Disturbed Object Processing in 5xFAD and 3xTG Mouse Models of Alzheimer’s Disease: Going Beyond “Object Recognition”

by

Samantha Danielle Creighton

A Thesis

presented to

The University of Guelph

In partial fulfilment of requirements

for the degree of

Master of Science

in

Psychology and Neuroscience

Guelph, Ontario, Canada

© Samantha Danielle Creighton, August, 2016

ABSTRACT

DISTURBED OBJECT PROCESSING IN 5XFAD AND 3XTG MOUSE MODELS

OF ALZHEIMER’S DISEASE: GOING BEYOND “OBJECT RECOGNITION”

Samantha Danielle Creighton Advisor:

University of Guelph, 2016 Dr. Boyer Winters

Object recognition not a unitary process, and there are many uncharacterized

facets of object processing that have relevance to Alzheimer’s disease (AD). To elucidate

the specific nature of object processing deficits in transgenic mouse models of AD, we

systematically evaluated performance on tasks that manipulate different types of object

information: object identity (i.e., object recognition: OR), spatial processing (object

location; OL), temporal processing (temporal order; TO), and multisensory perception

(multisensory object oddity; MSO) in 12-month-old male and female 5xFAD and 3xTG

mice. 5xFAD mice were impaired on OR, OL, TO and MSO. Conversely, 3xTG females

had intact short-term OR, and when spatial cues were minimized both males and females

had intact short-term OR. 3xTG mice had impaired OL, TO and MSO. Results reveal

dissociations across AD strain, sex, and type of object processing, and should help to

clarify the relationship between specific aspects of AD pathology and object-related

information processing.

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ACKNOWLEDGEMENTS

I would like to thank my advisor, Dr. Boyer Winters for his support and guidance. I

would also like to thank my advisory committee members Dr. Elena Choleris and Dr.

Craig Bailey, for their valuable feedback. Finally, I would like to thank everyone in the

Winters lab for their help. In particular, I would like to thank Daniel Palmer for this

assistance with object processing experiments.

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Table of Contents

Abstract Acknowledgments iii

Table of Contents iv List of Tables v List of Figures vi

List of Abbreviations vii Introduction 1

Alzheimer’s Disease Neuropathology 1 Episodic Memory Deficits in Alzheimer’s Disease 8 Modeling Alzheimer’s Disease in Rodents 10

Modeling Recognition Memory in Rodents 13 Recognition Memory Deficits in Rodent Models of AD 18

Methods 22 Animals 22 Behavioural Testing 23

Experiment 1: Open-field & Y-Apparatus Object Recognition 25 Experiment 2: Object Location 26

Experiment 3: Temporal Order 26 Experiment 4: Multisensory Object Oddity 27 Behavioural Data Analysis 28

Results 29 Experiment 1: 29

Open-field Object Recognition 29 Y-Apparatus Object Recognition 30

Experiment 2: Object Location 34

Experiment 3: Temporal Order 36 Experiment 4: Multisensory Object Oddity 37

Discussion 40 Object Recognition 41 Object Location 45

Temporal Order 48 Multisensory Object Oddity 50

General Discussion 51 References 57 Appendix 121

v

List of Tables

Table 1: Transgenic Mouse Models of Alzheimer’s Disease

Table 2: Object Recognition Deficits in Transgenic Mouse Models of Alzheimer’s Disease

Table 3: Correlation Between Total Sample Exploration and Novelty Preference Index

Table 4: Object Processing Results Summary

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List of Figures

Figure 1: Object processing test battery.

Figure 2: 5xFAD and 3xTG performance on short-term (5min) and long-term (3h) open field object recognition.

Figure 3: 5xFAD and 3xTG open-field object recognition total exploration.

Figure 4: 5xFAD and 3xTG performance on short-term (5min) and long-term (3h) Y-apparatus object recognition.

Figure 5: 5xFAD and 3xTG Y-apparatus object recognition total exploration.

Figure 6: 5xFAD and 3xTG performance on short-term (5min) and long-term (3h) object location.

Figure 7: 5xFAD and 3xTG object location total exploration.

Figure 8: 5xFAD and 3xTG performance on short-term (3min) object temporal order.

Figure 9: 5xFAD and 3xTG object temporal order total exploration.

Figure 10: 5xFAD and 3xTG performance on object oddity. Figure 11: 5xFAD and 3xTG object oddity total exploration.

vii

List of Abbreviations

Aβ - β-Amyloid

ACh - Acetylcholine

AD - Alzheimer’s Disease

aMCI - Amnesic Mild Cognitive Impairment

APP - Amyloid Precursor Protein

ChATi - Cholinesterase Inhibitors

CMOR - Cross-modal object recognition

CNS - Central Nervous System

DMS - Delayed Matching to Sample

DNMS - Delays Non-Matching to Sample

DR - Discrimination Ratio

HPC - Hippocampus

mPFC - Medial Prefrontal Cortex

MSO - Multisensory Object Oddity

MTL - Medial Temporal Lobe

OFC - Orbitofrontal Cortex

OL - Object Location

OR - Object Recognition

PPC - Posterior Parietal Cortex

PRh - Perirhinal Cortex

PS1 - Presenilin 1

viii

PS2 - Presenilin 2

SOR - Spontaneous Object Recognition

TG - Transgenic

TO - Temporal Order

VRM - Visual Recognition Memory

WT - Wild-type

1

Introduction

Alzheimer’s disease (AD) is a fatal incapacitating neurodegenerative disorder

characterized by a progressive dementia that is correlated with brain pathology. Alois

Alzheimer first described AD as a novel disease distinguishable from senile dementia by

rapid early-onset cognitive decline that co-occurred with an atrophic brain defined by the

deposition of plaques and tangles of fibrils in the cerebral cortex (Alzheimer, 1906, 1911;

Maurer, Volk, & Gerbaldo, 1997; Stelzmann, Schnitzlein, & Murtagh, 1995). AD is now

characterized by the neuropathological accumulation of β-amyloid peptide and

hyperphosphorylated tau protein, oxidative stress and inflammation in the brain (Cuello,

2005; Duyckaerts, Delatour, & Potier, 2009; Honda & Casadesus, 2004; McLaurin,

Yang, Yip, & Fraser, 2000). While the specific etiology of the sporadic (early onset) form

of AD is unknown, the rare familial (late onset) AD is triggered by autosomal dominant

mutations in genes implicated in amyloid processing, specifically the amyloid precursor

protein (APP) gene and presenilin genes (PS1, PS2) (Vilatela, López-López, & Yescas-

Gómez, 2012; Armstrong, 2013). The accumulation of AD pathology is associated with

cognitive decline, including early deficits in executive function and declarative memory.

Alzheimer’s Disease Neuropathology

Excessive production of β-amyloid causes the formation of extracellular amyloid

plaques. β-amyloid (Aβ) has numerous physiological functions, including neural stem

cell development, neuronal survival, growth, repair, synaptic excitability, synaptic

transmission, long-term potentiation (Dawkins & Small, 2014; Turner, O’Connor, Tate,

& Abraham, 2003; Whitson, Selkoe, & Cotman, 1989), and is important for memory

2

formation (Garcia-Osta & Alberini, 2009; Morley, Farr, Banks, Johnson, & Louis, 2010).

In AD, Aβ accumulates intracellularly and extracellularly following accelerated

processing and abnormal cleavage of the membrane bound APP protein in the

amyloidogenic pathway by β- and γ-secretases (McLaurin et al., 2000; Sisodia & St

George-Hyslop, 2002). Specifically, β-secretase (β-site APP-cleaving enzyme, or BACE)

cleavage of APP, favoured by mutations in the APP gene, yields APPsβ and a β-stub

(McLaurin et al., 2000; Sisodia & St George-Hyslop, 2002). The β-stub is subsequently

cleaved by γ-secretase, to produce Aβ peptides (soluble Aβ40 and fibrillogenic Aβ42

[mutations in PS promote the overproduction of pathogenic Aβ42]) (McLaurin et al.,

2000; Sisodia & St George-Hyslop, 2002; Thinakaran & Koo, 2008). Aβ42 accumulation

is favoured by mutations in the APP gene that produce a longer Aβ peptide via

potentiation of β-secretase, inhibition of α-secretase, and γ-secretase slice alteration

(Hardy, 1997). Mutations in PS1 and PS2 also favour a long pathogenic Aβ peptide,

potentially through competitive γ-secretase binding or altered γ-secretase trafficking in

the endoplasmic reticulum (Haass, 1997; Selkoe, 1998). Aβ peptides may have

numerous intracellular consequences, such as lysosome up-regulation, mitochondrial

dysfunction, dysregulation of CRE-directed gene expression and potentially tau

phosphorylation (Cuello, 2005). As Aβ accumulates, peptides aggregate to form amyloid

fibrils which can rupture the vascular membrane of neuronal cells leading to cell death

and the additional accumulation of extracelluar Aβ (Friedrich et al., 2010). β- and γ-

secretases may also cleave membrane bound APP, resulting in increased extracellular

concentrations of Aβ. Extracellular Aβ peptides and fibrils are associated with synaptic

dysfunction, depletion of glutamatergic and cholinergic tone, oxidative stress, altered

3

glucose metabolism and ultimately neuronal death (Bossy-Wetzel, Schwarzenbacher, &

Lipton, 2004; Cuello, 2005; Laursen, Mørk, Plath, Kristiansen, & Bastlund, 2013; Nizzari

et al., 2012; Rossor et al., 2015; Thinakaran & Koo, 2008).

Hyperphosphorylation of tau leads to the formation of intracellular

neurofibrillary tangles. Physiologically, tau proteins bind to tubulin and are crucial to the

stability of microtubules in central nervous system (CNS) axons. In AD tau

serine/threonine residues are phosphorylated by proline and non-proline directed proline

kinases which causes tau to dissociate and destabilizes microtubules (Avila, 2006; Wang,

Xia, Iqbal, 2012). Moreover, phosphorylated tau binds and aggregates with other tau

proteins to form neurofibrillary tangles, neuropil threads, and dystrophic neurites

(Alonso, Iqbal, 1996; Gong, Liu, Iqbal, & Iqbal, 2006; Maccioni, Vera, Dominguez, &

Avila, 1989; Wang et al., 2012). Intracellularly, phosphorylation and aggregation of tau

inhibits axonal trafficking and triggers apoptosis (Alonso et al., 1996; Bancher, Braak,

Fischer, & Jellinger, 1993; Gong et al., 2006; Wang et al., 2012).

Ultimately, AD is a multifactorial disease in which pathology, including amyloid

plaques and neurofibrillary tangles, is associated with extensive neuronal dysfunction, a

decrease in synaptic responsiveness, inflammation, oxidative stress, cell death and brain

atrophy (Braak & Braak, 1991, 1995; Griffin et al., 1998; Jacobsen et al., 2006; Selkoe,

1991). There are several models concerning the causal pathological element in the AD

neurodegenerative cascade.

4

The Cholinergic Hypothesis of Alzheimer’s Disease. The cholinergic hypothesis

suggests that the degeneration of basal forebrain cholinergic neurons and consequent

disruption of cholinergic neurotransmission in the cortex, striatum and hippocampus is

related to Aβ accumulation, hyperphosphorylation of tau and cognitive dysfunction in

AD patients (Bartus, 2000; Bartus, Iii, Beer, & Lippa, 1982; Francis, Palmer, Snape, &

Wilcock, 1999). A critical role of acetylcholine (ACh) in AD is supported by abnormal

cholinergic activity in the late stages of AD and a critical role of ACh in memory.

Specifically, late AD is associated with decreased choline uptake in the hippocampus

(Rylett, Ball, & Colhoun, 1983); decreased choline acetyltransferase in the cortex,

hippocampus and amygdala (Bowen, Smith, White, & Davison, 1976; Davies &

Maloney, 1976; Perry, Gibson, Blessed, Perry, & Tomlinson, 1977); decreased release of

ACh in the cortex (Nilsson, Nordberg, Hardy, Wester, & Winblad, 1986); and loss of

cholinergic neurons in the basal forebrain (Whitehouse, Price, Struble, Clark, 1982). The

cholinergic hypothesis has led to the approval of cholinesterase inhibitors (ChATi) for the

mitigation of cognitive symptoms in moderate AD (Birks, 2006; Cummings, 2003;

Lanctôt et al., 2003; Raschetti et al., 2005). However, in patients with mild-cognitive

impairment and early AD the level and activity of choline acetyltransferase is not

decreased and cholinergic neurons in the basal forebrain are conserved (Davis et al.,

1999; Dekosky et al., 2002; Gilmor et al., 1999). Thus, it is unlikely that deficits in

cholinergic neurotransmission directly cause AD neurodegeneration.

The Tau Hypothesis of Alzheimer’s Disease. The tau hypothesis postulates a

critical role for inflammation and excessive tau hyperphosphorylation in the formation of

neurofibrillary tangles, abnormalities in signaling pathways, neurotoxicity and

5

neurodegeneration in AD patients (Maccioni, Farias, Morales, & Navarrete, 2010).

Indeed, neurofibrillary tangles may be unrelated to or precede Aβ plaques (Braak &

Braak, 1991; Tabaton et al., 1989), hyperphosphorylated tau and neurofibrillary tangles

correlate with impairment in episodic memory in human AD patients (Ghoshal et al.,

2002; Maccioni et al., 2006), and pharmaceutical agents that target tau restore spatial

memory in transgenic mice (Min et al., 2015).

The Amyloid Cascade Hypothesis of Alzheimer’s Disease. Although controversial,

it has been suggested that Aβ accumulation causes hyperphosphorylation of tau in AD

(Cuello, 2005; Gamblin et al., 2003; Hardy, & Higgins, 1992; Hardy, 1997; Hardy &

Allsop, 1991; Selkoe, 1999). Specifically, the amyloid cascade hypothesis states that

abnormal production and cleavage of Aβ is the causative pathological feature of AD that

facilitates a hierarchical sequence of amyloid plaque formation, inflammation, oxidative

stress, tau hyperphosphorlation, neuronal death and dementia (Hardy et al., 1992; Hardy

& Allsop, 1991; Hardy & Selkoe, 2002; Lemere & Masliah, 2010). A causal role for Aβ

in AD was suggested based on the discovery that Aβ is the primary component of

amyloid plaques in patients with AD and Down syndrome, the localization of the APP

gene to chromosome 21 and the high prevalence of AD in individuals with Down

syndrome (Hardy & Allsop, 1991; Hardy & Higgins, 1992; Hardy & Selkoe, 2002). In

further support of the amyloid hypothesis: Aβ is toxic in vitro (Iversen, Mortishire-Smith,

Pollack, & Shearman, 1995); sporadic and familial AD are associated with genetic

mutations that alter Aβ production, processing and clearance (Schellenberg & Montine,

2012); overexpression of human APP in mice may produce amyloid plaques (Terai et al.,

6

2001; Webster, Bachstetter, Nelson, Schmitt, & Van Eldik, 2014), memory deficits

(Chen, Chen, Knox, Inglis, Bernard, Martin, Justice, McConlogue, et al., 2000), and in

some transgenic models tau hyperphosphorylation (Kanno, Tsuchiya, & Nishizaki,

2014b); and amyloid plaques increase the risk of AD (Chen et al., 2014). However, the

amyloid cascade hypothesis has several limitations: many older individuals have

extensive amyloid pathology without cognitive impairment (Villemagne et al., 2011);

anti-amyloid treatments in human patients reduce plaques but do not prevent further

cognitive decline or neurodegeneration (Holmes et al., 2008); transgenic mice with

overexpression of Aβ, but not APP, do not have behavioural deficits (Kim et al., 2013);

neurofibrillary tangles may develop prior to (Schönheit, Zarski, & Ohm, 2004) or

independently of amyloid plaques (Arriagada, Growdon, Hedleywhyte, & Hyman, 1992;

Bouras, Hof, Giannakopoulos, Michel, & Morrison, 1994; Price, Davis, Morris, & White,

1991); and tangles strongly correlate with neurodegeneration and cognitive decline

(Arriagada et al., 1992; Giannakopoulos et al., 2003).

