A rapidly acquired foraging-based working memory task, sensitive to hippocampal lesions, reveals age-dependent and age-independent behavioural changes in a mouse model of amyloid pathology.
TL;DR: Novel insight is provided into the role of the hippocampus and the effects of APP overexpression on memory and search behaviour in an open‐field foraging task in PDAPP mice.
About: This article is published in Neurobiology of Learning and Memory.The article was published on 2018-03-01 and is currently open access. It has received 7 citations till now. The article focuses on the topics: Working memory.
Summary (3 min read)
Jump to: [Introduction] – [Subjects:] – [Surgery:] – [Cresyl violet staining:] – [Apparatus:] – [Scoring] – [Statistical Analysis] – [Histology:] – [Discussion] – [Lesion Area Mean % Area] and [FIGURES:]
Introduction
- Spatial working memory tasks, such as the radial arm maze and Barnes maze, often take advantage of rodent’s natural propensity to forage for food.
- Pigeons were placed in a large open field area and presented with eight food-baited pots, each in different spatial location.
- The authors hypothesised that mice with hippocampal lesions would show increased working memory errors, i.e., return visits to depleted pots.
- Finally, Experiment 3 examined whether foraging behaviour was disrupted in PDAPP mice over the course of ageing.
Subjects:
- Thirteen mice received bilateral HPC excitotoxic lesions and 13 received control (SHAM) surgery (as described below).
- The same mice were tested at ages 6-8, 10-12 and 14-16 months of age to ascertain any age-dependent changes in performance in PDAPP mice.
- The cage floors were covered in sawdust, approximately 1cm deep, and contained a cardboard tube, wooden gnawing block and approved nesting material.
- Holding rooms were maintained at a stable temperature and relative humidity levels at around 21oC ± 2oC and 60 ± 10% respectively.
- All animals were health-checked weekly and maintained according to UK Home Office and EU regulations and the Animal Scientific Procedures Act (1986).
Surgery:
- Mice were anaesthetised with Isoflurane [2-chloro-2- -1, 1, 1- trifluoro- ] in O2 during stereotaxic surgery.
- A bone flap was removed overlying the infusion sites in each hemisphere (see Table 1A).
- Mice were also provided with sweetened porridge for 24 hrs.
- The brain was then extracted and post-fixed in 4% PFA at room temperature (RTP) for 6 hours before being transferred to 30% reagent grade sucrose in dH2O.
- Slides were left to dry for 48 hours prior to staining.
Cresyl violet staining:
- Staining of coronal sections was carried out by immersing slides in xylene for 4 minutes before immersion into descending concentrations of ethanol (100% 90% 70%) for 2 minutes per ethanol concentration.
- Slides were then immersed in dH2O for 2 minutes before 0.005% Cresyl violet was applied for 3 minutes.
- Sections were then imaged using a Leica DMRB microscope and images were captured using an Olympus DP70 camera and assessed using the programme analySIS-D. Lesion size.
- Ventral hippocampus was defined as starting from 2.54mm posterior to bregma as described by Paxinos and Franklin (2004).
Apparatus:
- All training and testing was carried out in a quiet testing room.
- The same arena was used for all experiments in this study.
- During initial training, mice were removed from their home cage and placed into an identical home cage with sawdust bedding together with one ceramic pot placed in the centre of the cage, for three successive trials separated by a 5-minute inter-trial-interval.
- During these sessions the arena was set up with six pots arranged in a circular shape, each 20cm apart .
- The pots were then wiped clean with 70% ethanol wipes and the milk solution replenished before the next mouse was tested.
Scoring
- A score of foraging behaviour was defined as a mouse jumping onto the rim of a pot and directing its nose in toward the bottom to consume a reward.
- As total error incorporated all types of errors made within the trial, the repeat error was able to provide a measure of within-trial memory for foraged pots that was independent of perseverative approach behaviours.
- The order in which the pots were visited was recorded.
- This measure assessed the extent to which chaining responses (such as circling behaviour) mediated task performance.
- In Experiment 3, PDAPP and WT mice were tested using the same procedure described above.
Statistical Analysis
- Data was analysed using Microsoft Excel for calculation of mean number of errors, times and standard error of the mean.
- IBM SPSS Statistics software was used to analyse all data statistically.
- Effect sizes were reported for all statistics: Cohen’s d (d) was calculated for independent sample t-tests, partial eta-squared (ηp2) for ANOVA analysis, Cohen’s r value for Mann-Whitney U tests (r) and Kendall’s W for Friedman tests (Cohen 1973, 1988; Fritz et al. 2012; Tomczak & TomcZak 2014).
- The data were checked for violations of distribution and homogeneity of variance by Shapiro-Wilk test and Levene’s test respectively.
- Therefore, data that violated these tests were subjected to transformation (i.e. square root, log-10) based on the level of positive/negative skew and reassessed.
Histology:
- An example of the maximum and minimum tissue damage obtained as a result of excitotoxic lesions are displayed in Figure 2 respectively.
- An analysis of these scores revealed that HPC lesioned mice had a significantly higher ratio of error scores in neighbouring pots compared to SHAM controls, t(22)=-2.14, p=0.044, d=0.13.
Discussion
- This study used a procedurally simple open-field uninterrupted foraging task to evaluate the role of the hippocampus (HPC) in both spatial and non-spatial working memory (SWM).
- PDAPP mice also displayed an age-independent deficit in non-spatial search strategies in the Barnes maze from 3-5 months of age (Huitrón-Reséndiz et al. 2002).
