Project 2

Animal Models of Suicide: Behavior, Neurobiological and Molecular Phenotype

We have previously established that mice exposed to postnatal maternal separation manifest increased depressive- and anxiety-like behaviors, reduction in behavioral inhibition in novel environments, and increased aggressive behavior (males only) during social interactions. Importantly, behavioral effects are sex-specific, with considerable individual difference in response to maternal separation. Through integration of the behavioral and molecular changes associated with maternal separation, we have found that the epigenetic suppression of neuroplasticity markers such as brain-derived neurotrophic factor (BDNF) is a particular signature of maternal separation-associated behavioral risk. The risk phenotype includes anhedonia, impulsivity and aggression and thus these characteristics may differentiate at-risk vs. resilient individuals.

Studying Epigenetic and Gene Expression Changes That May Contribute to Lifelong Effects of Early Adversity

Project 2 continues to work with this approach, using an early life stress mouse paradigm of limited bedding and maternal separation to model childhood adversity effects on depression, anxiety, and social behavior in offspring exposed to early life stress. In the brains of stress-exposed animals, we are examining epigenetic effects (changes in DNA methylation) and gene expression changes of the same genes as in Project 1, to identify molecular mechanisms that contribute to life-long effects of early adversity on brain function and behavior.

We will examine molecular changes in response to early life stress in key brain structures involved in cognitive function and emotional regulation, such as the hippocampus and the prefrontal cortex. We will also test whether targeting specific brain structures and molecular mechanisms, and using behavioral interventions such as an enriched social environment, could have potential as ways to reverse the adverse effects of prolonged early life stress.

If effective, our findings could guide new prevention efforts in the future that can begin in children at risk.