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Cited by 6Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMemory and Neural Mechanisms

Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory

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Murdy, Thomas J., Dunn, Amy R., Singh, Surjeet, Telpoukhovskaia, Maria A., Zhang, Shanrong, White, Jacqueline K., Kahn, Itamar, Febo, Marcelo +1 more·2023·Frontiers in Behavioral Neuroscience
DOI 10.3389/fnbeh.2022.1033975PMC PMC9871587
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Abstract

In human Alzheimer’s disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL/6J, DBA/2J, FVB/NJ) and two wild-derived strains (CAST/EiJ, WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sex*strain interactions, or strain*sex*5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strain*sex interaction were observed on baseline motor activity, and significant strain*sex and sex*5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory.

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Authors
Murdy, T. J., Dunn, A. R., Singh, S., Telpoukhovskaia, M. A., Zhang, S., White, J. K., Kahn, I., Febo, M., & Kaczorowski, C. C.
Affiliations
  • Jackson Laboratory (US)
  • Mortimer B. Zuckerman Mind Brain Behavior Institute (US)
  • University of Florida Health (US)
Corresponding author
Kaczorowski, Catherine C.
ORCID
Venue
Frontiers in Behavioral Neuroscience
Publisher
Frontiers Media SA
Published
2023-01-10
Volume
16
Pages
1033975-1033975
ISSN
1662-5153 (ISSN-L)
DOI
10.3389/fnbeh.2022.1033975
PMC
PMC9871587
OpenAlex
W4315433882
Cited by
6
References
105
Citations by year
2026: 2 · 2025: 3 · 2024: 1
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
Funders
National Institute on Aging (R01AG057914)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
Alzheimer's disease, brain reserve, brain microstructure, genetic diversity, 5xFAD mice, inbred mouse strains, diffusion MRI, contextual fear memory, sex differences, individual differences, memory decline, motor activity, natural genetic variation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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