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Journal ArticleDOI

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.

01 Mar 2018-Neurobiology of Learning and Memory (Elsevier)-Vol. 149, pp 46-57

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.

AbstractThree experiments examined the ability of mice to forage efficiently for liquid rewards in pots located in an open field arena. Search behaviour was unconstrained other than by the walls of the arena. All mice acquired the task within 4 days of training, with one trial per day. Experiment 1 tested the hypothesis that hippocampal lesions would disrupt foraging behaviour using extramaze cues. Mice with hippocampal lesions showed normal latency to initiate foraging and to complete the task relative to sham-operated mice. However, lesioned mice showed increased perseverative responding (sensitization) to recently rewarded locations, increased total working memory errors and an increased propensity to search near previously rewarded locations. In Experiment 2, the extramaze cues were obscured and each pot was identified by a unique pattern. Under these conditions, mice with hippocampal lesions showed comparable working memory errors to control mice. However, lesioned mice continued to display increased perseverative responding and altered search strategies. Experiment 3 tested the hypothesis that age-related accumulation of amyloid would disrupt foraging behaviour in transgenic PDAPP mice expressing the V717F amyloid precursor protein (APP) mutation. Consistent with previous findings, PDAPP mice showed both age-dependent and age-independent behavioural changes. More specifically, 14–16 month-old PDAPP mice showed a deficit in perseverative responding and working memory errors. In contrast, changes in search behaviour, such as systematic circling, were present throughout development. The latter indicates that APP overexpression contributed to some features of the PDAPP behavioural phenotype, whereas working memory and flexible responding was sensitive to ageing and β-amyloid burden. In conclusion, the present study provided novel insight into the role of the hippocampus and the effects of APP overexpression on memory and search behaviour in an open-field foraging task.

Topics: Working memory (51%)

Summary (3 min read)

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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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
Charles Evans
1, 2
, Martha Hvoslefeide
1, 4
, Rhian Thomas
2, 3
, Emma Kidd
2
& Mark A Good
1
1
School of Psychology, Cardiff University, Park Place, Cardiff, CF10 3AT, UK.
2
School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII
Avenue, Cardiff, CF10 3NB, UK.
3
Department of Applied Sciences, University of the West of England, Coldharbour
Lane, Bristol, BS16 1QY, UK
4
Department of Biosciences, University of Oslo, Postboks 1066, Blindern 0316, Oslo,
Norway.
Address for correspondence:
Mark Good
School of Psychology
Cardiff University
Park Place, Cardiff, CF10 3AT UK
E-mail:
Good@cardiff.ac.uk
Tel (+44) 02920 875867
Key words: Open-field foraging, hippocampus and amyloid, navigation
Funding sources: This works was supported by funding from the Alzheimer’s Society
and by a PhD studentship from the Cardiff School of Psychology and the Cardiff
School of Pharmacy and Pharmaceutical Sciences.
Conflict of Interest: None of the authors have any financial conflicts of interest.

Abstract
Three experiments examined the ability of mice to forage efficiently for liquid rewards
in pots located in an open field arena. Search behaviour was unconstrained other than
by the walls of the arena. All mice acquired the task within 4 days of training, with one
trial per day. Experiment 1 tested the hypothesis that hippocampal lesions would
disrupt foraging behaviour using extramaze cues. Mice with hippocampal lesions
showed normal latency to initiate foraging and to complete the task relative to sham-
operated mice. However, lesioned mice showed increased perseverative responding
(sensitization) to recently rewarded locations, increased total working memory errors
and an increased propensity to search near previously rewarded locations. In
Experiment 2, the extramaze cues were obscured and each pot was identified by a
unique pattern. Under these conditions, mice with hippocampal lesions showed
comparable working memory errors to control mice. However, lesioned mice
continued to display increased perseverative responding and altered search strategies.
Experiment 3 tested the hypothesis that age-related accumulation of amyloid would
disrupt foraging behaviour in transgenic PDAPP mice expressing the V717F amyloid
precursor protein (APP) mutation. Consistent with previous findings, PDAPP mice
showed both age-dependent and age-independent behavioural changes. More
specifically, 14-16 month-old PDAPP mice showed a deficit in perseverative
responding and working memory errors. In contrast, changes in search behaviour, such
as systematic circling, were present throughout development. The latter indicates that
APP overexpression contributed to some features of the PDAPP behavioural
phenotype, whereas working memory and flexible responding was sensitive to ageing
and -amyloid burden. In conclusion, the present study provided novel insight into the
role of the hippocampus and the effects of APP overexpression on memory and search
behaviour in an open-field foraging task.

