Deciphering the Role of Noradrenergic Receptors during Neuromodulation in Alzheimer's Disease

PROJECT SUMMARY Penetrating microelectrodes significantly advance our understanding of brain function and enable us to restore motor and sensory control lost from neurological disorders. However, the efficacy of intracortical microelectrodes for clinical therapy is limited by an inability to detect or modulate neurons over time and is presumed to be due to severe bodily reactions to a foreign body. While the biological mechanisms regulating device failure are poorly understood, emerging hypotheses suggests that neurovascular dysfunction plays a significant role in enabling progressive neuron loss and tissue failure after device implantation. Neurovascular health and function are governed in part by perivascular pericytes, specialized mural cells in direct apposition with cerebral blood vessels. Pericytes demonstrate important roles regulating vascular tone, blood-brain barrier integrity, and neuroimmune functions and have become increasingly recognized as prominent figures in the pathogenesis of brain inflammation and disease. How device implantation disrupts the structure and function of pericytes and the subsequent ramifications on neural health, glial activity, and vascular integrity are currently unknown. Preliminary data suggests that device insertion alters the distribution and morphology of pericytes, which occurs in tandem with neuronal calcium dysfunction, glial activation, and vascular deterioration. For the F99 phase, I will determine how electrode implantation affects functional pericyte activity in vivo using a genetically encoded calcium indicator GCaMP6s to characterize calcium signaling dynamics exclusively within PDGFRβ+ pericyte cells. Additionally, I will train in the use of optogenetics to target and modulate pericyte-specific responses during insertion and throughout implantation with the expected outcome of promoting pericyte health, neuroprotection, and vascular function after brain injury. Adeno-associated viral (AAV) transduction will be performed to visualize neuronal calcium dynamics following pericyte stimulation. Finally, substantial fellowship efforts will focus on activities in professional career development in anticipation of securing postdoctoral training during the K00 phase. For the K00 phase, I will leverage my expertise of neural interface technology and neuroimmune responses to continue identifying and characterizing mechanisms of neurodegeneration during brain injury and use advanced neuromodulating techniques to treat or reverse pathology in brain diseases such as Alzheimer’s disease and related dementia (ADRD). Activities during this phase will involve more directed career development training that is tailored toward becoming a fully realized, independent ADRD investigator. In summary, completion of the above-mentioned research aims and professional training backed by the generous support of an NIH D-SPAN award will enable me to carve out a novel and innovative area of research at the intersect of neural interface biology, neuromodulation, and neurodegenerative disease.