A NPAS4-NuA4 complex couples synaptic activity to DNA repair.

Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4-TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.

Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells.

Back-propagating action potentials (bAPs) regulate synaptic plasticity by evoking voltage-dependent calcium influx throughout dendrites. Attenuation of bAP amplitude in distal dendritic compartments alters plasticity in a location-specific manner by reducing bAP-dependent calcium influx. However, it is not known if neurons exhibit branch-specific variability in bAP-dependent calcium signals, independent of distance-dependent attenuation. Here, we reveal that bAPs fail to evoke calcium influx through voltage-gated calcium channels (VGCCs) in a specific population of dendritic branches in mouse cortical layer 2/3 pyramidal cells, despite evoking substantial VGCC-mediated calcium influx in sister branches. These branches contain VGCCs and successfully propagate bAPs in the absence of synaptic input; nevertheless, they fail to exhibit bAP-evoked calcium influx due to a branch-specific reduction in bAP amplitude. We demonstrate that these branches have more elaborate branch structure compared to sister branches, which causes a local reduction in electrotonic impedance and bAP amplitude. Finally, we show that bAPs still amplify synaptically-mediated calcium influx in these branches because of differences in the voltage-dependence and kinetics of VGCCs and NMDA-type glutamate receptors. Branch-specific compartmentalization of bAP-dependent calcium signals may provide a mechanism for neurons to diversify synaptic tuning across the dendritic tree.

Classical creativity: A functional magnetic resonance imaging (fMRI) investigation of pianist and improviser Gabriela Montero.

Improvisation is sometimes described as instant composition and offers a glimpse into real-time musical creativity. Over the last decade, researchers have built up our understanding of the core neural activity patterns associated with musical improvisation by investigating cohorts of professional musicians. However, since creative behavior calls on the unique individuality of an artist, averaging data across musicians may dilute important aspects of the creative process. By performing case study investigations of world-class artists, we may gain insight into their unique creative abilities and achieve a deeper understanding of the biological basis of musical creativity. In this experiment, functional magnetic resonance imaging and functional connectivity were used to study the neural correlates of improvisation in famed Classical music performer and improviser, Gabriela Montero. GM completed two control tasks of varying musical complexity; for the Scale condition she repeatedly played a chromatic scale and for the Memory condition she performed a given composition by memory. For the experimental improvisation condition, she performed improvisations. Thus, we were able to compare the neural activity that underlies a generative musical task like improvisation to 'rote' musical tasks of playing pre-learned and pre-memorized music. In GM, improvisation was largely associated with activation of auditory, frontal/cognitive, motor, parietal, occipital, and limbic areas, suggesting that improvisation is a multimodal activity for her. Functional connectivity analysis suggests that the visual network, default mode network, and subcortical networks are involved in improvisation as well. While these findings should not be generalized to other samples or populations, results here shed insight into the brain activity that underlies GM's unique abilities to perform Classical-style musical improvisations.