There is also substantial support for a critical role of neuroinflammation

(Cameron & Landreth, 2010; McGeer, Schulzer, & McGeer, 1996; Meraz-Ríos, Toral-

Rios, Franco-Bocanegra, Villeda-Hernández, & Campos-Peña, 2013; Mosher & Wyss-

Coray, 2011), oxidative stress and mitochondrial dysfunction (Lin & Beal, 2006; Schrag

et al., 2013; Swerdlow, Burns, & Khan, 2014; Valla et al., 2006), altered calcium

homeostasis and excitotoxicity (Bezprozvanny & Mattson, 2008; Demuro, Parker, &

Stutzmann, 2010; Green & LaFerla, 2008; Szwagierczak, Bultmann, Schmidt, Spada, &

Leonhardt, 2010), DNA damage (Bucholtz & Demuth, 2013; Lovell & Markesbery,

7

2007; Obulesu & Rao, 2010; Weissman, de Souza-Pinto, Mattson, & Bohr, 2009), and

loss of cell cycle control (Arendt, Brückner, Mosch, & Lösche, 2010; Busser,

Geldmacher, & Herrup, 1998; McShea, Harris, Webster, Wahl, & Smith, 1997; Yang,

Mufson, & Herrup, 2003) in AD. Thus, while there are many alternative theories

regarding the cause of AD dementia, Aβ and tau likely play a significant role in the

neurodegenerative cascade.

Early and extensive AD neuropathology in the medial temporal lobe (MTL).

Although the clinical staging of AD pathology is heterogeneous, histopathological and

imaging studies report pathological changes that begin in the MTL prior to AD diagnosis

and progress to widespread cortical and sub-cortical regions (Braak & Braak, 1991, 1995;

Hyman, Hoesen, Damasio, & Clifford, 1984; Scahill, Schott, Stevens, Rossor, & Fox,

2002; Schönheit et al., 2004; Whitwell et al., 2007). Braak & Braak (1991, 1995)

describe an Aβ and tau deposition pattern that begins in limbic regions, specifically the

hippocampus (HPC), association cortices, basal forebrain, thalamus and hypothalamus

and spreads to neocortex and various subcortical nuclei. It has been suggested that AD

pathology deposits in a non-random fashion following signaling pathways via cell-to-cell

transmission of Aβ and tau ( Hyman et al., 1984; Saper, Wainer, & German, 1987;

Steiner, Angot, & Brundin, 2011). The distribution of brain atrophy is consistent with

patterns of Aβ and tau deposition. Specifically, gray matter atrophy is present in the HPC,

amygdala, entorhinal cortex and fusiform gyrus prior to AD diagnosis, atrophy of the

MTL becomes quite extensive as mild cognitive impairment advances, and at AD

8

diagnosis atrophy extends to frontal and parietal lobes (Scahill et al., 2002; Whitwell et

al., 2007).

Episodic Memory Deficits in Alzheimer’s Disease

The degree of AD neuropathology is correlated with the severity of cognitive

deficits (Bancher et al., 1993; Riley, Snowdon, & Markesbery, 2002). Amyloid plaque

deposition is correlated with cognitive decline in early stages of AD, while

neurofibrillary tangles strongly correlate with cognitive deficits throughout AD (Braak &

Braak, 1991, 1995; Nelson et al, 2013; Nelson, Braak, & Markesbery, 2007). Deficits in

episodic memory, executive function, and perceptual processing may be apparent prior to

AD diagnosis (Bäckman, Jones, Berger, Laukka, & Small, 2004; Perry & Hodges, 1999;

Riley et al., 2002; Snowden et al., 2011).

Episodic memory for life events is a subtype of declarative memory (the

conscious memory for facts and events; Squire & Zola, 1996) and is facet of cognitive

function affected early in AD (Barbeau et al., 2008; Didic et al., 2013; Didic, Ranjeva,

Barbeau, Confort-gouny, & Le, 2010; Libon et al., 1998; Pike et al., 2007; Stoub et al.,

2006). Visual recognition memory is a subclass of episodic memory that is dependent on

the integrity of MTL structures and is commonly evaluated using delayed matching-to-

sample (DMS) and delayed nonmatching-to-sample (DNMS) tasks in rodents, non-

human primates and humans. Generally, in D(N)MS tasks subjects encode a sample

stimulus, and following a retention delay, in a forced-choice test participants must

9

indicate the stimulus that matches the sample stimulus (DMS) or that does not match the

sample stimulus (DNMS) (Huppert & Piercy, 1976).

Functional degeneration of medial temporal lobe structures such as the HPC,

entorhinal cortex, and perirhinal cortex (PRh) is associated with impairments in episodic

memory, including visual recognition memory (Barbeau et al., 2008; Didic et al., 2010).

Tests of visual recognition memory (VRM), including familiarity-based recognition and

delayed matching to sample paradigms, have been used to evaluate episodic memory in

patients with cognitive decline. Barbeau et al. (2008) evaluated VRM in patients with

amnesic mild cognitive impairment (aMCI) to assess the relationship between cortical

gray matter atrophy and memory impairment. VRM was evaluated using a delayed

matching to sample recognition memory (DMS48) paradigm. In DMS48 patients

incidentally learn 48 coloured drawings and, following a 1h long-term retention delay,

are evaluated on their ability to identify a learned drawing amongst distractors. aMCI

patients impaired in DMS48 had gray matter loss in the MTL and temporal-parietal

regions, including the PRh (Barbeau et al., 2008). Didic et al. (2010) evaluated VRM in

patients with amnesic mild cognitive impairment to determine if VRM deficits, using

DMS48, are associated with metabolic abnormalities in the MTL. Patients with impaired

VRM had decreased bilateral MTL metabolism, including regions of the HPC, and VRM

deficit correlated with MTL metabolism (Didic et al., 2010). Similarly, Wolk et al. (2008,

2011) evaluated recognition memory for associative (word-pairs) or featural information

(font colour) and found aMCI patients to be impaired on both tests of familiarity and

recognition memory in which the HPC and PRh play a dissociable role (such that the

10

HPC is required for recollection and the PRh is required for familiarity). Importantly,

familiarity recognition is spared in healthy aging (Davidson & Glisky, 2002; Yonelinas et

al., 2002); thus loss of familiarity recognition may be a marker for pathogenic aging.

Indeed, performance on visual recognition memory tests in aMCI patients is predictive of

AD diagnosis (Didic et al., 2013, 2010; Wolk, Signoff, & DeKosky, 2008).

In order to complement and extend the understanding of episodic memory deficits

in AD patients it may be advantageous to model AD and tests of visual recognition

memory in experimental animals in order to characterize cognitive deficits, identify new

therapeutic targets and evaluate the therapeutic potential of pharmaceutical agents.

Modeling Alzheimer’s Disease in Rodents

Most rodents do not develop Alzheimer’s pathology with age. Popular rodent

models of AD, however, recapitulate key features of amyloid and tau pathology via

genetic manipulation or injection of Aβ into the CNS (Ashe & Zahs, 2010; Bilkei-Gorzo,

2014; LaFerla & Green, 2012; Lecanu & Papadopoulos, 2013; Van Dam & De Deyn,

2011; Webster et al., 2014). Accumulation of Aβ and tau hyperphosphorylation is

followed by molecular and cellular cascades that contribute to neurodegeneration and

behavioural decline. In addition to behavioural profiling, rodent models of AD are

valuable for the characterization of oxidative stress, inflammation, abnormal

mitochondrial function, immune responses and other molecular abnormalities that may

identify novel substrates and increase applicability of findings to therapeutic drug

discovery.

11

Notably, no rodent model perfectly recapitulates neuropathological staging and

cognitive decline seen in the human disease. Many transgenic strains model the less

common familial form of AD via overexpression of APP and/or PS1 genes. 5xFAD and

3xTG are distinct and complementary transgenic mouse models of familial AD, and both

will be evaluated in the current study (see Table 1).

5xFAD. The 5xFAD transgenic mice were developed with three mutations in the

APP gene and two mutations in the PS1 gene. 5xFAD transgenic mice have a more

aggressive and earlier onset of amyloid pathology compared to other transgenic strains.

Specifically, Aβ42 is almost exclusively produced and accumulates intracellularly and

extracellularly in young mice at 1.5 and 2 months of age in the HPC and deep cortex,

respectively (Oakley et al., 2006). Amyloidosis is followed by loss of cholinergic and

noradrenergic neurons and tau hyperphosphorylation in old mice at approximately 12

months of age (Devi & Ohno, 2010; Kalinin et al., 2012; Kanno et al., 2014). While the

very early onset may compromise the translational validity of the 5xFAD strain, the

reduction in animal care expense and the severe amyloid pathology has made this model

popular. Behavioural deficits in spatial memory in spontaneous Y-maze alteration present

at 4 months of age (Oakley et al., 2006), followed by impaired contextual fear memory

and spatial learning in the Morris water maze by 6 months of age (Kimura & Ohno, 2009;

Ohno et al., 2006).

3xTG. The 3xTG model has high face validity because both the human amyloid

plaque and neurofibrillary tangle pathologies are recapitulated. In 3xTG mice, APP and

12

PS1 are overexpressed to induce amyloid pathology, and the MAPT gene is mutated to

induce tauopathy (Oddo, Caccamo, Shepherd, et al., 2003). Intracellular Aβ accumulation

has been observed at 3 to 4-months-of-age, and extracellular amyloid plaques develop at

approximately 6-months-of-age (Oddo, Caccamo, Shepherd, et al., 2003).

Hyperphosphorylation of tau is observed in the HPC at 6-months-of-age, followed by

hyperphosphorylation of tau in cortical regions and eventually, unlike the 5xFAD model,

the formation of neurofibrillary tangles (Oddo, Caccamo, Shepherd, et al., 2003; Rohn et

al., 2008). With age there is cholinergic and noradrenergic neuronal death, increased

microglia activity, inflammation, and alterations in glucose metabolism (Da Cruz et al.,

2012; Manaye et al., 2013; Mastrangelo & Bowers, 2008; Nicholson et al., 2010; Oddo,

Caccamo, Shepherd, et al., 2003; Sy et al., 2011). However, unlike the human disease,

HPC neurodegeneration is not reported and amyloidosis begins in the cortex (Manaye et

al., 2013; Oddo, Caccamo, Shepherd, et al., 2003). Young 3xTG mice have deficits on

the what-where-which episodic object memory task as early as 3 months of age (Davis,

Easton, Eacott, & Gigg, 2013), followed by impaired long-term Morris water maze and

contextual fear retention at 6 months of age (Billings, Oddo, Green, McGaugh, &

LaFerla, 2005).

Rodent AD models have been vital to enhancing our understanding of AD.

Assessing transgenic models that embody complementary aspects of the human disease –

one of the primary goals of this thesis - may elucidate behavioural deficits associated

with specific elements of AD pathology.

13

Modeling Recognition Memory in Rodents

A rodent variation of the DNMS task is spontaneous object recognition (SOR;

Ennaceur & Delacour, 1988). The SOR task does not require extensive training or

reward; therefore memory can be evaluated in a manner similar to daily human

interaction with objects (Dere, Huston, & De Souza Silva, 2007; Ennaceur & Delacour,

1988). Tests of spontaneous object recognition exploit rodents’ innate preference to

approach and explore novel stimuli (Winters, Saksida, & Bussey, 2008). The

neurobiological mechanisms required for object recognition are contingent on the specific

nature of the task. In the most common form of SOR, rodents are presented with two

identical objects during a sample phase and, following a retention delay, during a choice

phase rodents are presented with an object from the sample phase (familiar) and a new

stimulus (novel). The novelty preference is manifested by greater exploration of novel

stimuli or spatial locations compared to familiar stimuli (Ennaceur & Delacour, 1988;

Winters et al., 2008).

When evaluated in this fashion SOR is reliant on functional integrity of

cholinergic, glutamatergic and serotonergic signaling in structures including the PRh,

HPC and the medial prefrontal cortex (mPFC; (Barker & Warburton, 2011; Dere et al.,

2007; Winters et al., 2008).

There are many ways in which objects may be processed that have relevance to

AD. Interaction with objects may engage memory for specific object features, spatial

memory processing, temporal memory processing, and multisensory and perceptual

14

processing. By modifying the nature of the SOR paradigm it is possible to tax different

forms of object processing that have not entirely overlapping neural mechanisms.

Spontaneous object recognition and feature processing. The SOR paradigm has

been predominately performed using an open-arena and is used to assess rodents’ ability

to distinguish between a novel and familiar object. When tested in an open-field

apparatus, spatial and contextual information from within the apparatus and around the

testing room could potentially influence memory encoding and performance in the SOR

task. Previously, there has been debate concerning the contributions of the PRh and HPC

to object recognition memory. More recent experimental evidence from rats suggests the

PRh is necessary for SOR, while the HPC is not necessary for object recognition per se

(Barker & Warburton, 2011; Forwood, Winters, & Bussey, 2005; Winters, Forwood,

Cowell, Saksida, & Bussey, 2004; Winters et al., 2008), but can be involved depending

on the nature of encoding conditions. Specifically, while damage to the HPC has

occasionally been shown to impair SOR in rats in the open field (Clark, Zola, & Squire,

2000; Mumby, Gaskin, Glenn, Schramek, & Lehmann, 2002), Winters et al. (2004)

established a functional double dissociation between the necessity of the PRh and HPC

for object and spatial memory. Bilateral excitotoxic lesions of the PRh or HPC in male

rats impaired SOR and spatial memory in the 8 arm radial maze, respectively. Critically,

as it is difficult to determine what cues rodents use to perform the SOR task, object

recognition was tested in a Y-shaped apparatus with high opaque walls in an effort to

minimize influence of spatial and contextual information. Forwood et al. (2005) provided

further support for dissociable roles of the PRh and HPC in SOR such that rats with

15

bilateral excitotoxic lesions of the HPC were impaired on a spatial non-matching to

sample task but not SOR in the Y-apparatus. Similarly, Barker & Warburton (2011)

evaluated recognition memory using a variety of object paradigms for rats that required

feature or object identity information, spatial information, and temporal information

processing. Results suggested that the HPC is required for tests of object processing only

when spatial and/or temporal object information is involved. Thus, it has been suggested

that the PRh is necessary for memory of object identity, while HPC is not involved in

object recognition but rather is important for recognition memory for spatial and temporal

information. To my knowledge a similar double dissociation between the function of the

PRh and HPC in object and spatial memory has not been demonstrated in mice. It appears

that mice process objects differently, as the performance of rats and mice may

systematically differ in learning and memory paradigms (Cohen et al., 2013; Dere et al.,

2007), and inactivation of the HPC has been shown to impair SOR in mice (DeVito &

Eichenbaum, 2010; Hammond, Tull, & Stackman, 2004); it is important to note,

however, that findings from this study may also be confounded by spatial information

including object configuration and the open-field testing apparatus. Yet, the HPC does

appear to be necessary for object identity processing in mice, as SOR is intact in control

mice but impaired following inactivation of the HPC, by muscimol, when spatial and

contextual information was made irrelevant by presenting objects in unique contexts

(Cohen et al., 2013). SOR performance is also known to rely on the functional integrity

of the PRh in mice (Romberg et al., 2013), consistent with rat, monkey, and human

findings (Meunier, Bachevalier, Mishkin, & Murray, 1993; Murray & Mishkin, 1998;

Murray & Bussey, 1999; Winters et al., 2004; Winters, Saksida, & Bussey, 2010; Zola-

16

Morgan, Squire, Amaral, & Suzuki, 1989). Thus, while the open field version of SOR

may be more likely to recruit the HPC in mice, both open field and Y-apparatus SOR

evaluate forms of object memory considered to model facets of human declarative

memory, and both rely on MTL brain regions that are highly relevant to AD.

Spontaneous object recognition and spatial processing. Spatial memory may be

evaluated using the spontaneous object location (OL) task. The SOR paradigm can be

slightly modified to assess OL such that during the choice phase rodents are presented

with two copies of the sample object but one of which is placed in a novel location (Dix

& Aggleton, 1999; Murai, Okuda, Tanaka, & Ohta, 2007), to selectively evaluate

spatial/contextual object associations. OL is thought to be dependent on the HPC.

Specifically, lesion and inactivation of the HPC in rats and mice has been shown to

impair OL (Assini, Duzzioni, & Takahashi, 2009; Barker & Warburton, 2011; Mumby &

Pinel, 1994), while the PRh is not necessary for OL performance (Barker & Warburton,

2011). Additionally, lesion of the fornix and cingulate cortex have also been shown to

impair OL in rats (Ennaceur, Neave, & Aggleton, 1997).

