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ESR6 – Functional input/output connectivity of selected cerebellar neuronal subpopulations in fear and anxiety

Host institution: University Hospital Würzburg, Germany

To characterize the neuronal circuit architecture for information flow between the cerebellum and limbic system, we will anatomically map the neural circuits that link modules of the cerebellar cortex via different cerebellar nuclei (CN), to the PAG, amygdala and prefrontal cortex in mice. We will combine trans-synaptic rabies virus tracing and adeno-associated viral vectors with antero- and retrograde tracing capabilities to investigate the projection patterns of selected PAG, amygdala and prefrontal cortex cell types targeting cerebellar vermis and CN. Importantly, this will allow us to also characterize putative collaterals to other brain regions, such as cardiorespiratory centres in the brainstem. We will also identify the neuronal cell types that project from the CN to different cellular targets within PAG, amygdala and prefrontal cortex.

In a second step, and cross-informed by results obtained through calcium imaging approaches (e.g. by ESR3-4), we will address the functional significance of the identified cerebellar-limbic pathways. We will use viral strategies as described above to express excitatory or inhibitory optical actuators in selected circuit elements. Freely moving mice implanted with optical fibres as well as ECG/EMG electrodes will undergo behavioural assays for fear and anxiety, such as elevated plus maze, open field and conditioned flight paradigm. During different integrated defensive states (freezing/flight, brady-/tachycardia) and various stages of cued and contextual fear conditioning, we will interfere with cerebellar information flow, i.e. prediction error generation to manipulate defensive action selection upon threat exposure as well as fear learning. Anatomical results will be compared to cFos mapping in ESR7. Collaboration with Paris to compare anatomical with electrophysiological results.

Viral vector-mediated intersectional anatomical tracing strategies will provide new insights into cerebellar-brainstem connectivity with cell-type specificity. Temporally precise manipulation of cerebellar inputs to defined limbic neuronal subpopulations (and vice versa) will elucidate causal relationships of neuronal activity and prediction error generation as well as behavioural and autonomic defensive responses during fear and anxiety states.

Planned secondments: Paris, month 13-15, purpose: training in electrophysiological methods; Rehab Kettwig, month 25, purpose: training in translational research.