Biology subjects

Brown, S. P.

Publications and source records attributed to Brown, S. P..

At least 19 recordsLinked to original sources

bioRxiv2026

The Phage Time Continuum: Genome Organization Constrains Anti-CRISPR Success

Bacteria and lytic phages experience antagonistic co-evolution, with bacterial defenses (e.g., CRISPR-Cas) battling phage anti-defenses (e.g., anti-CRISPR (Acr) systems). We investigate whether CRISPR-Cas and Acr engage in a timing-dependent genetic conflict. If anti-CRISPR genes act too late in infection, they risk failing to neutralize CRISPR, if Cas cannot find its target in time, Acr may be able to neutralize it. Because phages typically inject their genomes in a linear manner, location along the genome acts as a proxy for time from start of infection. Given these restrictions, we suggest that phage genomes that contain Acr systems will have a distinct pattern of spacers when compared to those that do not, reflecting the time dependent interaction of infections, we have termed this the Phage Time Continuum. In our analysis of 1462 phage genomes and 105 mobile plasmid genomes infecting Pseudomonas aeruginosa, we found clear distribution of where P. aeruginosa spacers map back onto these mobile genetic elements genomes. Further CRISPR spacers significantly enriched against anti-CRISPR systems over other anti-defense systems from both phage and plasmids. Finally, in genomes with anti-CRISPR, spacers map to earlier positions, suggesting that success hinges not just on targeting a given gene, but where those spacers hit along a genome.

microbiology↗

bioRxiv2026

Canonical pathoadaptive cystic fibrosis genes in Pseudomonas aeruginosa are not CF-specific

Research on Pseudomonas aeruginosa adaptation in cystic fibrosis (CF) has historically relied on comparing chronic isolates to laboratory reference strains, or evolving reference strains in environments simulating chronic CF. This work has established a small set of genes, including lasR, mucA, and mexZ, as canonical markers of CF patho-adaptation. However, without broad non-CF comparators, it remains unclear how specific these signatures are to CF. We used a structured literature review to define 20 historically emphasized "canonical CF genes", then evaluated their mutational patterns across 4,475 genetically distinct P. aeruginosa genomes from seven defined clinical and environmental contexts. We tested four competing hypotheses: (1) enrichment in adult CF alone, (2) in adult and pediatric CF combined, (3) in chronic lung infections broadly (including non-CF bronchiectasis), or (4) no strong environment-specific enrichment. We found little evidence that canonical gene mutations were specifically enriched in adult CF or CF more broadly. Instead, loss-of-function and individual mutations in genes including mucA, mexB, and mexZ were enriched across chronic lung infections, while most canonical genes (including lasR) showed no strong environment-specific enrichment. These results demonstrate that a canon of genes believed to drive patho-adaptation in CF instead largely reflects the narrow comparative framework of past studies rather than CF-exclusive selection. Our findings emphasize shared evolutionary pressures between CF and non-CF bronchiectasis, highlighting opportunities to exchange research and therapeutic insights across chronic infection clinical contexts.

microbiology↗

bioRxiv2026

Preserving Native Cellulose-Xylan Architecture Enables Structure-Property Control in Holocellulose Nanofibrils and High-Performance Sustainable Materials

The hierarchical organization of cellulose microfibrils and their intimate interactions with hemicelluloses such as xylan underpin the exceptional mechanical performance of plant cell walls. However, translating these biological design principles into sustainable nanocellulosic materials remains limited by conventional cellulose nanofibril production routes, which rely on harsh chemical treatments that disrupt the native cellulose-hemicellulose architecture. Here, we present an optimized isolation strategy for holocellulose nanofibrils (hCNFs) that preserves native cellulose structure, xylan substitution and conformation, and cellulose-xylan interactions. Using wild-type Arabidopsis thaliana, a xylan glucuronidation-deficient gux1/2 mutant, and Brassica napus straw as model systems, we systematically elucidate how xylan content and substitution pattern govern nanofibril isolation, interfacial interactions, and macroscopic properties. Two-dimensional 13C magic-angle spinning NMR demonstrates retention of native cellulose glucosyl environments, the presence of two-fold and three-fold helical xylan conformations, and cellulose-associated two-fold helical xylan. Cryogenic transmission electron microscopy reveals fibril widths of [~]3 nm, consistent with elementary cellulose I{beta} microfibrils. We show that xylan glucuronidation regulates colloidal stability, hydration behavior, and interfibrillar cohesion, whereas xylan content controls nanofibrillation efficiency. These multiscale structural features translate directly into moisture sorption, thermal behavior, and mechanical performance. Notably, Brassica napus hCNF films exhibit exceptional strength and extensibility, surpassing many chemically modified CNF systems. This work demonstrates that preserving the native cellulose-hemicellulose architecture enables high-performance, sustainable nanocellulosic materials without chemical reconstruction.

