Noradrenaline (NA) is a strong modulator of neuronal activity, and many symptoms in patients with Autism Spectrum Disorder (ASD) can be attributed to the maladaptive activity of locus coeruleus (LC), the main source of forebrain NA; hence, it has garnered much attention as a potential lens through which to view and understand ASD. Our lab recently uncovered a role for dysregulated LC-NA function in motor learning delays in the 16p11.2 deletion mouse model of ASD (Yin et al., Nature Neuroscience 2021). We found that reduced NA levels in the primary motor cortex (M1) caused delays in motor learning and increased neuronal activity in pyramidal neurons (PNs) of M1 in 16p11.2 deletion mice. Strikingly, both the behavioral and neuronal phenotypes were rescued by chemogenetic activation of LC-NA.
In order to fully characterize the local dynamic NA levels during learning in the 16p11.2 deletion mice, we employ a newly developed optical NA sensor, GRABNE, with in vivo two-photon imaging to visualize the spatiotemporal release patterns of NA in M1 during motor learning. Intriguingly, we find that while wild-type (WT) mice exhibit consistently elevated NA levels during movements, 16p11.2 deletion mice show a delay in behaviorally induced NA increases. In addition to the delay in temporal dynamics, 16p11.2 deletion mice show altered spatial dynamics, with sparser and less behavior-specific NA release across M1 during the initial learning. In addition, we also assess the LC-NA axonal neuronal activity in M1 using in vivo Ca2+ imaging. We also observe that behavior-related activity transients are less reliable in 16p11.2 deletion mice with more unspecific activity transients during the baseline period. Intriguingly, pharmacological and closed loop optogenetic manipulations that disrupt the spatial and temporal specificity of NA release, respectively, in M1 were sufficient to induce delayed motor learning in WT mice. Our results offer new insights into the temporal dynamics of NA release at fine spatial scales within one brain region and how the specificities are critical for motor skill acquisition.