Publications by authors named "Emre Fertan"

11 Publications

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Age related weight loss in female 5xFAD mice from 3 to 12 months of age.

Behav Brain Res 2021 05 4;406:113214. Epub 2021 Mar 4.

Departments of Psychology and Neuroscience, Halifax, Nova Scotia, B3H 4R2, Canada; Departments of Physiology and Biophysics, Halifax, Nova Scotia, B3H 4R2, Canada. Electronic address:

In addition to cognitive decline, patients with Alzheimer's disease (AD) exhibit sensory, motor, and neuropsychiatric deficits. Many AD patients also show weight loss, suggesting that AD may involve a metabolic syndrome. The 5xFAD mouse model shows age-related weight loss compared to wildtype controls, and thus may exhibit metabolic dysfunction. This longitudinal study measured age-related weight loss in female 5xFAD and B6SJL/JF2 wild-type mice from 3 to 12 months of age, and examines some of the behavioural and physiological phenotypes in these mice that have been proposed to contribute to this weight loss. Because some mice had to be singly housed during the study, we also examined genotype by housing interactions. The 5xFAD mice weighed less and ate less than WT littermates starting at 6 months of age, exhibited less home cage activity, had higher frailty scores, less white adipose tissue, and lower leptin expression. At 9 and 12 months of age, heavier 5xFAD mice performed better on the rotarod, suggesting that metabolic deficits which begin between 6 and 9 months of age may exacerbate the behavioural deficits in 5xFAD mice. These results indicate that the 5xFAD mouse is a useful model to study the behavioural and metabolic changes in AD.
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http://dx.doi.org/10.1016/j.bbr.2021.113214DOI Listing
May 2021

The effect of background strain on the behavioral phenotypes of the MDGA2 mouse model of autism spectrum disorder.

Genes Brain Behav 2021 Mar 11;20(3):e12696. Epub 2020 Sep 11.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.

The membrane-associated mucin (MAM) domain containing glycosylphosphatidylinositol anchor 2 protein single knock-out mice (MDGA2 ) are models of ASD. We examined the behavioral phenotypes of male and female MDGA2 and wildtype mice on C57BL6/NJ and C57BL6/N backgrounds at 2 months of age and measured MDGA2, neuroligin 1 and neuroligin 2 levels at 7 months. Mice on the C57BL6/NJ background performed better than those on the C57BL6/N background in visual ability and in learning and memory performance in the Morris water maze and differed in measures of motor behavior and anxiety. Mice with the MDGA2 genotype differed from WT mice in motor, social and repetitive behavior and anxiety, but most of these effects involved interactions between MDGA2 genotype and background strain. The background strain also influenced MDGA2 levels and NLGN2 association in MDGA2 mice. Our findings emphasize the importance of the background strain used in studies of genetically modified mice.
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http://dx.doi.org/10.1111/gbb.12696DOI Listing
March 2021

Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.

J Neurosci Methods 2020 02 28;331:108532. Epub 2019 Nov 28.

Department of Natural Sciences, Manchester Metropolitan University, Manchester, M1 5GD, UK. Electronic address:

Background: Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains.

New Method: We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke.

Results: Sex, background strain, source breeder and genotype all affected whisker movements. All mouse models, apart from Parkinson's disease, revealed differences in whisker movements during locomotion. R6/2 CAG250 Huntington's disease mice had the strongest behavioural phenotype. Robo3R-CKO and RIM-DKOSert mouse models have abnormal somatosensory cortex development and revealed significant changes in whisker movements during object exploration.

Comparison With Existing Method(s): Our results have good agreement with past studies, which indicates the robustness and reliability of measuring whisking. We recommend that differences in whisker movements of mice with motor deficits can be captured in open field arenas, but that mice with impairments to sensory or cognitive functioning should also be filmed investigating objects. Scoring clips qualitatively before tracking will help to structure later analyses.

Conclusions: Studying whisker movements provides a quantitative measure of sensing, motor control and exploration. However, the effect of background strain, sex and age on whisker movements needs to be better understood.
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http://dx.doi.org/10.1016/j.jneumeth.2019.108532DOI Listing
February 2020

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice.

Front Pharmacol 2019 24;10:1044. Epub 2019 Sep 24.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada.

The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer's disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.
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http://dx.doi.org/10.3389/fphar.2019.01044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773979PMC
September 2019

Age and sex differences in motivation and spatial working memory in 3xTg-AD mice in the Hebb-Williams maze.

