Early Life Stress Programs Synaptic Development By Regulating a Novel Innate Immune Pathway in the Developing Mammalian Brain

Arie Kaffman, M.D., Ph.D.

Yale University

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2010, for 3 years

Funding Amount:


Lay Summary

How early life stress may alter brain development and modify behavior

Investigators will use cellular imaging in mice to help identify the molecular events involved in early life stress that may modify complex behaviors, such as anxiety, impulse control and memory, later in life. The animal studies are expected to have direct relevance to humans, because animals and humans appear to exhibit similar behavioral modifications induced by stress.

Each year in this country more than a million children are estimated to suffer from abuse and neglect. The Yale investigator is a psychiatrist, treating adults who suffered from such early life stress as children. He anticipates that cellular imaging in mice exposed to stress will provide the basis for understanding the molecular events involved in human responses to stress. Research has shown that mice and non-human primates exposed to early life stress undergo modifications in fearful behavior and cognition, and also suggests that stress in early life may alter their brain’s synaptic plasticity. Specifically, while ordinarily during brain development a myriad of synapses (connections between brain cells) develop and those that are not used are pruned back, stress appears to hinder this normal pruning process.

The reason for this lack of synaptic pruning, according to the Yale researchers’ recent studies,  may relate to an innate immune system protein called “LBP” (lipopolysaccharide binding protein). Ordinarily this protein appears to summon immune “microglial” cells to enter the brain’s hippocampus and prune and clear away unused synapses.  During acute or chronic stress, though, hippocampal LBP levels decrease. The investigators hypothesize that early life stress hormones reduce these LBP protein levels. Fewer microglia are summoned to the hippocampus to prune and remove unused synapses. Instead, thick synapses develop that later in the life of adult mice are associated with abnormal fearful and emotional behaviors. The researchers will test this hypothesis in young mice that undergo stress and see whether their synapses and behaviors are similar to those in mice that have been bred to have no LBP protein and therefore no ability to attract microglia into the brain to prune unused synapses. Additionally, they will see whether blood LBP levels are decreased in response to stress. If so, the research ultimately could lead to the ability to detect the effects of early life stress through blood tests, and to treat the physiological effects, and perhaps the emotional and cognitive effects, by bolstering levels of the LPB protein.

Significance: If this animal study helps to identify how early life stress and the innate immune system interact in the brain to alter healthy synaptic development in early life and complex behaviors later in life, the findings will provide the necessary first step toward studying and understanding this process in humans and ultimately may lead to early diagnosis and preventive measures.