- Olton, D.S. & Werz, M.A. (1978) Hippocampal function and behavior: Spatial discrimination and response inhibition.
Lesion Area Mean % Area
- Errors are defined and examples of when these errors are Error Measurement Definition Example of behaviour Total Error A mouse returning to a pot where the reward was previously consumed.
- The mouse then forages in pot B before foraging in pot A Distal pot error A mouse making an error in a pot one or more distant from a pot it has just foraged or made an error in.
- There were no significant group differences within trials.
FIGURES:
- Illustration of the pot locations during training and test periods, also known as Figure 1.
- (A) Two pots placed opposite each other in the arena-training phase.
- (B) Six pots are placed in a radial formation for the test phase of the foraging task.
- (C) Novel pot designs used in experiment 2.
- Position of the pots was changed each day, but the radial formation remained.
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Figures (5)
Table 5. Table showing the mean (and SEM) of the number of perseverative errors and chaining responses in the foraging task made by HPC lesion mice (n=11) and SHAM controls (n=13; Experiment 1 and 2) and WT (n=15) and PDAPP mice (n=14; Experiment 3). Numbers in bold represent significant differences in between group comparisons. 
Figure 3: Foraging behaviour in control mice and mice with HPC lesions. Measures of SWM in SHAM control (n=13) and HPC lesion mice (n=11). A) Total number of errors. B) Total number of repeat errors. C) The ratio of neighbouring and distal errors to total errors made. *p<0.05. Data were averaged across four trials for each mouse and mean score for each group is reported. Error bars represent the S.E.M. 
Figure 2. Reconstruction of the minimal (A) and maximal (B) extent of bilateral hippocampal lesions through coronal sections through the brain. Coordinates represent distance from bregma in mm. 
Figure 4: Foraging behaviour in mice with HPC lesions. Measures of SWM in SHAM control (n=13) and HPC lesion mice (n=11). A) Total number of errors. B) Total number of repeat errors. C) The ratio of neighbouring and distal errors to total errors made. **p<0.01. Data were averaged across four trials for each mouse and mean score for each group is reported. Error bars represent the S.E.M. 
Figure 5: Foraging behaviour and SWM performance in PDAPP (n=14) and WT control mice (n=15). Data were averaged across four trials for each mouse and mean score for each group is reported. Error bars represent the S.E.M. A) Total number of errors. B) Total number of repeat errors. C) The ratio of neighbouring and distal errors to total errors made. *p<0.05
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...A full description of errors can be found in Evans (2018)....
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References
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TL;DR: It is shown that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations, which indicates that Aβ overexpression and/or Aβ plaques are associated with disturbed cognitive function and suggests that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.
Abstract: Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive beta-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with beta-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that A beta overexpression and/or A beta plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.
787 citations
"A rapidly acquired foraging-based w..." refers background or methods in this paper
...Altered foraging responses and escape strategies have previously been reported in HPC lesioned mice and transgenic models of amyloid pathology, including PDAPP mice (Olton & Werz 1978; Chen et al. 2000; Huitrón-Reséndiz et al. 2002; Janus 2004)....
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...Indeed, a similar pattern of age-dependent and independent spatial memory deficits in PDAPP mice has also been reported using a serial position watermaze task (Chen et al., 2000; Daumas et al., 2008)....
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...Indeed, a similar pattern of age-dependent and independent spatial memory deficits in PDAPP mice has also been reported using a serial position watermaze task (Chen et al. 2000; Daumas et al. 2008)....
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Abstract: Recent years have witnessed a growing number of published reports that point out the need for reporting various effect size estimates in the context of null hypothesis testing (H0) as a response to a tendency for reporting tests of statistical significance only, with less attention on other important aspects of statistical analysis. In the face of considerable changes over the past several years, neglect to report effect size estimates may be noted in such fields as medical science, psychology, applied linguistics, or pedagogy. Nor have sport sciences managed to totally escape the grips of this suboptimal practice: here statistical analyses in even some of the current research reports do not go much further than computing p-values. The p-value, however, is not meant to provide information on the actual strength of the relationship between variables, and does not allow the researcher to determine the effect of one variable on another. Effect size measures serve this purpose well. While the number of reports containing statistical estimates of effect sizes calculated after applying parametric tests is steadily increasing, reporting effect sizes with non-parametric tests is still very rare. Hence, the main objectives of this contribution are to promote various effect size measures in sport sciences through, once again, bringing to the readers’ attention the benefits of reporting them, and to present examples of such estimates with a greater focus on those that can be calculated for non-parametric tests
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...Effect sizes were reported for all statistics: Cohen’s d (d) was calculated for independent sample t-tests, partial eta-squared (ηp2) for ANOVA analysis, Cohen’s r value for Mann-Whitney U tests (r) and Kendall’s W for Friedman tests (Cohen 1973, 1988; Fritz et al. 2012; Tomczak & TomcZak 2014)....
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...value for Mann-Whitney U tests ( r) and Kendall’s W for Friedman tests (Cohen 1973, 1988; Fritz et al. 2012; Tomczak & TomcZak 2014)....
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"A rapidly acquired foraging-based w..." refers background in this paper
...Mice typically exhibit win-shift foraging behaviours, whereby they explore previously un-entered arms in favour of those already entered (Hyde, Hoplight, & Denenberg, 1998; Anagnostaras et al., 2003)....
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...Mice typically exhibit win-shift foraging behaviours, whereby they explore previously un-entered arms in favour of those already entered (Hyde et al. 1998; Anagnostaras et al. 2003)....
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