Biology subjects

Kim, J. S.

Publications and source records attributed to Kim, J. S..

At least 19 recordsLinked to original sources

bioRxiv2026

A novel in vitro assay for quantifying endothelial cell and pericyte interactions

ObjectiveStructural adaptations of capillary networks, through angiogenesis, arterialization, and regression, are implicated in many diseases, and gaining a better understanding of the cell-cell interactions that underpin these adaptations may lead to novel therapeutic discoveries for disease management. Endothelial cells and pericytes are the two cell types that comprise capillary networks. Experimental model systems have been developed to study the dynamic interactions between endothelial cells and pericytes, providing valuable insights into capillary development, cell-to-cell communication, and responses to growth factors and therapeutic agents. MethodsIn this study, we present a novel and simple co-culture system that uses commercially available primary human endothelial cells and pericytes, does not require microfluidic perfusion, and allows simultaneous observation of cell morphologies and interactions over time in 60 samples, enabling high-throughput analysis of multiple culture conditions with replicates. ResultsImage analysis pipelines were created to quantify microvascular adaptations, including one to measure colocalization between endothelial cells and pericytes, capturing dynamic coupling and uncoupling associated with capillary stability, angiogenesis, and regression. We validated the ability of our co-culture system to reproducibly represent the effects of fibrotic and angiogenic activation signals, including an FDA-approved drug, on endothelial cells, pericytes, and their coupling. ConclusionThis novel, high-throughput microvascular screening assay enables quantification of microvascular dynamics in response to disease-relevant stimuli and therapeutics in a repeatable, real-time manner.

bioengineering↗

bioRxiv2026

Liquid Phase Backscattered Scanning Electron Microscopy of Bacillus subtilis Spores

Backscattered electron scanning electron microscopy (BSE-SEM) provides compositional image contrast but has found limited application to biological samples due to the low atomic number difference between constituent elements, the thickness of the surrounding environment, and the need for complex sample preparation. Here, we demonstrate the use of room temperature liquid phase BSE-SEM (LPBSEM) for imaging Bacillus subtilis spores encapsulated in graphene liquid cells, preserving native hydration and reducing the thickness of the sample environment. This approach eliminates the need for staining and enables high-contrast visualisation of subcellular structures. Distinct structural layers within B. subtilis spores have been observed with a contrast similar to conventional thin-section transmission electron microscopy but without the need for sample preparation that potentially compromises sample integrity. We further investigate the influence of beam energy on the interaction volume depth and image contrast and propose optimal conditions for subsurface visualisation. Monte Carlo simulations have been used to validate our experimental observations and provide a quantitative framework for understanding BSE generation from hydrated, low atomic number specimens.

microbiology↗

bioRxiv2026

Behavioral state-dependent norepinephrine dynamics in the primary somatosensory and prefrontal cortices during tactile detection tasks

Animals must integrate sensory information, ignore behaviorally irrelevant stimuli, and respond to behaviorally relevant stimuli to find food, find mates, avoid predators, and ultimately survive. In mammals, these goal-directed behaviors require the coordinated activity of many brain regions, including sensory and prefrontal cortices and neuromodulatory brainstem nuclei like the locus coeruleus (LC), which is the brains primary source of norepinephrine (NE). NE release resulting from LC activity and arousal indexed by pupil size exert strong influences on goal-directed behavior. We explored the relationships between pupil size, cortical noradrenergic dynamics, and behavior in a tactile signal detection task. We monitored pupil dynamics and fluorescent GRABNE signals in somatosensory and medial prefrontal cortices simultaneously during task execution and found that pupil size and synchronization of GRABNE signals at baseline were strong predictors of whether animals chose to respond. Baseline and post-reward cortical GRABNE levels varied strongly with pupil-linked arousal. We also employed a generalized linear model - hidden Markov model (GLM-HMM) framework to identify distinct, stable behavioral states throughout the task that characterize task performance. We found distinct psychometric curves, task-related pupil dynamics, and cortical NE dynamics across these behavioral states. Significance StatementBehavioral state strongly shapes goal-directed behavior, which in turn depends on the coordinated activity of distributed brain regions, including the sensory and prefrontal cortices. By simultaneously measuring pupil size and cortical noradrenergic dynamics, and by identifying psychophysically distinct behavioral states during a tactile detection task, this study establishes links between pupil-linked arousal, norepinephrine signaling in somatosensory and prefrontal cortices, and trial outcomes. These findings provide new insight into how the locus coeruleus - norepinephrine system regulates perception and decision-making.

