Biology subjects

Baker, K.

Publications and source records attributed to Baker, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Multimodal characterization of variation in neuronal types in the mouse basal ganglia

AbstractThe basal ganglia (BG) are a set of topographically organized, interconnected structures that are pivotal for regulating volitional movement and other aspects of cognitive, motivational, and affective behavior. Recently generated taxonomies of transcriptomically-defined cell types (T-types) have revealed both fine-grained distinctions in gene expression between neurons in these structures as well as continuous transcriptomic variation across similar T-types1-9, which are both related to location within a structure. However, it remains unclear to what extent these and other cellular properties co-vary with each other. Therefore, we performed Patch-seq experiments10,11 on over 900 neurons in mouse brain slices from BG to provide an integrated view of the co-variation between gene expression, location, physiology, and morphology measured from the same neurons. Medium spiny neurons (MSNs) from both the direct and indirect pathways across the dorsal and ventral striatum follow a gene expression gradient that varies in a dorsolateral to ventromedial direction; we find that this gradient also corresponds with systematic differences in action potential kinetics and dendritic arborization. Our analysis also characterizes additional multimodal dimensions of MSN variation, such as those between direct and indirect pathway neurons and between matrix and striosome neurons. Furthermore, through comparison with Patch-seq data from macaque, we demonstrate that the relationship between the transcriptomic/spatial gradient and electrophysiological and morphological properties is conserved across these two species. We also find that properties of striatal interneurons, such as action potential kinetics, vary across the striatum in a manner consistent with the MSN gradient. Outside the striatum, our multimodal Patch-seq dataset from the globus pallidus, subthalamic nucleus, and substantia nigra enabled us to characterize transcriptomically-defined types and link them to prior descriptions of cell types in these structures. Finally, we examined to what extent the MSN transcriptomic/spatial gradient persisted across different stages of the BG circuit by comparing Patch-seq neurons to reconstructed whole-neuron morphologies and the topography of their interareal projections, finding that the gradient is better preserved in GPe and GPi compared to SNr. Our study links transcriptomic variation across T-types in mouse BG to spatial localization and phenotypic differences at the level of individual cells, improving our understanding of cell type architecture in topographically organized circuits of the brain.

neuroscience↗

bioRxiv2026

Evolutionary Rewiring of Root Cell-Type Nitrogen Responses

Nitrate induces widespread transcriptional reprogramming in plants, but how transcription factors coordinate these responses across cell types and evolve across species with divergent root patterning remains unclear. Using single-cell transcriptomics in Arabidopsis thaliana and Solanum lycopersicum (tomato) under varying nitrate conditions, we demonstrate that many transcriptional responses are cell type and developmental stage-specific. Arabidopsis NIN-LIKE PROTEIN 7 (NLP7) directly modulates both broadly expressed and cell-type-specific targets, but is not required to establish the cell type specific nature of these patterns. Comparative analysis reveals evolutionary shifts; key nitrogen programs are localized to different cell types in tomato, with the exodermis as a major regulatory hub. Identification of tomato NLP7a and NLP7b direct targets at cellular resolution supports their role in direct modulation of cell type N-transcriptional programs. This is evidenced by NLP7-controlled exodermal cell wall remodeling in low nitrate, highlighting functional conservation despite divergent cellular topographies.

plant biology↗

bioRxiv2026

Peptide-Induced Formation of Extracellular Vesicles that are DistinctFrom Endogenous E. coli OMVs, and Provide an Enhanced Platformfor Protein Production and Purification.

