Abstract T P86: Paradoxical Motor Recovery From a First Stroke By Re-opening a Sensitive Period With a Second Stroke

Background and Purpose: After stroke, there is a time-limited period of increased responsiveness to training due to heightened plasticity, which is thought to be induced by ischemia itself. Using a mouse model we have previously shown that most training-associated recovery after a caudal forelimb area (CFA - rodent primary motor cortex) stroke occurs in the first week and is attributable to reorganization in the medial premotor area (also called agranular medial cortex - AGm). The idea of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and lead to paradoxically enhanced recovery from the first stroke. To test this prediction, we induced a second focal stroke in the medial premotor area of mice with incomplete recovery after a first focal stroke in CFA. Methods: C57Bl/6 mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance after which they underwent photocoagulation-induced stroke in CFA. After a 7 day post-stroke delay, the mice were then retrained for 21 days. A second photocoagulation-induced stroke was then induced in the medial premotor area and the mice were re-trained for 8 days after only a one-day delay. Results: Focal CFA stroke led to a decrement in skilled prehension. Training-associated recovery of prehension begun 7 days after stroke induction was incomplete even with 21 days of training. At post-stroke day 21, a second focal stroke in the medial premotor area was induced, which now led to a dramatic response to training with recovery to normal performance after 8 days of training. Conclusions: Together, these data indicate that new ischemia can re-open a sensitive period and mediate full recovery from a previous stroke. Future work will need to characterize what the critical molecular pathways are that ischemia triggers.