Biology subjects

de Strooper, B.

Publications and source records attributed to de Strooper, B..

4 recordsLinked to original sources

bioRxiv2022

A novel fully-automated system for lifelong continuous phenotyping of mouse cognition and behaviour

Comprehensive ethologically-relevant behavioural phenotyping in rodent experiments is essential for deciphering the neural basis of animal cognition. Automated home-cage monitoring systems present a valuable tool to fulfil this need. However, they often involve complex animal training routines, water or food deprivation, and probe a limited range of behaviours. Here, we present a new fully automated AI-driven home-cage system for cognitive and behavioural phenotyping in mice. The system incorporates spontaneous alternation T-maze, novel-object recognition and object-in-place recognition tests combined with monitoring of an animals position, water consumption, quiescence and locomotion patterns, all carried out continuously and simultaneously in an unsupervised fashion over long periods of time. Mice learnt the tasks rapidly without any need for water or food restrictions. We applied ethomics approach to show that combined statistical properties of multiple behaviours can be used to discriminate between mice with hippocampal, medial entorhinal and sham lesions and accurately predict genotype of Alzheimers disease mouse models on an individual animal level, surpassing the performance of several gold standard cognitive tests. This technology could enable large-scale behavioural screening for genes and neural circuits underlying spatial memory and other cognitive processes.

neuroscience↗

bioRxiv2022

The AppNL-G-F mouse model of Alzheimer's disease is refractory to regulatory T cell treatment

BackgroundAlzheimers Disease is a neurodegenerative disease with a neuroinflammatory component. Due to the multifunctional capacity of regulatory T cells to prevent and reverse inflammation, regulatory T cells have been proposed as a potential therapeutic in Alzheimers Disease, either as a direct cell therapy or through the use of IL2 as a biologic to expand the endogenous population. MethodsHere we characterize the longitudinal immunological changes occurring in T cells in the AppNL-G-F mouse model of Alzheimers disease. ResultsAge-dependent immunological changes, in both the brain and periphery, occurred in parallel in both AppNL-G-F mice and control AppNL mice. As the endogenous IL2 axis was disturbed with age, we sought to determine the effect of IL2 supplementation on disease progression. Using a genetic model of IL2 provision in the periphery or in the brain, we found that expanding regulatory T cells in either location was unable to alter the progression of key pathological events or behavioral changes. ConclusionThese results suggest that either the AppNL-G-F mouse model does not recapitulate key regulatory T cell-dependent process of Alzheimers disease, or that regulatory T cell therapy is not a promising candidate for APP-mutation-driven Alzheimers disease.

immunology↗

bioRxiv2021

Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer's Disease

In Alzheimers disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment 1,2. Neuronal hyperactivity is observed early in AD 3,4. Here, we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD 5, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene. MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory 6. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients. Our work identifies dysregulation of the MCH-system as a key player in aberrant neuronal activity in the early stages of AD.

neuroscience↗

bioRxiv2020

Single nucleus sequencing fails to detect microglial activation

Single nucleus RNA-Seq (snRNA-Seq) methods are used as an alternative to single cell RNA-Seq methods, as they allow transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-Seq is able to detect cellular state in human tissue. Indeed, snRNA-Seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimers Disease. A comparison of microglia from single cells and single nuclei of four human subjects reveals that ~1% of genes is depleted in nuclei compared to whole cells. This small population contains 18% of genes previously implicated in microglial activation, including APOE, CST3, FTL, SPP1, and CD74. We confirm our findings across multiple previous single nucleus and single cell studies. Given the low sensitivity of snRNA-Seq to this population of activation genes, we conclude that snRNA-Seq is not suited to detecting cellular activation in microglia in human disease.

neuroscience↗