For each element of the t stack, the correlation values were computed for all the intensity-normalized frames in the z series. The frame in the z series with the greatest correlation to a given t series was taken to be the relative z position of that see more frame. Within-trial z motion was calculated by first subtracting the

z position of each frame within a trial from the mean z position across all the frames of that trial and then taking the SD of all mean subtracted values. Trial-to-trial z displacement was defined as the SD of the mean z position for each trial across all trials within a training session. We thank K. Osorio and J. Teran for animal training, D. Aronov for translation of Girman (1980), and S. Lowe for assistance with hardware fabrication.

This work was supported by NIH challenge grant number LY2109761 in vivo RC1NS068148 and by NIH grant number R21NS082956. “
“Alzheimer’s disease (AD) is the most common form of dementia in the elderly, with more than five million patients in the U.S. alone. The greatest known risk factor for AD is advanced age, with incidence doubling every decade after 60 years of age. The second greatest risk factor for AD is family history. Heritability for AD is estimated to be as high as 80% (Gatz et al., 2006). Early-onset familial AD (EO-FAD) can be caused by fully penetrant mutations in three genes, APP and the two presenilins (PSEN1 and PSEN2). The most well-established late-onset AD (LOAD) gene is apolipoprotein E (APOE), in which the ε4 variant increases risk by 3.7-fold (one copy) to >10-fold (two copies) ( Bertram et al., 2010). AD

is characterized by the cerebral neuronal loss and deposition of amyloid-β protein (Aβ) in senile plaques. Vast amounts of clinical and biochemical data, in addition to the four established AD genes, support the hypothesis that abnormal processing of APP and the accumulation of Adenylyl cyclase its metabolite, Aβ, play key roles in the etiology and pathogenesis of AD ( Hardy and Selkoe, 2002). APP is a type one transmembrane protein that can be processed into a variety of proteolytic fragments. Aβ, a 4-kDa-sized fragment, is generated via serial cleavage of APP by β-secretase (BACE1) at ectodomain and γ-secretase at intramembranous sites. In contrast, cleavage of APP at the juxtamembrane by α-secretase precludes Aβ generation. α- versus β-secretase cleavage of APP may also lead to different functional consequences. The secreted APP ectodomain generated by α-secretase, sAPPα, has neurotrophic and neuroprotective properties in vivo and in vitro (Mattson et al., 1993 and Ring et al., 2007). In contrast, the β-secretase-derived product sAPPβ is not as neuroprotective, and upon further processing, can render proapoptotic and neurodegenerative effects on neuronal cells (Nikolaev et al., 2009).