Roadmap for linking neurological and locomotor deficits

August 24, 2020

Locomotion deficits, such as lack of coordination, a shuffling gait, or loss of balance, can result from neurological conditions, specifically those that affect motor areas of the nervous system. To develop treatments, scientists often turn to animal models of disease. This strategy is crucial not only for designing potential therapies, but also for gaining insight into fundamental questions about the organisation and function of the nervous system.

Until recently, scientists did not have tools to systematically characterise specific walking deficits in different mouse models of neurological conditions. To solve this problem, Megan Carey's lab, at the Champalimaud Centre for the Unknown in Portugal, developed LocoMouse: an automated movement-tracking system that captures the fine details of locomotion in mice.

"It's like Tolstoy said", remarks Carey, "all normal locomotion is alike, but every type of abnormal locomotion has its own neural basis." In this free-style paraphrasing of Tolstoy's opening sentence of the novel "Anna Karenina", she captures the essence of her group's most recent research project.

In a new study published in the scientific journal eLife, Carey's team uses LocoMouse to identify highly-detailed "locomotor signatures" for two different mouse models. These signatures effectively capture the full pattern of walking deficits of each mouse. Analysing the relationship between the locomotor signatures and the patterns of affected neural circuitry then provides a roadmap for linking neurological and locomotor deficits.

Linking neurological and locomotor deficits

Two mice walk across a linear path. They walk slowly with heavy and uncertain steps. It's clear that both mice suffer from motor deficits, but in a somewhat different way which is difficult to pinpoint by eye. What can their unique walking patterns say about the underlying cause?

"We published our initial results with LocoMouse a few years ago, focusing on one mouse model called pcd, which stands for Purkinje Cell Degeneration. These mice lack one of the main cell-types in the cerebellum (Purkinje cells). While the initial results of that study were interesting, we didn't know how general, or how specific, the pattern of deficits would turn out to be," Carey explains.

"Both pcd and reeler have inherited genetic mutations that affect a brain area called the cerebellum", says Ana Machado, a lead author of the study. "The cerebellum is important for coordinated movement and for normal walking across species."

Whereas the neural damage in pcd mice is restricted to the cerebellum, reeler mice have altered development and circuitry throughout the brain. "The locomotor behaviour of reeler and pcd mice is clearly different, reeler being more severely affected. Still, the locomotion deficits of both models appear broadly 'cerebellar' to a trained eye. We asked ourselves: 'can we quantitatively capture shared and specific features of locomotion in these mice?'," Machado recounts.

The answer was "yes." The researchers found remarkably similar impairments in how movement was coordinated across the limbs and body. Their tail movements were also affected. Typically, mice control their tail to ensure overall stability, but both pcd and reeler are unable to do that. As a result, their tails passively oscillate as a consequence of their limb movement. "We think this shared pattern of deficits reflects core features of cerebellar damage," says Carey.

In addition to the shared features, the team also identified specific walking deficits that were unique to reeler mice. "Movement variability was overall much higher in these mice. Also, they support their body weight with their front, rather than hind, limbs. As a consequence, they can't use them for steering, which results in an unstable trajectory", Machado explains. The researchers attribute these additional impairments to differences in brain circuitry both in the cerebellum and across the brain.

A roadmap for studying locomotor deficits

"When we began studying neural circuits for locomotion, there was always a tradeoff between specificity and interpretability of behavioral measurements," Carey recalls. "With LocoMouse, we have tried to provide both a comprehensive, quantitative description of locomotor behaviour as well as a conceptual framework within which to interpret that high-dimensional data."

"Now, we have a new roadmap that will allow us to move beyond these two mouse models and study many more," says Carey. "We have a quantitative way to map huge high-dimensional sets of behavioural data onto the intricacies of the underlying neural circuits. This approach can be extended to many more mouse models, with different manipulations of various brain areas and cell types," she concludes.

Video: https://youtu.be/jPy13PA8G-Q
-end-


Champalimaud Centre for the Unknown

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.