Study examines the mechanisms behind long-term consequences of childhood stress

Early-life adversity affects more than half of the world’s children and is a significant risk factor for cognitive and mental health problems later in life. In an extensive and up-to-the-minute review of research in this domain, scholars from the University of California, Irvine illuminate the profound impacts of these adverse childhood experiences on brain development and introduce new paths for understanding and tackling them.

Their study, published in Neuron, examines the mechanisms behind the long-term consequences of childhood stress (adversity). Despite extensive research spanning over seven decades, the authors point out that significant questions remain unanswered. For example, how do adults – from parents to researchers – fully comprehend what is perceived as stressful by an infant or child? Such conceptual queries, as well as the use of cutting-edge research tools, can provide a road map, guiding experts toward developing innovative methods and providing solutions to this pressing mental health issue.

Our research suggests that the unpredictability of a child’s early environment may be just as important as more traditionally recognized forms of adversity, such as abuse or neglect. Our review has important implications for how we approach early intervention and prevention strategies.”

Dr. Tallie Z. Baram, lead author, Donald Bren Professor of Pediatrics and one of the world’s leading researchers in this field

She and co-author Matthew Birnie, a UC Irvine postdoctoral scholar, identify several key areas for further investigation:

• What does the developing brain perceive as stressful?
• Which aspects of stress most significantly influence brain maturation?
• Which developmental ages are most vulnerable to adversity?
• What are the molecular mediators of stress effects on the brain?

• How can transient stressful experiences lead to enduring dysfunction?

One notable discovery is a novel form of early-life stress: unpredictable sensory inputs from caregivers and the environment. This factor plays a substantial role in adverse neurodevelopmental outcomes, even after controlling for well-known adverse childhood experiences, which are collectively referred to as ACEs.

The review highlights the limitations of current ACE scoring systems in accurately predicting individual outcomes and underscores the complexity of early-life stress. Emerging factors, such as societal and anthropogenic characteristics like inequality and pollution, are gaining recognition as potential contributors.

Animal models have been instrumental in unraveling the mechanisms underlying brain development effects. Research has revealed that different types of stress can yield distinct outcomes, influenced by the nature and timing of stress, as well as species, strain and sex variations.

At the molecular level, early-life stress can substantially alter neuronal gene expression through epigenetic mechanisms. These changes may lead to long-term modifications in how the brain responds to subsequent experiences. At the circuit level, early stress can disrupt the maturation of brain networks by interfering with crucial developmental processes, including neuronal oscillations and synaptic pruning.

“We’re gradually comprehending how early-life stress can ‘reprogram’ the brain at multiple levels, from individual molecules to entire neural circuits. This knowledge presents new avenues for targeted interventions,” Baram said.

The review also identifies key molecular mediators of early-life stress effects, including glucocorticoids and neuropeptides like corticotropin-releasing hormones. Ongoing research is uncovering novel roles for these molecules in specific neural circuits affected by early stress.

In light of these findings, the researchers propose redefining early-life stress as “early-life adversity” to better encompass the diverse experiences that can impact brain development, even those not traditionally perceived as stressful.

“This review emphasizes the need for a more comprehensive understanding of early-life adversity,” Baram said. “By focusing on how the developing brain processes and responds to these experiences, we can develop more effective strategies to prevent and mitigate their long-term effects.”

The researchers suggest increased funding for and attention to this critical area of study, highlighting its potential to enhance mental health outcomes and reduce the societal burden of early-life adversity.

Baram is also the Danette Shepard Chair in Neurological Studies and director of UC Irvine’s Conte Center, which is supported by a Silvio O. Conte Center grant from the National Institute of Mental Health. Conte Center grants are bestowed on the most promising multidisciplinary and often cross-species approaches to improving the diagnosis and treatment of mental health issues.

National Institutes of Health awards P50MH096889 and RO1 MH132680 as well as the Hewitt Foundation for Biomedical Research supported the work.