ELEVATED LOCUS COERULEUS OUTPUT DURING UNEXPECTED EVENTS IN A MOUSE MODEL OF FRAGILE X SYNDROME

The hyperarousal hypothesis of Fragile X syndrome (FXS) posits that excessive arousal contributes to symptoms such as hypersensitivity and hyperactivity. The locus coeruleus (LC) is a central noradrenergic system canonically implicated in arousal control, but evidence that LC activity differs in FXS is limited. Using pupillometry and fiber photometry of a noradrenaline sensor (GRAB_NE2m) in mice running in virtual reality, we aimed to understand how LC output differs between Fmr1-knockout (KO) mice and wildtype littermates. Significantly elevated LC output was indicated in Fmr1-KO mice during unexpected stimuli: pupil dilation responses to visuomotor mismatches and cortical GRAB_NE2m responses to unpredictable auditory stimuli were both larger in Fmr1-KO relative to wildtype mice. Interestingly, Fmr1-KO and wildtype mice did not display different responses to locomotion onsets, indicating a stimulus specificity to the elevated LC output. LC neuron and axon density measured histologically across brain areas was comparable between genotypes, demonstrating that anatomical differences in LC output cannot explain the differences in response. We next investigated whether activity differences upstream of the LC, in the neocortex, could explain the different LC responses. Using in vivo electrophysiology, we found a greater proportion of neurons in the primary visual cortex respond to visuomotor mismatch in Fmr1-KO compared to wildtype mice, consistent with their elevated pupil dilation responses. Overall, we conclude that while LC anatomy is intact, LC output is elevated during unexpected events in Fmr1-KO compared to wildtype mice – an effect which could in principle arise from increased cortical drive of the LC.