Neuropeptide signaling and the blood–brain barrier generate a persistent stress-induced internal state in Drosophila
- Abdalla G. Alia
- Xinyue Hu
- Yuzhe Gu
- Janviere Yau
- Guangnan Tian
- Julie L. Semmelhack
- Kokoro Saito
- Hiromu Tanimoto
- Koki Tsuyuzaki
- Shintaro Naganos
- Tomoyuki Miyashita
- Minoru Saitoe
- Yukinori Hirano
2026-07-01
Although fear conditioning has elucidated cue-evoked acute fear responses, the mechanisms by which stress experiences induce generalized internal states linked to anxiety or phobia are poorly understood. Here, we report that robust stress induces a persistent behavioral change characterized by avoidance of a confined space, claustrophobia-like behavior (CLB) in Drosophila . Unlike aversive memory formation, the development of CLB does not require dopamine receptors. Our neuronal screening determined that neuropeptide signaling via Allatostatin-A inactivates the downstream neurons via its receptor AstA-R1, causally inducing CLB. Moreover, gene expression profiling of individual fly heads revealed that innate immune response activation in the blood–brain barrier is involved in CLB. Our data demonstrate that stress-induced persistent behavioral change would not be related to a canonical mechanism of aversive memory formation, rather involves neuropeptidergic signaling and the blood–brain barrier, providing the mechanism determining internal states which persistently change into a phobia-like mode.