# Airway inflammation and fear: elucidating immune mediators and neural substrates

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $463,425

## Abstract

PROJECT SUMMARY:
Fear regulation is essential for optimal mental health. Maladaptive fear is a hallmark of posttraumatic stress
disorder (PTSD), a debilitating condition afflicting 22% of combat veterans. Impaired functioning of infralimbic
(IL) prefrontal cortex (PFC) contributes to fear dysregulation in PTSD, however factors contributing to IL deficits
are unclear. Not all trauma-exposed individuals develop PTSD, suggesting that predisposition factors may
contribute to IL dysfunction and PTSD risk. Elucidating the nature of such factors will help identify novel
therapeutics. Growing evidence supports a strong association between severe asthma and PTSD. Mechanisms
and cellular substrates whereby severe asthma associated factors regulate PTSD-relevant fear and IL-PFC
deficits remain unknown. Using unique mouse paradigms of aeroallergen house dust mite (HDM)-driven
inflammation we observe: 1) compromised fear extinction only in mice with allergen-induced Th2/Th17
expansion, an effect dependent on IL-17A and IL-17RA signaling and accompanied by reduced neuronal
activation in the IL-PFC; 2) significant upregulation of microglial Il17ra expression in blood-brain-barrier
compromised subfornical organ (SFO) inTh2/Th17 mice (but not in SFO non-microglial cells or PFC microglia);
3) IL-17A-induced activation of SFO neurons, and, 4) direct SFO►IL projections that modulate parvalbumin
interneurons that regulate IL excitability and fear. Collectively these observations inform our hypothesis: IL-17A
engages microglial IL-17RA and SFO-to-IL projections to modulate IL excitability and fear. This hypothesis will
be tested in 2 aims. Aim 1 will determine if SFO►IL PFC projections regulate compromised fear extinction
and IL neuronal excitability in mice with HDM-induced mixed Th2/Th17 inflammation. Using a retroCre-
dependent chemogenetic strategy, we will inhibit or activate SFO►IL projections to assess effects on fear
extinction in mice with Th2 versus Th2/Th17 responses. AAV-ChR2 transduction of SFO neurons and patch-
clamp recordings in IL neurons will be undertaken. Aim 2 will determine if microglial IL-17RA signaling in the
SFO drives HDM-induced fear extinction deficits. Using SFO targeted cell-specific AAV-Cre in Il17rafl/fl mice,
we will assess the necessity of IL17RA signaling in HDM-induced extinction deficits. The transcriptional profile
of SFO-derived microglia and non-microglial cells will be generated for cell-type specific gene expression
signatures to identify DEGs and downstream signaling pathways in Th2/Th17 mice. Finally, the impact of IL-17A
on IL-projecting SFO neurons will be assessed using patch-clamp electrophysiology in slices of brains Th2/Th17
mice, +/- targeted microglial IL-17RA ablation, inhibition of previously identified modulators of SFO microglia-
neuron signaling and other transcriptomic-identified targets. Impact: Our studies will inform on how adaptive
immune mediators modulate brain function and behavior and identify novel r...

## Key facts

- **NIH application ID:** 10979197
- **Project number:** 1R01MH133070-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Ian Paul Lewkowich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,425
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979197

## Citation

> US National Institutes of Health, RePORTER application 10979197, Airway inflammation and fear: elucidating immune mediators and neural substrates (1R01MH133070-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979197. Licensed CC0.

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