Spontaneous object recognition and temporal processing. Temporal processing

may be evaluated using the temporal order (TO) task. In TO rodents are exposed to two

distinct sets of identical stimuli in two different sample phases and following a delay are

tested on their ability to differentiate between the more remote and more recently

presented stimuli. As rodents have an innate preference for novelty, if temporal

processing is intact rodents will preferentially explore the stimuli that were presented less

17

recently (more novel). Evidence from lesion studies in rats suggests a critical role of the

PRh, HPC, mPFC and functional connectivity between the PRh and mPFC in TO

memory tasks (Barker, Bird, Alexander, & Warburton, 2007; Barker & Warburton, 2011;

Hannesson, Howland, & Phillips, 2004; Mitchell & Laiacona, 1998).

Spontaneous object recognition and multisensory integration. The object

recognition paradigm may also be adapted for the evaluation of multisensory integration.

For example, the cross-modal object recognition task (CMOR) may be used to evaluate

tactile-to-visual multisensory integration where rodents use a previously formed tactile

object representation to distinguish between novel and familiar visual stimuli (Winters &

Reid, 2010). In CMOR the sample phase is run under red light, restricting visual

exploration, such that only tactile object information is available. Following a retention

delay, the choice phase is run in white light with objects placed behind transparent

barriers, such that only visual information is available. The CMOR task has been shown

to be dependent on functional connectivity of the PRh, posterior parietal cortex (PPC),

and regions of the PFC, including the orbitofrontal cortex (OFC; Cloke, Jacklin, &

Winters, 2014; Reid, Jacklin, & Winters, 2012, 2014; Winters & Reid, 2010).

More recently, our lab has developed a multisensory object oddity task (MSO),

that is also likely dependent on integrity of the PRh, PPC, and OFC network for

multisensory binding (Cloke et al., 2014; Reid et al., 2012, 2014). Standard object oddity

tasks are advantageous for the evaluation of visual perception and are similarly dependent

on the functional integrity of the PRh (Bartko, Winters, Cowell, Saksida, & Bussey,

18

2007; Forwood, Bartko, Saksida, & Bussey, 2007). Object oddity paradigms are often run

without a retention delay; therefore the task has minimal mnemonic demand and provides

insight into the basic perceptual ability of rodents. The MSO task can be used to assess

multimodal perception under tactile-visual or olfactory-visual conditions. In this task

rodents are simultaneously presented with pairs of objects with shared combinations of

tactile-visual (or olfactory-visual) features and one dissimilar (‘odd’) object comprising a

unique combination of features. If perception is intact, rodents will preferentially explore

the odd object.

Recognition Memory Deficits in Rodent Models of Alzheimer’s Disease

Tests of object processing are advantageous to the study of AD because

performance is reliant on signaling pathways and brain regions affected by Alzheimer’s

pathology in humans. An extensive literature suggests that rodent models of AD are

impaired on object recognition (OR) when evaluated in an open-field apparatus. Deficits

in object recognition have been observed in several transgenic AD mice: APP (Ambrée et

al., 2009; Arrieta-Cruz, Pavlides, & Pasinetti, 2010; Balducci et al., 2011; Bardgett,

Davis, Schultheis, & Griffith, 2011; Beggiato et al., 2014; Cho et al., 2011; Dewachter et

al., 2002; Dobarro, Gerenu, & Ramírez, 2013; Dodart et al., 1999; Escribano et al., 2009;

Francis et al., 2012; Fukumoto et al., 2014; Galeano et al., 2014; Görtz et al., 2008; Greco

et al., 2010; Hernandez, Kayed, Zheng, Sweatt, & Dineley, 2010; Hillen et al., 2010; Jin

et al., 2014; Kauppinen et al., 2011; Knowles et al., 2013; Martín-Moreno et al., 2012;

Mouri et al., 2007; Nishida et al., 2006; Ohta, Arai, Akita, Ohta, & Fukuda, 2012; Polito

et al., 2014; Ribes, Torrente, Vicens, Colomina, & Domingo, 2012; Richter et al., 2008;

19

Saydoff et al., 2013; Simón et al., 2009; Sivilia et al., 2013; Verret et al., 2013; L. Zhang

et al., 2006, 2014); PS1/PS2 models (Huang, 2003; P. Wu et al., 2008; Zufferey et al.,

2013); APP/PS1 (Barbero-Camps, Fernández, Martínez, Fernández-Checa, & Colell,

2013; Donkin et al., 2010; Frye & Walf, 2008; Hafez et al., 2012; Howlett et al., 2004;

McClean & Hölscher, 2014; McClean, Parthsarathy, Faivre, & Hölscher, 2011; Mori,

Koyama, Guillot-Sestier, Tan, & Town, 2013; Scholtzova et al., 2008; Roach et al., 2004;

Vargas, Fuenzalida, & Inestrosa, 2014; Webster, Bachstetter, & Van Eldik, 2013; Woo et

al., 2010; Yao et al., 2013; Zhang et al., 2014; Zhang et al., 2013; Zhang et al., 2012);

5xFAD (Giannoni et al., 2013; Joyashiki, Matsuya, & Tohda, 2011; Seo et al., 2014;

Tohda, Nakada, Urano, Okonogi, & Kuboyama, 2011; Tohda, Urano, Umezaki, Nemere,

& Kuboyama, 2012; Wang et al., 2013) and 3xTG (Arsenault, Julien, Tremblay, &

Calon, 2011; Blanchard et al., 2010; Chen et al., 2014; Feld et al., 2014; Filali et al.,

2012; Guzmán-Ramos et al., 2012; Kazim et al., 2014; Onishi et al., 2011; St-Amour et

al., 2014).

However, the specific nature of the OR deficit in AD mice is controversial

(Grayson et al., 2014; Simón et al., 2009; Taglialatela, Hogan, Zhang, & Dineley, 2009),

and some studies have failed to report OR impairments (Cheng, Low, Logge, Garner, &

Karl, 2014; Davis, Eacott, Easton, & Gigg, 2013; Davis, Easton, et al., 2013; Fragkouli,

Tsilibary, & Tzinia, 2014; Good, Hale, & Staal, 2007; Gulinello et al., 2009; Hale &

Good, 2005; Karl, Bhatia, Cheng, Kim, & Garner, 2012; Yassine et al., 2013).

Differential performance on OR tasks may be related to procedural differences that alter

the conceptual nature of the task and thus tax distinct behavioural processes.

20

Discrepancies in the mnemonic index, the length of the retention delay, the age of

behavioural testing and/or the choice of sex and transgenic model may also affect OR

data. And in several cases, due to the nature of the OR paradigm, object recognition

results cannot be interpreted with confidence, as control mice were not able to perform

the task (Maroof, Ravipati, Pardon, Barrett, & Kendall, 2014; Scullion, Kendall,

Marsden, Sunter, & Pardon, 2011; Stover, Campbell, Van Winssen, & Brown, 2015).

According to previous reports transgenic AD mice appear to have intact short-term OR

memory, as a novelty preference has been observed with 2-3min retention delays (Davis,

Easton, et al., 2013; Good & Hale, 2007; Middei, Daniele, Caprioli, Ghirardi, &

Ammassari-Teule, 2006; Taglialatela et al., 2009). Yet, there is evidence that OR is

impaired in transgenic AD mice when the retention delay is ≥ 5min (Ambrée et al., 2009;

Bardgett et al., 2011; Dewachter et al., 2002; Dodart et al., 1999; Gerenu, Dobarro,

Ramirez, & Gil-Bea, 2013; Giuliani et al., 2013; Greco et al., 2010; Hillen et al., 2010;

Spilman et al., 2014; Yuede et al., 2009). Further, OR performance is age-dependent,

such that OR deficits have been described in transgenic mice 3 to 15-months-of-age.

Therefore, additional research is necessary to clarify when OR is impaired in various AD

transgenic mouse models. Few studies have systematically examined OR with varied

retention delays in multiple transgenic AD models. The understanding of object

processing in AD is far from comprehensive. In addition to the familiarity of object

identity there are many other types of object processing that are altered by AD

neuropathology in human patients. Indeed, AD patients also have deficits in spatial

processing (Caterini, Sala, Spinnler, Stangalino, & Turnbull, 2002; Snowden et al.,

2011), temporal processing (Becker, Wess, Hunkin, & Parkin, 1993), sensory integration

21

(Drzezga et al., 2005; Wu et al., 2012), and spatial, but not featural, perception (Lee et

al., 2006). Accordingly, a few studies have described deficits in object spatial processing

in AD transgenic mice (Bergin & Liu, 2010; Bollen et al., 2013; Dodel et al., 2011; Frye

& Walf, 2008; Gulinello et al., 2009). Further, despite impairment in human AD patients

and the necessity of the HPC in temporal tasks, Hale & Good (2005) and Davis et al.

(2013) have failed to demonstrate temporal order memory impairments in transgenic

APP, Tg2576, and 3xTG mice. However, the retention delay in temporal tasks was not

sufficiently long to induce deficits in object recognition (2 min). Extending the retention

delay may induce a temporal order memory deficit in transgenic AD mice. Therefore, it is

insufficient to conclude that AD transgenic mice are impaired on “object recognition”

without a full characterization of behavioural deficits in object processing; there are

numerous aspects of object processing related to recognition and AD that remain to be

thoroughly analyzed.

The purpose of the current study was to perform a systematic analysis of object

identity, spatial, temporal, multisensory, and perceptual processing in 5xFAD and 3xTG

mouse models of AD. It is hypothesized that transgenic AD mice will have abnormal

performance on object processing paradigms at 12 months of age. By manipulating the

nature and retention delay of the object recognition paradigm we were able to alter

mnemonic demand and tax different facets of object processing with relevance to AD to

clarify the nature of object information processing deficits.

22

Methods

Animals

Male and female wild-type 5xFAD wild-type (B6SJLF1/J) and transgenic

(B6SJLTg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax) and 3xTG wild-type

(B6129SF2/J) and transgenic (B6;129 Psen1tm1Mpm Tg(APPSwe,tauP301L)1Lfa/Mmjax)

mice were obtained from the Jackson Laboratory (Bar Harbor, ME, USA) at

approximately 2-months-of-age.

5xFAD transgenic mice have five mutations that overexpress familial AD genes:

human APP(695) with the Swedish (K670N, M671L), Florida (I716V), and London

(V717I) as well as two human PS1 mutations (M146L and L286V), inserted into exon 2

of the Thy gene and regulated by the Thy1 promoter to drive overexpression in the brain.

5xFAD mice have an extremely early accumulation of Aβ42 that advances to amyloid

plaque formation, and synaptic and neuronal loss (Oakley et al., 2006).

3xTG mice have familial AD transgene knockin of APPSwe and tauP301L that

recapitulate amyloid and tau pathology in the central nervous system. 3xTG mice were

generated by co-injection of APPSwe and tauP301L, under the control of Thy1.2

promoter, into presenilin-1 (M146V) knock-in mice embryos. The mutant transgenes

facilitate beta-amyloid deposition, amyloid plaque formation, hyperphosphorylation of

tau and eventually the formation of neurofibrillary tangles (Oddo, Caccamo, Shepherd, et

al., 2003).

23

To investigate object processing in transgenic AD mouse models we used 3xTG

transgenic (n = 21male, n = 35 female) and wild-type (n = 24 male, n = 35 female) and

5xFAD transgenic (n = 23 male, n = 33 female) and wild-type mice (n = 20 male, n = 33

female). Mice used in this study were previously tested in touchscreen-based operant

tasks, but were not exposed to objects. Sample sizes were selected to compensate for the

attrition rate. Mice were group housed in clear polyethylene cages (16 12 26 cm), with

corncob bedding, crink-l’Nest and cotton nest squares in a controlled environment (22

±2°C) on a 12h light/dark cycle (0800h lights on; 2000h lights off). Prior to the onset of

behavioural testing, food (Teklad Global 16% Protein Rodent Maintenance Diet, Harlan

Teklad, WI) and water were available ad libitum.

Behavioural testing commenced when mice were approximately 12-months-of-

age (when AD pathology is sufficiently developed). All behavioural testing was

conducted during the light phase of the light/dark cycle. All procedures adhered to the

guidelines of the Canadian Council on Animal Care and were approved by the Animal

Care Committee at the University of Guelph.

Behavioural Testing

Prior to behavioural testing all mice were extensively handled and habituated to

an empty testing apparatus for 10min on two consecutive days.

24

Apparatus, Objects & General Procedure. In all object processing paradigms, a

JVC everio camcorder was placed above the testing apparatus for recording and

subsequent analysis of behavioural data using ORscore. An unused set of objects was

used for each trial in a given cohort of mice. Objects were distinct, approximately 5-15cm

tall and made of glass, metal, or plastic. Objects had no apparent biological significance

to mice and were equally preferred within each pair. All objects were fixed to the floor of

the testing apparatus with white adhesive putty. Immediately prior to behavioural testing

mice were brought into the testing room in their home cage. To prevent ‘pre-exposure’ to

objects before the start of the testing phase, mice were placed into a bottomless cardboard

box (start box) located in the middle of the open-field or in the start arm of the Y-

apparatus. The trial began when the start box was opened or removed and the mouse

exited the start box/arm. Between behavioural trials objects were wiped with 50% ethanol

(to eliminate olfactory cues) and the testing apparatus was only wiped with a dry paper

towel.

Cohorts of mice were tested on several object processing paradigms. The first

cohorts of 5xFAD and 3xTG male and female were tested on open-field OR then Y-

apparatus OR (experiment 1). The second cohorts of 5xFAD and 3xTG male and female

mice were tested on object oddity (experiment 4) then object location (experiment 2). The

third cohort of 5xFAD and 3xTG females were tested on temporal order (experiment 3).

25

Experiment 1

Open-Field Object Recognition. The open-field SOR task (Figure 1a) assesses the

ability of rodents to distinguish a previously explored object from a novel object. Open-

field OR was conducted in a square open arena (45 45 30 cm) made entirely of white

corrugated plastic. When object recognition is evaluated in the open-field, mice are able

to see many contextual cues in the testing room; thus spatial information is readily

available. The object recognition task is comprised of a sample (learning) phase and

choice (test) phase. In the sample phase mice were presented with two identical objects in

the top corners of the arena 5cm from the wall for 10min. A retention delay of either

5min or 3h was used to alter the mnemonic demand of the task. Specifically, a 5min

delay was used to evaluate short-term memory and 3h delay to evaluate long-term

memory; all mice were tested with each delay on separate counterbalanced trials at least

48h apart. Following the retention delay, in the 2min choice phase mice were presented

with one object from the sample phase and a novel object. The location of the novel

object was counterbalanced between and within mice. If memory is intact, mice

preferentially explore the novel object.

Y-Apparatus Object Recognition. SOR was also evaluated in a Y-apparatus

(Figure 1b), which has walls 30.5cm high, and arms 15cm long and 7cm wide

constructed from white Plexiglas. The start arm of the Y-apparatus has a guillotine door

11cm from the back of the arm. When SOR is conducted in the Y-apparatus, spatial

information is minimized, allowing for systematic evaluation of object identity

processing (Winters et al., 2004, 2008). In the sample phase (10min) mice were presented

26

with two identical objects in the end of the arms. Following a retention delay (see above)

in the choice phase mice were presented with an object from the sample phase and a

novel object. The location of the novel object was counterbalanced between and within

mice. If memory is intact, mice preferentially explore the novel object.

Experiment 2

Object Location (OL). The OL task (Figure 1c) evaluates rodents’ ability to

distinguish between familiar and novel spatial locations. The OL task was conducted in

the same open-field arena used for open-filed object recognition testing (45 45 30 cm).

In the sample phase mice were presented with two identical objects for 10min. The

objects were placed in the top corners of the arena 5cm away from the walls. Following a

retention delay (see above), in the 2min choice phase, the identity of the two objects

remained unchanged, but one object was moved to an adjacent corner of the arena. The

relocated object was counterbalanced between and within mice. If memory is intact, mice

preferentially explore the object in the novel spatial location.

