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Exp Neurol. 2016 May;279:40-56. doi: 10.1016/j.expneurol.2016.02.005. Epub 2016 Feb 24.

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome.

Author information

1
Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord Street, L-1004, Boston, MA 02118, United States. Electronic address: lolmos@bu.edu.
2
Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord Street, L-1004, Boston, MA 02118, United States. Electronic address: wtyler@bu.edu.
3
Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118, United States. Electronic address: hjcab@bu.edu.
4
Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord Street, L-1004, Boston, MA 02118, United States. Electronic address: thaydar@bu.edu.

Abstract

Mouse models have provided insights into adult changes in learning and memory in Down syndrome, but an in-depth assessment of how these abnormalities develop over time has never been conducted. To address this shortcoming, we conducted a longitudinal behavioral study from birth until late adulthood in the Ts65Dn mouse model to measure the emergence and continuity of learning and memory deficits in individuals with a broad array of tests. Our results demonstrate for the first time that the pace at which neonatal and perinatal milestones are acquired is correlated with later cognitive performance as an adult. In addition, we find that life-long behavioral indexing stratifies mice within each genotype. Our expanded assessment reveals that diminished cognitive flexibility, as measured by reversal learning, is the most robust learning and memory impairment in both young and old Ts65Dn mice. Moreover, we find that reversal learning degrades with age and is therefore a useful biomarker for studying age-related decline in cognitive ability. Altogether, our results indicate that preclinical studies aiming to restore cognitive function in Ts65Dn should target both neonatal milestones and reversal learning in adulthood. Here we provide the quantitative framework for this type of approach.

KEYWORDS:

Aging; Alzheimer Disease; Cognition; Developmental disorder; Developmental milestones; Down syndrome; Mouse behavior; Mouse model; Reversal learning; Ts65Dn

PMID:
26854932
PMCID:
PMC5716476
DOI:
10.1016/j.expneurol.2016.02.005
[Indexed for MEDLINE]
Free PMC Article

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