biochemistry↗

bioRxiv2026

Apparent generalism in Pseudomonas aeruginosa is underpinned by Convergent, Cryptic Specialization

Microbes that span environmental reservoirs and diverse human infections are often described as generalists or as ubiquitous, yet ecological theory predicts generalism should be unstable when specialists outperform within any one niche. Here we show that Pseudomonas aeruginosas apparent ecological breadth reflects convergent, cryptic specialism (CCS) - repeatable, environment-linked genomic differentiation that is not confined to deep lineages - rather than strict specialism or generalism. An analysis of 6,627 genomes with source-environment metadata reveals that environments are broadly dispersed across the phylogeny, inconsistent with lineage-locked specialization. Despite this shallow phylogenetic structure, genome content predicted environment-of-isolation across nine genotype-discernible environments, including under cross-validation that blocks phylogenetic relatedness. Interpretable feature profiles recovered both shared and environment-specific signals, including genomic signatures distinguishing distinct chronic and acute human infections. Finally, phenotypes from 47 diverse strains clustered more strongly by environmental source than by phylogenetic relatedness. Together, these results indicate that widely distributed bacterial "generalists" can comprise mixtures of cryptic, convergent specialists. By mapping genotype-defined ecological structure, our approach can identify when apparent generalists harbor hidden structure relevant to infection risk.

microbiology↗

bioRxiv2026

Cell-type-specific sustained value representations in the claustrum

Flexible decision-making relies on interactions between frontal cortex and subcortical structures. The claustrum, a subcortical nucleus highly interconnected with frontal cortex, influences cortical activity and has been implicated in cognitive functions. Recording from claustrum neurons as mice performed a reinforcement learning task, we found that the activity of almost half of recorded neurons scaled with reward rate and predicted trial- by-trial adjustments in reaction time and choice switching. Individual neurons sustained this activity over seconds between trials. Our recordings identified two electrophysiologically distinct populations. One was excited during task execution and bidirectionally scaled its activity with reward rate. The other was suppressed during task execution, scaled activity inversely with reward rate and projected to frontal cortex, indicating that claustrocortical outputs produce graded increases in activity with decreasing reward rate. Our results identify the claustrum as a subcortical locus for stable value representations and integrate it into neuronal circuits for value-based decision-making.

neuroscience↗

bioRxiv2025

Quantifying antibiotic susceptibility and inoculum effects using transient dynamics of Pseudomonas aeruginosa

Antibiotics are a cornerstone of modern medicine, targeting pathogen cells by disrupting essential cellular processes. However, standard antibiotic susceptibility metrics (e.g. MIC) and textbook models neglect transient dynamics and density-dependent effects, despite their ubiquity in nature. In clinical infections, where bacterial populations are the units we treat, this can increase the risk of under treatment. To address this gap, we generate high resolution optical density time series data for Pseudomonas aeruginosa (3 antibiotics, 12 doses, 7 inoculum sizes, 4x replication), enabling gradient estimation and gradient-based model parameterization. We develop a dynamics-led computational pipeline that (1) evaluates population scale ordinary differential equation models in the context of estimated time derivative data, and (2) classifies transient dynamics in dose-inoculum space using unsupervised clustering. Applied to our data, the pipeline identifies an ordinary differential equation model with a saturating antibiotic-loss term and a threshold-dependent weak Allee term that recapitulates and quantifies classic rate, yield, and inoculum effects of antibiotics. In addition, our model and clustering approach suggest a set of novel metrics, defining thresholds separating distinct dynamical regimes. Beyond antibiotic data sets, our approach utilizing a derivative-based fitting algorithm and clustering of derivative trajectories is applicable to any biological time series with controlled perturbations and variable initial conditions. Author summaryWe show that standard math models and antibiotic susceptibility metrics fail to capture the regimes of dynamical behavior that result from combined antibiotic and inoculum effects when Pseudomonas aeruginosa (PAO1) is exposed to antibiotics. Using iterations of forward and data-driven modeling, we highlight the importance of transient dynamics, derivative-based model fitting, and higher-order nonlinearities in quantifying bacterial dynamics under perturbation. We identify an ordinary differential equation-based model that describes the observed inoculum effect as a type of weak Allee effect (positive density-dependence) and also captures antibiotic effects on population growth rate and yield governed by a saturating loss function. We show that these results generalize across antibiotic mechanisms of action and highlight the importance of fitting models using dynamics-based algorithms. Finally, we explore a clustering method for bacterial dynamics that, in combination with our mathematical model, advises a set of novel metrics for measuring antibiotic susceptibility.

