Eyelid conditioning in mice reveals an interaction between stress and familial Alzheimer's disease




Blevins, Cheasequah J.

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Detailed behavioral analysis can provide valuable information on the underlying neural machinery supporting learning. An associative learning model called eyelid conditioning is often used to study mechanisms and modulatory processes governing cerebellar motor learning. Here, I implemented this task in head-fixed mice, then probed learning in two mouse models of Alzheimer Disease. Triple-transgenic (3xTg) animals expressing mutant Amyloid Precursor Protein, Presenilin-1 (PS1) and tau proteins were conditioned at ages ranging from 3-16 months. Mutants displayed more rapid learning compared to controls at all ages tested. Additionally, 3xTg mice produced greater acoustic startle. Both behavioral phenotypes are consistent with heightened stress response. On the other hand, mice harboring a single knock-in PS1 mutation aged ~16 months learned the task poorly compared to littermate controls. Enhanced conditioning was observed in aged PS1 knock-in mice only after prolonged social isolation stress. Together, these support the existence of two distinct phenotypes in mutant mice: one that is related to heightened stress response, perhaps resulting from mutant transgene overexpression (3xTg model), and one that is related to learning impairment, seen in the PS1 model. Separately, I compared the effects of chronic and acute stress on conditioning in wild-type mice. Both chronic social isolation and acute shock enhanced learning, but with distinct characteristics. Isolation increased the rate of learning while shock did not; shock altered the timing of the motor response while isolation did not. To assess cerebellum-intrinsic phenotypes due to chronic stress, I replaced the peripheral CS with in vivo electrical stimulation of mossy fibers that supply CS information to the cerebellum. This experiment sought to distinguish cerebellum-intrinsic vs. extrinsic mechanisms driving rapid learning. I found that isolation-induced differences in learning rate disappeared when using a mossy fiber CS. This indicates that rapid learning observed after isolation is driven by inputs arriving via mossy fibers. Unexpectedly, stressed animals conditioned with stimulation displayed altered response timing, with longer latency to onset than controls. This result suggests that the cerebellum may adapt to long-term changes in input strength and thus offers a clue to why acute stress alters the motor response, but chronic stress does not.



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