Conference Agenda

Symposium Proposals Genes, Brain and Behavior 2024

Abstract

Symposium Chair

Chair Name:
Julie Dumont

Co-Chair Name (Optional):
Miguel Skirzewski

Email:
JDUMONT2@UWO.CA

Organization:

Department:
Western Research - BrainsCAN

Position:
Research Associate & Lab Manager

Species:
Mice & Rats

Description

Title:
Translational Insights into Neurodegenerative Disease: From Mice to Marmosets to Humans

Abstract (500 word limit):
Improving the use of translational animal models represents a crucial step towards bridging the gap between basic research and clinical applications. Four speakers representing diverse geographical regions, professional levels, and gender identities will share their insights into the use of state-of-the-art translational animal models to understand pathophysiological, genetic, and environmental mechanisms underlying neurodegenerative disease. The first presentation, by Professor Anthony Hannan--Head of the Epigenetics and Neural Plasticity Group, and Research Co-Lead for the Mental Health Mission at the Florey Institute in Melbourne, Australia--will focus on mouse models of Huntington's and Alzheimer's disease including mechanisms of pathogenesis, gene-environment interactions and cutting-edge assessment of cognitive deficits using automated touchscreen testing. Molecular and cellular investigations conducted by his team have revealed key pathways implicated in the therapeutic impacts of environmental stimuli and identified novel therapeutic targets. They have also discovered altered brain-body interactions, including the first evidence of gut dysbiosis (dysregulated microbiota) in Huntington’s disease. The implications of the research that he will present extend to potential “enviromimetics”: the use of environmental stimuli as therapy for neurological and psychiatric disorders. The second talk will feature Ms. Kate Onuska, a PhD student at the University of Western Ontario in London, Canada, who will present data from next-generation humanized mouse models and cognitively normal older adults at-risk for Alzheimer's disease. In both the mice and in humans, she has investigated whether Aβ load and ApoƐ4 genotype interact to influence attentional performance on identical versions of the continuous performance test (CPT) touchscreen task. She has found that mice modelling ApoƐ4 genotype but not Aβ pathology exhibit significantly higher discrimination sensitivity scores when compared to their ApoƐ3 counterparts and has observed a similar relationship between ApoƐ4 carriership and CPT discrimination sensitivity scores in the absence of Aβ pathology in her cohort of older adults at-risk for Alzheimer's disease. Interestingly, she has found that the relationship between ApoƐ4 genotype and attentional performance effectively inverts in the presence of Aβ, with mice that model increased Aβ pathologic load alongside the ApoƐ4 genotype exhibiting significantly worse discrimination sensitivity scores when compared to ApoƐ3 mice as well as mice without Aβ pathology. The third talk, by Dr. Brianne Kent, an Assistant Professor at Simon Fraser University in Burnaby, Canada, will focus on sleep disturbances as a symptom of and risk factor for dementia. A majority of patients with Alzheimer's disease experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (, and decreased rapid-eye-movement sleep. Clinical studies are investigating whether such sleep disturbances are a consequence of the underlying disease, and whether they also contribute to the clinical and pathological manifestations of Alzheimer’s disease. Emerging research has provided a direct link between several of these sleep disruptions and Alzheimer’s pathophysiology, suggesting that treating sleep disorders in this population may target basic mechanisms of the disease. Dr. Kent will bridge directly from mouse models to human participants, focusing on the necessity of identifying cognitive tests sensitive to sleep disruption in both clinical and pre-clinical models to assess sleep-targeting therapeutics. The final talk, by Dr. Stacey Rizzo, an Associate Professor of Neurobiology at the University of Pittsburgh, USA who previously spent 18 years in the pharmaceutical industry in Neuroscience Drug Discovery, will emphasize the crucial role of cross-species translational approaches in furthering our understanding of neurodegenerative diseases as well as the development and assessment of potential therapeutic interventions. She will focus on genetic and environmental factors that contribute to cognitive decline and will highlight the pivotal role of the marmoset in bridging the rodent to human translational gap.Collectively, these talks will highlight progress and challenges in the study of neurodegenerative diseases and the development of therapeutic strategies. This interdisciplinary symposium will emphasize the use of sophisticated translational approaches and collaborative efforts required to tackle the complex genetic and environmental factors leading to pathophysiological changes and cognitive decline in neurodegenerative disease. The speakers have agreed to participate in this symposium chaired by early career researchers Drs. Julie Dumont & Miguel Skirzewski.Tentative Talk Titles1.Gene-environment interactions modulating cognitive and affective disorders in mouse models of neurodegenerative brain diseases 2.ApoƐ4 genotype and Aβ load interact to potentiate differences in attentional performance on a translational touchscreen task in mice and humans at-risk for Alzheimer's disease3.Touchscreen-based cognitive tests to assess sleep-associated cognition in mice and humans4.Overcoming the preclinical to clinical translational gap in neurodegenerative disorders: application of cross-species touchscreen cognitive testing in mice and marmosets