Bacterial outer membrane vesicles (OMVs), are nano-sized, spherical structures released by Gram-negative bacteria that play diverse roles in bacterial physiology, including communication, nutrient acquisition, and host interactions. These vesicles bud from the bacterial outer membrane and contain lipopolysaccharides, periplasmic proteins, nucleotides, and other biomolecules. The Vesicle Nucleating peptide (VNp) is a short peptide tag that, when fused to the amino terminus of a protein of interest, promotes the formation of bespoke recombinant extracellular vesicles in Escherichia coli, enabling efficient production and simplified purification of recombinant proteins. Here, we characterise VNp-induced vesicles and compare their composition and organisation with naturally produced E. coli OMVs. While both vesicle types possess a single outer membrane-derived lipid bilayer, recombinant protein is highly enriched within the VNp vesicles compared to endogenous OMVs. VNp-fusions and periplasm-targeted recombinant proteins localize to distinct vesicle populations, with VNp-fusions showing markedly higher intra-vesicular concentrations and vesicular purity, compared to the OMV targeted protein. OmpX co-expression further enriched the VNp-fusion content of vesicles, further enhancing yield. The VNp-vesicle lumen is an oxidizing environment, thus supports formation of inter- and intra-molecular disulfide bonds within encapsulated proteins. Overall, VNp-induced vesicles represent a distinct class of recombinant extracellular vesicles that offer a simple and efficient route for producing and purifying concentrated, correctly folded recombinant proteins, expanding the utility of bacterial vesicle systems for biotechnological applications. Significance StatementBacterial extracellular vesicles are recognized as versatile tools for biotechnology yet engineering bacterial vesicle production in a controlled and efficient manner remains challenging. Here we describe how a short Vesicle Nucleating Peptide (VNp) tag, fused to a protein of interest, that can be used to program Escherichia coli to produce recombinant extracellular vesicles that are compositionally and structurally distinct from natural bacterial outer membrane vesicles (OMVs). VNp-induced vesicles are more homogeneous, and more highly enriched in target fusion proteins, providing a simple and efficient route for protein production and purification. The oxidizing lumen of these vesicles supports disulfide bond formation, and rapid compartmentalisation enables expression of otherwise challenging or toxic proteins. This work characterises a distinct class of recombinant bacterial vesicles and establishes a practical platform for producing correctly folded, concentrated, partially purified proteins in a self-packaged form, expanding the potential applications of bacterial extracellular vesicles in biotechnology and synthetic biology.

bioengineering↗

bioRxiv2026

Discovery and characterization of small molecule inhibitors of CBL-B that act as intramolecular glue to enhance T-cell anti-tumor activity

CBL-B is a RING-type E3 ubiquitin ligase that acts as a critical negative regulator of T-cell activation. It promotes T-cell anergy and suppresses immune responses through ubiquitin-mediated control of signaling proteins at the immunological synapse. T cells deficient in CBL-B activity lose their dependence on CD28 co-stimulation, exhibit heightened activation and increased cytokine production, and fail to re-establish anergy. In addition, mice deficient in CBL-B activity reject tumors. Together, this cellular mechanism and in vivo phenotype suggest inhibition of CBL-B may be a viable immuno-oncology therapeutic strategy. Here, we report the rational design and execution of a high-throughput screen (HTS) to identify small molecule inhibitors of CBL-B. This campaign led to the discovery of a scaffold that inhibits CBL-B E3 ligase activity with micromolar potency. Structural characterization revealed an intramolecular glue mechanism, in which the compound stabilizes the closed state of CBL-B, preventing phosphorylation of a tyrosine residue that is critical for activation and E2 binding. Iterative structure-activity optimization yielded compounds with nanomolar activity that enhanced T-cell activation and cytokine secretion in primary human T cells and suppressed tumor growth in a syngeneic colorectal mouse model. Together, these studies validate the biological rationale for pharmacological CBL-B inhibition and enabled the de novo discovery of intramolecular CBL-B glue inhibitors. This work culminated in the identification of NX-1607, a first-in-class oral CBL-B inhibitor now in clinical development for cancer immunotherapy.

