Neuroscientists reveal how cells form a coordinate system for behavioural sequences.

Neuroscientists have discovered brain cells that form multiple coordinate systems to tell us “where we are” in a sequence of behaviours. These cells can play out different sequences of actions, just like a music box can be configured to play different sequences of tones. The findings help us understand the algorithms used by the brain to flexibly generate complex behaviours, such as planning and reasoning, and might be useful in understanding how such processes go wrong in psychiatric conditions such as schizophrenia.

The research, published today in Nature, outlines how scientists at the Sainsbury Wellcome Centre at UCL and the University of Oxford studied mice learning different behavioural sequences but with the same structure. This allowed the team to uncover how mice generalise structures to new tasks, a hallmark of intelligent behaviour.  

“Every day we solve new problems by generalising from our knowledge. Take cooking for example. When faced with a new recipe, you are able to use your background knowledge of similar recipes to infer what steps are needed, even if you have never made the meal before. We wanted to understand at a detailed cellular level how the brain achieves this and also to infer from this brain activity the algorithms being used to solve this problem,” commented Dr Mohamady El Gaby, first author on the study and postdoctoral neuroscientist in the Behrens Lab at the Sainsbury Wellcome Centre at UCL and Nuffield Department of Clinical Neurosciences, University of Oxford. 

The researchers gave mice a series of four goal locations. While the details of the sequences were different, the general structure was the same. Mice moved between the goal locations (A B C and D) that repeated in a loop. 

“After experiencing enough sequences, the mice did something remarkable – they guessed a part of the sequence they had never experienced before. When reaching D in a new location for the first time, they knew to go straight back to A. This action couldn’t have been remembered, since it was never experienced in the first place! Instead, it’s evidence that mice know the general structure of the task and can track their “position” in behavioural coordinates,” explained Dr El Gaby.

To understand how the mice learned the general structure of the task, the researchers used silicon probes that allowed them to record the activity of multiple individual cells from an area of the brain called the medial frontal cortex. They found that the cells collectively mapped the animal’s “goal progress”. For example, one cell could fire when the animal is 70% of the way to its goal, regardless of where the goal is or how far it takes to reach it. 

“We found that the cells tracked the animal’s behavioural position relative to concrete actions. If we think of the cooking analogy, the cells cared about progress towards subgoals such as chopping the vegetables. A subset of the cells were also tuned to map the progress towards the overall goal, such as finishing preparing the meal. The “goal progress” cells therefore effectively act as flexible building blocks that come together to build a behavioural coordinate system,” said Dr El Gaby.

In effect, the team found that the cells form multiple coordinate systems, each telling the animal where it is relative to a specific action. In a similar way to a music box that can be configured to play any sequence of tones, the brain can instead “play” behavioural actions.

The team are now working to understand how these activity patterns are built into the brain’s connections, both when learning new behaviours, and how they start to emerge in the developing brain. In addition, early work from the group and their collaborators suggests similar brain activity is present in equivalent circuits in healthy humans. This has encouraged the team to work with psychiatrists to understand how these processes are affected in conditions like schizophrenia, which is known to involve the same brain circuits. This could help explain why people with schizophrenia overestimate their progress to goals leading to delusions.

This research was supported by a Wellcome Trust PhD studentship (220047/Z/19/Z), Wellcome Principal Research Fellowship (219525/Z/19/Z), Wellcome Collaborator award (214314/Z/18/Z), The Wellcome Centre for Integrative Neuroimaging and Wellcome Centre for Human Neuroimaging core funding from the Wellcome Trust (203139/Z/16/Z, 203147/Z/16/Z), the Sir Henry Wellcome Post-doctoral Fellowship (222817/Z/21/Z), the Gatsby Charitable Foundation, the Wellcome Trust career development award (225926/Z/22/Z), and a Wellcome Trust SRF (202831/Z/16/Z).

Source:
Read the full paper in Nature: ‘A cellular basis for mapping behavioural structure’ DOI: 10.1038/s41586-024-08145-x

Media contact:
For more information or to speak to the researchers involved, please contact:

April Cashin-Garbutt, Head of Research Communications and Engagement, Sainsbury Wellcome Centre

E: a.cashin-garbutt@ucl.ac.uk T: +44 (0)20 3108 8028

About the Sainsbury Wellcome Centre 
The Sainsbury Wellcome Centre (SWC) brings together world-leading neuroscientists to generate theories about how neural circuits in the brain give rise to the fundamental processes underpinning behaviour, including perception, memory, expectation, decisions, cognition, volition and action. Funded by the Gatsby Charitable Foundation and Wellcome, SWC is located within UCL and is closely associated with the Faculties of Life Sciences and Brain Sciences. 

About the Nuffield Department of Clinical Neurosciences 
The Nuffield Department of Clinical Neurosciences has an established research and teaching portfolio with a national and international reputation for excellence. It comprises six sections: the Centre for the Prevention of Stroke & Dementia, the Division of Clinical Neurology, the Medical Research Council Brain Network Dynamics Unit, the Nuffield Division of Anaesthetics, the Nuffield Laboratory of Ophthalmology and the Wellcome Centre for Integrative Neuroimaging. The Department is largely based in the John Radcliffe Hospital and has developed a highly integrated and interdisciplinary environment in which research, teaching, clinical training and clinical care interact. This enables new approaches to the understanding, diagnosis and treatment of brain diseases. www.ndcn.ox.ac.uk