Introduction
Spatial working memory tasks, such as the radial arm maze and Barnes maze,
often take advantage of rodents natural propensity to forage for food. Such studies
have informed our understanding of neural networks involved in spatial navigation and
helped characterise the functional properties of hippocampal place cell and entorhinal
grid cells in encoding location and movement information (Shapiro et al. 1997; Brunel
& Trullier 1998; Derdikman et al. 2009). There is a growing body of evidence that
hippocampal and entorhinal networks are sensitive to the early stages of Alzheimer’s
disease. 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 genotype (Kunz et al., 2015).
Changes in spatial behaviour are well-documented in patients with Alzheimer’s disease
(Graham 2015). 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 et al. 2014;
Mokrisova et al. 2016). 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).
Perhaps the most well-known foraging task is the radial arm maze designed by
David Olton (Walker & Olton 1979; Olton et al. 1982). In the simplest version of a
radial arm maze task, all arms of the maze are baited and the animal has one
opportunity to retrieve a food reward from an arm during the trial. As noted by Olton
(1987), rodents may adopt a number of different strategies to solve the radial arm maze
task. In order to restrict the development of certain spontaneous strategies, such as
circling behaviour, rats can be confined to the central hub of the maze between arm
selections. While the radial arm maze task can elicit accurate spatial working memory
performance in rodents, it can also take several days to achieve such high levels of
accuracy (e.g., Clark et al. 2015) and may limit assessment of alternative strategies that
may also guide performance.

In the present study, an unconstrained open-field task was used to assess the
nature of spontaneous foraging strategies that developed in mice following
hippocampal cell loss and in mice developing amyloid pathology with age. 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. The present procedure
was based on a task used by Pearce and colleagues (2005) to investigate foraging
behaviour in pigeons. In this task, pigeons were placed in a large open field area and
presented with eight food-baited pots, each in different spatial location. Pigeons had to
forage the food reward from all eight pots and any return visits to depleted pots during
the trial was considered a working memory (WM) error. We have adapted this task for
mice using an open arena that contained six pots. Each pot was baited with a single
liquid reward and mice were required to consume all six rewards in order to complete
the task. 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). Therefore, we hypothesized that wild type (WT) mice would
quickly adopt a win-shift strategy and minimise the number of errors or return visits to
previously depleted reward locations within a trial.
In order to characterise the effects of hippocampal (HPC) cell loss on the
foraging, the first experiment examined the performance of male C57Bl/6 mice on the
foraging task following excitotoxic lesions of the HPC (Experiment 1). We
hypothesised that mice with hippocampal lesions would show increased working
memory errors, i.e., return visits to depleted pots. In addition, based on evidence that
rats with hippocampal damage displayed an increased tendency to return to previously
visited locations (Whishaw & Tomie 1997; Honey et al. 2007), we also hypothesised
that lesioned mice would display perseverative behaviour by returning immediately to
locations recently visited and depleted of reward.
Previous studies have shown that the contribution of the hippocampus to
performance on the radial arm maze is related to the type of information (i.e.,
extramaze versus intra-maze cues) used to guide navigation. For example, Jarrard et al.
(2004) 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 performance
(see also, Jarrard, 1983; M’Harzi & Jarrard, 1992). To test the hypothesis that mice

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