immunology↗

bioRxiv2026

Human Neocortical Glutamatergic Neurons Revealed Through Multimodal Profiling

The human neocortex underlies higher cognition and is the engine of complex thought. Yet our understanding of its neuronal diversity is limited by sparse access to tissue, inconsistent sampling across studies, and a lack of multiple modality data. Although single-cell transcriptomic taxonomies are an important framework for characterizing cell type diversity, transcriptomic information alone cannot reveal the cellular properties that define neuronal computations. To address this, we performed Patch-seq, a method for collecting Morphology, Electrophysiology, and Transcriptomic data from a single neuron. We focused on glutamatergic, neocortical, excitatory neurons, the principal long-range projecting neurons of the cortex, and systematically integrated their morphoelectric features with transcriptomic identity. In combination with spatial transcriptomic data, we interrogated 39 of 42 transcriptomically-defined neuron types with a layer-centric perspective. Morphoelectric properties, such as cortical depth, apical dendrite structure, and excitability clearly distinguish transcriptomic subclasses and support many finer transcriptomic types. Morphoelectric properties are influenced by spatial location in supragranular layers, while deeper layers exhibit greater heterogeneity. Cross-species comparisons reveal conserved subclass organization but pronounced differences in apical dendrite arborization between mouse and human, and surprising similarities between human and macaque. Together, these datasets provide a unified multimodal reference that advances our understanding of human cortical circuitry and establishes a foundation for experimental and computational studies of human brain function and disease.

neuroscience↗

bioRxiv2025

Drought drives reversible disengagement of root-mycorrhizal symbiosis

The increasing frequency and severity of droughts pose a major threat to agriculture, food security and ecosystems. Plants respond to water deficit by adjusting growth and metabolism to enhance survival; these adjustments impact the soil microorganisms interacting with plant roots. Plants establish symbiotic relationships with arbuscular mycorrhizal fungi which supply soil nutrients in exchange for carbon metabolites via an intricate dual-species interface within roots. These fungi are dependent upon host-derived photosynthates and are thus potentially vulnerable to plant perturbations during drought. Here, we demonstrate that the plant-mycorrhizal relationship is dynamic when water becomes limiting. During water deficit, rice de-prioritizes nutrient acquisition gene regulatory networks, including its AM symbiotic program, in a strategy conserved with tomato. The fungal symbiont correspondingly represses its growth, undergoing metabolic quiescence, coupled with decommissioning of hyphae within the hosts root. Following re-watering, the host re-engages with its partner fungus, re-invigorating fungal growth and arbuscule establishment. This coordinate, reversible and enduring inter-organismal association may aid host survival under transient stress, but suggests that mutualisms in native and crop plants are potentially fragile in increasingly erratic climates.

plant biology↗

bioRxiv2025

Reelin Controls the Directional Orientation, Apical Localization and Length of Primary Cilia in Principal Neurons in the Cerebral Cortex

The primary cilia of pyramidal neurons in inside-out laminated regions orient predominantly toward the pia, reflecting reverse soma movement during postnatal neurodevelopment. However, the mechanisms underlying the directional cilia orientation are unknown. Here we show that the primary cilia of pyramidal neurons are localized near the base of the apical dendrites and aligned on the nuclear side opposite to the axon initial segment (AIS). However, this pattern is not observed in atypical pyramidal neurons in the deep neocortex, excitatory neurons in non-laminated regions, interneurons, or astrocytes, where cilia are irregularly positioned around the nuclei and lack preferred orientation. In Reelin-deficient mice (reeler), the directional orientation and apical location of cilia in late-born neocortical and CA1 neurons are disrupted. However, the initial impairments are partially corrected during postnatal development, along with a realignment of apical-basal orientation. In contrast, loss of Reelin drastically disrupts the directional orientation of cilia in early-born neocortical neurons and principal neurons in evolutionarily conserved cortical regions, which lack postnatal correction. Consistently, their cilia do not preferably localize to the apical side. Additionally, Reelin deficiency increases the cilia length of principal neurons across the cerebral cortex at a developmental stage when cilia stabilize in wild-type mice, but this effect is not observed in interneurons, astrocytes, or excitatory neurons in non-laminated regions. Together, Reelin controls the directional orientation, apical localization, and length of primary cilia in principal neurons in the cerebral cortex, underscoring the cilium as a key apical domain particularly prominent in late-born neurons.

neuroscience↗

bioRxiv2025

A High-Throughput Multiwell-Plate based Approach for the combined Expression, Export and Assay of Recombinant Proteins.

