Biology subjects

Murphy, S. E.

Publications and source records attributed to Murphy, S. E..

3 recordsLinked to original sources

bioRxiv2023

Direct serotonin release in humans shapes decision computations within aversive environments

The role of serotonin in human behaviour is critically informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes (e.g., SSRIs). Here we use a now accessible approach to directly increase synaptic serotonin in humans - a selective serotonin releasing agent - and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques including reinforcement learning and drift diffusion modelling were fit to observed behaviour. Reinforcement learning models revealed that increased synaptic serotonin reduced sensitivity specifically for outcomes in aversive but not appetitive contexts. Furthermore, increasing synaptic serotonin enhanced behavioural inhibition, and shifted bias towards impulse control during exposure to aversive emotional probes. These effects were seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increased synaptic serotonin on human behaviour, underlining its critical role in guiding decision-making within aversive and neutral contexts, and offering broad implications for longstanding theories of central serotonin function.

neuroscience↗

bioRxiv2022

Polycomb repression of Hox genes involves spatial feedback but not domain compaction or demixing

Polycomb group (PcG) proteins modulate higher-order genome folding and play a critical role in silencing transcription during development. It is commonly proposed that PcG dependent changes in genome folding, which compact chromatin, contribute directly to repression by blocking binding of activating complexes and demixing repressed targets from non-repressed chromatin. To test this model we utilized Optical Reconstruction of Chromatin Architecture (ORCA) to trace the 3-dimensional folding of the Hoxa gene cluster, a canonical Polycomb target, allowing us to analyze thousands of DNA traces in single cells. In cell types ranging from embryonic stem cells to brain tissue, we find that PcG-bound chromatin frequently explores decompact states and partial mixing with neighboring chromatin, while remaining uniformly repressed, challenging the repression-by-compaction model. Using polymer physics simulations, we show that the flexible ensembles we observe can be explained by dynamic contacts mediated by multivalent interactions that are too weak to induce phase separation. Instead, these transient contacts contribute to accurate propagation of the epigenetic state without ectopic spreading or gradual erosion. We propose that the distinctive 3D organization of Polycomb chromatin, reflects a mechanism of "spatial feedback" required for stable repression.

molecular biology↗

bioRxiv2021

Value-based decision-making between affective memories

Affective biases can influence how past events are recalled from memory. However, the mechanisms underlying how discrete affective events shape memory formation and subsequent recall are not well understood. Further understanding this is important given the central role of negative biases in affective memory recall in depression and antidepressant drug action. In order to capture cognitive processes associated with affective memory formation and recall, we studied value-based decision-making between affective memories in two within-subject experiments (n=45 and n=74). Our findings suggest that discrete affective events, created by large magnitude Wheel of Fortune (WoF) outcomes, influence affective memory formation processes during reinforcement-learning (RL). After 24 hours, we show that healthy volunteers display stable preferences during value-based recall of affective memories in a binary decision-making task. Computational modelling of these preferences demonstrated a positive bias during value-based recall, induced by previously winning in the WoF. We further showed that value-based decision-making between affective memories engages the pupil-linked central arousal systems, leading to pupil constriction prior to, and differential pupil dilation after the decision onset depending on the valence of the chosen options. Taken together, we demonstrate that mechanisms underlying human affective memory systems can be described by RL and probability weighting models. This approach could be used as a translational assay to study the effects of novel antidepressants.

neuroscience↗