Experiment 3

Temporal Order. The temporal order task (Figure 1d) assesses rodents ability to

recognize the relative recency of object presentation (Gareth R I Barker & Warburton,

2011), or how recently an object has been presented. This task was conducted in the same

open-field arena (45 45 30 cm) used for OR and OL tasks. There are two sample phases

in this task (10min each). In each sample phase, mice were presented with two identical

objects in the top corners of the arena 5cm away from the walls; distinct objects were

27

used in sample phase 1 and 2. Following a retention delay (3min), in the choice phase

(2min) mice were presented with one object from each sample phase; thus both objects

were equally familiar, but one was more recently presented. The location of the more

remotely presented object in the choice phase was counterbalanced between and within

mice. If memory is intact, mice preferentially explore the object presented less recently

(i.e. the object from sample phase 1).

Experiment 4

Multisensory Oddity (MSO). Tactile-visual object oddity (Figure 1e) evaluates

multisensory perceptual integration in mice. The oddity task was conducted in a modified

trapezoid-like open-field (front wall 39cm, side wall 14cm, angled side wall 10cm, back

wall 28cm) such that the mice were restricted to a smaller section of the arena. In the

oddity task, mice were presented two pairs of objects for 10min that share the same

combinations of tactile and visual features (e.g., AB/AB and CD/CD), as well as a fifth

object that comprises a unique (i.e., ‘odd’) combination of those features (e.g., AD). The

location of the odd object was counterbalanced. Tactile object features were manipulated

using varieties of sandpaper with different grades, while visual object features were

manipulated using 2-D stickers with distinctive visual markings. Unimodal control trials

were also performed where only two tactile object features or two visual object features

were available; critically, for these control trials, the associative nature of the task

remained the same, but the stimulus dimensions being manipulated were not

multisensory. The location of the odd object was counterbalanced between mice. If

perception is intact, rodents explore the object with the same configurations of tactile and

28

visual features equally (AB/AB and CD/CD), resulting in a preference for the dissimilar

object (e.g. AD).

Behavioural Data Analysis

Exploration was defined as active sniffing within ~1cm of the object and/or

touching the object with the nose. ORscore was used to quantify object exploration

(seconds). Specifically, the experimenter viewed the mouse on a television screen and

pressed a key corresponding to a given stimulus type at the onset of an exploratory bout

and again at the end of a bout. The total 10min of sample and 2min of choice exploration

were quantified.

For all object memory tasks, the novelty preference was quantified by calculating

a discrimination ratio (DR) [(novel object exploration – familiar object exploration)/

(total object exploration)]. In the sample phase, as all objects should be equally novel, a

discrimination ratio of zero is expected. In the choice phase, a discrimination ratio

significantly greater than zero is indicative of intact memory. In the object oddity tasks,

the primary index of performance was quantified by calculating a preference for the odd

object (exploration of the odd object/ total object exploration). Mice that spent less than

3% of the choice duration (3.6s) and choice DR outliers (>2 SD mean) were excluded

from analysis.

Repeated measures ANOVAs were used, where appropriate, to analyze

discrimination ratios and total exploratory behaviour (at sample and choice), with

retention delay as a within-subjects factor and sex and genotype as between-subjects

29

factors. Independent samples t-tests, with the Bonferroni correction, were used to analyze

between group differences in the sample and choice phases. A significant increase in the

discrimination ratio from sample to choice was taken as indicative of intact memory and

was assessed using paired-samples t-tests. For multisensory object oddity a one-way

ANOVA with genotype as the between subjects factor was conducted on the oddity score

and total object exploration. Pearson product moment correlation coefficients were used

to examine the relationship between total sample exploration and novelty preference

index. All statistical analyses were conducted with a significance level of α = .05, unless

otherwise specified, using IBM SPSS statistics. Only significant effects on total

exploration are reported.

Results

Experiment 1: Open-Field & Y-Apparatus Object Recognition

1.1 5xFAD Open-Field Object Recognition

Recognition Memory during the Choice Phase. A three-way repeated measures

ANOVA demonstrated significant main effects of genotype F(1, 32) = 6.392, p = .017,

and delay F(1, 32) = 22.725, p < .001, as well as a significant genotype by delay

interaction F(1, 32) = 7.791, p = .009.

WT and TG 5xFAD females DR’s were not significantly different at 5min

t(13.651) = 1.601, p = .132, but were significantly different at 3h as indicated by a

significant independent samples t-test t(15) = 5.24, p < .001. Paired samples t-tests

between sample and choice DR indicated intact memory in WT females at 5min t(7) =

30

4.657, p = .002 and 3h t(7) = 3.928, p = .006, but impaired memory in TG females at

5min t(10) = .668, p = .519 and 3h t(8) = .335, p = .746. Independent samples t-tests

demonstrated WT and TG 5xFAD male DR’s did not significantly differ at 5min t(19) =

.677, p = .507, but were significantly different at 3h t(18) = 4.324, p < .001. Paired

samples t-tests between sample and choice DR indicated intact memory in WT males at

5min t(10) = 6.219, p < .001 and 3h t(9) = 4.346, p = .002, but impaired memory in

TG males at 5min t(9) = 2.070, p = .068 and 3h t(8) = .415, p = .689 (Figure 2).

Exploratory Behaviour during the Sample and Choice Phase. There was a

significant main effect of genotype F(1, 36) = 17.764, p < .001, as 5xFAD mice generally

explored less than WT in the sample phase. There was a significant main effect of

genotype for choice phase exploration F(1, 36) = 14.606, p = .001, again as TG mice

explored less overall than WT. There was a significant main effect of delay on

exploration during the choice phase F(1, 36) = 23.855, p < .001, such that mice generally

explored less at 3h than at 5min (see total exploration figures for general exploratory data

and specific comparisons for all experiments; Figure 3).

1.2 5xFAD Y-Apparatus Object Recognition

Recognition Memory during the Choice Phase. A three-way repeated measures

ANOVA demonstrated significant main effects of genotype F(1, 36) = 19.198, p < .001,

and delay F(1, 36) = 9.560, p = .004, as well as a significant genotype by delay

interaction F(1, 36) = 8.563, p = .006.

31

Independent samples t-tests demonstrated that WT and TG female DR’s

significantly differed at 5min t(16) = 3.289, p = .005 and were trending at 3h t(17) =

2.071, p = .054. Paired samples t-tests between sample and choice DR indicated

significantly intact memory in WT females at 5min t(7) = 6.195, p < .001, trending 3h

t(7) = 2.244, p = .060, but impaired memory in TG females at 5min t(10) = .407, p =

.692 and 3h t(10) = .870, p = .405. Independent samples t-tests demonstrated that WT and

TG male DR’s did not significantly differ at 5min t(19) = .838, p = .413, but were

significantly different at 3h t(19) = 3.556, p = .002. Paired samples t-tests between

sample and choice DR indicated intact memory in WT males at 5min t(10) = 3.253, p =

.009 and 3h t(10) = 2.787, p = .019, tending in TG males at 5min t(9) = 2.062, p = .069

and significantly impaired at 3h t(9) = 1.009, p = .339 (Figure 4).

Exploratory Behaviour during the Sample and Choice Phase. There was a

significant genotype by sex interaction on exploration during the choice phase F(1, 35) =

4.127, p = .050, but all other comparisons were non-significant (Figure 5).

Correlation Between Exploratory Behaviour during the Sample Phase and

Discrimination Ratio in the Choice Phase. There was a significant positive correlation

between total sample exploration and choice DR in TG females at 5min r(11) = .653, p =

.029 (see Table 3 for specific correlations between sample exploration and choice DR for

all experiments).

32

1.3 3xTG Open-field Object Recognition

Recognition Memory during the Choice Phase. A three-way repeated measures

ANOVA demonstrated significant main effects of genotype F(1, 36) = 41.616, p < .001,

and delay F(1, 36) = 4.839, p = .034.

WT and TG female DR’s significantly differed at 5min t(20) = 2.220, p = .038

and 3h t(20) = 3.489, p = .002 as indicated by significant independent samples t-tests.

Paired samples t-tests between sample and choice DR indicated intact memory in WT

females at 5min t(11) = 7.094, p < .001, 3h t(11) = 4.835, p - .001 and TG females at

5min t(9) = 4.096, p .003, but impaired memory at 3h t(9) = 1.230, p = .250.

Independent samples t-tests demonstrated WT and TG male DR’s significantly differed at

5min t(17) = 3.918, p = .001 and 3h t(16) = 3.000, p = .008. Paired samples t-tests

between sample and choice DR indicated intact memory in WT males at 5min t(10) =

7.619, p < .001 and 3h t(10)= 3.369, p = .007, and impaired memory in TG males at

5min t(6) = .413, p = .694 and 3h t(6) = .708, p = 505 (Figure 2).

Exploratory Behaviour During the Sample and Choice Phase. There were no

significant effects on total exploration during the sample phase. There was a significant

main effect of genotype F(1, 36) = 6.023, p = .019 on total exploration during the choice

phase, as TG explored less than WT. There was a significant main effect of delay on

exploration during the choice phase F(1, 36) = 6.350, p = .016, such that at 3h mice

generally explored less than at 5 min (Figure 3).

33

1.4 3xTG Y-Apparatus Object Recognition

Recognition Memory during the Choice Phase. A repeated measures ANOVA

demonstrated significant main effects of genotype F(1, 36) = 26.260, p < .001, and delay

F(1, 36) = 19.172, p < .001, as well as a significant genotype by delay interaction F(1,

36) = 21.012, p < .001.

Independent samples t-tests demonstrated that WT and TG female DR’s did not

differ at 5min t(20) = .334, p = .742, but were significantly different at 3h t(20) = 6.276,

p < .001. Paired samples t-tests between sample and choice DR indicated intact memory

in WT females at 5min t(11) = 4.013, p = .002, 3h t(11) = 7.740, p < .001 and TG

females at 5min t(9) = 8.264, p < .001, but impaired memory at 3h t(9) = .963, p = .361.

Independent samples t-tests demonstrated that WT and TG male DR’s did not differ at

5min t(16) = .067, p = .947, but were significantly different at 3h t(16) = 4.673, p < .001.

Paired samples t-tests between sample and choice DR indicated intact memory in WT

males at 5min t(10) = 4.453, p = .001, 3h t(10) = 6.851, p < .001 and TG males at 5min

t(6) = 4.321, p = .005, but impaired at 3h t(6) = .135, p = 897 (Figure 4).

Exploratory Behaviour During the Sample and Choice Phase. There was a

significant delay by sex by genotype interaction F(1, 35) = 4.184, p = .048, on

exploration during the sample phase. During the choice phase there was a significant

main effect of sex on exploration F(1, 36) = 4.732, p = .036, as female mice generally

explored less than males (Figure 5).

34

Correlation Between Exploratory Behaviour during the Sample Phase and

Discrimination Ratio in the Choice Phase. There was a significant negative correlation

between total sample exploration and choice DR in TG females at 5min r(10) = -.646, p =

.044 (Table 3).

Experiment 2: Object Location

2.1 5xFAD Object Location

Recognition Memory during the Choice Phase. A repeated measures ANOVA

demonstrated a significant main effect of genotype F(1, 40) = 4.528, p = 040 and a

significant genotype by sex interaction F(1, 40) = 4.945, p = .032.

Independent samples t-tests demonstrated a trending difference between WT and

TG female DR’s at 5min t(11.370) = 1.966, p = .074 and a significant difference at 3h

t(19) = 4.209, p < .001. Paired samples t-tests between sample and choice DR indicated

intact memory in WT females at 5min t(11) = 4.013, p = .002 and 3h t(9) = 2.663, p =

.026, impaired memory in TG females at 5min t(10) = .522, p = .613, and a trending

familiarity preference at 3h t(10) = 2.098, p = .062. Independent samples t-tests

demonstrated a non-significant difference between WT and TG male DR’s at 5min t(20)

= .946, p = .356 and 3h t(20) = -1.058, p = .303. Paired samples t-tests between sample

and choice DR indicated impaired memory in WT t(9) = -1.359, p = 207 and TG males

t(11) = -1.467, p = .170 at 5min. Paired samples t-tests between sample and choice DR

indicated impaired memory in WT males at 3h t(9) = -1.335, p = .215, but intact memory

in TG males t(11) = -3.099, p = .010 (Figure 6).

35

Exploratory Behaviour During the Sample and Choice Phase. There was a

significant main effect of delay on exploration during the sample phase F(1, 40) =

12.649, p = .001, a significant delay by genotype interaction F(1, 40) = 5.917, p = 020,

and a significant delay genotype by sex interaction F(1, 40) = 4.445, p = .041. There was

a significant main effect of genotype on total exploration during the choice phase F(1,

40) = 6.021, p = 019, a significant main effect of sex F(1, 40) = 11.210, p = .002, and a

significant genotype by sex interaction F(1, 40) = 4.319, p = 044 (Figure 7).

2.2 3xTG Object Location

Recognition Memory during the Choice Phase. A repeated measures ANOVA

demonstrated significant main effects of genotype F(1, 50) = 43.417, p < .001, and delay

F(1, 50) = 16.387, p < .001.

Independent samples t-tests demonstrated a significant difference between WT

and TG female DR’s at 5min t(27) = 3.247, p = .003 and 3h t(17.965) = 7.090, p < .001.

Paired samples t-tests between sample and choice DR indicated intact memory in WT

females at 5min t(13) = 5.264, p < .001 and 3h t(14) = 10.856, p < .001, and impaired

memory in TG females at 5min t(13) = 1.149, p = .271 and 3h t(13) = .576, p = .575.

Independent samples t-tests demonstrated a significant difference between WT and TG

male DR’s at 5min t(25) = 3.071, p = .005 and 3h t(23) = 2.738, p = .012. Paired samples

t-tests between sample and choice DR indicated intact memory in WT males at 5min

t(12) = 3.850, p = .002 and trending at 3h t(10) = 1.978, p = .076, and significantly

36

impaired memory in TG males at 5min t(13) = 1.251, p = .233 and a significant

familiarity preference at 3h t(12) = 2.518, p = .027 (Figure 6).

Exploratory Behaviour During the Sample and Choice Phase. There was a

significant main effect of delay on exploration during the sample phase F(1, 49) = 5.126,

p = .028, and a significant delay by genotype interaction F(1, 49) = 25.305, p < .001, on

exploration during the sample phase. There was a significant main effect of sex on

exploration during the choice phase F(1, 50) = 17.202, p < .001, such that females

generally explored more than males (Figure 7).

Experiment 3: Temporal Order

3.1 5xFAD Temporal Order

Recognition Memory during the Choice Phase. Independent sample t-tests

demonstrated a non-significant difference between WT and TG female DR’s at 3min

t(23) = 1.402, p = .174. Paired sample t-tests between sample and choice DR indicated

impaired memory in WT t(13) = -.453, p = .658 and TG t(10) = 1.370, p = .201 females

at 3min (Figure 8).

Exploratory Behaviour During the Sample and Choice Phase. There was a

significant effect of genotype on total exploration during sample phase one t(25) = 2.979,

p = .006, such that TG generally explored less than WT mice (Figure 9).

37

Correlation Between Exploratory Behaviour and Oddity Preference. There was a

significant positive correlation between total sample exploratory behaviour and choice

DR in WT females r(14) = .584, p = .028. There was a significant negative correlation

between total sample exploratory behaviour and choice DR in TG females r(11) = -.648,

p = .031 (Table 3).

3.2 3xTG Temporal Order

Recognition Memory during the Choice Phase. Independent samples t-tests

demonstrated a significant difference between WT and TG female DR’s at 3min t(17) =

2.239, p = .039. Paired samples t-tests between sample and choice DR indicated intact

memory in WT females at 3min t(7) = 5.589, p = .001, but impaired memory in TG

females t(10) = .022, p = .983 (Figure 8).

Exploratory Behaviour During the Sample and Choice Phase. There were no

significant effects of genotype on total exploration during the sample and choice phases

(Figure 9).

Experiment 4: Multisensory Object Oddity

4.1 5xFAD Multisensory Object Oddity

Oddity Preference. A three-way repeated measures ANOVA demonstrated a

significant main effect of task F(2, 78) = 3.740, p = .035 and a significant task by sex

interaction F(2, 78) = 4.302, p = .022.

