Vulnerability Of Mice Research Articles

Low-stress Route Learning Using the Lashley III Maze in Mice

Many behavior tests designed to assess learning and memory in rodents, particularly mice, rely on visual cues, food and/or water deprivation, or other aversive stimuli to motivate task acquisition. As animals age, sensory modalities deteriorate. For example, many strains of mice develop hearing deficits or cataracts. Changes in the sensory systems required to guide mice during task acquisition present potential confounds in interpreting learning changes in aging animals. Moreover, the use of aversive stimuli to motivate animals to learn tasks is potentially confounding when comparing mice with differential sensitivities to stress. To minimize these types of confounding effects, we have implemented a modified version of the Lashley III maze. This maze relies on route learning, whereby mice learn to navigate a maze via repeated exposure under low stress conditions, e.g. dark phase, no food/water deprivation, until they navigate a path from the start location to a pseudo-home cage with 0 or 1 error(s) on two consecutive trials. We classify this as a low-stress behavior test because it does not rely on aversive stimuli to encourage exploration of the maze and learning of the task. The apparatus consists of a modular start box, a 4-arm maze body, and a goal box. At the end of the goal box is a pseudo-home cage that contains bedding similar to that found in the animal's home cage and is specific to each animal for the duration of maze testing. It has been demonstrated previously that this pseudo-home cage provides sufficient reward to motivate mice to learn to navigate the maze. Here, we present the visualization of the Lashley III maze procedure in the context of evaluating age-related differences in learning and memory in mice along with a comparison of learning behavior in two different background strains of mice. We hope that other investigators interested in evaluating the effects of aging or stress vulnerability in mice will consider this maze an attractive alternative to behavioral tests that involve more stressful learning tasks and/or visual cues.

Overexpression of SK2 Channels Enhances Efferent Suppression of Cochlear Responses Without Enhancing Noise Resistance

Cochlear hair cells express SK2, a small-conductance Ca(2+)-activated K(+) channel thought to act in concert with Ca(2+)-permeable nicotinic acetylcholine receptors (nAChRs) alpha9 and alpha10 in mediating suppressive effects of the olivocochlear efferent innervation. To probe the in vivo role of SK2 channels in hearing, we examined gene expression, cochlear function, efferent suppression, and noise vulnerability in mice overexpressing SK2 channels. Cochlear thresholds, as measured by auditory brain stem responses and otoacoustic emissions, were normal in overexpressers as was overall cochlear morphology and the size, number, and distribution of efferent terminals on outer hair cells. Cochlear expression levels of SK2 channels were elevated eightfold without striking changes in other SK channels or in the alpha9/alpha10 nAChRs. Shock-evoked efferent suppression of cochlear responses was significantly enhanced in overexpresser mice as seen previously in alpha9 overexpresser mice; however, in contrast to alpha9 overexpressers, SK2 overexpressers were not protected from acoustic injury. Results suggest that efferent-mediated cochlear protection is mediated by other downstream effects of ACh-mediated Ca(2+) entry different from those involving SK2-mediated hyperpolarization and the associated reduction in outer hair cell electromotility.

Involvement of superoxide in excitotoxicity and DNA fragmentation in striatal vulnerability in mice after treatment with the mitochondrial toxin, 3-nitropropionic acid.

Oxidative stress and excitotoxicity have been implicated in selective striatal vulnerability caused by the mitochondrial toxin, 3-nitropropionic acid (3-NP), which may simulate Huntington's disease in animals and humans. The detailed mechanism of the role of superoxide in striatal vulnerability induced by 3-NP is still unknown. The authors investigated oxidative cellular injury and DNA fragmentation after systemic 3-NP injection in wild-type (Wt) mice and mutant mice with a deficiency in manganese superoxide dismutase (MnSOD; Sod2 -/+). Furthermore, they investigated the effects of decortication after 3-NP treatment in Sod2 -/+ mice, and copper/zinc SOD (CuZnSOD) treatment in recently developed Sod2 -/+ mice that overexpress CuZnSOD (SOD1 +/- / Sod2 -/+ mice). Oxidized hydroethidine, 8-hydroxyguanosine immunoreactivity, and nitrotyrosine immunoreactivity were increased in the Sod2 -/+ mice compared with the Wt mice after 3-NP treatment (P < 0.001). Decortication completely abolished oxidative striatal damage after 3-NP treatment in the Sod2 -/+ mice. Increased CuZnSOD attenuated DNA fragmentation and striatal lesion volume after 3-NP treatment in the Sod2 -/+ mice (P < 0.001). These data suggest that production of superoxide may be a critical step to excitotoxicity and subsequent DNA fragmentation in selective striatal vulnerability after 3-NP treatment.

Expression of human apolipoprotein E downregulates amyloid precursor protein-induced ischemic susceptibility.

Epidemiological findings and experimental data on transgenic mice show that Alzheimer's disease-related changes render the brain more susceptible to ischemic damage. We studied whether the previously observed vulnerability in mice overexpressing the 751-amino-acid isoform of human amyloid precursor protein (APP751) is regulated by human apolipoprotein E (apoE) alleles, which determine the relative risk for Alzheimer's disease and the susceptibility to various forms of acute brain damage. Aged apoE knock out (KO) mice, mice overexpressing APP751 in the apoE KO background and mice expressing either human apoE3 or apoE4 and APP751 in the apoE KO background were exposed to permanent occlusion of the middle cerebral artery (MCA). Infarct volumes were quantified from T2-weighted magnetic resonance images 24 hours after the MCA occlusion. Local cortical blood flow was monitored by laser Doppler flowmetry. Ischemia-induced microgliosis was detected by immunohistochemistry. Overexpression of human APP751 significantly increased the infarct volumes in apoE KO mice. Furthermore, this APP751-induced ischemic vulnerability was attenuated by the coexpression of either human apoE isoform. MCA occlusion resulted in a similar relative reduction in cortical blood flow in all mouse groups. Vascular anatomy showed no variation in the MCA territory between the groups. Instead, the expression of human apoE isoforms reduced the ischemia-induced microgliosis. Expression of either the human apoE3 or apoE4 isoform protects against the increased ischemic vulnerability observed in aged mice overexpressing human APP751, probably by modulating the inflammatory response induced by MCA occlusion.