Adaptation of the circular platform spatial memory task for mice: use in detecting cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease.
A methodology is described for use of a 16-hole circular platform task to test spatial memory in mice. Both bright light and a fan were used to motivate mice to escape the platform surface through a single hole containing an attached escape box. For each daily trial, three correlated measures (escape latency, number of errors, and error rating) comprehensively evaluated cognitive performance. In an initial study, the 'spatial' nature of this task was demonstrated by the much poorer performance of non-transgenic mice when visual cues are removed. Behavioral sensitivity of the circular platform task was then shown through its ability to discern cognitive impairment in 7-month-old transgenic mice, carrying the mutant APP(SW) gene for early-onset Alzheimer's disease in humans, from non-transgenic litter-mates. Since there are currently only a few tasks available to definitively test cognitive performance in mice, the circular platform task offers a versatile, multiple-measure option with numerous advantages. Particularly in view of the increasing number of genetically manipulated mouse models being produced, the circular platform task should be most useful in providing a sensitive evaluation of cognition in mice.
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Effect of traumatic brain injury on mouse spatial and nonspatial learning in the Barnes circular maze.
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https://www.ncbi.nlm.nih.gov/pubmed/?term=9872460
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Controlled cortical impact (CCI) is a relatively new model of traumatic brain injury in the mouse, which, in combination with behavioral and histological methods, has potential for elucidating underlying mechanisms of neurodegeneration using genetically altered animals. Previously, we have demonstrated impaired spatial learning in a water maze task following CCI injury at a moderate level. There are many difficulties associated with this task, however, such as stress, physical demand, and the multiple trials over days required for satisfactory training. As a potential alternative to the water maze, we adapted the Barnes circular maze to our mouse model and assessed spatial/nonspatial learning following injury. Mice were trained to locate a dark tunnel, hidden beneath one of 40 holes positioned around the perimeter of a large, flat, plastic disk, brightly illuminated by four overhead halogen lamps. Sham-operated animals rapidly acquired this task, exhibiting reduced latency to find the tunnel and a more efficient search strategy as compared with injured mice. This difference was not due to visuomotor deficits, as all mice performed equally well in a cued version of the same task. These results demonstrate spatial learning impairment following CCI injury in a task that offers an efficient alternative to the water maze.
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Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency.
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https://www.ncbi.nlm.nih.gov/pubmed/?term=7781067
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We assessed hippocampal-dependent memory in mice with a Ca(2+)-independent form of CaMKII generated by the introduction of an aspartate at amino acid 286. The CaMKII-Asp-286 mice show normal LTP at high frequency stimulation, but in the 5-10 Hz range, they show a shift in the frequency-response curve favoring LTD. This range of frequencies is similar to the theta rhythm, which is associated with exploration in rodents. Using the Barnes maze to assess spatial memory, we found the transgenic mice could not learn to navigate to a specific location using spatial cues. In contrast, one line of transgenic mice performed normally in contextual fear conditioning, a task that is also hippocampal dependent. This dissociation between spatial and contextual memory suggests that even though both require the hippocampus, they may be mediated by different synaptic mechanisms.
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Cognitive deficits develop 1month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge.
Traumatic brain injury (TBI) elicits immediate neuroinflammatory events that contribute to acute cognitive, motor, and affective disturbance. Despite resolution of these acute complications, significant neuropsychiatric and cognitive issues can develop and progress after TBI. We and others have provided novel evidence that these complications are potentiated by repeated injuries, immune challenges and stressors. A key component to this may be increased sensitization or priming of glia after TBI. Therefore, our objectives were to determine the degree to which cognitive deterioration occurred after diffuse TBI (moderate midline fluid percussion injury) and ascertain if glial reactivity induced by an acute immune challenge potentiated cognitive decline 30 days post injury (dpi). In post-recovery assessments, hippocampal-dependent learning and memory recall were normal 7 dpi, but anterograde learning was impaired by 30 dpi. Examination of mRNA and morphological profiles of glia 30 dpi indicated a low but persistent level of inflammation with elevated expression of GFAP and IL-1β in astrocytes and MHCII and IL-1β in microglia. Moreover, an acute immune challenge 30 dpi robustly interrupted memory consolidation specifically in TBI mice. These deficits were associated with exaggerated microglia-mediated inflammation with amplified (IL-1β, CCL2, TNFα) and prolonged (TNFα) cytokine/chemokine expression, and a marked reactive morphological profile of microglia in the CA3 of the hippocampus. Collectively, these data indicate that microglia remain sensitized 30 dpi after moderate TBI and a secondary inflammatory challenge elicits robust microglial reactivity that augments cognitive decline.Traumatic brain injury (TBI) is a major risk factor in development of neuropsychiatric problems long after injury, negatively affecting quality of life. Mounting evidence indicates that inflammatory processes worsen with time after a brain injury and are likely mediated by glia. Here, we show that primed microglia and astrocytes developed in mice 1 month following moderate diffuse TBI, coinciding with cognitive deficits that were not initially evident after injury. Additionally, TBI-induced glial priming may adversely affect the ability of glia to appropriately respond to immune challenges, which occur regularly across the lifespan. Indeed, we show that an acute immune challenge augmented microglial reactivity and cognitive deficits. This idea may provide new avenues of clinical assessments and treatments following TBI.
