Ultrasound Mediated Mild Hyperthermia Resolves Neuroinflammation in an Animal Model

Seasons, Graham

Ultrasound Mediated Mild Hyperthermia Resolves Neuroinflammation in an Animal Model

dc.contributor.advisor	Pike, Bruce
dc.contributor.advisor	Kuipers, Hedwich
dc.contributor.author	Seasons, Graham
dc.contributor.committeemember	Pichardo, Samuel
dc.contributor.committeemember	Dunn, Jeff
dc.date	2025-06
dc.date.accessioned	2024-11-04T16:43:01Z
dc.date.available	2024-11-04T16:43:01Z
dc.date.issued	2024-11-01
dc.description.abstract	Chronic neuroinflammation is an often overlooked aspect of the development of neurodegenerative and autoimmune disease, especially in older populations, and there are few treatments capable of addressing this type of inflammation. We sought to address this gap by following up on our clinical finding where focused ultrasound resolved chronic radiation-related neuroinflammation Using ultrasound-mediated mild hyperthermia to treat chronic neuroinflammation in a preclinical mouse model, we investigated the impact on the immune response, and the resolution of inflammation. Seven days after peripheral infection, we targeted the mouse midbrain with focal hyperthermia (4 mins at 39 oC and 6 mins at 42 oC). Proteomic changes were analyzed, and demonstrated that hyperthermia reduced inflammation in female mice 24 hours after treatment, alleviating blood brain barrier disruption, antigen presentation, and anti-viral signalling. In contrast, male mice did not show a change in inflammatory mediators at 24 hours, but showed an upregulation in proteins associated with the heat shock response, chromatin maintenance, and chaperone mediated autophagy. At the cellular level, microglia and astrocytes demonstrated homeostatic phenotypes seven days after hyperthermia treatment in both males and females. We also investigated the role of the immunosuppressive CD200/CD200R signalling pathway in immune resolution, and discovered that it is dysregulated in chronic neuroinflammation – exacerbating inflammation in males, while maintaining a resolving function in females. Ultrasound mediated mild hyperthermia was able to restore homeostatic CD200/CD200R signalling, alleviating the pro-inflammatory rewiring observed in males. Consequently, we demonstrate that ultrasound mediated mild hyperthermia is capable of restoring the homeostatic function of receptors, and resolving chronic neuroinflammation across pathology, through the induction of the heat shock response. We propose a new application of clinically approved magnetic resonance guided focused ultrasound systems in the treatment of chronic neuroinflammation, with the potential for rapid clinical translation.
dc.identifier.citation	Seasons, G. (2024). Ultrasound mediated mild hyperthermia resolves neuroinflammation in an animal model (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/120036
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Heat shock response
dc.subject	CD200R
dc.subject	Inflammation
dc.subject	Ultrasound
dc.subject	Sex differences
dc.subject	Hyperthermia
dc.subject.classification	Neuroscience
dc.subject.classification	Immunology
dc.title	Ultrasound Mediated Mild Hyperthermia Resolves Neuroinflammation in an Animal Model
dc.type	master thesis
thesis.degree.discipline	Medicine – Neuroscience
thesis.degree.grantor	University of Calgary
thesis.degree.name	Master of Science (MSc)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.