Sex differences in response to threat: Role of the salience network in the development of depression across adolescence

PROJECT SUMMARY/ABSTRACT
Violence exposure is a major risk factor for depression across development, with depression severity rising steeply
during early adolescence, and especially among females. Threatening events such as violence exposure may be
especially impactful for females because they perceive future threatening events as less controllable than males.
In line with this perspective, researchers have shown that rumination mediates the association between exposure
to uncontrollable stressors and hopelessness among urban adolescent girls, but not their male peers. Further,
activity in areas of the brain responsible for threat processing respond more to threatening stimuli among women
who have experienced more violence, while previous violence exposure does not modulate males' responses
to threatening stimuli. It is unclear, however, threat differentially impacts brain networks across the sexes. One
network that could help explain sex differences in response to threat is the salience network (SN). The SN is
important for reorienting to unexpected stimuli that are behaviorally relevant, and as such, is often investigated
in the context of threat and fear learning paradigms. Violence exposure has been shown to be associated with
greater connectivity within the SN, and increases in within SN connectivity have been found to mediate the asso-
ciation between abuse and depression during adolescence. Notably, the SN physically occupies a greater portion
of cortex in females and those with depressive disorders. Being exposed to threatening experiences may result in
utilizing more cortical tissue for evaluating the salience of stimuli, considering experience impacts the expanse of
associated brain networks. Therefore, threat may be associated with altered SN properties. Properties of the SN
may also change during adolescence, as extinction retention increases for male rats over adolescence, while it
decreases for females. Importantly, this project proposes an integrative biopsychosocial model of sex differences
on depression in response to threat across development, investigating properties of the SN as potential mecha-
nisms. To address sex differences on SN properties in response to threat across development, I will utilize a new
method to define personalized brain networks, which is essential for estimating the expansiveness of networks.
This method employs an empirical Bayesian framework by using group templates as priors, allowing for efficient
and reliable estimates of individual vertex-level network membership. To maximize the power to detect effects,
I will combine data from two active R01s awarded to my primary sponsor, Dr. Nusslock, that together are col-
lecting data from 620 adolescents ages 14-18, each with three neuroimaging sessions spaced a year apart, and
threat exposure and depression symptoms measured concurrently with the neuroimaging sessions. In order to
execute this research, I have assembled an interdisciplinary mentorship team that will help me expand upon my
knowledge of developmental affective neuroscience (Nusslock, Insel), youth trauma (Suárez), and personalized
networks and statistics (Mejia, Samia).

Grant Number: 1F31MH140552-01
NIH Institute/Center: NIH
Principal Investigator: Ellyn Butler