microbiology↗

bioRxiv2025

Cell-type-selective synaptogenesis during the development of excitatory connectivity in the mammalian neocortex

The function of mammalian neocortex relies on the timing of axon extension and establishment of cell-type-biased patterns of excitatory synaptic connections. A subtype of excitatory neurons, layer 6 corticothalamic neurons (L6CThNs), ultimately exhibit a marked preference for synapsing onto parvalbumin-positive (PV) inhibitory interneurons over more common excitatory cells in layers 6 and 4 (L6, L4). We show that the intracortical axons of L6CThNs develop in phases, elongating within L6, then pausing before extending translaminar branches into L4. Decreasing L6CThN excitability selectively enhanced axon growth in L6 but not later elaboration in L4. For both layers, we tested whether preferential synaptogenesis onto rarer PV interneurons, or promiscuous synapse formation followed by selective pruning, generated adult connectivity. We found that L6CThNs formed functional AMPA-receptor-containing synapses preferentially onto PV interneurons. Silent L6CThN synapses were not detected. Our findings show that cell-type-biased synaptogenesis underlies the formation of functional cell-type-specific excitatory connections in the neocortex.

neuroscience↗

bioRxiv2025

CRISPR-Cas is beneficial in plasmid competition, but limited by competitor toxin-antitoxin activity when horizontally transferred

Bacteria can encode dozens of different immune systems that protect them from infection by mobile genetic elements (MGEs). MGEs themselves may also carry immune systems, such as CRISPR-Cas, to target competitor MGEs. It is unclear when this is favoured by natural selection, and whether toxin-antitoxin (TA) systems -- common competitive mechanisms carried by plasmids -- can alter their efficacy. Here, we develop and test novel theory to analyse the outcome of competition between plasmids when one carries a CRISPR-Cas system that targets the other plasmid. Our model and experiments reveal that plasmid-borne CRISPR-Cas is beneficial to the plasmid carrying it when the plasmid has not recently transferred to a new host. However, CRISPR-Cas is selected against when the plasmid carrying it transfers horizontally, if a resident competitor plasmid encodes a TA system that elicits post-segregational killing. Consistent with a TA barrier to plasmid-borne CRISPR-Cas, a bioinformatic analysis reveals that naturally occurring CRISPR-Cas-bearing plasmids avoid targeting other plasmids with TA systems. Our work shows how the benefit of plasmid-borne CRISPR-Cas is severely reduced against TA-encoding competitor plasmids, but only when plasmid-borne CRISPR-Cas is horizontally transferred. These findings have key implications for the distribution of prokaryotic defenses and our understanding of their role in competition between MGEs, and the utility of CRISPR-Cas as a tool to remove plasmids from pathogenic bacteria.

microbiology↗

bioRxiv2025

Tsc1 Deletion in Purkinje Neurons Disrupts the Axon Initial Segment, Impairing Excitability and Cerebellar Function

Loss-of-function mutations in tuberous sclerosis 1 (TSC1) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific Tsc1 deletion (Tsc1mut/mut) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in Tsc1mut/mut Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Interestingly, anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of Tsc1mut/mut Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of Tsc1mut/mut Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous Tsc1 deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to Tsc1 haploinsufficiency are delayed compared to age-matched Tsc1mut/mut Purkinje neurons. Together, these data reveal the loss of Tsc1 impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins necessary for AIS organization and function.

neuroscience↗

bioRxiv2024

A consensus definition for deep layer 6 excitatory neurons in mouse neocortex

To understand neocortical function, we must first define its cell types. Recent studies indicate that neurons in the deepest cortical layer play roles in mediating thalamocortical interactions and modulating brain state and are implicated in neuropsychiatric disease. However, understanding the functions of deep layer 6 (L6b) neurons has been hampered by the lack of agreed upon definitions for these cell types. We compared commonly used methods for defining L6b neurons, including molecular, transcriptional and morphological approaches as well as transgenic mouse lines, and identified a core population of L6b neurons. This population does not innervate sensory thalamus, unlike layer 6 corticothalamic neurons (L6CThNs) in more superficial layer 6. Rather, single L6b neurons project ipsilaterally between cortical areas. Although L6b neurons undergo early developmental changes, we found that their intrinsic electrophysiological properties were stable after the first postnatal week. Our results provide a consensus definition for L6b neurons, enabling comparisons across studies.

