Periodic Reporting for period 1 - HD-SC (Elucidating the Superior Colliculus-related network properties and modulation in Huntington's Disease mouse model to delay the onset and ameliorate severity of the motor symptoms)
Période du rapport: 2023-10-01 au 2025-10-31
Huntington’s disease (HD) is a rare but devastating neurodegenerative disorder that causes progressive motor, cognitive, and psychiatric symptoms. Across Europe and worldwide, thousands of individuals and their families are affected by the disease, often across multiple generations due to its hereditary nature. Current treatments can only alleviate symptoms; no approved therapy is available to halt or slow the progression of neurodegeneration. Understanding the early mechanisms of the disease at the level of brain circuits is therefore essential for developing effective, innovative therapeutic strategies.
The HD-SC project was designed to address a significant gap in our understanding of Huntington’s disease: how the sensorimotor circuits of the brain, particularly the superior colliculus (SC), contribute to early disease symptoms. The SC is a key structure involved in integrating visual information with movement planning, enabling rapid and coordinated behavioural responses. Emerging scientific and policy frameworks increasingly highlight the importance of “circuit-based” approaches for tackling neurological disorders. In this context, investigating functional changes within the SC provides a promising pathway for identifying novel therapeutic targets and early biomarkers of disease.
To achieve these goals, the project combines several state-of-the-art neuroscience techniques. These include high-sensitivity calcium activity recordings, fibre photometry, deep-learning-based behavioural analysis, and advanced imaging of neuroinflammatory pathways. By integrating these complementary approaches, the project maps how the SC functions in healthy conditions and how its activity is altered in experimental models of Huntington’s disease. Real-time behavioural monitoring allows the project to link specific circuit dysfunctions to measurable changes in sensory processing and movement control. This integrated perspective is essential for uncovering the earliest biological changes that drive disease progression.
The expected impacts of HD-SC extend beyond the immediate scientific findings. By generating detailed knowledge of circuit-level alterations, the project supports the long-term development of precision medicine approaches for neurodegenerative diseases. It contributes to European objectives in health research by improving understanding of disease mechanisms, enabling more targeted interventions, and strengthening the scientific foundation required for future therapeutic innovation. In the broader societal context, the project aims to improve the prospects for earlier diagnosis, more effective treatments, and a better quality of life for people affected by Huntington’s disease.
Overall, HD-SC sets the scene for a new line of research focusing on sensorimotor circuits as key players in Huntington’s disease. By linking behavioural changes to specific patterns of neural dysfunction, the project charts a clear pathway toward impactful discoveries that can support future clinical translation and benefit patients, families, and healthcare systems across Europe.
The HD-SC project was designed to address a significant gap in our understanding of Huntington’s disease: how the sensorimotor circuits of the brain, particularly the superior colliculus (SC), contribute to early disease symptoms. The SC is a key structure involved in integrating visual information with movement planning, enabling rapid and coordinated behavioural responses. Emerging scientific and policy frameworks increasingly highlight the importance of “circuit-based” approaches for tackling neurological disorders. In this context, investigating functional changes within the SC provides a promising pathway for identifying novel therapeutic targets and early biomarkers of disease.
To achieve these goals, the project combines several state-of-the-art neuroscience techniques. These include high-sensitivity calcium activity recordings, fibre photometry, deep-learning-based behavioural analysis, and advanced imaging of neuroinflammatory pathways. By integrating these complementary approaches, the project maps how the SC functions in healthy conditions and how its activity is altered in experimental models of Huntington’s disease. Real-time behavioural monitoring allows the project to link specific circuit dysfunctions to measurable changes in sensory processing and movement control. This integrated perspective is essential for uncovering the earliest biological changes that drive disease progression.
The expected impacts of HD-SC extend beyond the immediate scientific findings. By generating detailed knowledge of circuit-level alterations, the project supports the long-term development of precision medicine approaches for neurodegenerative diseases. It contributes to European objectives in health research by improving understanding of disease mechanisms, enabling more targeted interventions, and strengthening the scientific foundation required for future therapeutic innovation. In the broader societal context, the project aims to improve the prospects for earlier diagnosis, more effective treatments, and a better quality of life for people affected by Huntington’s disease.
