly associated with alterations in neuronal circuitry and synaptic function, leading to a heightened risk of developing a broad spectrum of behavioral, cognitive, and emotional disorders throughout life. Illustrations in the panel were created with Biorender.com.

Figure 2

Modeling early-life stress: long-term behavioral and neurobiological effects. Maternal separation (MS), maternal deprivation (MD), and limited bedding and nesting (LBN) are used as rodent models of early-life stress. This figure shows that stress experienced during the postnatal period (P2–21) can lead to significant and lasting changes in both behavioral and neurobiological outcomes in adulthood. Illustrations in the panel were created with Biorender.com.

Figure 3

Summary of the effects of (ELS) on brain remodeling and mental health disorders in mice and humans. This figure summarizes the impact of ELS (red wavy lines) on brain remodeling and the development of mental health disorders, drawing parallels between findings in mice (top brain) and humans (bottom brain). It highlights how ELS can lead to significant changes in brain structure and function, which are associated with an increased risk of various mental health disorders. AMY: amygdala; CC: cortical cortex; FPC: frontoparietal cortex; HIPP: hippocampus; HYP: hypothalamus; NAc: nucleus accumbens; PFC: prefrontal cortex; VTA: ventral tegmental area. Illustrations in the panel were created with Biorender.com.