Speaker 1

Name:
Anthony Hannan

Email:
anthony.hannan@florey.edu.au

Organization:
Florey Institute of Neuroscience and Mental Health, University of Melbourne

Department:

Position:
Research Lead, Mental Health Mission

Species:
Mice

Speaker 2

Name:
Kate Onuska

Email:
konuska@uwo.ca

Organization:
Western University

Department:
Schulich School of Medicine & Dentistry, Robarts Research Institute, Lawson Health Research Institute

Position:
Doctoral Student

Species:
Mice/Humans

Speaker 3

Name:
Brianne Kent

Email:
brianne_kent@sfu.ca

Organization:
Simon Fraser University

Department:
Department of Psychology, Institute for Neuroscience and Neurotechnology

Position:
Assistant Professor, Canada Research Chair in Translational Neuroscience and Dementia

Species:
Mice/Humans

Speaker 4

Name:

Stacey Rizzo

Email:

rizzos@pitt.edu

Organization:

University of Pittsburgh

Department:

Neurobiology

Position:

Associate Professor

Species:

Marmoset

A.J. Hannan 1,2

We have examined the role of various molecular and cellular mediators, and environmental modulators, as they influence healthy cognitive and affective function on the one hand, and cognitive and affective disorders on the other. This symposium presentation will focus on transgenic mouse models of Huntington’s disease (HD) and Alzheimer’s disease (AD), including gene-environment interactions, mechanisms of pathogenesis and the assessment of cognitive deficits modelling dementia, using Bussey-Saksida automated touchscreen testing of cognitive performance. We have used touchscreen testing to reveal translatable cognitive endophenotypes in a transgenic mouse model of AD. We have explored environmental interventions (e.g. environmental enrichment and exercise) and demonstrated that touchscreen testing can constitute a novel form of ‘cognitive training’ that can delay dementia in AD mice. We have also discovered altered brain-body interactions in HD, including the first evidence of gut dysbiosis (dysregulated microbiota), which we have translated with our clinical colleagues. We have also shown that fecal microbiota transplant from wild-type mice into a transgenic mouse model of HD ameliorates cognitive deficits modelling dementia. Furthermore, we found that a high-fibre diet targeting the gut microbiome is therapeutic with respect to both affective and cognitive deficits in HD mice. Ongoing studies are exploring the gut microbiome as a therapeutic target and the possibility that specific environmental factors may modulate brain function via microbiota-gut-brain interactions. These approaches to gene-environment interactions may facilitate the development of enviromimetics (including exercise mimetics as a subclass) for a variety of neurological and psychiatric disorders known to be modulated by environmental stimuli.

1 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

2 Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia

Funding Support: National Health and Medical Research (NHMRC) Ideas Grant, EU-JPND Grant, Flicker of Hope Foundation, DHB Foundation (Equity Trustees), Hunters Research Fund for HD, and the Margaret Friend Trust

ApoƐ4, the strongest genetic risk factor for late-onset Alzheimer's disease, is associated with the increased production as well as diminished clearance of Aβ pathology in the brain. However, whether the interaction between ApoƐ4 and Aβ load contributes to meaningful changes in cognitive function remains unclear. Using data from humanized mouse models and cognitively normal older adults at-risk for Alzheimer's disease, we investigated whether the relationship between Aβ pathology and ApoƐ4 genotype influences attentional performance on the continuous performance test (CPT) touchscreen task. Here, we find that ApoƐ4 mice without Aβ pathology exhibit superior CPT performance when compared to their ApoƐ3 counterparts. We also observe a similar relationship between ApoƐ4 carriership and CPT performance in the absence of Aβ pathology in our cohort of older adults at-risk for Alzheimer's disease. Interestingly, we find that the effect of ApoƐ4 on attentional processes effectively inverts in the presence of Aβ. Mice that model increased Aβ pathologic load alongside the ApoƐ4 isoform exhibit worse performance on the CPT touchscreen task when compared to ApoƐ3 mice with or without Aβ pathology.