Overall, HD-SC sets the scene for a new line of research focusing on sensorimotor circuits as key players in Huntington’s disease. By linking behavioural changes to specific patterns of neural dysfunction, the project charts a clear pathway toward impactful discoveries that can support future clinical translation and benefit patients, families, and healthcare systems across Europe.
Throughout the HD-SC project, a comprehensive set of experimental, analytical, and computational activities was carried out to uncover how the superior colliculus (SC) contributes to early sensorimotor dysfunction in Huntington’s disease (HD). The work combined circuit-level recordings, behavioural analyses, and molecular characterisation to build an integrated understanding of the disease mechanism.
The project began by establishing different cohorts to assess the possible changes in SC at defined symptomatic stages of the HD. The experiments performed to evaluate molecular and cellular changes of the superior colliculus in respective disease stages. These included quantitative assessment of various protein markers. Alterations in synaptic signalling pathways were detected in the model, suggesting that synaptic responses within the SC may play a role in circuit dysfunction. These results align with growing evidence that synaptic dysfunction contributes to the progression of neurodegenerative diseases.
A major technical component of the project involved validating the experimental platforms and technical details required for circuit-level investigation. High-precision fibre photometry systems were optimised to measure calcium activity in the superior colliculus with stable long-term signal quality. This allowed the continuous monitoring in addition to the coupled behavioural tasks targeting visual processing, sensorimotor integration, and responsive movement initiation to ensure precise interpretation of the neural signal and the respective behavioural traits.
The implementation of deep-learning-based behavioural tracking. Using custom-trained algorithms, the project generated high-resolution quantification of movement patterns and stimulus-evoked behavioural responses. This analytical pipeline enabled the detection of subtle behavioural impairments that would not be measurable through classical observation alone. These analyses revealed alterations in behavioural response and sensorimotor coordination consistent with sensorimotor circuit dysfunction.
The fibre photometry recordings provided the first functional insights into how SC activity changes across disease progression. In healthy conditions, visually evoked and spontaneous SC signals showed robust and well-structured dynamics. In contrast, recordings from Huntington’s disease models displayed altered responses and disrupted temporal patterns. The integration of behavioural, functional, and molecular datasets represents one of the project’s key achievements. By combining these dimensions, the project generated a multi-scale understanding of how SC circuits are altered, from cellular mechanisms to whole-animal behaviour.
As outcomes of the completed work, the project successfully:
• Established a reliable platform for real-time circuit monitoring in the superior colliculus.
• Demonstrated measurable functional alterations in the superior colliculus throughout stages of Huntington’s disease.
• Identified behavioural signatures of impaired visuomotor processing.
• Characterised molecular changes in the SC that may contribute to circuit instability.
• Created integrated datasets linking cellular pathology, circuit dysfunction, and behaviour.
These achievements significantly advance our understanding of how the superior colliculus circuit contributes to Huntington’s disease and open new avenues for the development of targeted therapeutic strategies.
The project began by establishing different cohorts to assess the possible changes in SC at defined symptomatic stages of the HD. The experiments performed to evaluate molecular and cellular changes of the superior colliculus in respective disease stages. These included quantitative assessment of various protein markers. Alterations in synaptic signalling pathways were detected in the model, suggesting that synaptic responses within the SC may play a role in circuit dysfunction. These results align with growing evidence that synaptic dysfunction contributes to the progression of neurodegenerative diseases.
A major technical component of the project involved validating the experimental platforms and technical details required for circuit-level investigation. High-precision fibre photometry systems were optimised to measure calcium activity in the superior colliculus with stable long-term signal quality. This allowed the continuous monitoring in addition to the coupled behavioural tasks targeting visual processing, sensorimotor integration, and responsive movement initiation to ensure precise interpretation of the neural signal and the respective behavioural traits.
The implementation of deep-learning-based behavioural tracking. Using custom-trained algorithms, the project generated high-resolution quantification of movement patterns and stimulus-evoked behavioural responses. This analytical pipeline enabled the detection of subtle behavioural impairments that would not be measurable through classical observation alone. These analyses revealed alterations in behavioural response and sensorimotor coordination consistent with sensorimotor circuit dysfunction.