neuroscience↗

bioRxiv2026

Attention modulates EEG spectral activity across serial positions

Electroencephalographic (EEG) activity has been associated with attentional processes such as task-irrelevant stimulus suppression and orienting. The aim of this study was to understand how spectral activity evolves as words are presented in a word list learning task and as multiple components of attention are engaged under multitasking demands. We recorded scalp EEG in a delayed free-recall task in which participants encoded common noun word lists either under full attention (encoding only) or divided attention (simultaneous target detection task). In the target detection task, participants pressed a response button when a word was paired with a target-colored square but not for words paired with a distractor-colored square (cue condition). Activity in the high gamma frequencies (50-100 Hz) decreased while alpha activity (8-12 Hz) increased throughout word list presentation (i.e., across serial positions), consistent with prior work demonstrating effects of cognitive load on EEG spectral power. Divided attention attenuated this change in gamma power across the list. Cue condition modulated alpha activity evenly across serial positions, with consistently lower power during target trials than distractor trials. Our findings suggest that frequency-specific characteristics of processing during list encoding may reflect multiple components of attention that vary over different time scales. Gamma frequencies capture the interactive effects of cognitive load and dual-task demands, while alpha power separately reflects gradual increases in cognitive load and momentary orienting.

neuroscience↗

bioRxiv2025

IgA antibodies against oxidation-specific epitopes are generated by double negative B cells and are associated with impaired lung function in fibrotic interstitial lung diseases.

BackgroundFibrotic interstitial lung diseases (fILD) are characterized by progressive scarring of the lung and high mortality. Oxidation-specific epitopes (OSEs) form on oxidized lipids and proteins, are abundant in lungs of patients with fILD and perpetuate lung injury and fibrosis in animal models. OSE-targeting antibodies bind to OSEs and modulate their downstream effects. The objective of this study was to determine the association of OSE-targeting antibodies with lung function and other clinical outcomes, and to characterize OSE-specific B cell phenotypes in fILD. MethodsTo determine the association of OSE-targeting antibodies and clinical outcomes in fILD, we measured plasma levels of OSE-specific antibodies against the malondialdehyde modified LDL mimotope P1 and anti-ApoB100 immune complex (anti-ApoB100 IC) in patients with fILD and age-matched controls. We then performed B cell phenotyping of patients with idiopathic pulmonary fibrosis (IPF) and healthy controls utilizing mass cytometry time of flight (CyTOF). To investigate effects of pro-fibrotic mediators on anti-OSE IgA antibody production, we measured B cell responses to OSEs in vitro. ResultsCohort of 109 patients with fILD (Hypersensitivity Pneumonitis, Idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia, Connective Tissue Disease-Associated Interstitial Lung Disease) and 55 healthy donors, and a second cohort of 20 patients with IPF and 9 healthy donors were included in the study. OSE-specific antibody levels anti-P1 and anti-ApoB100 IC IgA and IgG were significantly elevated in participants with fILD compared to healthy donors (p<0.0001). Higher anti-OSE IgA was associated with worse baseline lung function, including forced vital capacity (FVC) (p<0.001) and diffusing capacity for carbon monoxide (DLCO) (p<0.01). IgA+CD27-CD21-CD11c+ double negative type 2 (DN2) B cells correlated with anti-OSE IgA levels (p<0.05) and were enriched in OSE-specific cells. DN2 B cell precursors, CXCR5-CD11c+ naive B cells and IgA+CD27-CD21-CD11c- DN3 B cells, were significantly expanded in IPF compared to healthy donors. Both DN2 and DN3 B cells correlated with plasmablast pools in IPF patients and showed high baseline levels of IL-21 receptor, which was reduced in more differentiated cells. TGF-{beta} combined with OSEs, but not OSEs alone, induced OSE-specific IgA production in vitro. ConclusionsCirculating anti-OSE IgA antibodies are elevated in patients with fibrotic ILDs regardless of underlying pathology and negatively correlate with lung function. These antibodies correlated with the DN2 B cell subset which was enriched in OSE-specific cells. Phenotypic analysis of B cell subsets showed expression of markers consistent with DN to plasmablast differentiation. Finally, TGF-{beta} promoted OSE-IgA production in vitro. These findings show a novel link between oxidative tissue damage, anti-OSE antibodies and DN2 B cells in fILD which may provide opportunities for new targeted therapies.

