Stroke is a major cause of motor disability in veterans; Greater than 50% of stroke survivors continue to have motor deficits that limit independence. While a majority of past research has focused on how loss of descending pathways leads to loss of function, precisely what drives the emergence of abnormal flexor ‘synergies’ (gain of function with increased flexor tone) is not fully understood and there is also no specific treatment. Synergies in this context refers to abnormal coordinated activation of upper-limb muscles during reaching (i.e., flexor tone in shoulder & biceps and a closed hand). Consistent with observations in stroke patients, our preliminary data in mice reveals that increased flexor tone develops in a delayed manner and significantly alters reach-to-grasp. Using our model, we will test the specific hypothesis that the emergence of a delayed imbalance between the contralesional and ipsilesional corticoreticular pathways is associated with onset of flexor tone. We will use viral methods to label cortical projection pathways (premotor to the pontomedullary reticular formation, PMRF) and then track projection activity over recovery after experimental stroke. Our proposed specific aims will test this hypothesis using long-term pathway specific tracking as well as test two promising interventions to reduce flexor tone. The first aim is to determine if increased activity of the contralesional corticoreticular pathway together with reduced ipsilesional corticoreticular activity predicts delayed onset of increased flexor tone. In the second aim we will test if low frequency ipsilesional motor thalamus stimulation in chronic stroke can reduce flexor tone and improve reach to grasp function. This approach is based on our extensive data that low-frequency patterning is beneficial for cortical-subcortical communication. Our third aim is to test whether a novel class of small molecules that activate neurotrophin receptors can reduce flexor tone. Completion of these aims will provide critical information for designing therapeutic approaches that specifically target abnormal flexor synergies after stroke. Importantly, they will also provide important information about two promising therapeutic options to improve function.