Evaluation of behavior and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially dementia. Commonly used tests include Morris water maze, Barnes maze, object recognition, fear conditioning, radial arm water maze, and Y maze. Each of these tests reflects some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory, and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting, and manipulation of macronutrients. Dietary interventions have been shown to influence various cognitive and behavioral tests in rodents indicating that nutrition can influence brain aging and possibly neurodegeneration.

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Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia.

We are entering a new era of mouse phenomics, driven by large-scale and economical generation of mouse mutants coupled with increasingly sophisticated and comprehensive phenotyping. These studies are generating large, multidimensional gene–phenotype data sets, which are shedding new light on the mammalian genome landscape and revealing many hitherto unknown features of mammalian gene function. Moreover, these phenome resources provide a wealth of disease models and can be integrated with human genomics data as a powerful approach for the interpretation of human genetic variation and its relationship to disease. In the future, the development of novel phenotyping platforms allied to improved computational approaches, including machine learning, for the analysis of phenotype data will continue to enhance our ability to develop a comprehensive and powerful model of mammalian gene–phenotype space. Although the field of functional genomics is increasingly adopting genome-scale approaches, a comprehensive understanding of gene functions requires the parallel development of deep phenotyping platforms. This Review discusses strategies for broad-based mouse phenomics, applied both to gene knockout collections and to diverse strains harbouring natural genetic variation. The authors discuss technical challenges, analysis pipelines and insights into human disease genetics.

High-throughput mouse phenomics for characterizing mammalian gene function

ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer's disease.

Alpha-7 nicotinic receptor allosteric modulator PNU120596 prevents lipopolysaccharide-induced anxiety, cognitive deficit and depression-like behaviors in mice

Dietary Phospholipids: Role in Cognitive Processes Across the Lifespan

Genetically modified mouse models have proven useful to study learning and memory processes and the neurocircuitry and molecular mechanisms involved, as well as to develop therapies for diseases involving cognitive impairment. A variety of tests have been developed to measure cognition in mice, and here we present those established and regularly used in the German Mouse Clinic. The test paradigms have been carefully chosen according to reliability of results and disease relevance of the cognitive functions assessed. Further criteria were time efficiency and ease of application. All tests assess slightly different but also overlapping or interacting aspects of learning and memory so that they can be used to complement each other in a comprehensive assessment of cognitive function. The five protocols described are for spontaneous alternation in the Y-maze, social discrimination, object recognition, automated assessment of learning and memory using the IntelliCage, and olfactory discrimination learning.

Assessing Cognition in Mice.

Analysis of locomotor behavior in the German Mouse Clinic

Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target. 

https://www.nature.com/articles/s41598-022-25790-2.pdf

Petra Dirscherl

Papers

Assessing Cognition in Mice.

Analysis of locomotor behavior in the German Mouse Clinic

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein