A parabrachial hub for the prioritization of survival behavior during pain

Long-term sustained pain following acute physical injury is a prominent feature of chronic pain conditions. Populations of neurons that rapidly respond to noxious stimuli or tissue damage have been identified in the spinal cord and several nuclei in the brain. Understanding the central mechanisms that signal ongoing sustained pain, including after tissue healing, remains a challenge. In this study, spatial transcriptomics, neural manipulations, activity recordings and computational modeling demonstrate that activity in an ensemble of anatomically and molecularly diverse parabrachial neurons that express the NPY Y1 receptor is elevated following injury and predicts functional coping behavior. Regardless of the injury type, hunger, thirst, or predator cues suppressed sustained pain by inhibiting PBN Y1R neurons via the release of NPY. Together, our results demonstrate an endogenous analgesic hub at pain-responsive parabrachial Y1R neurons To identify brain regions and cell types involved in persistent pain, we performed spatial transcriptomic profiling of the parabrachial nucleus (PBN) in mice following formalin-induced inflammatory injury. Mice were injected with 2% formalin into the dorsal hind paw, and brain tissue was collected one hour post-injection to capture ongoing pain-related gene expression. Coronal sections of the hindbrain encompassing the PBN were subjected to high-plex spatial transcriptomics using the NanoString CosMx platform. The goal was to identify molecularly and spatially defined populations of neurons activated during sustained pain, with a particular focus on NPY Y1 receptor-expressing (Y1R) neurons. Spatial and computational analyses were used to define transcriptomic clusters, assess activity-induced gene expression, and map neuronal subpopulations implicated in chronic pain processing.