immunology↗

bioRxiv2025

Independent Basal Ganglia Neural Populations Encode Speech Production and Ambient-Noise Levels

The function of the basal ganglia (BG), a set of nuclei deep in the brain, is still under debate despite their clinical relevance. Lines of evidence from non-human primate and human experiments suggest that one key causal contribution of the adult primate BG is invigoration of movement according to environmental and energetic constraints. Previous studies have come to this conclusion using primarily limb motor control tasks. We hypothesized BG are also important for invigorating the respiratory, vocal, and articulatory motor systems during speech production. To test this, we used a rare clinical opportunity to record local field potentials-broadband gamma activity (LFP-BGA) and single unit (SU) activity from human basal ganglia during deep brain stimulation implant surgeries. Participants repeated sentences aloud in the operating room. We modulated environmental and energetic constraints of speech production by inducing the Lombard Effect, wherein people reliably increase the intensity of their voice in the presence of background noise. Participants increased voice intensity, pitch, vowel space size, and respiratory depth in the presence of ambient noise. [~]40% of LFP and SU sites were modulated by speech production. Comparing globus pallidus (GP) LFP-BGA, herein reported for the first time during speech, to subthalamic nucleus (STN) LFP-BGA revealed GP activated after STN. STN was more coincident with the speech preparatory period and GP more coincident with speech onset, suggesting differential roles in speech production. We found only weak evidence that STN or GP activity encodes the level of produced speech intensity. Instead, we found that LFP-BGA and SU-FR robustly track the ambient background noise levels. Linear decoding from SU-firing rate revealed we could infer the background noise levels with >75% accuracy in any given time point in the trial, including baseline. Importantly, the ambient-noise-modulated sites were an independent population from speech-modulated sites. We conclude that human BG encode the energetic constraints of communication. We theorize that the code is leveraged in downstream BG-cortical loop nodes to invigorate speech oro-motor gestures and co-speech manual limb gestures, both of which respond to ambient noise levels to maintain high-fidelity communication.

neuroscience↗

bioRxiv2025

Generative enhancement of non-invasive dataset for motor brain-computer interface by task-relevant neural signals

Despite the increasing adoption of deep neural networks (DNNs) in brain-computer interfaces (BCIs), developing high-degree-of-freedom (DOF) systems capable of decoding continuous movements, such as limb kinematics, remains a significant challenge. This difficulty stems from limited availability of task-specific neural features within individual neural signal datasets. To overcome this, we proposed a generative adversarial network (GAN) framework to enrich training features within neural signal datasets. Specifically, we synthesized artificial neural signal waveforms of the primary motor cortex (M1) from functionally related cortical regions, thereby enhancing neural datasets for improved motor kinematics decoding via DNN. Using magnetoencephalography (MEG) recordings during goal-directed arm-reaching tasks, our results showed that enhancing individual datasets with GAN-synthesized M1 signals significantly improved decoding performance by about 10% (p < 0.05). Such improved performance is sustained even in the absence of real M1 signals. We further generalized the proposed enhancement to the motor imagery BCI competition dataset to improve classification accuracy. Our results highlight the potential of signal-generative networks to improve and augment motor BCIs to achieve freely intended movements.

neuroscience↗

bioRxiv2025

Donor-Targeted Anti-HLA-A2 Antibody Shows Nanogram-Level Efficacy in a Novel GVHD Mouse Model