Behav Brain Res 2019 09 20;370:111937. Epub 2019 May 20.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. Electronic address:

The 3xTg-AD mouse model of Alzheimer's disease (AD) has both amyloid beta plaque and tau tangle pathology. However, the results of behavioural testing with these mice have been inconsistent due to age- and sex-related differences, as well as differences in the difficulty of the tests used to measure cognitive function. In order to better understand the sex- and age-related spatial working memory deficits in the 3xTg-AD mice compared to their B6129S/F2 wildtype controls, we tested 4 and 7-month-old males and females and 13-month-old females in the Hebb-Williams maze. In the acquisition phase, the 3xTg-AD mice performed better than the WT controls, but the females of both genotypes showed motivational deficits; often returning to the start box and not eating the food reward, thus taking longer than males to meet the criterion for acquisition. The 3xTg-AD mice showed more working memory deficits than WT mice during the test phase, and the difference increased as the problems increased in difficulty. The results of this study indicate that female 3xTg-AD mice may have motivational deficits in tests using food reward and that the cognitive deficits of the 3xTg-AD mice are not apparent when the tests are too easy; the more difficult the task, the more deficits are shown in the 3xTg-AD mice compared to WT controls. Thus, the inconsistency in previous results may result from differences in motivation and in test difficulty and these must be considered when evaluating cognitive deficits in the 3xTg-AD mice.
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http://dx.doi.org/10.1016/j.bbr.2019.111937DOI Listing
September 2019

Cognitive Decline, Cerebral-Spleen Tryptophan Metabolism, Oxidative Stress, Cytokine Production, and Regulation of the Txnip Gene in a Triple Transgenic Mouse Model of Alzheimer Disease.

Am J Pathol 2019 07 10;189(7):1435-1450. Epub 2019 Apr 10.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Brain Repair Centre, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address:

Pathologic inflammation in response to injury, infection, or oxidative stress is a proposed mechanism relating cognitive decline to dementia. The kynurenine pathway and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators, TXNIP, and oxidative damage in the cerebrum and spleen, including inflammatory cytokine production by stimulated splenocytes, from female triple transgenic (3xTg-AD) mice in early and late stages of disease progression, and characterized tissue-specific epigenetic regulation of Txnip gene expression. We show that cognitive deficits in 7-month-old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen tryptophan metabolites, with a concomitant increase in amyloid β 40 (Aβ)/Aβ and tau/hyperphosphorylated tau pathologies and a coordinated reduction in spleen proinflammatory cytokine production in 17-month-old mice. The enhanced cerebrum TXNIP expression is associated with increased histone acetylation, transcription factor [Aβ or CCCTC-binding factor (CTCF)] binding, and Txnip promoter hypomethylation, whereas the attenuated spleen TXNIP expression is associated with increased histone methylation, reduced CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan metabolism, inflammatory cytokine production, and cognitive decline; and they provide a potential mechanism for Txnip gene regulation in normal and pathologic conditions, suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aβ/Aβ targeted AD therapies.
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http://dx.doi.org/10.1016/j.ajpath.2019.03.006DOI Listing
July 2019

Interval timing is disrupted in female 5xFAD mice: An indication of altered memory processes.

J Neurosci Res 2019 07 11;97(7):817-827. Epub 2019 Apr 11.

Timing and Decision Making Laboratory, Psychology Department, Koç University, Istanbul, Turkey.

Temporal information processing in the seconds-to-minutes range is disrupted in patients with Alzheimer's disease (AD). In this study, we investigated the timing behavior of the 5xFAD mouse model of AD in the peak interval (PI) procedure. Nine-month-old female mice were trained with sucrose solution reinforcement for their first response after a fixed-interval (FI) and tested in the inter-mixed non-reinforced PI trials that lasted longer than FI. Timing performance indices were estimated from steady-state timed anticipatory nose-poking responses in the PI trials. We found that the time of maximal reward expectancy (peak time) of the 5xFAD mice was significantly earlier than that of the wild-type (WT) controls with no differences in other indices of timing performance. These behavioral differences corroborate the findings of previous studies on the disruption of temporal associative memory abilities of 5xFAD mice and can be accounted for by the scalar timing theory based on altered long-term memory consolidation of temporal information in the 5xFAD mice. This is the first study to directly show an interval timing phenotype in a genetic mouse model of AD.
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http://dx.doi.org/10.1002/jnr.24418DOI Listing
July 2019

Sex differences in the timing behavior performance of 3xTg-AD and wild-type mice in the peak interval procedure.

Behav Brain Res 2019 03 30;360:235-243. Epub 2018 Nov 30.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address:

We investigated interval timing behavior of 10-month-old male and female 3xTg-AD mice compared with their B6129F2/J wild type controls using the peak interval procedure with a 15 s target interval. Multiple parameters reflecting different aspects of timing performance were extracted from steady-state anticipatory nose-poking behavior using two different approaches: single trial analyses and average response curve analyses. These measures can dissociate the differences in performance due to distortions in the interval timing ability or to motivational decline (i.e. apathy); both of which have been reported in Alzheimer patients. We found that the interval timing ability of male and female 3xTg-AD mice did not differ from wild-type controls. However, in measures reflecting motivational state, we found significant sex differences regardless of genotype. Specifically, female mice initiated anticipatory responding later in the trial and had lower response amplitudes than males. Although our findings can also be interpreted in terms of differences in temporal control for response initiation, they more strongly suggest the effect of differential incentive motivation between sexes on timing behavior in these mice.
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http://dx.doi.org/10.1016/j.bbr.2018.11.047DOI Listing
March 2019

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration.