High-throughput screening (HTS) of proteins has a wide range of applications across the biology, biotechnology, and medicine disciplines. These include yield optimisation, drug or biomarker discovery, and protein engineering, among others. Factors that need to be considered in designing high throughput protein expression and screening methods, be that for expression, activity, stability, or binding as says, include the required yield, reproducibility, solubility, stability, purity and activity of the protein. Thus, larger culture volumes and time-consuming manual protein extraction and purification steps are normally required to produce sufficient quantity of protein of appropriate purity. This limits the type of assay, and number of protein variants that can be simultaneously tested in an experiment. Here we describe a HTS protocol that allows the overnight expression, export and assay of recombinant proteins from E. coli cells in the same multi-well plate tube. The protocol uses a recently described Vesicle Nucleating peptide (VNp) technology that promotes high yield vesicular export of functional proteins from E. coli into the culture media. The resulting protein is of sufficient purity and yield that in can be used directly in plate-based enzymatic assays without additional purification. This simple single plate protocol allows itself to a wide range of high-throughput research and development screening applications, ranging from streamlining protein production and identification of activity enhancing mutations, to ligand screening for basic research, biotechnological and drug discovery applications.

molecular biology↗

bioRxiv2025

Cytosolic DNA structures produced by mismatch-repair deficiency coordinate anti-tumor immunity in colorectal cancer

Patients with the microsatellite instable (MSI) subtype of colorectal cancer (CRC) have better prognosis and immunotherapy response than patients with the chromosomally instable (CIN) subtype due to improved cytotoxic T cell responses from high neoantigen levels and production of the chemokines CXCL10 and CCL5 that recruit cytotoxic T cells. This high chemokine production in MSI CRCs is due to constitutive activation of the cytosolic DNA (cyDNA) sensor STING by specific features of MSI cyDNA that lead to more effective STING pathway activation. Here, we investigate the features of MSI and CIN cyDNA to identify structures that more effectively activate STING. We find that MSI cyDNA is enriched in G-quadruplexes which improve STING and CD8+ T cell activation. Additionally, MSI micronuclei are also more efficient at inducing chemokine expression than CIN micronuclei. However, micronuclei are less effective than free cyDNA at inducing anti-tumor immunity and instead lead to increased Treg activation and IL10 production. Overall, these data highlight the role of specific cyDNA structures in anti-tumor immunity and provide essential knowledge for improved design of therapeutic DNA-based STING agonists that could be combined with immune checkpoint therapies to improve the prognosis of poorly immunogenic tumors like CIN CRCs.

cancer biology↗

bioRxiv2025

Whole genome sequencing reveals how plasticity and genetic differentiation underlie sympatric morphs of Arctic charr

Salmonids have a remarkable ability to form sympatric morphs after postglacial colonization of freshwater lakes. These morphs often exhibit differences in morphology, feeding, and spawning behaviour. Here we explore the genetics of morph differentiation by establishing a high-quality, annotated reference genome for the Arctic charr and use this as a resource for population genomic analysis of morphs from two Norwegian and two Icelandic lakes. The four lakes represent the spectrum of genetic differentiation between morphs from one lake with no genetic differentiation between morphs, implying phenotypic plasticity only, to two lakes with locus-specific genetic differentiation, implying incomplete reproductive isolation, and one lake with strong genome-wide divergence consistent with complete reproductive isolation. As many as 12 putative inversions ranging from 0.45 to 3.25 Mbp in size segregated among the four morphs present in one lake, Thingvallavatn, and these contributed significantly to the genetic differentiation among morphs. None of the putative inversions was found in any of the other lakes, but there were cases of partial haplotype sharing in similar morph contrasts in other lakes. The results are consistent with a highly polygenic basis of morph differentiation with limited genetic parallelism between lakes. The results support a model where morph differentiation is usually first established due to phenotypic plasticity that results in niche expansion and separation, followed by gradual development of reproductive isolation and locus-specific differentiation and eventually complete reproductive isolation and genome-wide divergence. A major explanation for salmonids ability to diversify into multiple sympatric morphs is likely the genome complexity caused by their ancient whole genome duplication that enhances evolvability.

evolutionary biology↗

bioRxiv2024

Chromosome-scale genome assembly and de novo annotation of Alopecurus aequalis.

