Chen, S. S. | Search bioRxiv

bioRxiv2025

Temporal dynamics of noradrenaline release at fine spatial scales during motor learning

Noradrenaline (NA) released from the locus coeruleus (LC) has been known to play pivotal roles in arousal, sensory processing, decision-making, and learning through global release across the entire neocortex. Recent studies have demonstrated heterogeneous and modular NA release in distinct brain regions and highlighted its spatiotemporal dynamics across the neocortex. However, the spatiotemporal specificity of NA release at fine scales within a single brain region remains unclear, and it has not been reported whether the release patterns evolve functionally throughout prolonged learning processes such as motor skill acquisition. Here, by employing in vivo two-photon imaging with various genetically encoded NA sensors, we reveal that behavior-induced NA release in the primary motor cortex (M1) is spatially heterogeneous at the scale of local microcircuitry. Over the course of learning, the release pattern is locally refined, achieving consistent spatial precision within M1. Intriguingly, pharmacological manipulations that disrupt the spatial specificity also alter local neurons activity and representations. Furthermore, LC-NA axonal calcium imaging uncovered two distinct temporal activity patterns, in which non-behavior-related rapid axonal activity (sub-second duration events) profoundly affect the temporally precise behavior-induced persistent axonal activity (seconds duration events). Closed-loop optogenetic manipulations that bi-directionally modulate non-behavior-related rapid events directly impacted the learning process. Together, our results provide novel insights into the temporal dynamics of NA release at fine spatial scales within one brain region and underscore the critical role of local NA specificity in regulating circuit plasticity during motor skill acquisition.

neuroscience↗

bioRxiv2019

Defining relative mutational difficulty to understand cancer formation and prevention

Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Furthermore, mutational difficulty analysis also points to potential means of cancer prevention. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such parameter, we can bring new angles to understanding cancer formation and prevention.

cancer biology↗