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 structure. 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.