DISRUPTED CYCLIC AMP DYNAMICS IN THE SECONDARY MOTOR CORTEX DURING SENSORIMOTOR AND MOTOR LEARNING BEHAVIOUR IN THE R6/1 MOUSE MODEL OF HUNTINGTON’S DISEASE

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene, leading to progressive motor, cognitive, and psychiatric impairments. A hallmark of HD pathology is the gradual dysfunction of the cortico-striatal pathway, accompanied by alterations in intracellular signalling cascades, including disrupted cAMP signalling, which may contribute to impaired neuronal plasticity. Here, we investigated neuronal cAMP dynamics in the R6/1 mouse model of HD during behavioural tasks that depend on M2 cortical function. To this end, we expressed the fluorescent cAMP sensor GFlamp1 (AAV9-hSyn-Gflamp1-WPRE) in M2 cortical neurons of 8‑week‑old mice and performed fiber photometry recordings during the Beetle Mania Task (BMT; 14 and 20weeks) and the accelerated rotarod (ARR; 14–15weeks). Baseline‑corrected ΔF/F (z‑score) signals revealed robust increases in cAMP levels in response to beetle exposure during the BMT. However, these responses were significantly blunted in HD mice at 20weeks, but not at 14 weeks, relative to wild-type littermates. This reduction was particularly evident in males, which showed decreased peak amplitude and AUC, while females remained unaffected. During the ARR, cAMP levels also rose upon task engagement. Although baseline levels did not differ between genotypes, female wild-type mice exhibited higher cAMP responses than HD females during the stimulus phase, an effect that was even more pronounced after task completion in the home cage. Altogether, these findings demonstrate task‑related increases in neuronal cAMP levels and support a role for altered cAMP signalling in HD pathophysiology.