Rewiring of Purkinje cell connectivity to enhance cerebellar functional recovery after injury

• Applicant: Dr. Laura Pérez Revuelta, Ph.D.
• Subject Area: Developmental Neurobiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558941938

The cerebellum plays pivotal roles in motor functions, cognition, and social behavior. Due to its extended development, the cerebellum is endowed with high levels of plasticity that can support neurogenesis and tissue repair after injury for a narrow postnatal time window. However, beyond this limited period of regenerative potential, it remains unclear how and to which extent damaged cerebellar circuits in the postnatal and adult brain may activate plasticity mechanisms to compensate for, or adapt to injury. In this project, I will focus on Purkinje cells (PCs) and their known connectivity pattern to investigate how cerebellar cortex circuits may be remodeled upon injury in mice. On account of preliminary data supporting a heightened experience-dependent cerebellar plasticity in young animals, I will pursue the central hypothesis that compensatory rewiring mechanisms of PC connectivity upon injury may differ significantly between early postnatal stages, when the circuit is still maturing, and adulthood, when the entire network has fully matured, and has become more resilient to reparative structural plasticity. To test this hypothesis, I will use an injury model of controlled neuronal genetic ablation, and use transsynaptic tracing approaches to determine input-specific rewiring of PC connectivity that may underlie age-dependent compensatory changes in cerebellar circuit plasticity. Leveraging on these experiments, I will then introduce targeted interventions to forcefully enhance PC and cerebellar cortex plasticity after injury. Specifically, I will use validated chemogenetic approaches as well as motor training to causally link changes in circuit activity/rewiring with improvements of functional motor recovery in injured mice. With these experiments I expect to provide key insights into the cerebellar circuit plasticity mechanisms after injury, and to hopefully lay the ground for refined rehabilitative approaches to treat cerebellar-related disorders.

• DFG Programme: WBP Position