Taken together, the results from this cross-species study suggest that the effect of ApoƐ4 on attentional performance is moderated by the degree of Aβ pathology in the brain. These findings motivate future explorations into potential mechanisms by which ApoƐ4 can affect different aspects of brain function across the Alzheimer’s disease continuum.

Kate M. Onuska^1-3, Madison R Longmuir^1,2, Aya Arrar^1,2, Daniel Palmer⁴, Tim J. Bussey^2,4, Lisa M. Saksida^2,4, R. Nathan Spreng^6-10, Vania F. Prado^2,4,5, Marco A.M. Prado^2,4,5, Taylor W. Schmitz^2-4, the PREVENT-AD Research Group

¹ Schulich Medicine and Dentistry, Western University, London, ON, Canada

² Robarts Research Institute, Western University, London, ON, Canada

³ Lawson Health Research Institute, London, ON, Canada

⁴ Department of Physiology and Pharmacology, Western University, London, ON, Canada

⁵ Department of Anatomy and Cell Biology, Western University, London, ON, Canada

⁶ Montreal Neurological Institute, McGill University, Montreal, QC, Canada

⁷ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

⁸ McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada

⁹ Research Centre of the Douglas Mental Health Institute, Montreal, QC, Canada

¹⁰ Centre for Studies in the Prevention of Alzheimer’s Disease, Douglas Mental Health University Institute, Montreal, Quebec, Canada

Funding: CIHR, ALZDISCOVERY, Alzheimer’s Society (Canada) Research Program

Sleep disturbances are a symptom of and risk factor for dementia. Identifying cognitive tests that are sensitive to sleep-associated cognition is needed for preclinical and clinical research assessing sleep-targeting therapeutics. In a cohort of younger (N=89, 18-30 years) and older (N=40, 50-100 years) adults, we show that performance on cognitive tests designed to assess pattern separation (e.g., Mnemonic Similarity Task and the Cambridge Neuropsychological Test Automated Battery- Delayed Matching to Sample task) is associated with sleep behaviour. In mice, we are using the Trial Unique Non-Matching to Location (TUNL) task, which is designed to assess pattern separation. We are also developing a semi-automated protocol to induce sleep fragmentation in mice, which is the most common sleep disturbance experienced by individuals with dementia. Our ongoing studies are investigating how sleep fragmentation and total sleep deprivation in mice affect performance on TUNL. We are taking a translationally focused approach to identify the cognitive tests sensitive to sleep-dependent cognition that can be used as clinical trial outcome measures for sleep-promoting treatments.

Department of Psychology, Institute for Neuroscience and Neurotechnology, Simon Fraser University

¹Stacey J. Sukoff Rizzo, PhD

Concerns over the limitations in translation from animal students to humans continue to persist, in particular with regards to an overwhelming number of reports of cognitive improvements reported in rodent models using traditional behavioral assays, that have failed to translate to meaningful clinical benefit in humans. This problem has been widely acknowledged, most recently in the field of neurodegenerative diseases, although this issue also crosses the spectrum of neurodevelopmental and neuropsychiatric disorders. In order to overcome this preclinical to clinical translational gap, recent efforts have focused on improving the animal models selected for specific studies that better recapitulate aspects of the human disease, as well as prioritizing more clinically relevant outcome measures that can be employed across species from mouse to non-human primate to human. Recently, the National Institute on Aging has funded two consortiums focused on improving translation for Alzheimer’s disease (AD) research. The MODEL-AD consortium is generating new mouse models that incorporate genetics, genomics, environmental factors, and pathological aspects of AD that undergo phenotypic characterization in alignment with the clinical staging of AD. The MARMO-AD consortium is leveraging genetically heterogenous outbred marmosets and genetically engineering AD risk mutations, then longitudinally characterizing these individuals and their germline offspring throughout their extensive lifespan using non-invasive measures similar to how patients are being studied in the clinic. Touchscreen based tasks are being utilized in both the mouse and marmoset models to study the association between disease onset and cognitive decline. Here we will describe these efforts as well as how potential novel therapeutics are being evaluated through a rigorous drug screening pipeline that leverages the mouse models being generated in MODEL-AD to establish translational in vivo target engagement and PK/PD relationships, and evaluating efficacy on cognitive tasks that can then be de-risked and extended to marmosets to study interventions across multiple cognitive domains.

1 Department of Neurobiology, University of Pittsburgh School of Medicine

Funding Support: National Institutes of Health, National Institute on Aging U54AG054345, R13AG060708, U19AG07486, R24AG073190