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.
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.
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.
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
Kohnke S
(2021)
Nutritional regulation of oligodendrocyte differentiation regulates perineuronal net remodeling in the median eminence.
in Cell reports
Buller S
(2023)
Median eminence myelin continuously turns over in adult mice
in Molecular Metabolism
Buller S
(2023)
Median eminence myelin continuously turns over in adult mice.
Buller S
(2023)
Median eminence myelin continuously turns over in adult mice.
Description | Enabling technologies |
Amount | £1,000,000 (GBP) |
Funding ID | MC_UU_00014/5 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2024 |
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 | Collaboration with eli Lilly |
Organisation | Eli Lilly & Company Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | TO study the mechanims of action of incretin-based with loss drugs |
Collaborator Contribution | Financial contribution through a research agreement |
Impact | Nine yet |
Start Year | 2020 |
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 |