This research will examine maladaptive myelination as a potential mechanism underpinning the structural and functional brain abnormalities associated with exposure to traumatic stress. Specifically, we will explore the mechanisms behind persistent sensitivity to acute threat (?fear?: RDoC domain) arising from traumatic stress during early adulthood. Myelination most likely evolved to improve conduction velocity but in gray matter (GM), it reduces axonal sprouting, synaptic density, and neuroplasticity. Exciting recent findings have shown that myelin development in both cortical and subcortical gray matter is highly plastic and strongly influenced by new experiences and learning, even during adult life. Importantly, myelin-forming oligodendrocytes are sensitive to environmental stressors and therefore may provide a novel mechanism by which aberrant structural and functional changes arise in the brain. Human brain imaging data from our labs show that subjects with a range of PTSD symptoms secondary to adult trauma exposure have increased myelin content in the hippocampal (HP), frontal, and temporal GM. Importantly, myelin content predicted symptom severity over and above potential confounding variables. Furthermore, we found that adult traumatic stress exposure in rodents produces an increase in oligodendrocytes (OGs) and myelin content in the dentate gyrus (DG), a GM structure13. Similar to human subjects, our preliminary data show that symptom severity (fear score) in rats is significantly correlated with DG OGs and myelin content. Overall, these findings provide a translational model to better understand the mechanisms of oligodendrocyte and myelin plasticity in the human. In this proposal, we will test the hypothesis that traumatic stress exposure during adulthood leads to increased myelination in cortical and subcortical GM in regions critical for fear memory. Specifically, we expect to see this increased myelination only in those that subsequently become sensitive to acute threat following stress exposure. Additionally, we hypothesize that increased myelination will constrain the proper functioning of the major intrinsic functional connectivity (IFC) networks. This integrated animal-human design enables an innovative multilevel and causal exploration. Additionally, we focus on a novel role for myelin plasticity in the adult brain as a mediator of trauma-induced acute threat symptoms.
Aim 1 is focused on the question of whether hippocampal gray matter myelination predict post-trauma sensitivity to acute threat.
Aim 2 is focused on the question of whether the effects of trauma exposure on cortical and subcortical GM myelination predict network connectivity and fear memory.

Public Health Relevance

The project will test the hypothesis that maladaptive myelin development in response to traumatic stress is a critical mechanism in the brain's response to trauma. The project involves both animal and human subjects and helps fill key gaps in our understanding of how trauma adversely impacts the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH115020-01A1
Application #
9662558
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Tuma, Farris K
Project Start
2019-01-11
Project End
2023-10-31
Budget Start
2019-01-11
Budget End
2019-10-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121