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Brain connectivity during Alzheimer's disease progression and its cognitive impact in a transgenic rat model.

ABSTRACT: The research of Alzheimer's disease (AD) in its early stages and its progression till symptomatic onset is essential to understand the pathology and investigate new treatments. Animal models provide a helpful approach to this research, since they allow for controlled follow-up during the disease evolution. In this work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph metrics to identify differences between the groups in connectivity, its evolution with age, and its influence on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, while the structural brain network influenced cognitive outcome in transgenic animals, functional network impacted how control subjects performed. TgF344-AD brain network alterations were present from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in these animals, involving structural network reorganization and its effects on cognition, opens a window to evaluate new treatments for the disease.

SUBMITTER: Munoz-Moreno E

PROVIDER: S-EPMC7286303 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Brain connectivity during Alzheimer's disease progression and its cognitive impact in a transgenic rat model.

Muñoz-Moreno Emma E Tudela Raúl R López-Gil Xavier X Soria Guadalupe G

Network neuroscience (Cambridge, Mass.) 20200401 2

The research of Alzheimer's disease (AD) in its early stages and its progression till symptomatic onset is essential to understand the pathology and investigate new treatments. Animal models provide a helpful approach to this research, since they allow for controlled follow-up during the disease evolution. In this work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 months, cognitive abilities were assessed by a memory-related task and magnetic reson ...[more]

PMID: 32537533

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Project description:Abstract Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase-activating protein domains have been deleted (Syngap+/Δ−GAP), we analysed the duration and occurrence of wake, non-rapid eye movement and rapid eye movement brain states during 6 h multi-electrode EEG recordings. We find that although Syngap+/Δ−GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and non-rapid eye movement bouts are reduced and there is an increase in the average duration of both wake and non-rapid eye movement epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during non-rapid eye movement is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep abnormalities were mostly uncorrelated to the electrophysiological signature of absence seizures, spike and wave discharges, as was the imaginary coherence deficit. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/Δ−GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high-connectivity instances between short-distance electrode pairs. Finally comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. This matched a significant reduction in connectivity during spindles when averaged regional comparisons were made. These data suggest that Syngap+/Δ−GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP1 haploinsufficiency in humans. Buller-Peralta et al. found sleep and connectivity deficits in a rat model of SYNGAP1 haploinsufficiency from multi-channel EEG recordings. Mutants displayed altered brain state distributions and decreased connectivity between short-distance electrodes during non-REM sleep. Mutants had decreased high-connectivity instances during sleep spindles, which was specific to certain cortical electrodes. Graphical Abstract Graphical abstract

Dataset Information

Brain connectivity during Alzheimer's disease progression and its cognitive impact in a transgenic rat model.

Publications

Brain connectivity during Alzheimer's disease progression and its cognitive impact in a transgenic rat model.

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