Periodic Reporting for period 2 - CEN (Cerebellum and Emotional Networks)
Période du rapport: 2023-06-01 au 2025-10-31
The cerebellum has long been considered a sensorimotor control structure, but emerging evidence suggests its function extends to the regulation of motor and cognitive aspects of emotional behaviour. However, the knowledge gap in understanding of cerebellar contributions to emotional behaviour limits our understanding of brain function and hampers progress in treating emotional and neurodevelopmental disorders.
IMPORTANCE TO SOCIETY
Emotional disorders—including anxiety, PTSD, and autism—affect millions worldwide, imposing a heavy socio-economic burden. By uncovering cerebellar mechanisms underlying emotional behaviour, this project has the potential to contribute to novel therapeutic strategies, improving mental health care and reducing societal costs.
OBJECTIVES
•Advance understanding of cerebellar contributions to emotional behaviour in health and disease.
•Map neural circuits linking cerebellum to limbic and neocortical regions.
•Train 15 Early Stage Researchers through an interdisciplinary ETN, involving 8 Universities and 9 non-academic partners.
•Promote open science, dissemination, and engagement with academic, industrial, and societal stakeholders.
CEN successfully delivered on all of its objectives, producing novel scientific insights, high-impact publications (with more in the pipeline), and a new generation of highly skilled researchers. The consortium established strong academic–industry partnerships; advanced open science practices; and created a sustainable international network for future EU collaborations.
IMPORTANCE TO SOCIETY
Emotional disorders—including anxiety, PTSD, and autism—affect millions worldwide, imposing a heavy socio-economic burden. By uncovering cerebellar mechanisms underlying emotional behaviour, this project has the potential to contribute to novel therapeutic strategies, improving mental health care and reducing societal costs.
OBJECTIVES
•Advance understanding of cerebellar contributions to emotional behaviour in health and disease.
•Map neural circuits linking cerebellum to limbic and neocortical regions.
•Train 15 Early Stage Researchers through an interdisciplinary ETN, involving 8 Universities and 9 non-academic partners.
•Promote open science, dissemination, and engagement with academic, industrial, and societal stakeholders.
CEN successfully delivered on all of its objectives, producing novel scientific insights, high-impact publications (with more in the pipeline), and a new generation of highly skilled researchers. The consortium established strong academic–industry partnerships; advanced open science practices; and created a sustainable international network for future EU collaborations.
RESEARCH OBJECTIVES - INTRODUCTION AND ACHIEVEMENTS
--RO1:How do different cerebellar modules contribute to emotional behaviour?
The objective of RO1 was to elucidate how distinct elements of cerebellar circuitry govern and integrate motor, autonomic, and cognitive dimensions of emotional behaviour. The WP used rodents to determine whether dynamic modifications (plasticity) in defensive responses during aversive states correspond to structured neuronal activity within individual cerebellar modules.
Key Achievements
•Identified a reciprocal cerebellar-brainstem pathway involved in fear learning and extinction in mice
•Demonstrated timing-dependent modulation of medial prefrontal cortex oscillations by cerebellar output
•Established feasibility of in vivo calcium imaging in the cerebellum combined with ECG monitoring in freely moving mice
•Showed cerebellar cortical inhibition accelerates fear extinction
•Discovered that endocannabinoid signaling in in the cerebellum modulates anxiety-like behaviour in rats
--RO2:What are the neural pathways that functionally link individual cerebellar modules to other brain regions instrumental for emotional behaviour?
RO2 focused on characterising reciprocal connections between the cerebellum and key limbic and brainstem structures involved in emotional behaviour, including the periaqueductal grey (PAG), amygdala, and prefrontal cortex. Using rodents, we aimed to define anatomical and functional connectivity and determine how cerebellar output contributes to emotional, affective, and autonomic control.
Key Achievements
•Mapped bidirectional connectivity between cerebellar nuclei and the PAG using viral tracing in mice
•Discovered dopaminergic integration within cerebello-PAG circuits
•Demonstrated phenotype-dependent modulation of affective state in a rat neuropathic pain model
•Identified visceral input integration through noradrenergic nucleus tractus solitaris projections in mice
--RO3:What is the mode of operation of these anatomically and functionally defined pathways?
