iCase: Minimally invasive fiber imaging for deep brain activity mapping in mice

MRC’s iCASE awards provide students with experience of collaborative research with a non academic partner, enabling the student to spend a period of time with the non-academic partner (usually no less than three months over the lifetime of the PhD).

Students who are successfully awarded an iCASE studentship are entitled to an additional £2,500 per year as a supplement to their stipend and an annual cash contribution of at least £1,400 towards the cost of the project.  The iCase project is only secured once contracts between the industrial partner and University of Edinburgh are signed. 

Background

Deep brain imaging remains one of the central challenges in neuroscience, as existing technologies often face trade-offs between resolution, invasiveness, and the ability to access deep structures. Hair-thin fiber-based imaging offers a promising solution, combining minimal invasiveness with the ability to reach and monitor neuronal activity in deep brain regions. Such fibers could provide high-resolution optical access without substantial tissue disruption, enabling chronic recordings and repeated measurements in the same animal. Testing this technology in mice offers a critical proof of concept, as it allows evaluation of spatial resolution, signal quality, and biocompatibility in a well-established model system. 

The aim of the project is to use and develop this technology for imaging neuronal activity in the Locus Coeruleus of mice. The locus coeruleus is a small brainstem nucleus located in the pons that serves as the brain's primary source of norepinephrine (noradrenaline). These cells project extensively throughout the central nervous system, influencing arousal, attention, stress responses, and cognitive functions. In neurological diseases, the locus coeruleus plays significant roles. It's one of the earliest brain regions affected in Parkinson's disease, with neuronal loss occurring before motor symptoms appear. In Alzheimer's disease, locus coeruleus degeneration contributes to cognitive decline and may accelerate tau pathology spread. The structure is also implicated in depression, anxiety disorders, and ADHD, where norepinephrine dysregulation affects mood and attention.

Research suggests that locus coeruleus disfunction may act as an early biomarker for various conditions. Its widespread connections make it both vulnerable to pathological processes and a promising therapeutic target for neuroprotective interventions.

This project investigates locus coeruleus alterations in neurodevelopmental disorders by comparing neuronal activity in a mouse model of Syngap mutations with control mice. Syngap haploinsufficiency causes intellectual disability and autism spectrum disorders, with emerging evidence linking these mutations to noradrenergic system dysfunction. We recently published an article with second supervisor Dr Stanfield showing the noradrenergic-dependent restoration of visual discrimination in a mouse model of SYNGAP1-related disorder (Katsanevaki et al., 2025).

By using advanced minimally-invasive neuroimaging technique developed by the company partner Deepen (Turtaev et al., 2018), we aim at revealing structural and functional changes in the locus coeruleus between wild-type and Syngap-deficient mice.

The study aims to characterize how Syngap mutation impact this critical noradrenergic nucleus. Findings could reveal whether locus coeruleus abnormalities contribute to cognitive deficits, attention problems, and behavioral phenotypes observed in Syngap-related disorders. This research may inform targeted therapeutic approaches addressing noradrenergic dysfunction in neurodevelopmental conditions and potentially in other diseases.

Aims

• Develop multimode fiber imaging and holographic stimulation of the mouse Locus Coeruleus.
• Image neuronal activity in the locus coeruleus of mouse models of Neurodevelopmental disorders (Syngap mutation) and wild type controls.
• Test the impact of drugs (noradrenergic agonists such as Guanfacine) on the activity of Locus Coeruleus neurons.

Training outcomes

• In vivo recordings in awake behaving mice: training in calcium imaging; In vivo surgery, viral injections in mouse brain
• Hands-on experience in holographic microendoscopy, including system operation, customisation, and optimisation for in vivo imaging
• Photonics: Active light shaping in modern microscopy, including aberration correction, patterned illumination with spatial light modulators
• Computational methods: big data analysis, programming skills in Python, model-based analysis of the data.
• Exposure to technology translation: product development, commercialisation considerations, and market trends in neuroimaging
• Data Management: managing and analyzing large datasets
• Research Ethics, animal research regulations
• Presentation of data, written and orally

References

• S Turtaev, IT Leite, T Altwegg-Boussac, JMP Pakan, NL Rochefort, T Cizmar, High-fidelity multimode fibre-based endoscopy for deep brain in vivo imaging, Light: Science & Applications 7 (1), 92. 2018.
• Danai Katsanevaki, Nathalie Dupuy, Sam A Booker, Damien Wright, Aisling Kenny, Zihao Chen, Nina Kudryashova, Pippa Howitt, Andrew C Stanfield, Peter C Kind, Nathalie L Rochefort, Noradrenergic-dependent restoration of visual discrimination in a mouse model of SYNGAP1-related disorder bioRxiv, 2025.04. 09.647923
• Pakan JM, Francioni V, Rochefort NL. Action and learning shape the activity of neuronal circuits in the visual cortex. Curr Opin Neurobiol. 2018;52(52):88-97.