Biology subjects

Coulson, B.

Publications and source records attributed to Coulson, B..

3 recordsLinked to original sources

bioRxiv2024

Conserved mitochondrial reactive oxygen species and HIF1-alpha signalling during an embryonic critical period directs subsequent nervous system development

As developing networks transition from spontaneous irregular to patterned activity, they undergo plastic tuning phases, termed "critical periods"; "critical" because disturbances during these phases can lead to lasting changes in network development and output. Critical periods are common to developing nervous systems, with analogous features shared from insects to mammals, yet the core signalling mechanisms that underly cellular critical period plasticity have remained elusive. To identify these, we exploited the Drosophila larval locomotor network as an advantageous model system. It has a defined critical period and offers unparalleled access to identified network elements, including the neuromuscular junction as a model synapse. We find that manipulations of a single motoneuron or muscle cell during the critical period lead to predictable, and permanent, cell-specific changes. This demonstrates that critical period adjustments occur at a single cell level. Mechanistically, we identified mitochondrial reactive oxygen species (ROS) as causative. Specifically, we show that ROS produced by complex I of the mitochondrial electron transport chain, generated by the reverse flow of electrons, are necessary and instructive for critical period-regulated plasticity. Downstream of ROS, we identified the Drosophila homologue of hypoxia inducible factor (HIF-1), as required for transducing the mitochondrial ROS signal to the nucleus. This signalling axis is also sufficient to cell autonomously specify changes in neuronal properties and animal behaviour but, again, only when activated during the embryonic critical period. Thus, we have identified specific mitochondrial ROS and HIF-1 as primary signals that mediate critical period plasticity.

developmental biology↗

bioRxiv2024

Heterogeneous responses to embryonic critical period perturbations among different components of the Drosophila larval locomotor circuit

As developing neural circuits become functional, they undergo a phase of heightened plasticity that facilitates network tuning in response to intrinsic and/or extrinsic stimuli. These developmental windows are termed critical periods (CPs), because perturbations during, but not outside, the CP can lead to lasting changes, such as the formation of sub-optimal or unstable networks. How separate, but connected elements, within a network might respond differently to a CP perturbation is not well understood. To study this, we used the locomotor network of the Drosophila larva as a model and heat stress as a CP stimulus that has ecological relevance. When embryos experienced heat stress the subsequent development of their locomotor network is changed, creating larvae with reduced crawling speed and decreased network stability. Developing body wall muscles and central neurons are sensitive to heat stress perturbations during distinct, consecutive phases of embryogenesis. Within the CNS, transient embryonic CP perturbation leads to increased synaptic drive from premotor interneurons to motoneurons, which in turn adopt reduced excitability. In contrast, the peripheral neuromuscular junction maintains normal synaptic transmission, despite significant structural changes. Thus, connected elements respond differentially to a CP perturbation, suggesting a sequence, or hierarchy, of network adjustment during the CP.

neuroscience↗

bioRxiv2023

Balance of Activity during a Critical Period Tunes a Developing Network

Developing neural circuits are influenced by activity and are especially sensitive to changes in activity during critical periods (CPs) of development. Changes occurring during a CP often become locked-in so that they affect the mature network. Indeed, several neurodevelopmental disorders have been linked to excessive activity during such periods. It is, therefore, important to identify those aspects of neural circuit development that are influenced by neural activity during a CP. In this study, we take advantage of the genetic tractability of Drosophila to show that activity perturbation during an embryonic CP permanently alters properties of the locomotor circuit. Specific changes we identify include increased synchronicity of motoneuron activity, and greater strengthening of excitatory over inhibitory synaptic drive to motoneurons. These changes are sufficient to reduce network robustness, evidenced by increased sensitivity to induced seizure. We also show that we can rescue these changes when increased activity is mitigated by inhibition provided by mechanosensory neurons. Similarly, we demonstrate a dose-dependent relationship between inhibition experienced during the CP, and the extent to which it is possible to rescue the hyperexcitable phenotype characteristic of the parabss mutation. This suggests that developing circuits must be exposed to a properly balanced sum of excitation and inhibition during the CP to achieve normal mature network function. Our results, therefore, provide novel insight into how activity during a CP shapes specific elements of a circuit, and how activity during this period is integrated to tune neural circuits to the environment in which they will likely function.

neuroscience↗