Wednesday, December 4, 2024
12/4/2024
The central hypothesis of this R01 renewal focuses on a subset of B cells that provide neurotrophic support to counter cognitive impairment and improve motor function after ischemic stroke, a key risk factor for the development of vascular contributions to cognitive impairment and dementia (VCID). These neurotrophic B cells secrete brain-derived neurotrophic factor (BDNF) and may be critical to countering the development of VCID. Unfortunately, the patient population most at risk for stroke and VCID aged individuals have impaired B cell development and secretion of growth factors that could limit protection from post-stroke depression and dementia. Sex is also a factor, as elderly women with post-stroke dementia have the lowest levels of circulating BDNF, though no prior studies have directly linked a loss of neurotrophic immune cell populations and the development of VCID. Based on our pilot data, we will test: if a subset of post-stroke B cells (i.e. B cellsBDNF+) upregulate BDNF after encountering glutamate; if B cellsBDNF+ limit the development of VCID and support motor recovery; and if B cell-derived BDNF is impaired in aged females. We will use 4 mos. (“young”) and 16 mos. (“aged”) female and male mice to test if B cellsBDNF+ support neuronal function, plasticity, motor, and multi-domain cognitive recovery post-stroke. Aim 1 will test if after stroke, (1A) glutamate binds to B cells to increase BDNF production and drive recovery-linked intracellular Ca2+ signaling that is sex- and age-dependent. We will (1B) use B cellsNtrk2tm1Ddg/J in vitro to test if the BDNF receptor TrkB is required for BDNF production and in vitro neuroprotection. Aim 2 will test if B cellsBDNF+ support remote plasticity, as well as cognitive and motor recovery in a primary motor cortex (M1) photothrombosis stroke model. Inducible depletion of (2A) all B cells or (2B) specific B cell-derived BDNF in young and aged female hCD20TamCre/ BDNFfl/fl mice and littermate controls will occur either acute (day 0) or delayed (beginning day 7 post-stroke). Primary outcomes will include 1) preservation of Pavlovian stimulus-reinforcer learning on an automated touchscreen task, 2) improved forelimb precision reaching, and 3) peri-infarct and contralesional M1 plasticity. Aim 3 will test if B cell-derived BDNF augments long-term cognitive and motor recovery. Aged C57BL/6J female mice will receive tMCAo or sham surgery and adoptive transfer of B cells that (3A) overexpress BDNF or (3B) lack BDNF, the latter derived from hCD20TamCre/BDNFfl/fl donor mice, beginning day 7 post-stroke. Primary outcomes will include 1) ameliorated hippocampal-specific cognitive deficits tested via touchscreen pattern separation, 2) improved precision skilled reaching, and 3) regional ipsi- and contralesional diapedesis of B cells, as determined via whole brain serial two-photon tomography, that correlates to within-animal magnitude of brain circuit-specific cognitive function and motor recovery. These studies will confirm an age-dependent loss of a novel subset of B cells, B cellsBDNF+, in females that develop VCID. They will also confirm that therapeutically targeting B cells can counter post-stroke dementia and motor deficits a potential treatment supporting plasticity-based recovery after any CNS injury or disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
