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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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: PI is affected in aMCI and AD, possibly as a function of neurodegeneration in the medial temporal lobe structures and the parietal cortex and may be useful for identification of patients with incipient AD.
46 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 processes in tasks analogues to the watermaze and the radial maze (Laczó et al., 2010; Lee, Kho, Yoo, Park, & Choi, 2014; Mokrisova et al., 2016)....
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...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: It is demonstrated that individuals with DS are impaired at using an AS representation to learn and remember discrete locations in a controlled environment, suggesting persistent and pervasive deficits in hippocampus-dependent memory in DS.
Abstract: Studies have shown that persons with Down Syndrome (DS) exhibit relatively poor language capacities, and impaired verbal and visuoperceptual memory, whereas their visuospatial memory capacities appear comparatively spared. Individuals with DS recall better where an object was previously seen than what object was previously seen. However, most of the evidence concerning preserved visuospatial memory comes from tabletop or computerized experiments which are biased towards testing egocentric (viewpoint-dependent) spatial representations. Accordingly, allocentric (viewpoint-independent) spatial learning and memory capacities may not be necessary to perform these tasks. Thus, in order to more fully characterize the spatial capacities of individuals with DS, allocentric processes underlying real-world navigation must also be investigated. We tested 20 participants with DS and 16 mental age-matched, typically developing (TD) children in a real-world, allocentric spatial memory task. During local cue (LC) trials, participants had to locate three rewards marked by local color cues, among 12 locations distributed in a 4 m X 4 m arena. During allocentric spatial (AS) trials, participants had to locate the same three rewards, in absence of local cues, based on their relations to distal environmental cues. All TD participants chose rewarded locations in LC and AS trials at above chance level. In contrast, although all but one of the participants with DS exhibited a preference for the rewarded locations in LC trials, only 50% of participants with DS chose the rewarded locations at above chance level in AS trials. As a group, participants with DS performed worse than TD children on all measures of task performance. These findings demonstrate that individuals with DS are impaired at using an allocentric spatial representation to learn and remember discrete locations in a controlled environment, suggesting persistent and pervasive deficits in hippocampus-dependent memory in DS.
44 citations
"A rapidly acquired foraging-based w..." refers background in this paper
...In addition, foraging for rewards in an open field arena has revealed deficits in allocentric memory in patients with Down syndrome, who are at increased risk of developing dementia (Lavenex et al. 2015)....
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...locentric memory in patients with Down syndrome, who are at increased risk of developing dementia (Lavenex et al., 2015)....
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TL;DR: It is shown that the synaptic dynamics in the recurrent neural network rapidly modify the discharge correlates of the place cells: Cells tend to become omnidirectional place cells in open fields, while their directionality tends to get stronger in radial‐arm mazes.
Abstract: We propose a computational model of the CA3 region of the rat hippocampus that is able to reproduce the available experimental data concerning the dependence of directional selectivity of the place cell discharge on the environment and on the spatial task. The main feature of our model is a continuous, unsupervised Hebbian learning dynamics of recurrent connections, which is driven by the neuronal activities imposed upon the network by the environment-dependent external input. In our simulations, the environment and the movements of the rat are chosen to mimic those commonly observed in neurophysiological experiments. The environment is represented as local views that depend on both the position and the heading direction of the rat. We hypothesize that place cells are intrinsically directional, that is, they respond to local views. We show that the synaptic dynamics in the recurrent neural network rapidly modify the discharge correlates of the place cells: Cells tend to become omnidirectional place cells in open fields, while their directionality tends to get stronger in radial-arm mazes. We also find that the synaptic learning mechanisms account for other properties of place cell activity, such as an increase in the place cell peak firing rates as well as clustering of place fields during exploration. Our model makes several experimental predictions that can be tested using current techniques.
43 citations
TL;DR: This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimer's disease, further supporting the validity of transgenic models of the disease.
Abstract: Two experiments were conducted to investigate the possibility of faster forgetting by PDAPP mice (a well-established model of Alzheimer’s disease as reported by Games and colleagues in an earlier paper). Experiment 1, using mice aged 13–16 mo, confirmed the presence of a deficit in a spatial reference memory task in the water maze by hemizygous PDAPP mice relative to littermate controls. However, after overtraining to a criterion of equivalent navigational performance, a series of memory retention tests revealed faster forgetting in the PDAPP group. Very limited retraining was sufficient to reinstate good memory in both groups, indicating that their faster forgetting may be due to retrieval failure rather than trace decay. In Experiment 2, 6-mo-old PDAPP and controls were required to learn each of a series of spatial locations to criterion with their memory assessed 10 min after learning each location. No memory deficit was apparent in the PDAPP mice initially, but a deficit built up through the series of locations suggestive of increased sensitivity to interference. Faster forgetting and increased interference may each reflect a difficulty in accessing memory traces. This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimer’s disease, further supporting the validity of transgenic models of the disease.
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"A rapidly acquired foraging-based w..." refers background or methods in this paper
...Nevertheless, Huitron-Resendiz et al., (2002; see also Daumas et al., 2008) reported that young PDAPP mice (3-5 months of age) showed a tendency to display repeat visits to previously located areas in an open field escape task....
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...There was no report of a tendency to re-visit previously reinforced locations in the Daumas et al (2008) study....
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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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TL;DR: Investigation of the ability of rats to learn a 12-arm radial maze task that requires the concurrent utilization of both spatial and intramaze cue information found that a spatial strategy was employed first followed by a cue strategy.
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"A rapidly acquired foraging-based w..." refers background in this paper
...…showed that rats with hippocampal lesion had severe deficits in spatial working and reference memory components of an 8 arm radial maze but lesioned rats were capable of acquiring a non-spatial version of the task to control levels of perf rmance (see also, Jarrard, 1983; M’Harzi & Jarrard, 1992)....
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