The fibre photometry recordings provided the first functional insights into how SC activity changes across disease progression. In healthy conditions, visually evoked and spontaneous SC signals showed robust and well-structured dynamics. In contrast, recordings from Huntington’s disease models displayed altered responses and disrupted temporal patterns. The integration of behavioural, functional, and molecular datasets represents one of the project’s key achievements. By combining these dimensions, the project generated a multi-scale understanding of how SC circuits are altered, from cellular mechanisms to whole-animal behaviour.
As outcomes of the completed work, the project successfully:
• Established a reliable platform for real-time circuit monitoring in the superior colliculus.
• Demonstrated measurable functional alterations in the superior colliculus throughout stages of Huntington’s disease.
• Identified behavioural signatures of impaired visuomotor processing.
• Characterised molecular changes in the SC that may contribute to circuit instability.
• Created integrated datasets linking cellular pathology, circuit dysfunction, and behaviour.
These achievements significantly advance our understanding of how the superior colliculus circuit contributes to Huntington’s disease and open new avenues for the development of targeted therapeutic strategies.
The HD-SC project generated a set of behavioural, molecular, structural, and functional data that collectively advance the understanding of how the superior colliculus (SC) contributes to Huntington’s disease. By examining multiple disease stages and integrating automated behavioural quantification with histological and circuit-level measurements, the project provides new insights into the early mechanisms underlying sensorimotor dysfunction.
The behavioural studies revealed that SC-dependent defensive responses change progressively across disease development. Using optimised testing paradigms, the project detected early alterations in specific visuomotor reactions and spontaneous behaviours in the R6/1 model. Newly implemented AI-based algorithms enabled automated detection of rearing, grooming, escape, avoidance, and approach, and tolerance, ensuring reproducible and high-throughput behavioural analysis. These results show that subtle SC-related deficits emerge earlier than previously reported, helping to pinpoint the onset of functional impairment.
Complementary molecular and structural analyses provided further evidence of stage-dependent changes in the SC. Tissue processing pipelines were optimised for a broad set of synaptic and neuronal markers, including those related to glutamatergic, GABAergic, cholinergic, and pre/post-synaptic signalling. Preliminary findings indicate alterations in synaptic organisation that evolve with disease progression, suggesting that cellular and structural changes may precede or accompany behavioural symptoms. By integrating molecular signatures with behavioural metrics, the project established a multi-level timeline of SC dysfunction in this model.
Fibre photometry recordings from medial and lateral SC regions offered technical and conceptual advances. Although region-specific differences were not detected under the stimuli used in this reporting period, the project identified sex-dependent variability in calcium responses. The optimisation of stereotaxic coordinates, viral delivery, fibre placement, and analytical workflows forms a strong methodological foundation for subsequent phases.
Work related to SC neuromodulation, originally planned for the final work package, highlighted important translational opportunities. Due to the extended time required to finalise full SC functional mapping, phytochrome-based modulation could not yet be initiated in the SC. However, parallel progress in the major SC afferent—the M2 motor cortex—demonstrated that photoactivated adenylyl cyclase can modulate cAMP signalling and influence behavioural outcomes in the HD model. These findings, published in iScience (2025) with contributions from the project, provide essential mechanistic insights that will directly support the next steps once SC circuit datasets are complete.
Overall, the project has produced several impactful outcomes:
• Identification of early SC-dependent behavioural impairments using high-precision and AI-enhanced analysis tools.
• Detection of disease-stage-specific molecular and synaptic changes in the SC.
• Establishment of reliable technical platforms for fibre photometry in the superior colliculus.
• Recognition of sex-specific variability that will improve the accuracy of future SC mapping.
• Generation of an integrated dataset linking behavioural, molecular, and circuit-level signatures of SC dysfunction in Huntington’s disease.
These advances have significant potential to influence future research directions. The integrated dataset created by the project can serve as a foundation for identifying early biomarkers and developing targeted circuit-based interventions. It also contributes to a broader scientific shift toward understanding early and region-specific contributions to neurodegenerative disorders. To ensure further uptake and maximise the project’s impact, several key needs have been identified:
• Further research and validation: Completing SC circuit mapping and expanding analyses to additional behavioural contexts will be essential for confirming early biomarkers.
