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

Allgire, E.; McAlees, J. W.; Ahlbrand, R. A.; Mancz, E.; Vollmer, L. L.; Winter, A.; McMurray, K.; Maile, L.; Sanders, B.; Ryan, W. G.; Pool, A.-H.; Ifergan, I.; Wohleb, E. S.; Davidson, S.; McCullumsmith, R. E.; Lewkowich, I. P.; Sah, R.

doi:10.1101/2025.07.16.664367

bioRxiv · 10.1101/2025.07.16.664367

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

Allgire, E.·McAlees, J. W.·Ahlbrand, R. A.·Mancz, E.·Vollmer, L. L.·Winter, A.·McMurray, K.·Maile, L.·Sanders, B.·Ryan, W. G.·Pool, A.-H.·Ifergan, I.·Wohleb, E. S.·Davidson, S.·McCullumsmith, R. E.·Lewkowich, I. P.·Sah, R.

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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 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.

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Allgire, E., McAlees, J. W., Ahlbrand, R. A., Mancz, E., Vollmer, L. L., Winter, A., McMurray, K., Maile, L., Sanders, B., Ryan, W. G., Pool, A.-H., Ifergan, I., Wohleb, E. S., Davidson, S., McCullumsmith, R. E., Lewkowich, I. P., Sah, R.. 2025-07-18. A novel interoceptive subfornical organ to infralimbic cortex circuit relays airway inflammation effects on fear extinction. https://doi.org/10.1101/2025.07.16.664367

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