Genes Brain Behav 2020 03 16;19(3):e12532. Epub 2018 Nov 16.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.

Active whisking in mice and rats is one of the fastest behaviours known in mammals and is used to guide complex behaviours such as exploration and navigation. During object contact, whisker movements are actively controlled and undergo robust changes in timing, speed and position. This study quantifies whisker movements in 6- to 7-month old male and female 5xFAD mice, and their C57/SJL F1 wild-type (WT) controls. As well as genotype, we examined sex differences and the effects of retinal degeneration (rd). Mice were filmed using a high-speed video camera at 500 frames per second (fps), under infrared light while behaving freely in three tasks: object exploration, sequential object exploration and tunnel running. Measures of whisker position, amplitude, speed and asymmetry were extracted and analysed for each task. The 5xFAD mice had significantly altered whisker angular positions, amplitude and asymmetry during object contacts and female 5xFAD mice with rd had lower mean angular positions during object contact. There were no significant effects of genotype on sequential object exploration or on tunnel running but differences due to sex and rd were found in both tasks, with female mice making larger and faster whisker movements overall, and mice with rd making larger and faster whisker movements during object contact. There were sex differences in whisker movements during sequential object exploration and females with rd had higher whisker retraction speeds in tunnel running. These data show that measuring whisker movements can quantify genotype and sex differences and the effects of rd during exploratory behaviour in these mice.
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http://dx.doi.org/10.1111/gbb.12532DOI Listing
March 2020

Motor deficits in 16-month-old male and female 3xTg-AD mice.

Behav Brain Res 2019 01 9;356:305-313. Epub 2018 Sep 9.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia Canada, B3H 4R2, Canada. Electronic address:

Motor deficits are some of the most prevalent non-cognitive symptoms of Alzheimer's disease (AD) with patients showing impairments in speech, gait and fine motor skills. We investigated motor behaviour in 16-month-old male and female 3xTg-AD mice and their B6129SF2 wildtype (WT) controls. The 3xTg-AD mice develop extracellular Aβ plaques and tau tangles in the hippocampus and motor cortex between 6 and 9 months of age. Previously we showed that at 6 months of age, 3xTg-AD mice performed better on tests of motor coordination and motor learning than WT mice. The aim of our experiment was to use a battery of motor behaviour tests to determine if this superior motor performance was present in older mice. On the Rotarod, the aged 3xTg-AD mice showed better motor coordination and learning than WT mice. Although females performed better than males, this sex difference was confounded by body weight as females weighed less than males. There were no significant genotype or sex differences on the wire hang or grid suspension tasks, nor in stride length or stride width, but 3xTg-AD mice performed worse than WT mice on the balance beam. In comparison to the 6-month-old mice, an age-related decline in most aspects of motor behaviour was apparent. These results indicate that different sub-domains of motor function are affected differently in the 3xTg-AD mice and that aging does not have the same effect on all motor behaviours.
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http://dx.doi.org/10.1016/j.bbr.2018.09.006DOI Listing
January 2019

Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Front Aging Neurosci 2018 12;10:172. Epub 2018 Jun 12.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada.

Mouse models of Alzheimer's disease (AD) exhibit marked differences in life expectancy depending on their genotype and sex. The assessment of frailty could provide a measure of healthspan to facilitate comparisons between different AD models. We used a validated mouse frailty index (FI) assessment tool to explore genotype and sex differences in lifespan and healthspan of 3xTg-AD mice and their B6129F2 wild-type (WT) controls. This tool is based on an approach commonly used in people and quantifies frailty by counting the accumulation of age-related health deficits. The number of deficits in an individual divided by the total number measured yields an FI score theoretically between 0 and 1, with higher scores denoting more frailty. Male 3xTg-AD mice aged 300-600 days had higher FI scores (Mean FI = 0.21 ± 0.03) than either male WT (Mean FI = 0.15 ± 0.01) or female 3xTg-AD mice (Mean FI = 0.10 ± 0.01), and the elevated frailty scores were accompanied by parallel increases in mortality. Frailty increased exponentially with age, and higher rates of deficit accumulation elevated mortality risk in all groups of mice. When mice were stratified by FI score, frailty predicted mortality, at least in females. Therefore, the mouse clinical FI provides a valuable tool for evaluating healthspan in mouse models of AD with different lifespans.
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http://dx.doi.org/10.3389/fnagi.2018.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005856PMC
June 2018
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