• Advanced neuromodulation studies: Finalising WP3 will allow systematic testing of whether precise modulation of SC networks can reduce behavioural deficits.
• Technical refinement: Continued development of automated behavioural and imaging pipelines will improve sensitivity and reproducibility.
• Data sharing and interoperability: Open access to curated behavioural, molecular, and photometry datasets will accelerate comparisons across models and laboratories.
• Regulatory and gender-inclusive frameworks: Ensuring balanced sex representation and considering regulatory aspects in future neuromodulation strategies will strengthen translational potential.
The HD-SC project has therefore established a strong scientific and technical basis for future developments aimed at early detection and targeted modulation of SC circuits in Huntington’s disease.
The behavioural studies revealed that SC-dependent defensive responses change progressively across disease development. Using optimised testing paradigms, the project detected early alterations in specific visuomotor reactions and spontaneous behaviours in the R6/1 model. Newly implemented AI-based algorithms enabled automated detection of rearing, grooming, escape, avoidance, and approach, and tolerance, ensuring reproducible and high-throughput behavioural analysis. These results show that subtle SC-related deficits emerge earlier than previously reported, helping to pinpoint the onset of functional impairment.
Complementary molecular and structural analyses provided further evidence of stage-dependent changes in the SC. Tissue processing pipelines were optimised for a broad set of synaptic and neuronal markers, including those related to glutamatergic, GABAergic, cholinergic, and pre/post-synaptic signalling. Preliminary findings indicate alterations in synaptic organisation that evolve with disease progression, suggesting that cellular and structural changes may precede or accompany behavioural symptoms. By integrating molecular signatures with behavioural metrics, the project established a multi-level timeline of SC dysfunction in this model.
Fibre photometry recordings from medial and lateral SC regions offered technical and conceptual advances. Although region-specific differences were not detected under the stimuli used in this reporting period, the project identified sex-dependent variability in calcium responses. The optimisation of stereotaxic coordinates, viral delivery, fibre placement, and analytical workflows forms a strong methodological foundation for subsequent phases.
Work related to SC neuromodulation, originally planned for the final work package, highlighted important translational opportunities. Due to the extended time required to finalise full SC functional mapping, phytochrome-based modulation could not yet be initiated in the SC. However, parallel progress in the major SC afferent—the M2 motor cortex—demonstrated that photoactivated adenylyl cyclase can modulate cAMP signalling and influence behavioural outcomes in the HD model. These findings, published in iScience (2025) with contributions from the project, provide essential mechanistic insights that will directly support the next steps once SC circuit datasets are complete.
Overall, the project has produced several impactful outcomes:
• Identification of early SC-dependent behavioural impairments using high-precision and AI-enhanced analysis tools.
• Detection of disease-stage-specific molecular and synaptic changes in the SC.
• Establishment of reliable technical platforms for fibre photometry in the superior colliculus.
• Recognition of sex-specific variability that will improve the accuracy of future SC mapping.
• Generation of an integrated dataset linking behavioural, molecular, and circuit-level signatures of SC dysfunction in Huntington’s disease.
These advances have significant potential to influence future research directions. The integrated dataset created by the project can serve as a foundation for identifying early biomarkers and developing targeted circuit-based interventions. It also contributes to a broader scientific shift toward understanding early and region-specific contributions to neurodegenerative disorders. To ensure further uptake and maximise the project’s impact, several key needs have been identified:
• Further research and validation: Completing SC circuit mapping and expanding analyses to additional behavioural contexts will be essential for confirming early biomarkers.
• Advanced neuromodulation studies: Finalising WP3 will allow systematic testing of whether precise modulation of SC networks can reduce behavioural deficits.
• Technical refinement: Continued development of automated behavioural and imaging pipelines will improve sensitivity and reproducibility.
• Data sharing and interoperability: Open access to curated behavioural, molecular, and photometry datasets will accelerate comparisons across models and laboratories.
• Regulatory and gender-inclusive frameworks: Ensuring balanced sex representation and considering regulatory aspects in future neuromodulation strategies will strengthen translational potential.
The HD-SC project has therefore established a strong scientific and technical basis for future developments aimed at early detection and targeted modulation of SC circuits in Huntington’s disease.