38

Independent samples t-tests demonstrated a significant difference between WT

and TG females on the MSO task t(19) = 3.547, p = .002. One-sample t-tests indicated

MSO oddity scores above chance in WT females t(9) = 6.018, p < .001, but not in TG

females t(10) = .058, p = .955. Independent samples t-tests demonstrated a significant

difference between WT and TG females on the visual task t(19) = 3.547, p = .002. One-

sample t-tests demonstrated visual perception above chance performance in WT females

t(9) = 4.4092, p = .003 and TG females t(10) = 3.366, p = .007. Independent samples t-

tests demonstrated a non-significant difference between WT and TG females on the

tactile task t(19) = .303, p = .765. One-sample t-tests demonstrated tactile perception

above chance performance in WT females t(9) = 3.062, p = .014 and TG females t(10) =

4.502, p = 4.502, p = .001. Independent samples t-tests demonstrated a non-significant

difference between WT and TG males on the MSO task t(20) = .863, p = .398. One-

sample t-tests demonstrated impaired multisensory perception in WT t(9) = -.409, p =

.692 and TG males t(11) = -1.978, p = .073. Independent samples t-tests indicated no

difference between WT and TG males on the visual tsk t(20) = .189, p = .852. One-

sample t-tests demonstrated intact visual perception in WT males t(9) = 2.749, p = 023,

but impaired visual perception in TG males t(11) = 1.619, p = .134. Independent samples

t-tests demonstrated a non-significant difference between WT and TG males on the tactile

task t(20) = .778, p = .447. One-sample t-tests demonstrated impaired tactile perception

in WT t(9) = 2.123, p = 066 and TG males t(11) = 1.127, p = .286 (Figure 10).

Total Exploratory Behaviour. There was a significant main effect of task on

exploration during the sample phase F(2, 78) = 27.775, p < .001 and a significant task by

39

genotype interaction on exploration during the sample phase F(2, 78) = 3.628, p = .043.

There was a significant main effect of sex F(1, 39) = 22.560, p < .001 and genotype F(1,

39) = 12.781, p = .001 on exploration during the sample phase (Figure 11).

Correlation Between Exploratory Behaviour and Oddity Preference. There was a

significant negative correlation between total exploratory behaviour and MSO oddity

preference TG females r(11) = -.822, p = .002. There was a significant positive

correlation between total exploratory behaviour and visual oddity preference in TG males

r(12) = .737, p = .006 (Table 3).

4.2 3xTG Multisensory Object Oddity

Oddity Preference. A three-way repeated measures ANOVA demonstrated a

significant main effect of task , F(2, 104) = 4.795, p = .010 and a significant task by

genotype interaction F(1, 104) = 6.967, p = .001.

Independent samples t-tests demonstrated a significant difference between WT

and TG females on the MSO task t(27) = 3.218, p = .003. One-sample t-tests

demonstrated multisensory perception above chance performance in WT females t(14) =

5.333, p < .001, and in TG females t(13) = 2.156, p = .050. Independent samples t-tests

demonstrated a non-significant difference between WT and TG females on the visual task

t(27) = .295, p = .770. One-sample t-tests demonstrated visual perception above chance

performance in WT females t(14) = 5.627, p < .001, and in TG females t(13) = 4.027, p =

.001. Independent samples t-tests demonstrated a non-significant difference between WT

40

and TG females on the tactile task t(27) = 1.232 , p = .229. One-sample t-tests

demonstrated tactile perception above chance performance in WT females t(14) = 6.460,

p < .001, and in TG females t(13) = 3.788, p = .002. Independent samples t-tests

demonstrated a significant difference between WT and TG males on the MSO task t(25)

= 3.059, p = .005. One-sample t-tests demonstrated multisensory perception above

chance performance in WT males t(12) = 4,572, p =.001, but impaired multisensory

perception in TG males t(13) = .401, p = .695. Independent samples t-tests indicated no

difference between WT and TG males on the visual task t(25) = 1.901, p = .069. One-

sample t-tests demonstrated visual perception above chance performance in TG males

t(13) = 3.609, p = .003, but not WT males t(12) = 1.274, p = .227. Independent samples t-

tests demonstrated a non-significant difference between WT and TG males on the tactile

task t(25) = .858, p = .399. One-sample t-tests demonstrated visual perception above

chance performance in WT males t(12) = 4.535, p = .001 and TG males t(13) = 5.065, p <

.001 (Figure 10).

Total Exploratory Behaviour. There was a significant main effect of task on

exploration during the sample phase F(2, 104) = 18.988, p < .001, as mice generally

explored the objects more in the tactile oddity task (Figure 11).

Discussion

Results are consistent with a multifaceted impairment in object processing in

5xFAD and 3xTG transgenic mice. Memory for object identity, as evaluated using open-

field and Y-apparatus OR paradigms, is dissociable across transgenic AD strain and sex.

41

Specifically, 5xFAD males and females were impaired on open-field OR when the

retention delay was 5min or 3h. However, when spatial and contextual cues were

minimized, using a modified Y-apparatus, 5xFAD males and females are impaired at

5min and 3h. However, the 5xFAD female WT were unable to perform open-field OR at

3h. 3xTG males were impaired on open-field OR at 5min and 3h, whereas females were

selectively impaired at 3h. 3xTG males and females were selectively impaired on Y-

apparatus OR at 3h. Conversely, memory for the spatial location of objects, assessed

using the object location paradigm, was impaired in 5xFAD females and 3xTG females

with 5min and 3h delays. 3xTG males had impaired OL at 5min but a familiarity

preference at 3h. 5xFAD WT and TG males had impaired OL at 5min, whereas only WT

males had impaired OL at 3h. Temporal processing was also impaired in WT and

transgenic 5xFAD females and transgenic 3xTG females at 3min. Lastly, multisensory

perception was impaired in 5xFAD females, as well as 3xTG males and females, despite

intact basic visual and tactile object perception. 5xFAD WT and TG males had impaired

multisensory perception. 5xFAD TG males were also impaired on visual and tactile

object perception and 5xFAD WT males had impaired tactile perception (Table 4). It is

important to note that when WT performance is impaired it is difficult to make

conclusions about object processing in TG mice.

Object Recognition

In agreement with previous research, we have demonstrated impaired object

recognition when tested in an open-field with a retention delay ≥ 5min (Ambrée et al.,

2009; Bardgett et al., 2011; Dewachter et al., 2002; J. Dodart et al., 1999; Gerenu et al.,

42

2013; Giuliani et al., 2013; Greco et al., 2010; Hillen et al., 2010; Spilman et al., 2014;

Yuede et al., 2009). However, when we evaluated OR in the Y-apparatus behavioural

deficits appeared to be less severe in some cases, as indicated by intact short-term

memory in 3xTG males.

Better OR performance in the Y-apparatus is likely related to facilitated

processing of the objects themselves. There are several significant differences between

WT and TG exploration in the open-field that were not observed in the Y-apparatus,

particularly in the 5xFAD strain. Although object exploration during the sample phase

can positively correlate with DR’s (5xFAD female 5min Y-apparatus OR; 5xFAD WT

male visual oddity; Albasser, Davies, Futter, & Aggleton, 2009), in our recognition

experiments object exploration does not consistently correlate with choice DR’s. Indeed,

increased object exploration does not necessarily improve object encoding (Akkerman et

al., 2012; Gaskin et al., 2010). Gaskin et al. (2010), for example, found that the degree of

preference for the novel object does not correlate with total object exploration during the

sample phase, but rather a minimum amount of exploration is required to observe a

novelty preference. Therefore, increased exploration may not explain better OR

performance in the Y-apparatus. Still, the Y-apparatus appears to increase focus on

objects and has less potentially distracting or interfering contextual stimuli than the open-

field. Perhaps transgenic AD mice have insufficient mnemonic resources for object and

environmental information in the open-field. Indeed, familiarity with the testing

environment can influence DR’s (Besheer & Bevins, 2000; Gaskin et al., 2010;

Wilkinson, Herrman, Palmatier, & Bevins, 2006); Wilkinson et al. (2006), for example,

43

demonstrated that rats familiarized with the test environment had greater exploration of

the novel object.

Enhanced OR memory at short retention delays and when spatial information is

limited may also be indicative of the severity of AD neuropathology in the HPC.

Shortening the retention delay and limiting spatial information may alter the necessity of

the HPC in OR memory. Hammond et al., (2004) temporarily inactivated the HPC and

evaluated short (5min) and long-term OR memory in mice. OR was intact at 5min but

impaired at 24h. This finding suggests the HPC is critically involved in OR at long

retention delays, whereas at short delays the PRh is likely sufficient to support OR

memory. Furthermore, a contextually rich open-field OR paradigm may encourage

increased processing of the spatial environment and require functional integrity of the

HPC as well as the PRh (Barker & Warburton, 2011; Forwood et al., 2005; Winters et al.,

2004). Although Aβ, hyperphosphorylated tau and neuronal loss are present in the HPC

and association cortices areas, including the PRh (Braak & Braak, 1991, 1995; Davis,

Easton, et al., 2013; Oakley et al., 2006; Oddo, Caccamo, Shepherd, et al., 2003; Scahill

et al., 2002; Whitwell et al., 2007) by 12 months of age, our findings, and others (Davis,

Easton, et al., 2013), suggest that HPC-dependent object processing may be more

sensitive to AD pathology. Interestingly, 5xFAD mice appear to be more impaired in

SOR than 3xTG, as shown by a delay-independent impairment in OR paradigms.

Behavioural deficits may be more severe in the 5xFAD model because 3xTG mice do not

have hippocampal neuronal loss and have a less aggressive Aβ pathology (Kastyak-

44

Ibrahim et al., 2013; Li, Ebrahimi, & Schluesener, 2013; Manaye et al., 2013; Oakley et

al., 2006; Oddo, Caccamo, Shepherd, et al., 2003).

AD prevalence, incidence and Aβ plaque deposition is higher in women than men

(Corder et al., 2004; Rocca, Amaducci, & Schoenberg, 1986; Ruitenberg, Ott, Van

Swieten, Hofman, & Breteler, 2001). Similarly, 5xFAD mice have an early and

aggressive Aβ pathology that is more severe in female mice (Bhattacharya, Haertel,

Maelicke, & Montag, 2014; Oakley et al., 2006; Reid & Darvesh, 2015). Since Aβ

pathology correlates with impaired synaptic plasticity and memory (Chapman et al.,

1999; Oddo, Caccamo, Shepherd, et al., 2003; Puoliväli et al., 2002; Shankar et al.,

2008), perhaps a more aggressive amyloid pathology is sufficient to block the beneficial

effects of short retention delays and limited spatial information on OR memory in female

5xFAD mice. Conversely, 3xTG females had a less severe OR deficit than males.

Specifically, short-term OR memory was intact in 3xTG females in open-field and Y-

apparatus OR, whereas 3xTG males had short-term open-field OR deficits that were not

observed at short retention delays in the Y-apparatus by limiting spatial information and

increasing object exploration. Our finding is consistent with sexual dimorphism in

working memory, such that 3xTG males have a more severe behavioural deficit

beginning at two-months-of-age (Stevens & Brown, 2015). Although a more aggressive

amyloid pathology has been reported in 3xTG females (Carroll et al., 2010; Clinton et al.,

2007; Hirata-Fukae et al., 2008), there may be differential effects of organizational and

activational sex hormones on AD pathology (Carroll et al., 2007, 2010). Perinatal female

sex hormones increase adult 3xTG vulnerability to Aβ (Carroll et al., 2010). Conversely,

45

activational estrogens are believed to be neuroprotective against Alzheimer’s pathology.

Ovariectomy-induced depletion of sex hormones in 3xTG females increases Aβ

accumulation and impairs HPC-dependent memory, an effect that can be attenuated by

estrogen treatment (Carroll & Pike, 2008; Carroll et al., 2007; Levin-allerhand,

Lominska, Wang, & Smith, 2002; Zheng et al., 2002). Interestingly, tauopathy correlates

more strongly with behavioural deficits in human AD patients (Giannakopoulos et al.,

2003; Guillozet, Weintraub, Mash, & Mesulam, 2003) and mnemonic improvement

requires alteration of both Aβ and tau pathology in 3xTG mice (Oddo, Caccamo, et al.,

2006a). Sexual dimorphism in 3xTG tauopathy has not been reported (Hirata-Fukae et

al., 2008); however adult progesterone and estrogen treatment reduces tau

hyperphosphorylation in 3xTG females and 3xTG males, respectively (Carroll et al.,

2007; Rosario, Carroll, & Pike, 2010). Thus, it is possible that female adult sex hormones

are protective against AD neuropathology and object recognition deficits in 3xTG

females but not 5xFAD females. It is also possible that differences in male and female

longevity contributed to sex differences in 3xTG mice. Specifically, 3xTG TG females

have a longer lifespan than TG males (Rae & Brown, 2015).

Object Location

Processing of object spatial location was also compromised in transgenic AD

mice. Impaired object location memory in 5xFAD and 3xTG mice is consistent with

abnormal spatial processing of objects (abnormal canonical orientation and mental

rotation; Caterini et al., 2002) and spatial memory (Amieva et al., 2005; Blackwell,

Vesey, Semple, Robbins, 2003; Lee et al., 2014; Toledo-Morrell & Dickerson, 2000) in

46

human AD patients, as well as impaired contextual fear conditioning (Espana et al., 2010;

Jacobsen et al., 2006; Kimura & Ohno, 2009; Medeiros et al., 2014); Morris water maze

(Billings, Green, McGaugh, & LaFerla, 2007; Billings et al., 2005; Chen et al., 2000;

Clinton et al., 2007; Gulinello et al., 2009; Kotilinek et al., 2002; Lesné et al., 2006;

Medeiros et al., 2014; Puoliväli et al., 2002; Schneider, Baldauf, Wetzel, & Reymann,

2014; Zhang et al., 2013); and object location (Bollen et al., 2013; Davis, Easton, et al.,

2013; Dodel et al., 2011; Frye & Walf, 2008; Good et al., 2007; Gulinello et al., 2009;

Kornecook, McKinney, Ferguson, & Dodart, 2010; Kroker et al., 2014; Ma et al., 2013;

Masciopinto et al., 2012; Middei et al., 2006) memory in transgenic AD mice.

Paradoxically, OL was selectively intact in 5xFAD males at 3h. Short- but not

long-term memory deficits have been reported in rodents, and suggest STM and LTM

have some distinct non-overlapping neurobiological mechanisms (Barker, 2006;

Izquierdo, Medina, Vianna, Izquierdo, & Barros, 1999; Morice et al., 2008). Given the

OL impairment at 5min, the inability of WT males to perform OL at 3h and impaired

long-term memory on all other object processing tasks, it may be problematic to conclude

spatial memory is intact in 5xFAD males at 3h. It is possible other non-mnemonic factors

may have contributed to task performance. A significant OL familiarity preference was

observed in transgenic 3xTG males at 3h. A familiarity preference may imply intact

memory, and could reflect abnormities in habituation, dishabituation or novelty

preference. Abnormal dishabituation, but not habituation, and neophobia to a novel

context have been observed in APP transgenic mice (Hsiao et al., 1995; Sanchez et al.,

2012). However, we occasionally observe familiarity preferences in object recognition

47

data that do not consistently reflect mnemonic abilities. For example, a preference for the

familiar side-to-be is present in the sample phase of open-field OR in 5xFAD females at

3h. Further, the familiarity preference was not observed at the 5min delay. In this case, it

is possible the familiarity preference is due to a sample DR greater than zero.

Impaired OL across strain and sex suggests that spatial processing of objects may

be more difficult for transgenic AD mice than the processing of object features. Indeed,

previous findings with APP/PS1 and 3xTG mice have demonstrated impaired OL but not

OR (Davis, Easton, et al., 2013; Frye & Walf, 2008; Gulinello et al., 2009), which may

be related to the development of OL impairments prior to standard OR (Middei et al.,

2006). At 12 months of age Aβ and hyperphosphorylated tau are present in the HPC of

5xFAD and 3xTG mice (Kanno, Tsuchiya, & Nishizaki, 2014a; Oakley et al., 2006;

Oddo, Caccamo, Shepherd, et al., 2003), while 5xFAD mice also have hippocampal

synaptic loss (Oakley et al., 2006). As OL is a HPC-dependent task this finding provides

additional support for susceptibility of HPC-dependent processes to AD pathology

(Assini et al., 2009; Oakley et al., 2006; Oddo, Caccamo, Shepherd, et al., 2003).

However, 5xFAD male WT mice were unable to perform the OL task at both retention

delays and 3xTG WT males were unable to perform OL at 3h, and it is possible that some

OL deficits in males may be related to general aging rather than AD pathology. Indeed,

female rodents can outperform males on OL tasks (Saucier, Shultz, Keller, Cook, &

Binsted, 2008), and HPC dependent OL is impaired in aged mice (Wang, Li, Dong, Lv,

& Tang, 2009; Wimmer, Hernandez, Blackwell, & Abel, 2012).

