The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function

Abstract

Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity.

Keywords: cognition; early-life infection; early-life neuroimmune activation; early-life nutrition; early-life stress; hippocampus; neurogenesis.

FIGURE 1

Schematic representation of the interrelated role of different early-life elements for the consequences of early-life adversity. Early-life adversities in the form of early-life stress, under/malnutrition and infection are known to modulate hippocampal development and altogether determine hippocampal structure and function in adulthood with adverse effects on learning and memory. During the early sensitive period of development the offspring is fully dependent on the mother. Maternal care encompasses several elements (sensory stimuli, transfer of nutrition, hormones, and antibodies). In fact it is mostly via disruption of maternal care (with exception of early-life infection which can directly act upon the offspring) that early adversities will elicit disruptions in hormonal, (neuro)inflammatory and nutritional profiles in the offspring. Because these elements affect one another, they will ultimately act synergistically to modulate hippocampal structure and function throughout life.