RO3 aimed to determine how intrinsic cerebellar circuitry operates during emotional behaviour through complementary experimental and computational approaches. The WP explored regional specialisation in cerebellar signal processing in mice and integrated these findings into multiscale computational models linking microcircuits to human whole-brain emotion networks.
Key Achievements
•Revealed regional specialisation in cerebellar signal processing using high density-microelectrode array (HD-MEA) electrophysiological recordings in vitro
•Developed computational models of cerebellar microcircuits and whole-brain emotion networks based on data from CEN
•Demonstrated cross-scale integration reproducing realistic cerebellar and PAG activity patterns
•Established a human whole-brain model correlating connectivity dynamics with emotional reactivity
--RO4:How do changes in cerebellar circuits contribute to pathology?
RO4 investigated how structural and functional disruptions of cerebellar circuits contribute to emotional dysfunction in disease contexts, including neurodevelopmental disorders, anxiety, and cerebellar degeneration. The WP combined rodent models and human studies using behavioural paradigms, neuroimaging, electrophysiology, and genetics to identify biomarkers and mechanisms underlying emotional dysregulation.
Key Achievements
•Human 7T fMRI studies during fear extinction established cerebellar interactions with a key reward centre in the brain
•Identified altered cerebellar connectivity in SYNGAP1 and Fmr1 rat models of neurodevelopmental disorders
•Demonstrated sex-dependent structural and functional cerebellar changes in neurodevelopmental disorders in rats
•Studies of human twins revealed high heritability of cerebellar morphology and neural variability
•Discovered important differences in human cerebellar grey matter and cerebro-cerebellar coupling during human development
•Identified cerebellar alterations in social anxiety disorder and proposed neural variability as a biomarker
TRAINING AND CAPACITY BUILDING
•CEN delivered over 30 workshops on neuroscience, ethics, open science, and career development
•Introduced wellbeing and leadership training for ESRs and supervisors
•Supported secondments for all ESRs across academic and non-academic sectors
DISSEMINATION AND EXPLOITATION
•Publications to date:13 peer-reviewed papers;11 manuscripts in preparation
•Conferences:ESR-led mini-symposium at SFN 2024 & International symposium ‘The Emotional Brain’
•Outreach:Brain Awareness Week events, art exhibitions, and active social media campaigns
•Industry impact:Collaboration with 3Brain validated HD-MEA technology
•Open Science:Adoption of EBRAINS repository for CEN to ensure long-term accessibility and FAIR data compliance
--RO1:How do different cerebellar modules contribute to emotional behaviour?
The objective of RO1 was to elucidate how distinct elements of cerebellar circuitry govern and integrate motor, autonomic, and cognitive dimensions of emotional behaviour. The WP used rodents to determine whether dynamic modifications (plasticity) in defensive responses during aversive states correspond to structured neuronal activity within individual cerebellar modules.
Key Achievements
•Identified a reciprocal cerebellar-brainstem pathway involved in fear learning and extinction in mice
•Demonstrated timing-dependent modulation of medial prefrontal cortex oscillations by cerebellar output
•Established feasibility of in vivo calcium imaging in the cerebellum combined with ECG monitoring in freely moving mice
•Showed cerebellar cortical inhibition accelerates fear extinction
•Discovered that endocannabinoid signaling in in the cerebellum modulates anxiety-like behaviour in rats
--RO2:What are the neural pathways that functionally link individual cerebellar modules to other brain regions instrumental for emotional behaviour?
RO2 focused on characterising reciprocal connections between the cerebellum and key limbic and brainstem structures involved in emotional behaviour, including the periaqueductal grey (PAG), amygdala, and prefrontal cortex. Using rodents, we aimed to define anatomical and functional connectivity and determine how cerebellar output contributes to emotional, affective, and autonomic control.
Key Achievements
•Mapped bidirectional connectivity between cerebellar nuclei and the PAG using viral tracing in mice
•Discovered dopaminergic integration within cerebello-PAG circuits
•Demonstrated phenotype-dependent modulation of affective state in a rat neuropathic pain model
•Identified visceral input integration through noradrenergic nucleus tractus solitaris projections in mice
--RO3:What is the mode of operation of these anatomically and functionally defined pathways?
RO3 aimed to determine how intrinsic cerebellar circuitry operates during emotional behaviour through complementary experimental and computational approaches. The WP explored regional specialisation in cerebellar signal processing in mice and integrated these findings into multiscale computational models linking microcircuits to human whole-brain emotion networks.
