Biology subjects

Wilson, L. G.

Publications and source records attributed to Wilson, L. G..

6 recordsLinked to original sources

bioRxiv2024

Role of a single MCP in evolutionary adaptation of Shewanella putrefaciens for swimming in planktonic and structured environments

Bacteria can adapt to their environments by changing phenotypic traits by mutations. However, improving one trait often results in deterioration of another one, a trade-off which limits the degree of adaption. The gammaproteobacterium Shewanella putrefaciens CN-32 has an elaborate motility machinery comprising two distinct flagellar systems and an extensive chemotaxis array with 36 methyl-accepting chemotaxis sensor proteins (MCPs). In this study we performed experimental selection on S. putrefaciens for increased spreading through a porous environment. We readily obtained a mutant that showed a pronounced increase in covered distance. This phenotype was almost completely caused by a deletion of 24 bp from the chromosome, which leads to a moderately enhanced production of a single MCP. Accordingly, chemotaxis assays under planktonic conditions and cell tracking in soft agar showed that the mutation improved navigation through nutritional gradients. The study demonstrates how differences in the abundance of a single MCP can lead to an efficient upgrade of directed flagella-mediated motility in specific environments at a low expense of cellular resources. ImportanceExperimental evolution experiments have been used to determine the trade-offs occurring in specific environments. Several studies that have used the spreading behavior of bacteria in structured environments identified regulatory mutants that increase the swimming speed of the cells. While this results in a higher chemotaxis drift, the growth fitness decreases as the higher swimming speed requires substantial cellular resources. Here we show that rapid chemotaxis adaptation can also be achieved through modification of the chemotaxis signal input at a low metabolic cost for the cell.

microbiology↗

bioRxiv2023

Hypnotic treatment reverses NREM sleep disruption and EEG desynchronization in a mouse model of Fragile X syndrome to rescue memory consolidation deficits.

Fragile X syndrome (FXS) is a highly-prevalent genetic cause of intellectual disability, associated with disrupted cognition and sleep abnormalities. Sleep loss itself negatively impacts cognitive function, yet the contribution of sleep loss to impaired cognition in FXS is vastly understudied. One untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We hypothesized that restoration of sleep-dependent mechanisms could improve functions such as memory consolidation in FXS. We examined whether administration of ML297, a hypnotic drug acting on G-protein-activated inward-rectifying potassium channels, could restore sleep phenotypes and improve disrupted memory consolidation in Fmr1-/y mice. Using 24-h polysomnographic recordings, we found that Fmr1-/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM sleep architecture, alterations in NREM EEG spectral power (including reductions in sleep spindles), and reduced EEG coherence between cortical areas. These alterations were reversed in the hours following ML297 administration. Hypnotic treatment following contextual fear or spatial learning also ameliorated disrupted memory consolidation in Fmr1-/y mice. Hippocampal activation patterns during memory recall was altered in Fmr1-/y mice, reflecting an altered balance of activity among principal neurons vs. parvalbumin-expressing (PV+) interneurons. This phenotype was partially reversed by post-learning ML297 administration. These studies suggest that sleep disruption could have a major impact on neurophysiological and behavioral phenotypes in FXS, and that hypnotic therapy may significantly improve disrupted cognition in this disorder.

neuroscience↗

bioRxiv2022

Atypical hypnotic compound ML297 restores sleep architecture following emotionally-valenced learning, to promote memory consolidation and hippocampal network activation during recall

Sleep plays a critical role in consolidating many forms of hippocampus-dependent memory. While various classes of hypnotic drugs have been developed in recent years, it remains unknown whether, or how, some of them affect sleep-dependent memory consolidation mechanisms. We find that ML297, a recently-developed candidate hypnotic agent targeting a new mechanism (activating GIRK1-subunit containing G-protein coupled inwardly rectifying potassium [GIRK] channels), alters sleep architecture in mice over the first 6 h following a single-trial learning event. Following contextual fear conditioning (CFC), ML297 reversed post-CFC reductions in NREM sleep spindle power and REM sleep amounts and architecture, renormalizing sleep features to what was observed at baseline, prior to CFC. Renormalization of post-CFC REM sleep latency, REM sleep amounts, and NREM spindle power were all associated with improved contextual fear memory (CFM) consolidation. We find that improvements in CFM consolidation due to ML297 are sleep-dependent, and are associated with increased numbers of highly-activated dentate gyrus (DG), CA1, and CA3 neurons during CFM recall. Together our findings suggest that GIRK1 channel activation restores normal sleep architecture - including REM sleep, which is normally suppressed following CFC - and increases the number of hippocampal neurons incorporated into the CFM engram during memory consolidation. Significance StatementBoth REM and NREM sleep are thought to be important for consolidating hippocampus-dependent memories. We find that GIRK1 activator ML297, administered after single-trial fear learning, restores REM sleep that is normally suppressed after learning fearful associations. This restoration is associated with improvements in fear memory storage, resulting in more robust hippocampus activation in the context of subsequent memory recall. Thus this drug, which also has antiepileptic and anxiolytic properties, may be useful for promoting normal, restorative sleep that benefits memory storage.

