Abstract WP291: Genome-Wide Transcriptomic Analysis of Sex- and Social Isolation–Dependent Gene Expression Following Ischemic Stroke

Introduction: Genetic variation is known to contribute to stroke risk and outcomes, yet the molecular mechanisms remain poorly defined. Transcriptomic profiling enables precise characterization of systemic responses to stroke, offering opportunities to link molecular pathways with clinical recovery. Emerging evidence indicates that social isolation (SI) and sex strongly influence stroke outcomes; however, the biological pathways mediating these effects are not understood. Critically, no prior studies have examined how SI and sex together shape gene expression after stroke, representing a major gap with direct implications for patient care. Hypothesis: We hypothesize that stroke triggers distinct gene expression changes influenced by sex and social isolation, which contribute to differences in recovery trajectories, post-stroke depression, and long-term outcomes. Methods: We performed bulk RNA sequencing on whole blood samples from ischemic stroke patients (N = 100, 65±12 y, 35 females, 65 males) collected 24 hours after last known well. SI was assessed using the Lubben Social Network Scale and loneliness by the UCLA Loneliness Scale during hospitalization. Blood samples were collected using Paxgene tubes. Results: Several upregulated genes identified in socially isolated men are linked to neuroplasticity, neuroinflammation, and depression. In addition, several immune-related upregulated genes suggest active neuroimmune crosstalk after stroke that differ in isolated males. Conversely, downregulated gene sets included targets whose loss may impair neuroprotection and resolution of immune activation. In SI women, several upregulated targets converged on stress endocrine signaling, neuroimmune activation, and synaptic remodeling, pathways that can enhance depressive symptoms and social withdrawal after stroke. A second cluster involved inhibitory transmission and synapse and homeostatic remodeling, which can influence both affect and social behavior. Notably, downregulated transcripts included IFNG, suggesting dampened Th1 and adaptive tone alongside heightened innate signaling in women. Conclusion: Both sexes showed transcriptional remodeling of neuroimmune and synaptic networks, potentially increasing vulnerability to chronic neuroinflammation, depression, and social withdrawal after stroke. Defining these sex- and SI-dependent changes may reveal therapeutic targets to improve recovery and long-term outcomes.