Acute graft-versus-host disease (GVHD) remains a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited treatment options for steroid-refractory cases. Current therapies broadly suppress immune responses, increasing infection risk and impairing graft function. We hypothesized that selective depletion of donor immune cells through HLA allele-specific targeting could offer a safer and more precise alternative. To test this, we developed a monoclonal antibody (AN7) against HLA-A2 by immunizing HLA-A24 transgenic mice with recombinant HLA-A2 tetramers, followed by hybridoma screening. AN7 specifically recognized HLA-A2 and HLA-A68, and was reformatted into murine IgG2a and human chimeric IgG1 recombinant antibodies. These retained binding specificity and mediated robust complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) against HLA-A2+ target cells. To evaluate therapeutic potential, we established a fully MHC-mismatched allo-HSCT model using HLA-A2 transgenic donor bone marrow in lethally irradiated BALB/c recipients. A single ultra-low dose of AN7 (1-100 ng) administered post-transplant significantly improved survival and reduced GVHD while preserving donor hematopoiesis. These findings highlight the potential of allele-specific antibody-mediated clearance as a mechanistically distinct approach to donor immune modulation in GVHD.

immunology↗

bioRxiv2025

Electron diffraction captures high-resolution structures from in vivo protein nanocrystals of Bacillus thurigiensis

Bacillus thuringiensis is one of the most widely used biopesticides worldwide. This is owing to the highly-specific pesticidal-proteins various strains produce in the form of nanocrystals. Structure determination from such crystals remains difficult because their small size makes them unsuitable for conventional X-ray crystallography. Here we explore two emerging (cryo-) electron diffraction techniques, namely Microcrystal electron diffraction and serial electron diffraction, as tools for studying the structures of these crystals. Using the mosquitocidal protein Cry11Aa as an example, we compare electron diffraction with state of the art results obtained with an X-ray free electron laser. Our work demonstrates that electron diffraction is a viable alternative for structure determination from such challenging crystals, matching previous results obtained with X-ray free electron lasers. We present a workflow based on readily available instrumentation enabling structure determination directly from the crystals grown in vivo, unperturbed by dissolution and therefore preserved in their native state.

biophysics↗

bioRxiv2025

Siderophores can alter the population dynamics of fungal-bacterial communities by inhibiting specialized metabolism

Siderophores are microbial metabolites with a strong affinity for Fe(III) ions, in addition to other roles beyond iron acquisition. In this study, we propose that bacillibactin, a siderophore produced by the bacterium Bacillus subtilis, provides an advantage to its producer by inhibiting the specialized metabolism of antagonistic Penicillium fungi. Metabolome and transcriptome analyses indicate that iron deficiency caused by bacillibactin plays a critical role in downregulating the specialized metabolism of competing Penicillium species. Since many specialized metabolites of Penicillium spp. have antibacterial properties, we hypothesize that bacillibactin cross-protects other bacteria during fungal-bacterial community interactions. A tripartite coculture model demonstrated that bacillibactin production influences community dynamics by reducing the growth of specialized metabolite-producing Penicillium species, thereby facilitating the colonization of B. subtilis and other co-inhabiting bacterial species.

microbiology↗

bioRxiv2025

Evaluating the impact of NPC1 SNPs on entry efficiency of Filovirus in vitro: agent-based model approach

The interaction between the Niemann-Pick C1 (NPC1) protein and the glycoprotein (GP) of filoviruses is essential for viral entry into host cells. Single nucleotide polymorphisms (SNPs) in NPC1, which lead to amino acid substitutions, can significantly alter viral entry efficiency. However, the quantitative impact of these SNPs remains unclear. To address this, we investigate in vitro cell-to-cell infection using a plaque assay with vesicular stomatitis virus (VSV) expressing Ebola and Marburg GP. We employe an agent-based model (ABM) to estimate entry efficiency by simulating plaque growth, enabling a comparative analysis of SNP-specific effects on viral entry. Our quantitative analysis reveals that D508N, P424A, and S425L substitutions in NPC1 reduce entry efficiency in both viruses. These findings provide insights into host-pathogen interactions and demonstrate the value of ABM in virology research, potentially guiding therapeutic strategies targeting viral entry mechanisms. Author summaryEbola and Marburg viruses are highly pathogenic filoviruses that cause severe hemorrhagic fever in humans, with case fatality rates reaching around 50%. These viruses pose significant public health challenges due to their potential for large-scale outbreaks. A key step in their infection process is the interaction between the Niemann-Pick C1 (NPC1) protein on host cells and the viral glycoprotein, which facilitates viral entry. Genetic variations in NPC1 caused by single nucleotide polymorphisms (SNPs) can lead to amino acid substitutions, potentially altering the efficiency of viral entry. To better understand this process, we developed an agent-based model, a computational approach that simulates individual cell interactions and provides spatial resolution not achievable with traditional modeling techniques, to simulate viral plaque growth in vitro. By applying this model, we quantified how specific NPC1 substitutions, such as D508N, P424A, and S425L, affect the entry efficiency of Ebola and Marburg viruses. Our findings highlight the potential of computational modeling to uncover the impact of genetic variations on viral infections and provide insights that may inform therapeutic strategies against these deadly viruses.