neuroscience↗

bioRxiv2024

In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons

Autosomal dominant mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 (Fgf14-/-) exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that control the high frequency repetitive firing of Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the pathophysiological mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus (Fgf14F145S), we determined the impact of in vivo expression of the mutant Fgf14F145S allele on the motor performance of adult animals and on the firing properties of mature Purkinje neurons in acute cerebellar slices. Electrophysiological experiments revealed that repetitive firing rates are attenuated in adult Fgf14F145S/+ cerebellar Purkinje neurons, attributed to a hyperpolarizing shift in the voltage-dependence of steady-state inactivation of Nav channels. More severe effects on firing properties and Nav channel inactivation were observed in homozygous Fgf14F145S/F145S Purkinje neurons. Interestingly, the electrophysiological phenotypes identified in adult Fgf14F145S/+and Fgf14F145S/F145S cerebellar Purkinje neurons mirror those observed in heterozygous Fgf14+/- and homozygous Fgf14-/-Purkinje neurons, respectively, suggesting that the mutation results in the loss of the iFGF14 protein. Western blot analysis of lysates from adult heterozygous Fgf14F145S/+ and homozygous Fgf14F145S/F145Sanimals revealed reduced or undetectable, respectively, iFGF14 expression, supporting the hypothesis that the mutant allele results in loss of the iFGF14 protein and that haploinsufficiency underlies SCA27A neurological phenotypes.

neuroscience↗

bioRxiv2024

New insights into the structure of cellulose in plant cell walls

The structure of plant cellulose microfibrils remains elusive, despite the abundance of cellulose and its utility in industry. Using 2D solid-state NMR of 13C labelled never-dried plants, six major glucose environments are resolved which are common to the cellulose of softwood, hardwood and grasses. These environments are maintained in isolated holo-cellulose nanofibrils, allowing more detailed microfibril characterisation. We show there are only two glucose environments that reside within the microfibril interior. These have the same NMR 13C chemical shifts as tunicate cellulose I{beta} centre and origin chains, with no cellulose I being detected. The third major glucose site with a carbon 4 chemical shift near 89 ppm, previously assigned to the crystalline microfibril interior, is now shown to be one of four surface glucose environments. The NMR peak widths of all four surface glucose environments are similar to those of the core indicating that their glucose local order is comparable; there is no significant amorphous cellulose in the microfibrils. Consequently, the ratio of the carbon 4 peaks at [~]89 and [~]84 ppm, which has often provided a sample cellulose crystallinity index, is not a meaningful measure of crystallinity or the interior to surface ratio. The revised ratio for poplar wood microfibrils is estimated to be 1:2, which is consistent with a cellulose I{beta} 18-chain microfibril having 6 core and 12 surface chains, although other microfibril sizes are possible. These advances change substantially both the interpretation of solid-state NMR studies of cellulose and the understanding of cellulose microfibril structure and crystallinity.

biochemistry↗

bioRxiv2024

Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons drives sex-specific behavioral impairments linked to autism

There is a striking sex bias in the prevalence and severity of autism spectrum disorder (ASD) with 80% of diagnoses occurring in males. Because the molecular etiology of ASD is likely combinatorial, including interactions across multiple genetic and environmental factors, it is difficult to investigate the physiological mechanisms driving sex-specific differences. Loss of function mutations in TSC1 result in dysregulated mTORC1 signaling and underlie a multi-system disorder known as tuberous sclerosis (TSC). Interestingly, more than 50% of individuals diagnosed with TSC are also diagnosed with ASD, making TSC mutations one of the most prevalent monogenic causes of ASD. Mice harboring targeted deletion of Tsc1 selectively in cerebellar Purkinje neurons, referred to here as Tsc1mut/mut, have multiple ASD-linked behavioral impairments, including deficits in social interactions, motor coordination, and vocalizations. However, these ASD-linked behavioral deficits have only been investigated using male Tsc1mut/mut animals. Here, we used cohorts of male and female Tsc1mut/mut animals to determine if behavioral impairments, previously identified in this model, are similar across sex. Specifically, we measured balance and motor coordination and social interaction behaviors in two age groups across sex. We determined balance and motor coordination deficits are similar in male and female Tsc1mut/mut mice, and that deficits in the firing of Tsc1mut/mut Purkinje neurons located in the cerebellar vermis are also similar across sex. However, impairments in social approach behavior were found to be significantly more severe in Tsc1mut/mut males compared to females. These results indicate the selective deletion of Tsc1 in Purkinje neurons differentially impairs cerebellar circuits based on sex.

neuroscience↗

bioRxiv2023

A reinterpretation of the relationship between persistent and resurgent sodium currents

