Characterisation of oligodendrocyte plasticity in the adult median eminence and its role in the regulation of energy balance

Lead Research Organisation: University of Cambridge
Department Name: Institute of Metabolic Science

Abstract

Oligodendrocytes are brain cells that isolate axons to allow fast transmission of electrical signals. They are formed during the first years of life in humans, but recent studies show that some continue to be formed in adulthood in response to environmental challenges, for example during the acquisition of new motor skills. We found that nutritional signals regulate the formation of new oligodendrocytes in adults in a region of the brain that controls appetite and weight gain. Our aim is to determine how these new cells contribute to the regulation of appetite and the maintenance of body weight, and whether this process is impaired in obesity.
This research will increase our understanding of how nutrition regulates 1-the formation of new oligodendrocytes in adults, and 2- brain pathways controlling appetite and body weight. Potential applications include new therapeutic strategies for the treatment of obesity and demyelinating diseases like multiple sclerosis.

Technical Summary

The median eminence (ME) of the hypothalamus serves as an interface between peripheral and hypothalamic neuroendocrine circuits. It undergoes rapid structural remodelling in response to changes in peripheral energy availability and this plasticity determines how nearby neurons access and respond to blood-borne fuel-related signals. Its unique vasculature lacks a blood-brain-barrier, suggesting other specialized roles for local glia.
Our pilot data indicate that new oligodendrocytes (OLs) are continuously formed in the adult ME and that OL production and differentiation in the ME are regulated by nutritional signals. We hypothesize that this adaptive OL-encoded response is required for the maintenance of energy homeostasis and impaired in obesity. Accordingly, our aims in this proposal are to determine how nutritional signals regulate OL differentiation, to determine how obesity affects OL plasticity in the human and murine ME, and to directly test the role of OL plasticity in the regulation of energy balance in mice.
This research will increase our understanding of the role of glial cells in metabolic sensing and the regulation of neurocircuits controlling appetite and metabolism. It will also test a novel role for nutritional signals in the control of OL differentiation. Collectively, this research will promote important novel conceptual advances in the fields of obesity and adult brain plasticity, with potential implications for the treatment of metabolic and demyelinating diseases.

Planned Impact

This research will directly benefit all staff involved in this project: increased technical and scientific training and career development for the students and research fellows who will perform the research, increased international recognition for the Blouet Lab, and novel collaborative research perspectives for the Rowitch and Franklin labs, linking nutrition research to the study of adult brain plasticity and oligodendrocyte biology.
This research will also benefit the MRC MDU, the IMS, the University of Cambridge and the Medical Research Council by demonstrating academic excellence and collaborative innovation between research teams from various specialties of neuroscience. Globally this research will promote the UK's position as leading country in academic neuroscience research.
Results from this research will benefit the fields of obesity, systems neuroscience of body weight control, oligodendrocyte biology and adult brain plasticity. We are proposing to investigate new concepts both in terms of a role for oligodendrocytes in weight control, and a role for nutrition in regulating adult oligodendrocyte plasticity and possibly adult myelination.
Via public engagement activities, key findings from this research will be disseminated to the greater public locally, nationally and internationally. In particular, the concept that the adult brain is plastic and still develops to adapt to new environment conditions is quite appealing and will likely interest a wide range of non-scientists. This will increase awareness for neuroscience and the benefits of neuroscience research.
On the longer-term, this research may lead to new therapeutic strategies in the treatment of obesity and demyelinating diseases, which could be both nutritional or pharmacologic. New dietary advices and public health policies informed by our findings may be developed in the future. Long term impacts include better health and well-being and decreased health care costs.

Publications

10 25 50
 
Title scRNAseq of murine median eminence samples 
Description We performed scRNASeq of mouse median eminence samples which created a new transcriptomic database 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? No  
Impact Discovery of how nutrition regulates oligodendrocyte plasticity 
 
Description Alec Gow Claudin 11 
Organisation Wayne State University
Country United States 
Sector Academic/University 
PI Contribution analysis
Collaborator Contribution sent samples
Impact data
Start Year 2019
 
Description Collaboration with David Rowitch, Wellcome Trust Stem Cell Institute 
Organisation University of Cambridge
Department Department of Paediatrics
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide a new model in which the Rowitch team can make their routine mesurements.
Collaborator Contribution Performed RNAScope analysis
Impact New research results and 1 publication in Biorxiv
Start Year 2017
 
Description Collaboration with Robin Franklin, Wellcome Trust Stem Cell Institute 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided a new model in which the Franklin team performed some of their routine assessments.
Collaborator Contribution Performed EM analysis
Impact Research results and 1 publication in Biorxiv
Start Year 2016
 
Description Collaboration with Thora Karadottir, 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided a new research model in which the Karadottir team performed some of their routine assessments
Collaborator Contribution Ephys on brain slices
Impact research results
Start Year 2019
 
Description Michael Schwartz 
Organisation University of Washington
Country United States 
Sector Academic/University 
PI Contribution We performed assays, analysis and send research samples
Collaborator Contribution OUr partners performed assays, analysis and send research samples
Impact research data
Start Year 2019
 
Description Wendy macklin 
Organisation University of Colorado Denver
Country United States 
Sector Academic/University 
PI Contribution performed analysis and assays
Collaborator Contribution sent samples
Impact research data
Start Year 2018
 
Description myelin lipidomics 
Organisation University of Cambridge
Department Institute of Metabolic Science (IMS)
Country United Kingdom 
Sector Academic/University 
PI Contribution performed analysis
Collaborator Contribution shared samples
Impact data
Start Year 2019