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
Citations
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Cites background from "A rapidly acquired foraging-based w..."
...A full description of errors can be found in Evans (2018)....
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References
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TL;DR: Spatial working memory is less impaired in aMCI while reference memory is similarly damaged in AD, and more severe spatial reference memory deficit is a neuropsychological marker for AD conversion.
Abstract: Objective This study aims to apply the virtual radial arm maze (VRAM) task to find spatial working memory and reference memory impairments in patients of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Spatial memory functions between aMCI converters and nonconverters are also compared using VRAM results. Methods We assessed the spatial memory in 20 normal controls, 20 aMCI, and 20 mild AD subjects using VRAM. The Mini-Mental State Examination, Clinical Dementia Rating scale, and other neuropsychological tests were given to the subjects in conjunction with the VRAM test. Scores in working memory errors and reference memory errors were compared among the three groups using repeated measures analysis of variance. In addition, aMCI patients were followed-up after 5 years and surveyed for AD conversion rate. Results In AD patients, both spatial working and reference memory were impaired. However, in aMCI subjects, only spatial reference memory was impaired. Significant spatial reference memory impairment was found in the aMCI converter group when compared to the nonconverter group. Conclusion Spatial working memory is less impaired in aMCI while reference memory is similarly damaged in AD. In aMCI patients, more severe spatial reference memory deficit is a neuropsychological marker for AD conversion. VRAM may be well utilized in humans to assess spatial memory in normal aging, in aMCI, and in AD.
34 citations
"A rapidly acquired foraging-based w..." refers background in this paper
...For example, formal assessment of navigation strategies in patients indicates an early decline in path integration and allocentric memory pr cesses in tasks analogues to the watermaze and the radial maze (Laczó et al. 2010; Lee et al. 2014; Mokrisova et al. 2016)....
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TL;DR: This study demonstrates that rodents select exploratory actions according to a novelty management framework and suggests a plausible mechanism by which mammalian exploration primitives can be learned during development and integrated in adult exploration of complex environments.
Abstract: When encountering novel environments, animals perform complex yet structured exploratory behaviors. Despite their typical structuring, the principles underlying exploratory patterns are still not sufficiently understood. Here we analyzed exploratory behavioral data from two modalities: whisking and locomotion in rats and mice. We found that these rodents maximized novelty signal-to-noise ratio during each exploration episode, where novelty is defined as the accumulated information gain. We further found that these rodents maximized novelty during outbound exploration, used novelty-triggered withdrawal-like retreat behavior, and explored the environment in a novelty-descending sequence. We applied a hierarchical curiosity model, which incorporates these principles, to both modalities. We show that the model captures the major components of exploratory behavior in multiple timescales: single excursions, exploratory episodes, and developmental timeline. The model predicted that novelty is managed across exploratory modalities. Using a novel experimental setup in which mice encountered a novel object for the first time in their life, we tested and validated this prediction. Further predictions, related to the development of brain circuitry, are described. This study demonstrates that rodents select exploratory actions according to a novelty management framework and suggests a plausible mechanism by which mammalian exploration primitives can be learned during development and integrated in adult exploration of complex environments.
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"A rapidly acquired foraging-based w..." refers background or methods in this paper
...The use of an unconstrained procedure can provide insights into the structure of mouse behaviour (c.f., Fonio et al., 2009; Benjamini et al., 2011), the underlying brain circuitry (Gordon et al., 2014) and thus the impact of disease on brain function....
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..., 2011), the underlying brain circuitry (Gordon et al., 2014) and thus the impact of disease on brain function....
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TL;DR: It is found that amyloid precursor protein (APP) mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 h later.
Abstract: Impaired spatial memory characterizes many mouse models for Alzheimer's disease, but we understand little about how this trait arises. Here, we use a transgenic model of amyloidosis to examine the relationship between behavioral performance in tests of spatial navigation and the function of hippocampal place cells. We find that amyloid precursor protein (APP) mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 h later. At a single cell level, place fields from control mice become more stable and spatially restricted with repeated exposure to a new environment, while those in APP mice improve less over time, ultimately producing a spatial code of lower resolution, accuracy, and reliability than controls. The limited refinement of place fields in APP mice likely contributes to their delayed water maze acquisition, and provides evidence for circuit dysfunction underlying cognitive impairment.
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"A rapidly acquired foraging-based w..." refers background in this paper
...For example, hippocampal place cells in amyloid precursor protein (APP) transgenic mice show reduced spatial resolution (Cacucci et al. 2008; Zhao et al. 2014) and mice expressing human tau mutations show disrupted grid cell activity (Fu et al., 2017); similar to individuals possessing an APOE4…...
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TL;DR: While little difference is found in the basic properties of space representation in these two species, it appears that the stability of this representation changes more drastically over time in mice than in rats.
Abstract: The increasing use of mice models in cognitive tasks that were originally designed for rats raises crucial questions about cross-species comparison in the study of spatial cognition. The present review focuses on the major neuroethological differences existing between mice and rats, with particular attention given to the neurophysiological basis of space coding. While little difference is found in the basic properties of space representation in these two species, it appears that the stability of this representation changes more drastically over time in mice than in rats. We consider several hypotheses dealing with attentional, perceptual, and genetic aspects and offer some directions for future research that might help in deciphering hippocampal function in learning and memory processes. WIREs Cogn Sci 2016, 7:406-421. doi: 10.1002/wcs.1411 For further resources related to this article, please visit the WIREs website.
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"A rapidly acquired foraging-based w..." refers background in this paper
...For example, mice tend to show less stable place fields and subtle differences in navigational strategies to solve similar tasks, such as the watermaze (see rview by Hok et al., 2016)....
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TL;DR: In this paper, the authors examined the involvement of the hippocampus in short-term changes in exploratory behavior in an open field (Experiment 1) and experimental contexts (experiment 2) and found that rats with excitotoxic lesions were more likely to revisit recently visited zones within the open field than were control rats.
Abstract: We examined the involvement of the hippocampus in short-term changes in exploratory behaviour in an open field (Experiment 1) and experimental contexts (Experiment 2). In Experiment 1, rats with excitotoxic lesions of the hippocampus were more likely to revisit recently visited zones within the open field than were control rats. Similarly, in Experiment 2 rats with hippocampal lesions showed greater exploration of a context that they had recently explored than a context that they had less recently explored. This short-term sensitization effect was not evident in control rats. These findings are consistent with the suggestion that the recent presentation of a stimulus has two opposing effects on behaviour, sensitization, and habituation, and that hippocampal lesions disrupt the short-term process responsible for habituation, but not that responsible for sensitization.
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