Browsing by Subject "Learning and memory"

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Eyelid conditioning in mice reveals an interaction between stress and familial Alzheimer's disease
(2019-09-19) Blevins, Cheasequah J.; Zemelman, Boris V.; Mauk, Michael D; Aldrich, Richard W; Harris, Kristen M; Messing, Robert O
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.
Investigating the interplay between early life stress, acute secondary pathogenesis, and chronic hippocampal impairments in young mice with traumatic brain injury
(2023-07-27) Parker, Kaila N.; Noble-Haeusslein, Linda J.; Curley, James P; Champagne, Frances A; Gore, Andrea C; Fonken, Laura K; Jones, Theresa A
While Traumatic brain injury (TBI) is the leading cause of disability in children, it is unclear how early life stress (ELS) may act as a determinant of long-term recovery in brain-injured children. A murine model of ELS preceding TBI at postnatal day (P)21 addressed the following: regionally specific acute pathogenesis of the hippocampus after ELS+TBI, are these early changes predictive of hippocampal damage and impairment at adulthood. Males and females were exposed to ELS (P2-9) with the limited bedding nestlet (LBN) model, randomized to TBI or sham, and euthanized at P22 or adulthood. At P22, ELISAs revealed an upregulation of IL1B, IL-6, TNFα, and IFNγ in both sexes after injury. ELS+TBI elevated IL-1B, IL-10, TNFα, and IFNγ in males compared to TBI. Iba-1 and caspase-3 were evaluated in hippocampal subregions. While TBI increased microglial density in both sexes, ELS+TBI increased microglial density in male CA2 and CA3 but only in the CA3 in females compared to TBI. Quantification of caspase-3 revealed apoptosis in males and females after TBI. ELS + TBI increased apoptosis in CA1 and CA3 in males and females compared to TBI. Adulthood learning and memory were assessed with the NOR and Barnes Maze. Compared to TBI, ELS+TBI reduced novelty preference in females and increased path length to target in both sexes. Hippocampal neuron loss after ELS+TBI was evaluated at adulthood. TBI significantly reduced neurons in all subregions; ELS+TBI reduced neurons in the CA1 region in females only. These findings highlight hippocampal vulnerability after ELS+TBI and ELS prior to a TBI may enhance acute pathogenesis in males. Correlation matrices determined hippocampal acute pathogenesis is predictive of neuronal loss at adulthood and is associated with learning and memory impairments. Males and females were assessed for all outcomes. Both sexes showed similar vulnerability to secondary pathogenesis following TBI and adulthood impairments in learning and memory; males showed greater vulnerability to acute pathogenesis and females showed greater vulnerability to adulthood outcomes. These findings may advocate for opportunities to tailor therapies specific to each sex. Thus, developing pre-clinical biomarkers to predict long-term recovery may continue to bolster care management.