48

Temporal Order

We also report that temporal processing of object information is impaired in AD

models. 5xFAD and WT female mice were unable to perform the temporal order task,

whereas transgenic 3xTG females failed to differentiate between objects presented in

sequential order. Impaired temporal object processing is in agreement with impaired

temporal context memory in human AD patients (Becker et al., 1993; Kopelman, 1989).

Specifically, AD patients were impaired at identifying when news and autobiographical

events occurred in time and how recently an object or image had been presented.

Previous examination of temporal order memory in AD transgenic mice has failed to

demonstrate an impairment in temporal processing (Davis, Easton, et al., 2013; Hale &

Good, 2005). However, differences in strain, age of testing and retention delay might

account for discrepancies in mnemonic impairment. Hale & Good (2005) evaluated

temporal order in Tg2576 male mice (a model of Aβ pathology) at 14 months of age with

a 2min retention delay. Unlike the 3xTG model, Tg2576 does not recapitulate tauopathy

and a slightly shorter retention delay should have reduced the mnemonic demand. Davis

et al. (2013) assessed temporal order in 3xTG female mice at 4.5 months of age with a 5

min retention delay. Although mnemonic deficits can be detected at 4.5-months-of-age in

3xTG mice (Billings et al., 2005), Aβ and tau pathologies do not develop until 6 and 12

months of age, respectively (Oddo, Caccamo, Shepherd, et al., 2003). Therefore,

impaired temporal processing at 12 months of age, as reported here, is likely related to a

more developed AD pathology (Oakley et al., 2006; Oddo, Caccamo, Shepherd, et al.,

2003).

49

The TO impairment reported here in 3xTG mice reveals a distinct behavioural

impairment in temporal processing of objects. Given the need for a shorter retention

delay (WT and TG could not perform TO with 5min retention delays; data not shown),

and the fact that a deficit in the standard OR paradigm would predict preferential

exploration of the first (more remote) object rather than equal preference for both objects,

TO appears to be more difficult than basic OR and it is unlikely that impairments are due

to an inability to recognize the objects per se. Thus, object processing required for TO

may be differentially affected by AD pathology. Since the HPC, PRh, and mPFC network

is necessary for temporal object processing, TO deficits reemphasize the vulnerability of

the MTL to AD pathology and suggests impaired connectivity between the HPC+PRh

and HPC+mPFC (Barker & Warburton, 2011; Hannesson et al., 2004; Mitchell &

Laiacona, 1998). Consistent with this idea, AD neuropathology causes degeneration of

myelin (Xu et al., 2001) and may damage neural networks (Bartzokis, 2004). Extensive

Aβ and tau pathology in the perforant pathway (the principle pathway relaying input from

entorhinal cortex to the HPC; Steward, 1976; Van Hoesen, Pandya, & Butters, 1972),

CA1 and subiculum (HPC output; Rosene & Van Hoesen, 1977; Swanson, Wyss, &

Cowan, 1978) in AD patients may effectively disconnect the HPC from cortical

structures (Hyman et al., 1984; Hyman, Van Hoesen, Kromer, & Damasio, 1986; Wang

et al., 2006). Alzheimer’s patients have reduced functional connectivity between the

prefrontal cortex and HPC and impaired memory when performing a delayed match to

sample paradigm (Grady, Furey, Pietrini, Horwitz, & Rapoport, 2001). Aβ also disrupts

connectivity in transgenic AD mice (Hsai et al., 1999), and disconnection between the

cortex and HPC is present in PDAPP mice. Specifically aged PDAPP mice have atrophy

50

of the corpus callosum, fornix and HPC (Gonzalez-Lima, Berndt, Valla, Games, &

Reiman, 2001). In 3xTG mice, white matter atrophy in the entorhinal cortex and HPC is

evident by 2 months of age (Desai et al., 2009), and may disrupt the HPC, PRh and

mPFC network required for temporal memory.

Multisensory Object Oddity

Multisensory integration is a neglected facet of object processing in the field of

AD research. Notably, the current results represent the first demonstration of impaired

multisensory processing in transgenic models of AD. Here, we have shown a selective

impairment on visual-tactile perceptual binding in 5xFAD female and 3xTG mice,

whereas visual-only and tactile-only object perception were intact. Both TG and WT

5xFAD male mice were impaired on visual-tactile and tactile-only object perception.

Further, 5xFAD male TG were also impaired on visual-only object perception.

Previous findings with human patients also suggest abnormal multisensory

integration in AD (Wu et al., 2012). Control, MCI and AD patients performed audio-

visual tasks in which they responded to either audio, visual, or audio-visual stimuli. AD

patients could accurately perform multimodal audio-visual trials but reaction times were

significantly longer, suggesting that AD pathology attenuates the well-established

beneficial effects of multisensory integration. Delbeuck et al. (2007) have also

demonstrated impaired audio-visual speech perception in AD patients. Specifically, AD

patients, unlike age-matched controls, failed to combine dissimilar audio and visual

speech information.

51

Multisensory perception involves the binding of information across sensory

modalities, which can require functional connectivity of modality-specific sensory

processing and multisensory areas (Cloke et al., 2014; Hindley, Nelson, Aggleton, &

Vann, 2014; Jacklin, Cloke, Potvin, Garrett, & Winters, 2016; Winters & Reid, 2010).

Consistent with multisensory impairment, Aβ plaques and neurofibrillary tangles disrupt

cortical connectivity, specifically areas that receive input from multimodal areas (de

LaCoste & White, 1993; Delbeuck, Van der Linden, & Collette, 2010). Indeed, Golob et

al. (2001) demonstrated abnormal sensory cortical evoked potentials elicited by pairs of

audio-visual stimuli. Specifically, only when a visual stimulus was presented prior to an

auditory stimulus was a refractory effect not present in AD patients. This finding suggests

a disconnection between, but not within, visual and auditory cortices (Delbeuck et al.,

2010; Golob et al., 2001). In aged APP/PS1 mice cortico-cortical fibers, including those

originating in the visual cortex, are preferentially disrupted compared to fibers originating

from subcortical structures (Delatour, Blanchard, Pradier, & Duyckaerts, 2004). Although

transgenic AD mice have distinct pathological profiles, impaired connectivity between

cortical regions may impair binding of visual and tactile object information, but not

unimodal visual or tactile information, in 5xFAD and 3xTG mice.

General Discussion

Memory deficits in AD are widespread and are related to impaired working

memory (Baddeley, Logie, Bressi, Sala, & Spinnler, 1986; Baddeley, Bressi, Della Sala,

Logie, & Spinnler, 1991), as well as the inability to learn, encode and store new

52

information (Delis et al., 1991; Golby et al., 2005; Granholm & Butters, 1988; Hodges,

Salmon, & Butters, 1990; Pihlajamaki, O’Keefe, O’Brien, Blacker, & Sperling, 2011;

Sperling et al., 2003; Weintraub, Wicklund, & Salmon, 2012; White & Ruske, 2002). For

example, AD patients have difficulty performing multiple tasks at once and recalling

word lists, geometric shapes, and face-name pairs. Recently, selective HPC-dependent

memory encoding deficits have also been reported in young APP/PS1 mice (Roy et al.,

2016). However, as AD pathology progresses behavioural deficits become more severe

and various mnemonic processes may be compromised.

The current results suggest that 12-month-old 5xFAD and 3xTG mice do not have

universal deficits in object perception and memory. Specifically, we have observed

impairments in cognitive processes, ranging from object identity and spatial memory to

multisensory object feature binding. Given that basic unimodal tactile and visual object

perception are intact across strains as well as short-term OR memory in 3xTG mice, basic

encoding of objects is likely intact. Although we have observed short-term object

processing impairments for object identity, location and temporal recency, these deficits

may be attributed to increased susceptibility of complex conjunctive object

representations and short-term or working memory to AD pathology. HPC, PRh, mPFC

networks that are required for hierarchical object representations in which the PRh is

important for storage of complex conjunctive object feature representations, whereas the

HPC and mPFC combine object representations with space, context and time (Barker &

Warburton, 2011; Cowell, Bussey, & Saksida, 2006, 2010) are vulnerable to AD

pathology (Gonzalez-Lima et al., 2001; Grady et al., 2001). This network is affected in

53

5xFAD and 3xTG mice. In 3xTG mice, by 12 months of age Aβ is prevalent in the

frontal cortex, entorhinal cortex, and hippocampus and hyperphosphorylated tau is

evident in the HPC (Janelsins et al., 2005; Oddo, Caccamo, Kitazawa, Tseng, & LaFerla,

2003; Oddo, Caccamo, et al., 2006b; Oddo, Caccamo, Shepherd, et al., 2003; Oddo,

Vasilevko, et al., 2006). An association between type of object processing and retention

delay was not generally observed in 5xFAD mice. It could be argued that broad delay-

independent impairments in 5xFAD mice are due to a more aggressive AD pathology.

Specifically, by 12 months of age 5xFAD mice have a very extensive Aβ pathology in the

frontal and entorhinal cortices and HPC, hyperphosphorylation of tau in the HPC, as well

as synaptic, neuronal and glial loss in the cortex and HPC (Bhattacharya et al., 2014;

Giannoni et al., 2013; Kanno et al., 2014a; Oakley et al., 2006). Critically, WT 5xFAD

mice were impaired on several object processing paradigms, ergo behavioural

impairments may also be related to accelerated aging and other abnormalities in the

5xFAD background strain. Indeed, the longevity of the 5xFAD WT background strain

SJL/J may be lower than the 3xTG background strain 129S1/SV1mJ (D’Antona et al.,

2010; Jaszberenyi et al., 2012; Rae & Brown, 2015). A more robust impairment was

observed in 5xFAD WT males and may be related to a shorter lifespan (Rae & Brown,

2015).

Due to the widespread damage from AD pathology in aged 5xFAD and 3xTG

mice that includes Aβ deposition and neuronal loss in the frontal cortex and HPC,

impaired short-term and working memory have relevance to object processing deficits.

For example, the putative visuo-spatial sketchpad is a human working memory scheme

54

involved in the temporary storage and manipulation of visual information, allowing the

time-limited maintenance of object features necessary to recognize a recently

encountered object (Baddeley, 2003). In our rodent object processing paradigms, working

memory may be required during the choice phase to maintain information about the

relative familiarity of objects.

Abnormal cholinergic function could be a central mechanism of object processing

dysfunction in transgenic AD mice. Cholinergic transmission is altered in these strains

(Da Cruz et al., 2012; Machová et al., 2008; Watanabe et al., 2009), and ACh is critical to

various facets of object processing. Specifically, ACh is implicated in working memory

(Fadda, Melis, & Stancampiano, 1996; Seeger et al., 2004), object recognition memory

(Aigner, Walker, & Mishkin, 1991; Bartko, Winters, Saksida, & Bussey, 2014; Prado et

al., 2006; Tinsley et al., 2011; Warburton et al., 2003; Winters et al., 2006), object

location (Murai et al., 2007), and temporal order (De Castro et al., 2009). There is also

evidence that ACh may be involved in synaptic plasticity (Bashir, 2003; Massey, Bhabra,

Cho, Brown, & Bashir, 2001; Warburton et al., 2003), which suggests a function of ACh

in object memory consolidation (Abe, Ishida, & Iwasaki, 2004). Furthermore, drugs that

increase cholinergic transmission attenuate object recognition deficits in transgenic AD

mice (Francis et al., 2012; Medeiros et al., 2014; Zhang et al., 2012).

It is important to consider non-mnemonic confounds on task performance because

some object processing impairments reported here were delay-independent. As object

oddity was generally intact in visual-only and tactile-only trials (excluding 5xFAD

55

males), basic object perception appears to be intact. However, abnormal emotional,

motor, and attention behaviour has been reported in transgenic AD mice. Attention

appears to be abnormal in transgenic AD mice. Unpublished data from our group, and

others (Romberg, Mattson, Mughal, Bussey, & Saksida, 2011), has shown impaired

attention on the 5-choice serial reaction time test in 3xTG and 5xFAD male and female

mice. Alterations in exploratory behaviour are consistent with previous studies (Arsenault

et al., 2011) and may relate to abnormal anxiety-like behaviour, and motor function in

transgenic AD mice. Aged 3xTG mice have increased anxiety- like behaviours including

increased restlessness, startle responses, and freezing (Espana et al., 2010; García-Mesa

et al., 2012; St-Amour et al., 2014; Sterniczuk, Antle, Laferla, & Dyck, 2010), whereas

motor behaviour is more complex with accounts of hypoactivity (García-Mesa et al.,

2012) or normal locomotion in the open-field (St-Amour et al., 2014), as well as

enhanced performance on other motor tasks (Filali et al., 2012; Stover et al., 2015).

Conversely, 5xFAD mice have reduced anxiety- like behaviours and motor deficits

(Jawhar, Trawicka, Jenneckens, Bayer, & Wirths, 2012; Schneider et al., 2014).

However, abnormal exploratory behaviour did not consistently correlate with OR

memory in the current study. Differences between WT and TG exploration, where TG

explored objects less than WT, were present in the OR, OL and MSO open-field

paradigms. In OR, exploration differences were not present in the Y-apparatus, but

similar behavioural patterns were observed. Thus, abnormal exploratory behaviour does

not consistently explain OR deficits in the current study.

56

In conclusion, object recognition is not a unitary cognitive function. In the current

study, the systematic characterization of different facets of object processing (object

identity, spatial location, temporal relationships, and multisensory features), reliant on the

integrity of distinct neurobiological substrates, across strain and sex has helped to clarify

the nature of behavioural deficits and the regional susceptibility to AD pathology in

transgenic mouse models.

57

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Appendix

Table 1

Transgenic Mouse Models of Alzheimer’s Disease

Transgenic Mouse Models of

Alzheimer’s

Disease

Genetic Manipulation Amyloid-β Hyperphosphorylated Tau &

Neurofibrillary Tangles Reference

5xFAD APP(695) with Swedish (K670N, M671L), Florida (I716V), and

London (V717I) mutations.

Aβ (2-months-of-age)

Hyperphosphorylated tau (~6-months-of-age). No tangles.

(Oakley et al., 2006)

3xTG Psen1 mutation and co-injected APPSwe and tauP301L.

Aβ (~3-4-months-of-age)

Hyperphosphorylated tau (6-months-of-age). Tangles (late ~12-15-months-of-age).

(Oddo, Caccamo, Shepherd, et al., 2003)

122

Table 2

Object Recognition Deficits in Transgenic Mouse Models of Alzheimer’s Disease

Transgenic

Strain

Sex Age Genetic,

Pharmacological, Surigcal or

Environmental Intervention

Inter-

Trial-Interval

Behavioural

Task

Behavioural

Result

Reference

J20 Male ~2

months of age

1h OR Tg intact OR. (Karl et

al., 2012)

J20 - 5-8

months of age

CX3CR1 GFP knock-in 24h OR APPTg intact

OR. CX3CR1 APP Tg impaired OR.

(Cho et

al., 2011)

J20 Male 6 months

of age

Poly(ADP-ribose) polymerase-1 (PARP-1;

nuclear protein that regulates cellular inflammatory responses)

24h OR Tg impaired OR. PARP-1

KO attenuated OR impairment in

Tg.

(Kauppinen et al.,

2011)

J20 Male & Female

4.5-6 months of age

Tropisetron (increase the ratio of the trophic, neurite-extending peptide sAPPα to the anti-trophic,

neurite-retractive peptide Aβ)

1h OR Tg impaired OR. Tropisetron attenuated

OR impairment in Tg.

(Spilman et al., 2014)

J20 & B254 Male 2-3, 5-7 months

of age

4h OR J20 and B254 impaired at 2-

3 and 5-7 months.

(Harris et al., 2010)

hAβPPswe-ind - 2, 4, 8 months of age

24h OR Tg impaired OR at 4 and 8 months.

(Simón et al., 2009)

hAPP - 4, 9-10 months

of age

Rosiglitazone (agonist at peroxisome proliferator-

activated receptor gamma (PPARc))

24h OR Tg impaired OR at 4 and

9-10 months. Rosiglitazone attenuated OR

impairment in Tg.

(Escribano et al.,

2009)

APP69K595N/M596L

Male 7 months of age

Xanthoceraside (triterpenoid saponin) and donepezil

24h OR Tg impaired OR at 1h and 24h.