Alopecurus aequalis is a winter annual or short-lived perennial bunchgrass which has in recent years emerged as the dominant agricultural weed of barley and wheat in certain regions of China and Japan, causing significant yield losses. Its robust tillering capacity and high fecundity, combined with the development of both target and non-target-site resistance to herbicides means it is a formidable challenge to food security. Here we report on a chromosome-scale assembly of A. aequalis with a genome size of 2.83 Gb. The genome contained 33,758 high-confidence protein-coding genes with functional annotation. Comparative genomics revealed that the genome structure of A. aequalis is more similar to Hordeum vulgare rather than the more closely related Alopecurus myosuroides and has undergone an expansion of cytochrome P450 genes, a gene family involved in non-target-site herbicide resistance.

plant biology↗

bioRxiv2024

Under Cover of Darkness: Refuge from Artificial Light at Night may Mitigate Risks to Stranded Seabirds

Artificial light at night is an anthropogenic pollutant that has wide-ranging effects on wildlife. Fledgling seabirds of the order Procellariiformes exhibit phototaxis toward artificial lights on their first flights from the nest, causing them to become grounded in human settlements where they are subject to increased risk of predation. Limited evidence suggests that certain light types may be less attractive than others, yet there is also evidence for an aversion to light under certain circumstances. We investigated differences in phototactic behaviour, activity level, and shelter-seeking behaviour of grounded Hydrobates leucorhous (Leachs storm-petrel) fledglings exposed to artificial light in three experiments: a Y-maze choice experiment, an open field test, and a modified open field test with a hide box provided ("Safe Haven test"). When provided with combinations of different light types in the Y-maze, storm-petrels typically remained stationary in the darkest part of the apparatus and exhibited no response toward one light type over another. This was consistent with results from the open field test, in which individuals were less active in darkness than when exposed to two out of three light conditions (Warm White Light-Emitting Diode and High Pressure Sodium). More than half of birds entered the hide box in light conditions, compared to none in the dark. Considered together, our results indicate Leachs storm-petrel fledglings exhibit photophobic behaviour after stranding, which may be part of a behavioural strategy to avoid predation. Further, we demonstrate the utility of providing hide boxes to protect stranded seabird fledglings in locations where lighting cannot be eliminated or where rescue efforts may be limited in spatial or temporal coverage. However, hide boxes would have limited utility in dark locations. Hide boxes constitute a novel mitigation measure that merits future testing for its ability to reduce stranding-induced mortality, especially in imperiled procellariiform species. LAY SUMMARYO_LIGlobally, fledglings of many seabird species become stranded in towns and at industrial sites near their breeding colonies C_LIO_LIStrandings are thought to be caused by attraction to lights, although some species appear to avoid light C_LIO_LIWe tested behavioural responses and activity levels of Leachs storm-petrel fledglings toward several different light types C_LIO_LIWhen presented with different types of light in a choice experiment, most birds remained stationary C_LIO_LIFledglings were more active in warm-hued lights than in darkness C_LIO_LIBirds sought shelter when it was provided in light conditions, but not when provided in darkness C_LIO_LIOur results suggest that rescue programs targeting Leachs storm-petrels should include searches in dark, hidden locations where fledglings are likely to hide, and support the use of small shelters to protect stranded seabirds when lights cannot be turned off C_LI

animal behavior and cognition↗

bioRxiv2024

Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

Tumor heterogeneity poses a significant challenge in combating treatment resistance. Despite Polo-like kinase 1 (PLK1) being universally overexpressed in cancers and contributing to chromosomal instability (CIN), direct PLK1 inhibition hasnt yielded clinical progress. To address this, we utilized the synthetic dosage lethality (SDL) approach, targeting PLK1s genetic interactions for selective killing of overexpressed tumor cells while mitigating heterogeneity-associated challenges. Employing computational methods, we conducted a genome-wide shRNA screen, identifying 105 SDL candidates. Further in vivo CRISPR screening in a breast cancer xenograft model and in vitro CRISPR analysis validated these candidates. Employing Perturb-seq revealed IGF2BP2/IMP2 as a key SDL hit eliminating PLK1-overexpressing cells. Suppression of IGF2BP2, genetically or pharmacologically, downregulated PLK1 and limited tumor growth. Our findings strongly propose targeting PLK1s genetic interactions as a promising therapeutic approach, holding broad implications across multiple cancers where PLK1 is overexpressed.

