IMMUNE DYNAMICS AND B CELL CONTRIBUTIONS TO NEUROPLASTICITY AND RECOVERY AFTER STROKE

This dissertation explores the dynamic interplay between the immune system and the brain across stroke and aging using clinical, post-mortem, and pre-clinical models. The immune system plays critical roles in shaping brain function, responding to injury, and mediating recovery. These studies aim to enhance our understanding of neuroimmune dynamics across spatial and temporal dimensions. In the first part, we conducted longitudinal sampling of aneurysmal subarachnoid hemorrhage (aSAH) patients to track immune cell and cytokine changes at days 3, 5, 7, 10, and 14 post-stroke, with a focus on delayed cerebral ischemia (DCI), a common complication. We observed distinct temporal patterns, including an early cytokine surge in the cerebrospinal fluid (CSF) preceding immune cell expansion. Specifically, IL-1β, IL-6, and tumor necrosis factor (TNF)-α production peaked at day 7, coinciding with typical DCI onset. Our findings revealed a time-dependent immune response following aSAH. The early cytokine peak in the CSF preceding immune cell changes proposes a possible mechanistic link. This early cytokine activity may drive immune cell expansion and prime peripheral cells for inflammation, contributing to DCI risk. These findings highlight potential immune targets for future therapies. In the second part, we utilized a rapid post-mortem tissue collection pipeline to examine immune cell dynamics in the perimortem brain, a largely unexplored phase of neuroimmune activity. We profiled parenchymal immune populations in aging donors to highlight cells relevant to normal aging and neurological disease. While we found no hemispheric differences, we observed sex differences, especially in the cerebellum, including large microglia populations and a unique subpopulation of CD19+CD23+CCR7+ B cells, distinct from CVD (cardiovascular disease) and stroke samples. Additional B cell subsets expressed CD23+ and CD11c+. These studies inform us on immune profiles in neuroinflammatory states linked to aging and disease. Lastly, we investigated how neuronal networks rely on neurotrophic support for functional plasticity after stroke in a preclinical model. We focused on B cells since they infiltrate the brain bilaterally after ischemic injury and are found in non-infarct regions like the hippocampus, suggesting roles in supporting neurogenesis and recovery. Using Synapsin-Cre/GCaMP6s mice, we visualized spontaneous calcium activity in hippocampal CA1 and dentate gyrus (DG) neurons during B cell depletion and stroke. Transient ischemic stroke increased amplitudes in both regions, while B cell depletion reduced DG amplitudes but increased event frequency. Robust linear regression revealed significant effects of injury on activity, and B cell depletion influenced DG dynamics through both main effects and higher-order interactions (depletion × sex × age × injury). The DG appears more sensitive to modulation by B cell depletion and age effects. These results suggest that B cells may play a neuroprotective role in the post-stroke brain depending on the host’s age and sex. The selective vulnerability of the DG to depletion-age-injury interactions opens a possible avenue for future studies on region-specific neuroimmune crosstalk in stroke recovery. Together, these studies demonstrate a multifaced role of the immune system in influencing brain function after injury. We identified time-dependent immune changes linked to DCI, unique immune populations in the post-mortem brain, and B cell-mediated modulation of hippocampal activity. These findings show that B cells could play a role in neurotrophic support in the ischemic brain and expand our understanding of neuroimmune dynamics across multiple models. Ultimately, this work pushes forward research aimed at developing immune-based therapeutics that harness the supportive effects of B cells to mitigate neurological pathology.