Xanthoceraside and donepezil attenuated

OR impairment in Tg.

(Jin et al., 2014)

APPL/S Female 5.5-7.5 months

of age

LM11A-31 (p75^NTR ligand; neurotrophin

receptor ligand)

24h OR Tg impaired OR. LM11A-

31 attenuated OR impairment in Tg.

(Knowles et al.,

2013)

APP23 - 3.3

months of age

heterozygous neprilysin-

deficient background

24h OR APP23Tg

intact OR. Neprilysin deficiency induced OR

impairment in

(S.-M.

Huang et al., 2006)

123

APP23Tg.

APP23 Female 10 months of age

DSP-4 1h OR Tg impaired OR.

(Heneka et al., 2006)

PDAPP Male 8, 24 months of age

m226 Aβ antibody 3h OR Tg impaired OR at 8 and 24h months.

m226 attenuated OR

impairment in Tg at 24 months.

(J.-C. Dodart et al., 2002)

PDAPP Male 6-9, 13-15, 18-

21 months of age

10s, 1 min, 10min, 1h,

4h

OR Tg intact OR. (Chen, Chen,

Knox, Inglis, Bernard, Martin,

Justice, Mcconlogue, et al., 2000)

PDAPP Male 3, 6, 9-

10 months of age

3h OR Tg impaired

OR at 6, 9-10 months.

( Dodart

et al., 1999)

PDAPP Male &

Female

4, 10, 16

months of age

2,3,5,4'-tetrahydroxystilbene-2-O-

B-d-glucoside (TSG)

24h OR Tg impaired or at 4, 10, 16

months. TSG attenuated TG OR impairment at

10 and 16 months.

(Zhang et al., 2006)

APP/London Male & Female

4.5 months of age

A-887755 (Aβ globulomer specific antibody)

2.5h OR Tg impaired OR. A-887755

attenuated OR impairment in Tg.

(Hillen et al., 2010)

APPV7171 Male

& Female

4, 10

months of age

Icarrin (component of

herb-Epimedium)

24h OR Tg impaired

OR at 10 months Icarrin attenuated

OR impairment in Tg.

(Zhang et

al., 2014)

TgCRND8 Male ~3-4 months

of age

Levodopa ~1h OR (Note: Two object

tests over 2 days. First test used to habituate

mice to objects)

Tg impaired OR.

Levodopa attenuated OR impairment in

Tg.

(Ambrée et al.,

2009)

TgCRND8 Male ~5 months of age

Wheel runing 1h OR Tg impaired OR. Wheel running did

not alter Tg OR performance.

(Richter et al., 2008)

TgCRND8 - 3.5 months

of age

Dexefaroxan (a2-adrenoceptors antagonist)

and rivastigmine

3h OR Tg impaired OR.

Dexefaroxan

(Francis, Yang, et

al., 2012)

124

and rivastigmine attenuated OR deficit in

Tg.

TgCRND8 Male ~2 months of age

Deep brain stimulation (midline thalamic region)

1h OR Tg impaired OR. Deep brain stimulation

improved OR in Tg.

(Arrieta-Cruz et al., 2010)

TgCRND8 - 1, 2, 6-8 months of age

5min, 1h, 3h

OR Tg intact OR at 1 month. Tg impaired

OR with 5min or 3h retention

delay at 2 months. Tg impaired OR with 5min, 1h

and 3h retention delay at 6-8 months.

(Francis, Kim, et al., 2012)

TgCRND8 - 1, 2

months of age

Leptin 1h OR Tg impaired

OR at 1 and 2 months. Leptin attenuated

OR impairment in Tg.

(Greco et

al., 2010)

TgCRND8 Female ~3.8 months

of age

Environmental enrichment

90min OR Tg impaired OR.

Environmental enrichment improved OR in Wt and Tg.

(Görtz et al., 2008)

TgCRND8 - ~2

months of age

Memantine (N -methyl-D-

aspartic acid receptor antagonist) and sensory deprivation

1h False

recognition

Tg have false

recognition. Memantine and sensory deprivation

blocked false recognition in Tg.

(Romberg

et al., 2012)

TgCRND8 Female 14-16 months

of age

Nabs-Aβ (natural Aβ antibody)

30min OL Tg impaired OL. Nabs-Aβ

attenuated OL impairment in Tg.

(Dodel et al., 2011)

APP23 Male 7 months

of age

Environmental enrichment

24h OR Tg impaired OR.

Environmental enrichment attenuated OR deficit in

Tg.

(Polito et al., 2014)

Tg2576 Male & Female

~9 months of age

Voluntary or forced exercise

50min OR Voluntary exercise attenuated OR

impairment in Tg. (Note: did not evaluate

Wt).

(Yuede et al., 2009)

125

Tg2576 Female 6, 12 months of age

NK-4 (neurotrophic and antioxidant activity)

24h OR Tg impaired OR. NK-4 attenauted OR

impairment in Tg.

(Ohta et al., 2012)

Tg2576 Female ~14 months of age

Cognitive stimulation (food rewarded Lashley-like mazes)

1h, 24h OR Tg impaired OR at 1h and 24h.

Cognitive stimulation attenuated

OR deficit at 24h in Tg.

(Gerenu et al., 2013)

Tg2576 Male & Female

5 months of age

a7 nAChR knockout 24h OR Tg 2576 and a7KOTg2576 impaired OR.

(Hernandez et al., 2010)

Tg2576 - 12 months of age

T tpa-/- Mice (a-tocopherol transfer protein knockout)

24h, 28h OR Ttpa-/-Tg2576 mice impaired OR

at 24h and 48h.

(Nishida et al., 2006)

Tg2576 Male & Female

12-14 months of age

Ciproxifan (H3 receptor antagonist)

5min OR Tg impaired OR. Ciproxifan

attenuated OR impairment

(Bardgett et al., 2011)

Tg2576 Female 7 months

of age

CHF5074 (microglia modulator, non-steroidal

anti-inflammatory) and LY450139 (semagacestat) (gamma-secretase inhibitor)

4h OR Tg impaired OR.

CHF5074 attenuated OR impairment in

Tg.

(Giuliani et al.,

2013)

Tg2576 Female 7 months of age

24h OR Tg impaired OR.

(Beggiato et al., 2014)

Tg2576 Male & Female

5 months of age

FK506 (calcineurin inhibitor)

2min, 4h, 24h

OR Tg intact OR at 2min. Tg impaired OR

at 4h and 24h. FK506 attenuated OR

impairment in Tg.

(Taglialatela et al., 2009)

Tg2576 - 12 months of age

Nebivolol (B1 adrenergic receptor antagonist)

1h, 24h OR Nebivolol improved OR in Tg at 1h.

Nebivolol did not alter OR in Tg at 24h.

(Wang et al., 2013)

Tg2576 Female 18 months

of age

CHF5074 (non-steroidal anti-inflammatory

derivative, gamma secretase modulator)

4h OR Tg impaired OR.

CHF5074 attenuated OR impairment.

(Sivilia et al., 2013)

Tg2576 Female 6, 10,

13 months of age

Oral vaccine with a

recombinant adeno-associated viral vector carrying Aβ cDNA (AAV/Aβ)

24h OR Tg intact OR

at 6 months. Tg impairded OR at 10 and 13 months.

AAV/Aβ attenuated OR impairment in

TG at 13

(Mouri et

al., 2007)

126

months.

Tg2576 Male 11 months of age

WIN 55,212-2 and JWH-133 (cannabinoids)

24h OR Tg impaired OR. JWH-133

attenuated OR deficit in Tg.

(Martín-Moreno et al., 2012)

Tg2576 Female 9 months

of age

Propranolol (antihypertensive)

1h OR Tg impaired OR.

Propranolol attenuated OR deficit .

(Dobarro et al.,

2013)

Tg2576 Male 9 months

of age

Aluminum 24h OR Tg impaired OR.

(Ribes et al., 2012)

Tg2576 Male 5 months

of age

TAK-070 (BACE1 inhibitor)

24h OR Tg impaired OR. TAK-

070 attenuated OR

impairment in Tg.

(Fukumoto et al.,

2010)

Tg2576 Female ~6 months of age

CHF5074 (gamma-secretase modulator)

24h OR Tg impaired OR. CHF5074

attenuated OR impairment in Tg.

(Balducci et al., 2011)

Tg2576 Female 13

months of age

Environmental

enrichment

48h OR Tg impaired

OR. Transient environmental enrichment attenuated

OR deficit in Tg.

(Verret et

al., 2013)

Tg2576 Female 7-13 months of age

PN401 (Uridine prodrug) 24h OR Tg impaired OR. PN401 attenuated

OR impairment in Tg.

(Saydoff et al., 2013)

Tg2576 Male &

Female

12-14 months

of age

Ciproxifan (H3 antagonist)

5min OR Tg impaired OR.

Ciproxifan attenuated OR impairment in

Tg.

(Bardgett et al.,

2011)

Tg2576 Male 13 months of age

Antisense oligonucleotide (OL-1) against amyloid-β precursor protein

24h Object-Place Tg impaired object-place. OL-1 attenuated

object-place deficit in Tg.

(Farr, Erickson, Niehoff, Banks, &

Morley, 2014)

Tg2576 - 10 months of age

BAY 73-6691 (PDE9A inhibitor)

4min OL Tg impaired OL. BAY 73-6691

attenuated OL impairment in Tg.

(Kroker et al., 2014)

Tg2576 Female

8, 16 months

of age

3-4min OL Tg impaired OL at 8, 16

months.

(Yassine et al.,

2013)

OR (after spatial

novelty with

Tg intact OR at 8, 16

months.

127

same objects)

Tg2576 Male 16 months of age

2min OR Tg intact OR. (Good & Hale, 2007)

OL Tg impaired OL.

Object-in-Place

Tg impaired familiar

object and familiar location.

Tg2576 Male 7, 14 months

of age

3min spatial novelt (5 objects)

Tg impaired spatial

novelty at 7 months. Wt and Tg impaired

spatial novelty at 14 months.

(Middei et al., 2006)

Object novelty (after

OL with same objects; 5 objects)

Tg intact object novelty

at 7 months. Wt and Tg impaired object novelty

at 14 months.

Tg2576 Male & Female

14 months of age

2min, 30min, 24h

OR Tg intact OR at 2min, 30min. Wt and Tg may

be impaired at 24h.

(Hale & Good, 2005)

2min OL Tg impaired OL.

2min TO Tg intact recency.

Tg2576 Male 10-12 months

of age

2min OL Tg impaired OL.

(Good et al., 2007)

Episodic

Memory What-Where-When

Wt mice

preferred objects presented earlier in time

and in a different spatial location. Tg

only preferred objects presented less recently.

PS1 PS2

DKO

Male

& Female

8

months of age

4-month calorie restriction

(CR)

1h, 24h OR Tg impaired

OR at 1h and 24h. CR attenuated OR deficit in

Tg at 1h and 24h.

(Wu et al.,

2008)

PS1 L286V - 12-16 months of age

3h, 5h OR Tg facilitated OR at 3h. Tg impaired OR

(Vaucher et al., 2002)

128

at 5h.

PS1 L235P Male 6 months of age

5min OR Tg impaired OR.

(Huang, 2003)

APP/swe Male 7 months of age

7,8-DHF (TrkB agonist) 24h OL Tg mice impaired OL. 7,8-DHF

attenuated OL deficit .

(Bollen et al., 2013)

APP/PS1 Male & Female

10-12+ months of age

Camk2a-cre-Eif2ak3loxP/loxP transgene (PERK)

1h OL Tg impaired OL. Intact OL in APP/PS1

mice with PERK deletion.

(Ma et al., 2013)

hAPP/swe - 5, 8 months

of age

24h OR Tg intact OR at 5 months.

Tg impaired OR at 8 months.

(Simón et al., 2009)

TASTPM - 4,5,6,7,8

months of age

Fluparoxan (a2-adrenoceptor antagonist)

4h OR Tg and Wt and

fluparoxan mice had intact OR at

4; at 5 months OR was impaired in Tg mice and

fluparoxan Wt mice but intact in Wt and

fluparoxan Tg mice; at 6 months OR was impaired

in Wt and fluparoxan Tg mice but intact in

fluparoxan Wt mice and Tg mice.

(Scullion et al.,

2011)

TASTPM Male &

Female

3,4,6,8,10

months of age

4h OR Tg not impaired on

OR at 3 and 4 months; Tg impaired at

6,8 and 10 months

(Howlett et al.,

2004)

TASTPM Male & Female

5.5+ months

F- spondin (lentiviral vector-mediated overexpression of reelin

homolog) and green-fluorescent protein (GFP)

3h OR GFP treated Tg impaired OR. F-

spondin treated Tg intact OR.

(Hafez et al., 2012)

APP/PS1 Male 7+ months

of age

Sterol regulatory element-binding protein-2

(SREBP-2; involved in cholesterol homeostasis)

1h OR Tg mice overexpressin

g SREBP-2 impaired OR. Intact OR in Tg mice.

(Barbero-Camps et

al., 2013)

APP/PS1 Female 9+

months of age

GW3965 (liver X receptor

agonist) and ABCA1-/- (cholesterol transpoter ATP-binding cassette

4h OR Tg impaired

OR. GW3965 attenuated OR

(Donkin et

al., 2010)

129

transporter A1) performance only when ABCA1 was present.

PSAPP Male

& Female

15

months of age

Anti-CD40L antibody and

IgG

1h OR IgG treated

Tg mice impaired SOR. Anti-CD40L Tg

mice intact OR.

(Roach et

al., 2004)

APP/PS1 Male 5+ months of age

Cannabidol (CBD) 24h OR Tg impaired OR. CBD attenuated

OR impairment.

(Cheng, Low, Logge,

Garner, & Karl, 2014a)

APP/PS1 Male &

Female

7,11,15,24

months of age

1h OR Tg impaired OR starting at

15 months of age.

(Webster et al.,

2013)

APP/PS1 Male & Female

12 months of age

Ferulic acid (FA) 24h OR Tg impaired OR. FA attenuated

OR impairment.

(Mori et al., 2013)

APP/PS1 Male & Female

7 (Female) and

9.5 (Male) months

of age

56Fe particle irradiation 1h OR Irradiation

impaired OR in male and

female Tg mice.

(Cherry et al., 2012)

APP/PS1 Female 4,6,12

months of age

Neurotoxin N-(2-

chloroethyl)-N-ethyl-bromo- benzylamine (dsp4) intra-Locus ceruleus

1h OR Tg intact OR

at 4 and 6 months. Tg impaired OR at 12 months.

No effect of dsp4 on OR.

(Jardanhaz

i-Kurutz et al., 2010)

APP/PS1 - 4 months of age

Iron-sulfate exposure and MK-801

15min OR Tg intact OR. Iron impaired OR in Tg.

(Becerril-Ortega, Bordji,

Fréret, Rush, & Buisson,

2014) APP/PS1 Male

& Female

~4

months of age

Minocycline (microglia

activation inhibitor)

20min OR Tg impaired

OR. Minocycline attenuated

OR impairment.

(Paper et

al., 2012)

APP/PS1 Male 7 months of age

WASP-1 and FOXY- 5 (activation of Wnt signaling)

2.5h OR Tg impaired OR. WASP-1 and FOXY-5

attenuated OR impairment.

(Vargas et al., 2014)

APP/PS1 Female 7 months

of age

- 1h OR Tg intact OR. (Cheng et al., 2014b)

APP/PS1 Male 9

months of age

Lixisenatide and

liraglutide (GLP-1 receptor agonist-facilit iates insulin

signaling)

3h OR Tg impaired

OR. No effect of lixisenatide and

liraglutide on OR in Tg.

(McClean

& Hölscher, 2014)

APP/PS1 Male 15 Sildenafil (PDE5 24h OR Tg impaired (Zhang et

130

months of age

inhibitor) and Rp-8-Br-PET-cGMPS (c-GMP-dependent protein kinase)

OR. Sildenafil, without Rp-8-Br-PET-

cGMPS, attenuated OR

impairment in Tg.

al., 2013)

APP/PS1 Male & Female

7 months of age

Donepezil (acetylcholinesterase inhibitor) and naltrindole

(opoid receptor antagonist)

1h OR Tg mice impaired OR. Donepezil

and naltrindole attenuated OR in Tg.