systems biology↗

bioRxiv2025

Visual experience contributes to separation of face and language responses in the ventral stream

Human ventral occipitotemporal cortex (vOTC) contains specialized regions that support visual recognition of behaviorally-relevant categories, including faces, written language and places (e.g., 1-4). An open question is how experience interacts with innate constraints to enable functional specialization. We investigate this question by comparing vOTC function across sighted and congenitally blind adults. In sighted adults, a region in lateral vOTC called the fusiform face area (FFA) responds preferentially to faces, whereas distinct left-lateralized portions of vOTC respond to written language 1,2,5-12. In blind people, lateral vOTC responds to face touching, braille and speech, but their functional co-localization has not been tested 13-16. The same group of congenitally blind adults (n=20) touched faces and spatial layouts (Experiment 1) and performed a reading (braille) and spoken language task (Experiment 2). Sighted adults performed analogous tasks in the visual modality (n=28). Using within subject analyses, we replicate the separation of faces and written language in sighted adults: written language responses are found only in left vOTC and within that hemisphere they are separate from faces. By contrast, left and right vOTC responds to language in people born blind and in the left hemisphere face and language responses overlap. These findings suggest that visual experience contributes to segregating responses to face and language in vOTC. Co-localization of face and language responses suggests an innate predisposition for communication-relevant processing in lateral vOTC.

neuroscience↗

bioRxiv2024

Reduction of SEM charging artefacts in native cryogenic biological samples.

Scanning electron microscopy (SEM) of frozen-hydrated biological samples allows imaging of subcellular structures at the mesoscale in their native state. Combined with focused ion beam milling (FIB), serial FIB/SEM can be used to build a 3-dimensional picture of cells and tissues. The correlation of specific regions of interest with cryo-electron microscopy (cryoEM) can additionally enable subsequent high-resolution analysis. However, the adoption of serial FIB/SEM imaging-based methods is limited due to artefacts arising from insulating areas of cryogenically preserved samples. Here, we demonstrate the use of interleaved scanning to reduce charging artefacts, allowing the observation of biological features that otherwise would be masked or perturbed. We apply our method to samples where inherent features are not visible. These examples include membrane contact sites within mammalian cells, visualisation of the degradation compartment in the algae E.gracilis and observation of a network of membranes within different types of axons in an adult mouse cortex. We further propose an alternative scanning method that could also be widely applicable to imaging any non-conductive.

cell biology↗

bioRxiv2024

Structural diversity of mitochondria in the neuromuscular system across development

As an animal matures, its neural circuit undergoes alterations, yet the developmental changes in intracellular organelles to facilitate these changes is less understood. Using 3D electron microscopy and deep learning, we developed semi-automated methods for reconstructing mitochondria in C. elegans and collected mitochondria reconstructions from normal reproductive stages and dauer, enabling comparative study on mitochondria structure within the neuromuscular system. We found that various mitochondria structural properties in neurons correlate with synaptic connections and these properties are preserved across development in different neural circuits. To test the necessity of these universal mitochondria properties, we examined the behavior in drp-1 mutants with impaired mitochondria fission and discovered that it caused behavioral deficits. Moreover, we observed that dauer neurons display distinctive mitochondrial features, and mitochondria in dauer muscles exhibit unique reticulum-like structure. We propose that this specialized mitochondria structure may serve as an adaptive mechanism to support stage-specific behavioral and physiological needs.

neuroscience↗

bioRxiv2024

Ultradian rhythms of CRHPVN neuron activity, behaviour and stress hormone secretion