cancer biology↗

bioRxiv2024

Navigating the Night: Effects of Artificial Light on the Behaviour of Atlantic Puffin Fledglings

Every year in Newfoundland, young Atlantic Puffins (Fratercula arctica) departing their nests at night for the first time become stranded in towns near their breeding colonies, a phenomenon thought to be caused by attraction toward artificial light. To test this hypothesis, we conducted three behavioural experiments. First, we illuminated beaches near a breeding colony to determine whether more fledglings would become stranded in illuminated versus dark conditions. Next, we conducted a Y-maze experiment to test stranded fledglings for phototactic behaviour in general and for preferences among High Pressure Sodium (HPS), Warm White Light-Emitting Diode (LED), Cool White LED, Blue LED, and Orange LED light. Lastly, we quantified activity levels of stranded fledglings in an open field test during exposure to several different light types. We found significantly more fledglings stranded when beaches were illuminated, and fledglings significantly preferred light over darkness in the Y-maze, supporting our hypothesis that Atlantic Puffin fledglings become stranded due to light attraction. Fledglings displayed no preferences for certain light types over others in the Y-maze, potentially suggesting that strandings in this species may not be mitigable by changing the streetlight type in stranding-prone towns. Interestingly, fledglings exhibited higher activity levels in darkness and HPS light than in LED light, potentially holding implications for rescue, rehabilitation, and husbandry programs. Overall, our findings demonstrate that the only evidence-based strategy for the reduction of Atlantic Puffin strandings remains to be the reduction of coastal artificial lighting; however, further research is needed to determine if aspects of artificial light besides bulb type may be altered to effectively reduce light attraction in this species.

animal behavior and cognition↗

bioRxiv2024

Simple recombinant monoclonal antibody production from E. coli.

AO_SCPLOWBSTRACTC_SCPLOWAntibodies are valuable biological reagents used in a wide range of discovery research, biotechnology, diagnostic and therapeutic applications. Currently both commercial and lab scale antibody production is reliant on expression from mammalian cells, which can be time consuming and requires use of specialist facilities and costly growth reagents. Here we describe a simple, rapid and cheap method for producing and isolating functional monoclonal antibodies and antibody fragments from bacterial cells that can be used in a range of laboratory applications. This simple method only requires access to basic microbial cell culture and molecular biology equipment, making scalable in-house antibody production accessible to the global diagnostics, therapeutics and molecular bioscience research communities.

molecular biology↗

bioRxiv2024

The genome sequence of the Violet Carpenter Bee, Xylocopa violacea (Linnaeus, 1785): a hymenopteran species undergoing range expansion.

We present a reference genome assembly from an individual male Violet Carpenter Bee (Xylocopa violacea, Linnaeus, 1758). The assembly is 1.02 gigabases in span. 48% of the assembly is scaffolded into 17 pseudo-chromosomal units. The mitochondrial genome has also been assembled and is 21.8 kilobases in length. The genome is highly repetitive, likely representing a highly heterochromatic architecture expected of bees from the genus Xylocopa. We also use an evidence-based methodology to annotate 10,152 high confidence coding genes. This genome was sequenced as part of the pilot project of the European Reference Genome Atlas (ERGA) and represents an important addition to the genomic resources available for Hymenoptera.

genomics↗

bioRxiv2024

Synaptic function and sensory processing in ZDHHC9-associated neurodevelopmental disorder: a mechanistic account