(Zhang et al., 2012)

APP/PS1 Female 12

months of age

Ferulic acid (anti-oxidant

and anti-inflammatory)

24h OR Tg mice

impaired OR. Ferulic acid attenuated OR

impairment in Tg.

(Jing et

al., 2013)

PSAPP Male & Female

6, 12 months of age

Flavonoid tannic acid (TA)

24h OR Tg impaired OR. Flavonoid

attenuated OR impairment in Tg.

(Mori et al., 2012)

APP/PS1 Male 7

months of age

Liraglutide (incretin

hormone glucagon-like peptide-1 analog)

3h OR Tg impaired

OR. Liraglutide attenuated OR deficit in

Tg.

(McClean

et al., 2011)

APP/PS1 Male & Female

8 months of age

Prescription number 1 (PN-1) (Chinese medicine) and donepezil

24h OR Tg impaired OR. PN-1 and donepezil attenuated

OR deficit in Tg.

(Yao et al., 2013)

APP/PS1 - 7 months of age

Memantine (NMDA receptor antagonist)

3h OR Tg impaired OR. Memantine

attenuated OR deficit in Tg.

(Scholtzova et al., 2008)

APP/PS1 - 8 months

of age

Aβ1–42-containing transcutaneous

immunization

1h OR Tg impaired OR. Aβ

immunization attenuated OR deficit in Tg.

(Matsuo et al., 2014)

APP/PS1 - 3-6

months of age

3h OR Tg impaired

OR.

(Dewachte

r et al., 2002)

APP/PS1 - 9-12 months of age

Progesterone (P4) 4h OL Tg impaired OL.

(Frye & Walf, 2008) OR P4 improved

OR in Wt and

Tg. APP/PS1 Male 4,6,8

months of age

80 min OL Tg intact OR

at 4 months. Tg and Wt impaired OR

at 6, 8 months.

(Maroof et

al., 2014)

OR Tg intact OL

131

at 4, 6, 8 months. Wt impaired OL at 6, 8

months.

5xFAD Female ~2 months of age

RS 67333 (5-HT4 receptor agonist)

1h OR Tg impaired OR. RS attenuated OR deficit in

Tg.

(Giannoni et al., 2013)

5xFAD Male 4-7 months of age

Kamikihi-to (KKT; traditional Japanese medicine)

30min OR Tg impaired OR. KKT attenuated OR deficit in

Tg.

(Tohda et al., 2011)

5xFAD Female 6-8 months

of age

diosgenin (steroidal sapogenin; Regenerates

neurite atrophy and syaptic loss) and memantine

24h OR Tg impaired OR.

Diosgenin attenuated OR deficict in Tg.

Memantine did not alter OR performance

in Tg.

(Tohda et al., 2012)

5xFAD Male 6-8 months of age

Sominone (steroidal sapogenin)

30min OR Tg impaired OR. Sominone attenuated

OR deficit in Tg.

(Joyashiki et al., 2011)

5xFAD Female 6.5 months of age

Neuronal overexpression of MMP-9 (amatrixmetalloproteinase

critically involved in neuronal plasticity, acts as α-secretase)

15min OR Tg impaired OR. MMP-9 attenuated

OR impairment in Tg.

(Fragkouli et al., 2014)

5xFAD - 12 months

of age

24h OR Tg impaired OR.

(Wang et al., 2013)

5xFAD - 6 months of age

Cinnamon extract - OR Tg impaired OR. Cinamon extract attenuated

OR deficit in Tg.

(Frydman-Marom et al., 2011)

Tg4510 - 6 months of age

Calorie restriction (CR) 5min OR Tg impaired OR. CR attenuated

OR impairment in Tg.

(Brownlow et al., 2014)

htau Male 4, 12 months

of age

5min, 30min

OR Tg intact OR at 4 months.

Tg impaired OR at 12 months.

(Polydoro, Acker,

Duff, Castillo, & Davies, 2009)

PLB1 4, 12

months of age

5min OR Tg impaired

OR at 4, 12 months

(Ryan et

al., 2013)

OL Tg impaired OL at 4, 12 months

PLB1 Male

& Female

8, 12

months of age

2min OR Tg impaired

OR at 8, 12 months.

(Platt et

al., 2011)

132

OL Tg impaired OL at 12 months.

3xTG Female 6 months

of age

Streptozotocin (STZ; a dibetogenic compound)

15min OR Tg impaired OR. STZ

exacerbated OR deficit in Tg.

(Chen et al., 2014)

3xTG - 5, 6 months

of age

PD098059 (A MEK inhibitor)

24h OR Tg impaired OR at 5

months. PD098059 attenuated OR

impairment in Tg at 6 months.

(Feld et al., 2014)

3xTG Female 12-14 months

of age

3h OR Tg impaired OR

(Filali et al., 2012)

3xTG Male ~11 months of age

2-methyl-5-(3-{4-[(S)-methylsulfinyl] phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO;

GSK-3 inhibitor)

5h OR Tg impaired OR. MMBO attenuated OR deficit in

Tg,

(Onishi et al., 2011)

3xTG - 12 months of age

Minocycline (anti-inflammatory)

1.5h, 24h OR Tg impaired OR. Minocycline improved OR

in TG.

(Parachikova, Vasilevko, Cribbs,

LaFerla, & Green, 2010)

3xTG Female 7+ months

of age

Peptide 6 (an 11-mer peptide which activates

ciliary neurotrophic factor)

15min OR Tg impaired OR. Peptide 6

attenuated OR impairment in Tg.

(Blanchard et al.,

2010)

3xTG Male 5, 10

months of age

Nomifensine (dopamine

reuptake inhibitor)

24h OR Tg intact OR

at 5 months. Tg impaired OR at 10 months.

Nomifensine attenuated OR deficit in

Tg at 10 months.

(Guzmán-

Ramos et al., 2012)

3xTG Female 15-16 months of age

P021 (ciliary neurotrophic factor)

24h OR Tg impaired OR. P021 attenuated

OR deficit in Tg.

(Kazim et al., 2014)

3xTG Female 12, 16 months

Immunoglobulin (IVIg) 1h OR Tg impaired OR at 12 and 16 months.

IVIg attenuated OR deficit at 16 months.

(St-Amour et al., 2014)

3xTG - 14

months of age

Docosahexaenoic acid

(DHA)

1h OR Tg impaired

OR. DHA attenuated OR impairment in

Tg.

(Arsenault

et al., 2011)

3xTG Male & Female

6.5 months of age

15min OR Wt and Tg impaired OR.

(Stover et al., 2015)

133

3xTG Male & Female

15-18 months of age

30-60s OR Tg intact OR. (Gulinello et al., 2009) 3min OL Tg impaired

OL.

3xTG Female 11 months

of age

2min OR Tg intact OR. (Davis et al., 2013)

OL Tg impaired OL.

9 months of age

5min What-Where Tg impaired egocentric What-Where.

Tg and Wt impaired allocentric What-Where

12

months of age

2min What-Which Tg intact

What-Which

6 months of age

2min, 5min, 10min,

15min, 30min

Episodic memory What-Where-

Which

Tg impaired What-Where-Which at all

delays. Wt impaired What-Where-Which at

15min and 30min.

14 months of age

2min Episodic memory What-Where-

When

What-Where-When intact in Wt and Tg,

but Tg impaired relative to Wt.

3xTG Female 4.5

months of age

5min TO Tg intact TO. (Davis et

al., 2013)

3, 6, 12 months of age

2min, 5min 10min, 15min,

30min

What-Where-Which

Tg impaired What-Where-Which at 3, 6,

12 months.

5-8 months of age

10min, 20min

What-Where-When

Tg intact What-Where-When

3xTG & PS1-KIM146V

Male & Female

12 months of age

Pioglitazone (PIO; TZD- aimed to improve insulin signaling)

24h OL PS1 impaired OL. PIO improved OL

in PS1. 3xTG impaired OL. PIO did not alter OL

performance in 3xTG.

(Masciopinto et al., 2012)

human APOC11/0

Female 12 months of age

1h OR Tg impaired OR.

(Abildayeva et al., 2008)

ApoE-/- Male 3-5

months of age

Thioperamide and

clobenpropit (H3 antagonists)

24h OR Tg intact OR.

H3 antagonists impaired OR in Tg.

(Bongers,

Leurs, Robertson, & Raber, 2004)

Apoc1–/– Female ~12

months of age

1h OR Tg impaired

OR.

(Berbée et

al., 2011)

ApoE3 and ApoE4 mice

Male 4+ months of age

Docosahexaenoic acid (DHA)

24h OR ApoE4 impaired OR. DHA

attenuated OR

(Kariv-Inbal et al., 2012)

134

impairment in ApoE4.

ApoE3, ApoE4, and Apoe-/-

Male 6-7 months

Castration 5min OR Castration impaired OR in Apoe-/-.

(Pfankuch, Rizk, Olsen,

Poage, & Raber, 2005)

OL Castration

impaired OL in ApoE4.

APP-Yac/apoE3-TR

(’apoE3’) and APP-Yac/apoE4-TR

(’apoE4’) mice

Female 6-7 months of age

24h OL Impaired OL in TG APP/apoE4,

but not APP/apoE3.

(Kornecook et al., 2010)

135

Table 3

Correlation Between Total Sample Exploration and Novelty Preference Index

Note. Pearson product-moment correlation coefficients between total sample exploration

and novelty preference index (discrimination ratio or oddity preference) are not significant unless otherwise reported. * p < .05, ** p < .001

Correlation Coefficient (r)

Experiment WT TG

Strain Task Sex Delay

5xFAD O -OR Female 5min .169 .400

3h -.206 .537

Male 5min .320 .298

3h .042 .024

Y-O R Female 5min -.154 .653*

3h .502 -.037

Male 5min .031 .014

3h .188 -.195

O L Female 5min .164 .143

3h .334 .047

Male 5min .545 -.052

3h .469 .195

Temporal O rder

Female 3min .584* .648*

Male 3min

MSO Female -.418 -.822**

Male -.286 -.051

Visual Oddity Female .169 -.252

Male .737** -.154

Tactile Oddity Female .124 -.100

Male .189 .073

3xTG O -OR Female 5min -.192 -.398

3h -.330 .363

Male 5min -.385 .587

3h -.121 -.367

Y-O R Female 5min .379 -.646*

3h -.006 -.492

Male 5min .106 -.338

3h .273 -.113

O L Female 5min .267 -.167

3h -.193 -.291

Male 5min .090 .039

3h -.135 -.200

Temporal

O rder

Female 3min -.146 -.220

Male 3min

MSO Female -.178 .347

Male .296 .532

Visual Oddity Female .235 .070

Male .500 -.042

Tactile Oddity Female .566* -.254

Male .091 .469

136

Table 4

Object Processing Results Summary

Note. Individual comparisons between sample DR and choice DR for mnemonic

paradigms as well as chance performance and sample OP for perceptual oddity tasks (

indicates intact performance, indicates impaired performance).

3xTG 5xFAD

WT TG WT TG

Female Male Female Male Female Male Female Male

O R O pen-

field OR 5min

3h

Y-O R 5min

3h

O L 5min

3h Familiarity Preference

TO 3min

Not completed

Not completed

Not completed

Not completed

O ddity MSO

Visual

Tactile

137

Figure 1. Object processing test battery. a) Object recognition: open-field. b) Object recognition: Y-apparatus. c) Object location. d) Temporal order. e) Multisensory object

oddity.

138

Figure 2. 5xFAD and 3xTG performance on short-term (5min) and long-term (3h) open-field object recognition. (A) Female 5xFAD mice did not discriminate significantly

between novel and familiar objects in either retention delay condition. (B) Male 5xFAD mice did not discriminate significantly between novel and familiar objects in either retention delay condition. (C) Female 3xTG mice did not discriminate significantly

between novel and familiar objects in the 3h retention delay condition. (D) Male 3xTG mice did not discriminate significantly between novel and familiar objects in either

retention delay condition. *p < .05, **p < .01 ***p < .001

Female Male

5xFAD

3xTG

A B

C D

139

Figure 3. 5xFAD and 3xTG total exploration during short-term (5min) and long-term (3h) open-field object recognition. (A) Female 5xFAD TG mice explored less than WT

during the 5min sample, 3h sample, and 3h choice. (B) Male 5xFAD TG mice explored less than WT during the 5min sample and choice. (C) Female 3xTG TG mice explored less than WT during the 5min choice phase. (D) No significant difference between WT

and TG 3xTG male total exploration. *p < .05, **p < .01 ***p < .001

Female Male

5xFAD

3xTG

A B

C D

140

Figure 4. 5xFAD and 3xTG performance on short-term (5min) and long-term (3h) Y-apparatus object recognition. (A) Female 5xFAD mice did not discriminate significantly

between novel and familiar objects in either retention delay condition. WT mice did not discriminate between not discriminate between novel and familiar object at 3h. (B) Male

5xFAD mice did not discriminate significantly between novel and familiar objects in either retention delay condition. (C) Female 3xTG mice did not discriminate significantly between novel and familiar objects in the 3h retention delay condition. (D) Male 3xTG

mice did not discriminate significantly between novel and familiar objects in the 3h retention delay condition. **p < .01 ***p < .001

Female Male

5xFAD

3xTG

A B

C D

141

Figure 5. 5xFAD and 3xTG total exploration during short-term (5min) and long-term (3h) Y-apparatus object recognition. (A) No significant difference between WT and TG

5xFAD female total exploration. (B) Male 5xFAD TG explored more than WT during the 3h choice phase. (C) No significant difference between WT and TG 3xTG female total exploration. (D) No significant difference between WT and TG 3xTG male total

exploration. *p < .05

Female Male

5xFAD

3xTG

A B

C D

142

Figure 6. 5xFAD and 3xTG performance on short-term (5min) and long-term (3h) object

location. (A) Female 5xFAD mice did not discriminate significantly between novel and familiar object spatial locations at 5min or 3h. (B) Male 5xFAD mice did not

discriminate between novel and familiar object spatial locations at 5min. WT mice did not discriminate between novel and familiar object spatial locations at 5min and 3h. (C) 3xTG females did not discriminate between novel and familiar object spatial locations at

5min or 3h. (D) 3xTG males did not discriminate between novel and familiar object spatial locations at 5min. WT mice did not discriminate between novel and familiar

object spatial locations at 3h. At 3h TG mice had a significant familiarity preference. *p < .05, **p < .01 ***p < .001

Female Male

5xFAD

3xTG

A B

C D

143

Figure 7. 5xFAD and 3xTG total exploration during short-term (5min) and long-term (3h) object location. (A) Female 5xFAD TG explored less than WT during the 3h choice

phase. (B) No significant difference between WT and TG 5xFAD male total exploration. (C) Female 3xTG TG explored less than WT during the 3h sample. (D) Male 3xTG TG explored more than WT during the 5min sample and choice. *p < .05, ***p < .001

Female Male

5xFAD

3xTG

B

D

A

C

144

Figure 8. Female 5xFAD and 3xTG performance on temporal order. (A) Female 5xFAD

TG and WT did not differentiate between novel and familiar stimuli at 3min. (B) 3xTG females were impaired on temporal order at 3min. *p < .05, **p < .01

Female

5xFAD

3xTG

A

B

145

Figure 9. Female 5xFAD and 3xTG total exploration during object temporal order. (A) Female 5xFAD TG explored less than WT during sample phase 1. (B) No significant difference between WT and TG 3xTG female total exploration. **p < .01

Female

5xFAD

3xTG

A

B

146

Figure 10. 5xFAD and 3xTG performance on object oddity. (A) 5xFAD females were

selectively impaired on MSO. (B) 5xFAD males were impaired on MSO, visual, and tactile oddity. WT males were impaired on MSO and tactile oddity. (C) 3xTG females were selectively impaired on MSO. (D) 3xTG males were selectively impaired on MSO.

WT males were impaired on visual oddity. *p < .05, **p < .01 ***p < .001

Female Male

5xFAD

3xTG

A B

C D

147

Figure 11. 5xFAD and 3xTG total exploration during object oddity. (A) Female 5xFAD TG explored more than WT during MSO, visual, and tactile oddity. (B) No significant difference between WT and TG 5xFAD males. (C) No significant difference between

WT and TG 3xTG females. (D) No significant difference between WT and TG 3xTG males. *p < .05, **p < .01

Female Male

5xFAD

3xTG

A B

C D