Adolescent Social Isolation Facilitates Tau Spread in Raphe Nuclei, Linking Depression and Hyperalgesia in Alzheimer’s Disease

Tau pathology in brainstem serotonergic circuits drives early neuropsychiatric dysfunction in Alzheimer's disease (AD), yet mechanisms linking the exposome, particularly social stress exposures to depression and altered pain perception, remain unclear. Here, we demonstrate that adolescent social isolation, a critical psychosocial exposome factor and major trigger of depression, facilitates tau propagation in the dorsal raphe nucleus (DRN) and downstream raphe nuclei, producing both neuropsychiatric and pain-related sequelae. Tau[P301L] was transduced into the DRN of 30-day socially isolated or group housed C57BL/6J mice using AAV, with control mice receiving AAV-GFP. Four weeks post-transduction, anxiety, social behavior, and pain sensitivity were assessed, and phosphorylated tau (ptau) within the DRN and spread to the median raphe (MRN) and raphe magnus (RMg) serotonergic neurons were evaluated. Socially isolated tau[P301L] mice exhibited hyperlocomotion, anxiety-like behavior, social deficits and hyperalgesia. Histological analysis revealed elevated ptau within TPH2 neurons in the DRN and trans-synaptic tau spread to MRN and RMg, accompanied by reduced TPH2 and increased ptau at the downstream raphe nuclei. Fluorescence <i>in situ</i> hybridization confirmed altered expression of <i>Slc6a4</i> and <i>Tgm2</i> , a stress-responsive gene implicated in AD. These results indicate that DRN tau under social stress drives neuropsychiatric phenotypes, while tau spread to MRN and RMg disrupts serotonergic modulation of pain. This study provides the first evidence that adolescent stress promotes tau propagation within the raphe nuclei, linking early neuropsychiatric and pain-processing deficits to prodromal Alzheimer's disease and identifying a critical pathway through which psychosocial exposome risk converges with tau pathology to enable early intervention.