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates. Significance StatementAcross neuronal cell types, the resurgent sodium current (INaR) is often implicated in driving high rates of repetitive firing. Using dynamic clamp, we determined INaR is ineffective at driving subsequent action potentials, and that the subthreshold persistent sodium current (INaP) is the critical parameter for scaling repetitive firing rates. We propose INaR measured in native neurons may reflect a mechanism by which the magnitude of INaP is fine-tuned.

neuroscience↗

bioRxiv2023

The impact of phage and phage resistance on microbial community dynamics

Where there are bacteria, there will be bacteriophages. These viruses are known to be important players in shaping the wider microbial community in which they are embedded, with potential implications for human health. On the other hand, bacteria possess a range of distinct immune mechanisms that provide protection against bacteriophages, including the mutation or complete loss of the phage receptor, and CRISPR-Cas adaptive immunity. Yet little is known about how interactions between phages and these different phage resistance mechanisms affect the wider microbial community in which they are embedded. Here, we conducted a 10-day, fully factorial evolution experiment to examine how phage impact the structure and dynamics of an artificial four-species bacterial community that includes either Pseudomonas aeruginosa wild type or an isogenic mutant unable to evolve phage resistance through CRISPR-Cas. Our results show that the microbial community structure is drastically altered by the addition of phage, with Acinetobacter baumannii becoming the dominant species and P. aeruginosa being driven nearly extinct, whereas P. aeruginosa outcompetes the other species in the absence of phage. Moreover, we find that a P. aeruginosa strain with the ability to evolve CRISPR-based resistance generally does better when in the presence of A. baumannii, but that this benefit is largely lost over time as phage is driven extinct. Combined, our data highlight how phage-targeting a dominant species allows for the competitive release of the strongest competitor whilst also contributing to community diversity maintenance and potentially preventing the reinvasion of the target species, and underline the importance of mapping community composition before therapeutically applying phage.

microbiology↗

bioRxiv2023

Microglial cannabinoid receptor type1 mediates social memory deficits produced by adolescent THC exposure and 16p11.2 duplication

Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.

neuroscience↗

bioRxiv2023

Calcium-permeable AMPA receptors govern PV neuron feature selectivity

The brain helps us survive by forming internal representations of the external world1,2. Excitatory cortical neurons are often precisely tuned to specific external stimuli3,4. However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective5. PV interneurons differ from excitatory cells in their neurotransmitter receptor subtypes, including AMPA receptors6,7. While excitatory neurons express calcium-impermeable AMPA receptors containing the GluA2 subunit, PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find a low expression stoichiometry of GluA2 mRNA relative to other subunits in PV interneurons which is conserved across ferrets, rodents, marmosets, and humans, causing abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Sparse CP-AMPAR manipulations demonstrated that this increase was cell-autonomous and could occur well beyond development. Interestingly, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, suggesting that the selectivity of PV interneurons can be altered without drastically changing connectivity. In GluA2 knockout mice, where all AMPARs are calcium-permeable, excitatory neurons showed significantly reduced orientation selectivity, suggesting that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Remarkably, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, indicating that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a novel role of CP-AMPARs in maintaining a low-selectivity sensory representation in PV interneurons and suggest a conserved molecular mechanism that distinguishes the unique synaptic computations of inhibitory and excitatory neurons.

neuroscience↗

bioRxiv2023

The las and rhl Quorum Sensing Systems in Pseudomonas aeruginosa Form a Multi-Signal Reciprocal Network Which Can Tune Reactivity to Variations in Physical and Social Environments

Researchers often view the multi-signal quorum sensing systems of Pseudomonas aeruginosa as a hierarchy, topped by the las system which acts as a master regulator. By experimentally controlling the concentration of auto-inducer signals in a signal null strain (PAO1{Delta}lasI{Delta}rhlI), we show that the two primary quorum sensing systems--las and rhl--act reciprocally rather than hierarchically. Just as the las systems 3-oxo-C12-HSL can induce increased expression of rhlI, the rhl systems C4-HSL increases the expression level of lasI. We develop a mathematical model to quantify relationships both within and between the las and rhl quorum sensing systems and the downstream genes they influence. The results show that not only do the systems interact reciprocally, but they do so cooperatively and nonlinearly, with the combination of C4-HSL and 3-oxo-C12-HSL increasing expression level far more than the sum of their individual effects. We computationally assess how our parameterized model responds to variation in social (population density) and physical (mass transfer) environment and demonstrate that a reciprocal architecture is more responsive to density and more robust to mass transfer than a strict hierarchy.

microbiology↗