Early-life inflammation, such as trauma and viral infections, strongly increases the risk of individual for depression in adulthood. However, the mechanisms are not clear.

In a study published in Neuron on July 6, a team led by Prof. ZHANG Zhi from Division of Life Sciences and Medicine of the University of Science and Technology of China (USTC), collaborating with Prof. XU Lin from CAS, revealed the mechanism by which early-life inflammation induces adolescent depression symptoms.

Clinical studies have shown decreased anterior cingulate cortex (ACC) synaptic density and increased inflammation in the brain of depressed patients. Microglial cells are resident immune cells of the brain, and they transform into reactive states in response to stress challenges. Under the pathological state, activated microglia are the commander of the inflammatory state of the brain tissue, which is closely related to the occurrence and development of depression.

In this study, the researchers found that early-life inflammation would lead to the susceptibility of microglial in the ACC to random stress events during adolescent development, and microglia then overengulfed dendritic spines of neurons. This weakened the ability of ACC glutamatergic neuronal ACCGlu) to fight stress, inducing adolescent depression.

Scheme of how early-life inflammation promoting depressive symptoms in adolescent mice. (Image by CAO Peng et al.)

To explore the response of ACC microglia to stress during mouse development from childhood to adolescence (45 days after birth), the researchers established inflammatory model by intraperitoneal administration of lipopolysaccharide (LPS) during the critical time window of mouse brain development (14 days after birth).

They found that six hours after LPS injection, multiple activation indexes of ACC microglia in mice significantly increased and recovered after 24 hours, and during the later development, a series of unpredictable life stress events (such as weaning, caging, noise and fighting) could lead to the re-activation of ACC microglia in LPS mice, being more susceptible than normal mice.

Moreover, the researchers found that before stress, the sharply increase of ACCGlu activity helped mice resist the attack of stress and protect themselves, however, ACC microglia of mice with early-life inflammation were frequently activated by persistent stress in adolescence, and overengulfed the ACCGlu dendritic spines via CX3CR1 signals mediate, consequently reducing the activity of ACCGlu . As a result the body’s ability to cope with stress was impaired, which promoted depression in adolescent mice.

This study offers a plausible and experimentally tractable framework to demonstrate the molecular and cellular basis for how early-life inflammation manifests depressive symptoms in adolescents.

Paper link: https://doi.org/10.1016/j.neuron.2021.06.012

(Written by LU Hongyu, edited by HOU Luyao, USTC News Center)