The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN) control both the neuroendocrine stress axis as well as stress-associated behaviours. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behaviour and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRHPVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRHPVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-hour day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRHPVN neurons was also sufficient to induce behavioural arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRHPVN neurons display an ultradian rhythm of activity over the 24-hour day that is coordinated with behavioural arousal, the relationship between CRHPVN activity and pulses of corticosteroid secretion is not one-to-one. Significance StatementUltradian rhythms are present in many biological systems, however, the underlying neural mechanisms responsible for generating these rhythms is unclear. Corticotropin-releasing hormone (CRH) neurons control corticosteroid levels in the body as well as arousal and behaviour. Here we show that CRH neurons exhibit a pronounced ultradian rhythm in neural activity over the 24-hour day. CRH neural activity was highly correlated with, and predictive of, behavioral arousal. However, CRH neural activity was not as well correlated with pulses of corticosteroid secretion. Together, these data revel the patterns of CRH neuron activity over the 24-hour day and their relationship with behaviour and stress hormone secretion.

neuroscience↗

bioRxiv2024

Liquid phase electron microscopy of bacterial ultrastructure.

Recent advances in liquid phase scanning transmission electron microscopy (LP-STEM) have enabled the study of dynamic biological processes at nanometre resolutions, paving the way for live-cell imaging using electron microscopy. However, this technique is often hampered by the inherent thickness of whole cell samples and damage from electron beam irradiation. These restrictions degrade image quality and resolution, impeding biological interpretation. Here we detail the use of graphene encapsulation, STEM, and energy-dispersive X-ray (EDX) spectroscopy methods to mitigate these issues, providing unprecedented levels of intracellular detail in aqueous specimens. This work demonstrates the potential of LP-STEM to examine and identify internal cellular structures in thick biological samples, in a radiation resistant, gram-positive bacterium, Deinococcus radiodurans using a variety of imaging techniques.

microbiology↗

bioRxiv2024

In vitro neutrophil-bacteria assay in whole blood microenvironments with single-cell confinement

Blood is a common medium through which invasive bacterial infections disseminate in the human body. In vitro neutrophil-bacteria assays allow flexible mechanistic studies and screening of interventional strategies. In standard neutrophil-bacteria assays, both the immune cells and microorganisms are typically interrogated in an exogenous, homogeneous, bulk fluid environment (e.g., culture media or bacterial broth in microtiter plates), lacking the relevant physicochemical factors in the heterogenous blood-tissue microenvironment (e.g., capillary bed) with single-cell confinement. Here we present an in vitro neutrophil-bacteria assay by leveraging an open microfluidic model known as "-Blood" that supports sub-microliter liquid microchannels with single-cell confinement. In this study we compare the exogenous and endogenous fluids including neutrophils in RPMI (standard suspension cell culture media) and whole blood in response to Staphylococcus aureus (S. aureus, a gram-positive, non-motile bacterium) in phosphate buffered saline (PBS), Mueller Hinton Broth (MHB), and human serum. Our results reveal a significant disparity between the exogenous and endogenous fluid microenvironments in the growth kinetics of bacteria, the spontaneous generation of capillary (i.e., Marangoni) flow, and the outcome of neutrophil intervention on the spreading bacteria.

biophysics↗

bioRxiv2023

A cerebellar disinhibitory circuit supports synaptic plasticity

How does the cerebellum learn how to control motion? The cerebellar motor learning critically depends on the long-term depression of the synapses between granule cells and Purkinje cells, which encode motor commands and inhibitory modifications to motor outputs, respectively, for simultaneous granule cell inputs and climbing fibre inputs, the latter of which encode the error signals1-3. However, recent studies have revealed that inhibitory inputs to Purkinje cells may disrupt long-term depression4-8, and it is not clear how long-term depression can occur without disruption. In search of a clue, we investigated the synaptic connectivity among the neurons reconstructed from serial electron microscopy images of the cerebellar molecular layer9,10. We discovered synapses between climbing fibres and a subset of inhibitory interneurons, which synapse onto the remaining interneurons, which in turn synapse onto Purkinje cells. Such connectivity redefines the interneuron types, which have been defined morphologically or molecularly11-13. Together with climbing fibres to Purkinje cell connections, those cell types form a feedforward disinhibitory circuit14. We argued that this circuit secures long-term depression by suppressing inhibition whenever climbing fibre input is provided and long-term depression needs to occur15, and we validated the hypothesis through a computational model. This finding implies a general principle of circuit mechanism in which disinhibition supports synaptic plasticity16,17.

neuroscience↗