Azulay-Debby, H. | bioRxiv Science

bioRxiv2026

Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses

Pain is a cardinal sign of inflammation, constructed by the brain from peripheral nociceptive input. Yet, its role in the brain's response to inflammation remains unknown. Here, we demonstrate that nociceptive signaling is essential for the brain to represent and replay inflammatory states. Analysis of human fMRI and mouse activity mapping revealed that peripheral inflammation generates a distinct brain state. In mice, ablation of TRPV1+ sensory neurons or pharmacological analgesia disrupted this organization and prevented the insular cortex from forming retrievable immune representations. Conversely, augmenting nociceptive signaling during inflammation strengthened subsequent immune recall. These findings identify nociceptive input as a critical signal in brain-immune dialogue, enabling the encoding and retrieval of inflammatory events.

neuroscience↗

bioRxiv2025

Circadian-Related Dynamics of the Endocannabinoid System in Male Mouse Brain

Endocannabinoids (eCBs) and related lipids play crucial roles in brain function, including the regulation of circadian rhythms and sleep. To comprehensively map these molecules, we employed liquid chromatography high-resolution tandem mass spectrometry (LC/HRMS/MS) to quantify 78 lipids across 14 families in seven brain areas of male mice at four time points throughout the day (every six hours), and during sleep initiation. We found that most eCBs from the fatty acids (FAs) family, particularly arachidonic acid (AA), were highly abundant in the mouse brain in all brain areas and during the circadian rhythm. High eCBs abundance was shown in deeper brain areas, while temporal differences using the Cosinor analysis revealed 26 eCBs behaving in a circadian rhythm response, with linolenic acid (LnA) being the only lipid to show rhythmicity across all brain areas. Sleep initiation (ZT1) was associated with increased N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) activity and N-acylethanolamide (NAE) levels in the cortex and hippocampus, while wake extension (WEx) altered 2-monoacylglycerol (2-MAG) metabolism and increased cannabinoid receptor 1 (CB1) expression. These findings provide a detailed lipidomic map of eCBs and related lipids in the male mouse brain, highlighting their area-specific distribution, circadian regulation, and involvement in sleep/wake transitions. Given the link between sleep disruption and neurodegeneration, future studies should investigate whether the observed eCB dysregulation contributes to sleep disturbances in these conditions, and if targeting these pathways offers novel therapeutic strategies. Significant StatementThis comprehensive study provides a high-dimensional map of eCBs and related lipids in the male mouse brain, revealing intricate spatial and temporal dynamics highlighting the role of these lipids in regulating fundamental physiological processes such as circadian rhythm and sleep.

neuroscience↗

bioRxiv2020

Remembering immunity: Neuronal ensembles in the insular cortex encode and retrieve specific immune responses

Increasing evidence indicates that the brain regulates peripheral immunity. Yet, it remains unclear whether and how the brain represents the state of the immune system. Here, we show that immune-related information is stored in the brains insular cortex (InsCtx). Using activity-dependent cell labeling in mice (FosTRAP), we captured neuronal ensembles in the InsCtx that were active under two different inflammatory conditions (DSS-induced colitis and Zymosan-induced peritonitis). Chemogenetic reactivation of these neuronal ensembles was sufficient to broadly retrieve the inflammatory state under which these neurons were captured. Thus, we show that the brain can encode and initiate specific immune responses, extending the classical concept of immunological memory to neuronal representations of immunity.

neuroscience↗