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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.

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)

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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Journal ArticleDOI
TL;DR: In this article, diminazene aceturate (DIZE), an established activator of ACE2, was shown to reduce hippocampal Aβ and restore cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice.
Abstract: Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer’s disease (AD). The classical renin–angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13–14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9–10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12–13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

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Abstract: Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.

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