Targeted neuromodulation to enhance recovery of the aged brain after ischemic stroke

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Abstract Ischemic stroke, a devasting disease that primarily affects the elderly, is a leading cause of long-term disability worldwide. Current treatment relies primarily on restoring blood flow during the acute phase after stroke. However, this reperfusion treatment is applicable to only a small fraction of stroke patients, and even among these patients, many still suffer life-long neurologic impairment. Thus, there is an urgent need for new recovery- enhancing treatments during the chronic stroke phase. In the chronic phase after stroke, spontaneous, but typically slow and partial, recovery of neurologic function occurs due to activation of endogenous restorative processes not only in the peri-infarct region but also in remote brain regions. These processes involve neuronal plasticity. To enhance neuronal plasticity, neuromodulation strategies, including brain stimulation, have been explored in neurorehabilitation stroke therapy. However, the clinical results have been inconsistent, highlighting a deficiency in our knowledge about the role of specific neuronal activity in neurorestoration after stroke. Our long-term goal is to help design effective neuromodulatory stroke therapy that enhances recovery, particularly in the aged brain. Our objective here is to combine novel and state-of-the-art approaches to clarify the role of neuronal activity in the chronic stroke recovery phase, through a detailed dissection of mechanisms at cellular and network levels in aged mice of both sexes. In particular, we will capitalize on the power of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)-based chemogenetics to modulate specific neurons in the post-stroke brain. Our central hypothesis is that after ischemic stroke, proper modulation of targeted neuronal activity during the chronic recovery phase promotes vascularization, corticospinal tract (CST) reorganization, interhemispheric connectivity, and restoration of brain function. To test this hypothesis, we will pursue 2 specific aims: 1) Modulate excitatory neurons in peri-infarct regions during chronic stroke recovery phase; and 2) Modulate excitatory neurons in the contralateral M1 region during chronic stroke recovery phase. The proposed research is significant because knowledge we will gain from this study is expected to inform future development of novel interventions that promote recovery of brain function after ischemic stroke through targeted neuromodulation, thus improving quality of life in stroke patients.