Extracellular vesicles as biomarkers of trauma exposure and PTSD risk

Exposure to interpersonal violence (IPV) is associated with long-term negative mental health consequences,
including an increased risk for posttraumatic stress disorder (PTSD), especially in women. The specific
developmental timing of IPV is likely to play a significant role in disease outcomes where trauma experienced in
late adolescence increases PTSD risk by 3-fold. However, little is known as to timing effects of IPV and PTSD
risk related to sensitive periods of brain development and maturation. Our previous studies examined IPV
experienced during specific developmental windows on health outcomes in a predominantly Black cohort of adult
women. Our results revealed that psychophysiological reactivity related to PTSD risk, skin conductance
response (SCR) and fear-potentiated startle, was uniquely observed when IPV was experienced between 14-18
yrs. Using an unbiased proteomic approach in extracellular vesicles (EV) to identify potential biomarkers specific
to timing of IPV experience, we found a unique EV protein signature belonging to a 17q21 gene cluster and
associated with skin keratinocytes, specifically unique to Merkel cells. Merkel cells are mechanosensitive
neuroendocrine cells in the skin innervated by sensory Ab neurons that detect light touch stimuli via Piezo2
cation channels. We found similar changes in a mouse model in which multimodal sensory stress was
experienced during the pubertal period, including EV proteins associated with the mouse keratin I gene cluster
11qD, and increased adult fear-potentiated startle responses and freezing behaviors. Taken together, these
results support tactile-based trauma exposure during late adolescence may increase sensitivity of threat circuitry:
the proposed cross-species translational study will examine molecular and physiological levels of analyses of
the RDoC Acute Threat construct. In this proposal, we have the unique opportunity to investigate a 30-yr
prospective longitudinal Black cohort who have been followed since birth, including collection of IPV data during
late adolescence, and to capture their transition through young adulthood, providing insight into the mechanisms
and biomarkers related to PTSD risk. Our overarching hypothesis to be tested is that IPV occurring during a
sensitive period of late adolescence specifically programs distinct biological pathways along the threat-response
axis involving the skin Merkel cell-neurite complex, and that these changes are detectable as accessible
biomarkers to be tested in the following Aims: 1) To establish that a sensitive period of late adolescence for IPV
experience uniquely associates with psychophysiological measures of acute threat, including SCR, fear-
potentiated startle, and quantitative sensory testing in a prospective longitudinal birth cohort of Black men and
women; 2) To identify biomarkers from examination of EV proteomics and characteristics relevant to PTSD risk
from a prospective longitudinal cohort; and 3) To identify the Merkel cell involvement in production of EVs and
alteration of behaviors relevant to PTSD risk using pubertal multimodal sensory stress in a mouse.

Grant Number: 5R01MH129495-04
NIH Institute/Center: NIH
Principal Investigator: Tracy Bale