neuroscience↗

bioRxiv2022

Binocular visual experience and sleep promote visual cortex plasticity and restore binocular vision in a mouse model of amblyopia

Amblyopia arises from an altered balance of input from the two eyes to the binocular zone of primary visual cortex (bV1) during childhood, causing long-lasting visual impairment. Amblyopia is commonly treated by patching the dominant eye, however, the relative impacts of monocular vs. binocular visual experiences on restoration of bV1 function remains unclear. Moreover, while sleep has been implicated in V1 plasticity in response to vision loss, its role in recovery from amblyopia is unknown. We used monocular deprivation (MD) in juvenile mice to model amblyopia in bV1. We compared recovery of visual responses for the two eyes among bV1 regular spiking (RS, putative principal) neurons and fast-spiking (FS, putative parvalbumin-expressing [PV+]) interneurons after identical-duration, identical-quality binocular recovery (BR) or monocular, reverse occlusion (RO) experiences. We find that BR is quantitatively superior to RO with respect to renormalizing both bV1 populations visual responses. However, this recovery was seen only in freely-sleeping mice; post-BR sleep deprivation prevented functional recovery. Thus, both binocular visual experience and subsequent sleep are required to optimally renormalize bV1 responses in a mouse model of amblyopia.

neuroscience↗

bioRxiv2020

Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation and survival

Differentiation between distinct stages is fundamental for the life cycle of intracellular protozoan parasites and for transmission between hosts, requiring stringent spatial and temporal regulation. Here we applied kinome-wide gene deletion and gene tagging in Leishmania mexicana promastigotes to define protein kinases with life cycle transition roles. Whilst 162 were dispensable, 44 protein kinase genes were refractory to deletion in promastigotes and are likely core genes required for parasite replication. Phenotyping of pooled gene deletion mutants using bar-seq and projection pursuit clustering revealed functional phenotypic groups of protein kinases involved in differentiation from metacyclic promastigote to amastigote, growth and survival in macrophages and mice, colonisation of the sand fly and motility. This unbiased interrogation of protein kinase function in Leishmania allows targeted investigation of organelle-associated signalling pathways required for successful intracellular parasitism.

microbiology↗

bioRxiv2020

High speed, three-dimensional imaging reveals chemotactic behavior specific to human-infective Leishmania parasites

Cellular motility is an ancient eukaryotic trait, ubiquitous across phyla with roles in predator avoidance, resource access and competition. Flagellar-dependent motility is seen in a variety of parasitic protozoans and morphological changes in flagellar structure and function have been qualitatively described during differentiation. However, whether the dynamics of flagellar motion vary across lifecycle stages and whether such changes serve to facilitate human infection is not known. Here we used holographic video microscopy to study the pattern of motility in insect midgut forms of Leishmania (procyclic promastigotes; PCF) and differentiated human infective metacyclic promastigotes (META). We discovered that PCF swim in a slow, corkscrew motion around a gently curving axis while META display run and tumble behaviour in the absence of stimulus, reminiscent of bacterial behaviour. In addition, we demonstrate that META specifically respond to a macrophage-derived stimulus, modifying swimming direction and speed to target host immune cells. Thus, the motility strategy employed by Leishmania appears as a random search that is replaced with a ballistic swimming motion in the presence of an immunological stimulus. These findings shed unique insights into how flagellar motion adapts to the particular needs of the parasite at different times in its lifecycle and define a new pre-adaptation for infection of the human host.

biophysics↗