Childhood abuse and neglect are major risk factors for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses that are refractory to treatment in adulthood. The molecular mechanisms by which early life stress (ELS) modifies vulnerability to stress and cognition in humans are currently poorly understood. However, similar observations in rodents and nonhuman primates suggest that at least some aspects of this process are conserved and can be further studied in animal models. Here we present preliminary data that suggest that ELS impairs hippocampal function in adulthood by down regulating expression of genes, such as the lipopolysaccharide binding protein (LBP), that are necessary to support microglia-mediated synaptic pruning during a critical period of development. Abnormal synaptic pruning leads to the establishment of inefficient wiring grid that persists into adulthood and affects complex behavior. This hypothesis is consistent with a growing body of work showing that microglia cells play an essential role in synaptic pruning and that exposure to ELS is associated with increased spine density in limbic areas that persist into adulthood. In addition, the ability of glucocorticoids to suppress microglia activity in vivo and in vitro makes them a likely cellular target for ELS. These findings provide the first evidence to suggest that some of the developmental consequences of ELS are mediated by impairing microglia function and synaptic pruning in the mouse. We predict that similar dysregulation of MG function will be confirmed in children and adolescents and that our mouse model will generate novel strategies to diagnose and treat psychopathologies caused by exposure to ELS in humans. .

Public Health Relevance

Children exposed to abuse or neglect are more likely to develop depression, anxiety and psychotic symptoms that in many cases become chronic and refractory to treatment later in life. We identified a novel molecular pathway in the developing brain that may explain how stress influences neurodevelopment in a manner that affects brain functioning throughout life. Our hope is that this work will establish new diagnostic and interventional strategies to help children that have been abused early in life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH100078-01A1
Application #
8630734
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Desmond, Nancy L
Project Start
2013-12-15
Project End
2018-11-30
Budget Start
2013-12-15
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$416,250
Indirect Cost
$166,250
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520