# A novel interoceptive subfornical organ to infralimbic cortex mechanism relays airway inflammation effects on fear extinction

## TL;DR

The study reveals how severe lung inflammation affects mental health by altering brain circuits related to fear extinction, and suggests a potential treatment using anti-inflammatory antibodies.

## Contribution

The paper identifies a novel interoceptive mechanism involving the subfornical organ and infralimbic cortex in the context of airway inflammation.

## Key findings

- Severe airway inflammation impairs fear extinction in mice, an effect reversed by anti-IL-17A antibodies.
- Microglial IL-17RA in the subfornical organ is upregulated in severe airway inflammation and contributes to impaired fear extinction.
- Chemogenetic inhibition of the SFO-to-infralimbic cortex circuit improves fear extinction in mice with severe airway inflammation.

## Abstract

There is growing interest in the impact of internal body states on the brain and behavior. The detrimental effects of chronic lung inflammation on mental health are well recognized, however, underlying mechanisms are not known. Here, using a murine model of allergic asthma we report compromised fear extinction in mice with severe but not mild airway inflammation (AI); an effect abolished by anti-interleukin-17A (IL-17A) antibodies. Investigation of innate immune cells, microglia as-well-as transcriptomic signatures in the subfornical organ (SFO), a brain interoceptive node lacking a traditional blood-brain-barrier, revealed significant alterations in severe AI mice. IL-17 Receptor A (IL-17RA) was expressed in SFO microglia and upregulated in severe AI mice. Notably, ablation of microglial IL-17RA improved fear extinction in severe AI mice. Furthermore, we identified direct SFO projections to the infralimbic (IL) cortex, a key area regulating extinction. Importantly, chemogenetic inhibition of the SFO-IL circuit led to improved fear extinction in severe AI mice. Collectively, we report a unique body-to-brain interoceptive mechanism engaging the SFO microglia and an SFO-to-IL circuit, through which airway inflammatory mediators compromise fear extinction. Beyond asthma, our findings are relevant to other pulmonary pathologies (e.g. bacterial pneumonia, ARDS, COVID-19) highlighting a risk for cortical dysfunction and fear pathologies such as PTSD.