Loss-of-function ZDHHC9 variants are associated with X-linked intellectual disability (XLID), rolandic epilepsy (RE) and developmental language difficulties. This study integrates human neurophysiological data with a computational model to identify a potential neural mechanism explaining ZDHHC9-associated differences in cortical function and cognition. Magnetoencephalography (MEG) data was collected during an auditory roving oddball paradigm from eight individuals with a ZDHHC9 loss-of-function variant (ZDHHC9 group) and seven age-matched individuals without neurological or neurodevelopmental difficulties (control group). Evoked responses to auditory stimulation were larger in amplitude and showed a later peak latency in the ZDHHC9 group but demonstrated normal stimulus-specific properties. Magnetic mismatch negativity (mMMN) amplitude was also increased in the ZDHHC9 group, reflected by stronger neural activation during deviant processing relative to the standard. A recurrent neural network (RNN) model was trained to mimic recapitulate group-level auditory evoked responses, and subsequently perturbed to test the hypothesised impact of ZDHHC9-driven synaptic dysfunction on neural dynamics. Results of model perturbations showed that reducing inhibition levels by weakening inhibitory weights recapitulates the observed group differences in evoked responses. Stronger reductions in inhibition levels resulted in increased peak amplitude and peak latency of RNN prediction relative to the pre-perturbation predictions. Control experiments in which excitatory connections were strengthened by the same levels did not result in consistently stable activity or AEF-like RNN predictions. Together, these results suggest that reduced inhibition is a plausible mechanism by which loss of ZDHHC9 function alters cortical dynamics during sensory processing. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/587155v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1f9bd36org.highwire.dtl.DTLVardef@f54610org.highwire.dtl.DTLVardef@caff66org.highwire.dtl.DTLVardef@145a4d2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG In the current study, we employed a bottom-up approach to study the impact of synaptic-level alterations associated with ZDHHC9 variants on cortical function in healthy and ZDHHC9-deficient participants. To achieve this, a recurrent neural network model was developed to recapitulate MEG-derived auditory evoked responses and subsequently perturbed in order to determine effects on resulting dynamics. We show that reduced network inhibition recapitulates empirical observations, specifically increased response amplitudes, delayed peak latencies and increased mismatch negativity. These results offered a mechanistic account on the impact of ZDHHC9-associated synaptic alterations on auditory processing.

neuroscience↗

bioRxiv2024

Distinct Motor Map Characteristics for Biceps and Triceps Muscles in Persons with Chronic Tetraplegia: Implications for Arm Function

Following spinal cord injury (SCI), intact neural resources undergo widespread reorganization within the brain. Animal models reveal motor cortical representations devoted to spared muscles above injury expand at the expense of territories occupied by weaker muscles. In this study, we investigated whether motor representations are similarly reorganized between a relatively spared biceps muscle and a weakened triceps muscle in persons with chronic tetraplegia following traumatic cervical SCI in association with upper limb motor function. Twenty-four adults with cervical SCI and 15 able-bodied participants underwent motor mapping using transcranial magnetic stimulation. We determined following map characteristics: area, amplitude (maximal motor evoked potential and volume), and center of gravity. Maximal voluntary contraction (MVC) and motor function (Capabilities of the Upper Extremity Test or CUE-T) were also assessed. Findings reveal that participants with SCI had hyper-excitable biceps maps than triceps, and hyper-excitable biceps maps also compared to biceps maps in able-bodied participants. Higher amplitude of biceps and triceps maps was associated with better motor function (higher CUE-T) and more distal injury (i.e., more spared segments) in persons with SCI. Amplitudes of biceps but not the triceps maps were associated with higher muscle MVCs. In conclusion, over-excitable biceps than triceps map in SCI may represent deafferentation plasticity. For the first time, we demonstrate how map reorganization of spared and weaker muscles in persons with chronic cervical SCI is associated with upper limb motor status. Use-dependent mechanisms may shift neural balance in favor of spared muscles, supporting potential use as response biomarkers in rehabilitation studies. New & NoteworthyOur study reports evidence in humans with cervical SCI that motor representation for the relatively spared muscle becomes hyper-excitable compared to that for the weaker muscle to the extent that hyper-excitability is even higher compared to biceps maps in uninjured individuals. Use-dependent mechanisms likely favor such heightened excitability of spared maps. For the first time, we demonstrate clinical relevance of map excitability in humans with SCI, supporting potential use as a biomarker of recovery.

neuroscience↗