PROJECT SUMMARY:
Effective regulation of fear is essential for optimal mental health. Fear dysregulation is a hallmark of post-
traumatic stress disorder (PTSD), a debilitating condition afflicting 22% of combat veterans. Impaired prefrontal
cortex (PFC) functioning contributes to fear dysregulation in PTSD. Not all trauma-exposed individuals develop
PTSD suggesting pre-trauma risk factors. Elucidating the nature of such factors will help identify novel
therapeutics. Recent evidence supports an association between chronic inflammation and PTSD risk.
Accordingly, many inflammatory diseases are linked to increased PTSD. Growing evidence supports a strong
association between severe asthma and PTSD, however the severe asthma associated factors and mechanisms
that regulate PTSD relevant PFC deficits remain unknown. Our published and recent data using unique mouse
paradigms of aeroallergen house dust mite (HDM)-induced driven inflammation, show compromised fear
extinction only in mice with Th17/IL17A expansion, an effect dependent on IL17A receptor signaling and
peripheral IL17A. Importantly, this is accompanied by 1) reduced neuronal activation in the PFC an extinction-
regulatory area and 2) microglial/T cell/endothelial alterations within the subfornical organ (SFO), a BBB-devoid
area projecting to the PFC. Collectively these observations inform our hypothesis: severe asthma relevant IL-
17A activates a complex, multi-cellular signaling cascade within the SFO which engages the PFC to regulate
fear. This hypothesis will be tested in 3 aims. Aim 1 will determine if IL-17A signaling, and Th17 cell activity
is necessary and sufficient for HDM-Th17/IL17A driven fear extinction deficits The ability of IL-17A
blockade (neutralizing mAb) or Th17 antagonism (small molecule inhibitor) to reverse fear extinction
deficits/neuroimmune alterations in mice with Th2/Th17 responses, or recombinant IL17A to induce fear
extinction deficits/neuroimmune alterations in mice with Th2 responses will be assessed. Aim 2 will determine
if SFO?IL projections are necessary and sufficient for HDM-Th17/IL17A driven fear extinction deficits
Using a retroCre-dependent chemogenetic strategy we will inhibit or activate SFO?IL projections to assess
effects on fear extinction in HDM treated mice with Th2 versus Th2/Th17A Aim 3 will identify transcriptomic
profiles in the SFO and PFC associated with HDM-Th2/Th17 effects and fear Using single-cell RNAseq, the
transcriptional profile of SFO and PFC derived cells will be generated with cell-specific signatures of immune
cells, glia, endothelial cells and neurons to identify DEGs and signaling pathways uniquely activated in HDM
TH2 vs Th2/Th17 mice. Validation and association with HDM-Th2/Th17 effects on fear will be performed using
Aim 1/Aim 2 tissue. Impact: Our data reveals a unique core mechanism by which adaptive immune mediators
associated with chronic lung inflammation regulate cortical deficits and fear, relevant to mental health.
Completion of these studies will broaden our understanding of how peripheral inflammatory mediators modulate
brain function and behavior and identify novel risk factors and therapeutic targets for fear-associated pathologies.