Objective: To advance translational research by revealing detailed relationships between neural circuit activity and behavioural symptoms in preclinical models

Background: Conventional preclinical tests for CNS disorders, which depend on behavioural or histological outcomes, frequently struggle to distinguish between various mechanisms. The lack of mechanistic insights are often causative of translational failure at the clinical stage. More sensitive and predictive assays shall speed up the progression of effective new therapies into clinical settings.

Method: The miniscope imaging platform allows cellular resolution activity measurements from hundreds of genetically defined neurons simultaneously. These large-scale neural activity recordings, paired with simultaneous behavioural measurements in freely moving animals, present an opportunity to advance translational research by revealing detailed relationships between neural circuit activity and behavioural symptoms and allowing for the construction of predictive preclinical assays based on the treatment-induced response of large populations of neurons.

Results: As a proof of concept, we have established a robust pharmacological dataset with FDA-approved medications for Parkinson’s Disease (PD) to compare this approach with traditional behaviour-based assays. In 6-OHDA lesioned mice, we have gathered a multidimensional dataset which includes cell-type specific activity of striatal D1 receptor-expressing medium spiny neurons (D1-MSNs) with synchronised locomotor metrics during free exploration under a breadth of conditions: pre-lesion, post-lesion, therapeutic and dyskinesia-inducing doses of L-DOPA, and dyskinesia-alleviating doses of amantadine. We have observed distinct neural activity patterns across these disease and treatment conditions.

Conclusion: Utilising these neural profiles to inform preclinical assessments of target engagement and drug efficacy holds the potential for greater predictability in clinical outcomes compared to current behaviour-centric assays. This approach will accelerate the advancement of next-generation therapeutics for a wide range of CNS disorders, beginning with PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/miniscope-based-neural-circuit-profiling-in-freely-behaving-animals-for-preclinical-therapeutic-assessment/