Key Achievements
•Revealed regional specialisation in cerebellar signal processing using high density-microelectrode array (HD-MEA) electrophysiological recordings in vitro
•Developed computational models of cerebellar microcircuits and whole-brain emotion networks based on data from CEN
•Demonstrated cross-scale integration reproducing realistic cerebellar and PAG activity patterns
•Established a human whole-brain model correlating connectivity dynamics with emotional reactivity
--RO4:How do changes in cerebellar circuits contribute to pathology?
RO4 investigated how structural and functional disruptions of cerebellar circuits contribute to emotional dysfunction in disease contexts, including neurodevelopmental disorders, anxiety, and cerebellar degeneration. The WP combined rodent models and human studies using behavioural paradigms, neuroimaging, electrophysiology, and genetics to identify biomarkers and mechanisms underlying emotional dysregulation.
Key Achievements
•Human 7T fMRI studies during fear extinction established cerebellar interactions with a key reward centre in the brain
•Identified altered cerebellar connectivity in SYNGAP1 and Fmr1 rat models of neurodevelopmental disorders
•Demonstrated sex-dependent structural and functional cerebellar changes in neurodevelopmental disorders in rats
•Studies of human twins revealed high heritability of cerebellar morphology and neural variability
•Discovered important differences in human cerebellar grey matter and cerebro-cerebellar coupling during human development
•Identified cerebellar alterations in social anxiety disorder and proposed neural variability as a biomarker
TRAINING AND CAPACITY BUILDING
•CEN delivered over 30 workshops on neuroscience, ethics, open science, and career development
•Introduced wellbeing and leadership training for ESRs and supervisors
•Supported secondments for all ESRs across academic and non-academic sectors
DISSEMINATION AND EXPLOITATION
•Publications to date:13 peer-reviewed papers;11 manuscripts in preparation
•Conferences:ESR-led mini-symposium at SFN 2024 & International symposium ‘The Emotional Brain’
•Outreach:Brain Awareness Week events, art exhibitions, and active social media campaigns
•Industry impact:Collaboration with 3Brain validated HD-MEA technology
•Open Science:Adoption of EBRAINS repository for CEN to ensure long-term accessibility and FAIR data compliance
SCIENTIFIC IMPACT
CEN has established the cerebellum’s role in all aspects of emotional behaviour (motor, autonomic & cognitive) uncovering novel pathways and mechanisms that open new therapeutic avenues.The integration of experimental and computational approaches across species represents a paradigm shift in neuroscience.
SOCIO-ECONOMIC AND SOCIETAL IMPACT
•Healthcare:Findings will inform future interventions for anxiety, PTSD, and neurodevelopmental disorders
•Industry:Technology validation strengthened innovation pipelines in neurotechnology
•Policy:Recommendations on mobility and equal access made to the EC
•Public Engagement:Outreach activities increased awareness of brain research and its societal relevance
LEGACY AND SUSTAINABILITY
•Open-access data via EBRAINS ensures long-term scientific value
•Strategic planning for a Horizon Europe Doctoral Network to provide the basis for the next phase of collaboration
•Established a global collaborative network integrating academia, industry, and patient organisations ensuring the impact of CEN continues beyond its original funding
CEN has established the cerebellum’s role in all aspects of emotional behaviour (motor, autonomic & cognitive) uncovering novel pathways and mechanisms that open new therapeutic avenues.The integration of experimental and computational approaches across species represents a paradigm shift in neuroscience.
SOCIO-ECONOMIC AND SOCIETAL IMPACT
•Healthcare:Findings will inform future interventions for anxiety, PTSD, and neurodevelopmental disorders
•Industry:Technology validation strengthened innovation pipelines in neurotechnology
•Policy:Recommendations on mobility and equal access made to the EC
•Public Engagement:Outreach activities increased awareness of brain research and its societal relevance
LEGACY AND SUSTAINABILITY
•Open-access data via EBRAINS ensures long-term scientific value
•Strategic planning for a Horizon Europe Doctoral Network to provide the basis for the next phase of collaboration
•Established a global collaborative network integrating academia, industry, and patient organisations ensuring the impact of CEN continues beyond its original funding