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Does the radial arm maze necessarily test spatial memory?
Since its design 25 years ago (Olton & Samuelson, 1976), the eight-arm radial maze has become very popular and is now widely used to assess spatial memory in rodents. Two versions of the full-baited maze protocol are present in the literature: with or without confinement between the visit of each arm. The confinement was introduced by Olton himself as early as 1977 (Olton, Collison, & Werz, 1977) to eliminate stereotypic behaviors that he had previously observed. It is widely regarded that the confinement prevents rodents from developing these response patterns, and as such it is considered an improved procedure to test spatial memory. Surprisingly, to the best of our knowledge, no study has been especially designed to demonstrate the efficacy of the confinement in blocking the stereotypic behaviors of the animals. The present study compares the strategies of rats trained with or without a confinement procedure. The results show that, after nine days of training, rats submitted to a 5- or a 10-s confinement reach the same level of performance as rats without confinement. The confinement totally prevents stereotypic behaviors like clockwise serial searching strategies which are often observed without confinement. Even a 0-s confinement is sufficient to prevent clockwise strategies, but rats seem to develop other stratagems which do not imply spatial memory. Furthermore, rats previously trained without confinement are unable to perform the task when confinement is introduced on a test day. In contrast, rats previously trained with confinement perform the task correctly when the confinement is no longer present. Thus, without confinement, good levels of performance can be achieved without precise spatial representations.
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Value of water mazes for assessing spatial and egocentric learning and memory in rodent basic research and regulatory studies.
Maneuvering safely through the environment is central to survival of all animals. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and sometimes proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures (e.g., subiculum); in humans this system encodes declarative memory (allocentric, semantic, and episodic, i.e., memory for people, places, things, and events). This form of memory is assessed in laboratory animals by many methods, but predominantly the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned becomes implicit or procedural memory. Several allocentric methods for rodents are reviewed and compared with the MWM with particular focus on the Cincinnati water maze (CWM). MWM advantages include minimal training, no food deprivation, ease of testing, reliable learning, insensitivity to differences in body weight and appetite, absence of non-performers, control methods for performance effects, repeated testing capability and other factors that make this test well-suited for regulatory studies. MWM limitations are also reviewed. Evidence-based MWM design and testing methods are presented. On balance, the MWM is arguably the preferred test for assessing learning and memory in basic research and regulatory studies and the CWM is recommended if two tests can be accommodated so that both allocentric (MWM) and egocentric (CWM) learning and memory can be effectively and efficiently assessed.
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Value of water mazes for assessing spatial and egocentric learning and memory in rodent basic research and regulatory studies.
Smith Douglas H., Hicks Ramona R., Johnson Victoria E., Bergstrom Debra A., Cummings Diana M., Noble Linda J., Hovda David, Whalen Michael, Ahlers Stephen T., LaPlaca Michelle, Tortella Frank C., Duhaime Ann-Christine, and Dixon C. Edward. Journal of Neurotrauma. -Not available-, ahead of print. doi:10.1089/neu.2014.3861.
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Johnson, S.B., Whitney, G., McAuliffe, M., Wang, H., McCreedy, E., Rozenblit, L., and Evans, C.C. (2010). Using Global Unique identifiers to link autism collections. J. Am. Med. Inform. Assoc., in press. Published online July 17, 2010. 10.1136/jamia.2009.002063.
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Aurlie Jean, Michelle K. Nyein, James Q. Zheng, David F. Moore, John D. Joannopoulos and Ral Radovitzky, An animal-to-human scaling law for blast-induced traumatic brain injury risk assessment, 2014, PNAS, http://www.pnas.org/content/111/43/15310. Ye Xiong, Asim Mahmood and Michael Chopp, Animal models of traumatic brain injury, 2013 Macmillan Publishers Limited. All rights reserved
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Alexander MS, Biering-Sorensen F, Elliott S, Kreuter M, Saanksen J. International Spinal Cord Injury Female Sexual and Reproductive Function Basic Data Set. Spinal Cord. 2011 Jul;49(7):787-90. Alexander MS, Biering-Sorensen F, Elliott S, Kreuter M, Saanksen J. International Spinal Cord Injury Male Sexual Function Basic Data Set. Spinal Cord. 2011 Jul;49(7):795-8.
Bauman WA, Biering-Sorensen F, Krassioukov A. International spinal cord injury endocrine and metabolic function basic data set. Spinal Cord. 2011 Oct;49(10):1068-72.
Biering-Sorensen F, Craggs M, Kennelly M, Schick E, Wyndaele JJ. International Lower Urinary Tract Function Basic Spinal Cord Injury Data Set. Spinal Cord 2008 May;46(5):325-30.
Krogh K, Perkash I, Stiens SA, Biering-Sorensen F. International bowel function extended spinal cord injury data set. Spinal Cord. 2009 Mar;47(3):235-41.
Widerstraam-Noga E, Biering-Sorensen F, Bryce T, Cardenas DD, Finnerup NB, Jensen MP, Richards JS, Siddall PJ. The international spinal cord injury pain basic data set. Spinal Cord. 2008 Dec;46(12):818-23.