Biology subjects

Koch, C.

Publications and source records attributed to Koch, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Behavioral strategy shapes activation of the Vip-Sst disinhibitory circuit in visual cortex

In complex environments, animals can adopt diverse strategies to find rewards. How distinct strategies differentially engage brain circuits is not well understood. Here we investigate this question, focusing on the cortical Vip-Sst disinhibitory circuit. We characterize the behavioral strategies used by mice during a visual change detection task. Using a dynamic logistic regression model we find individual mice use mixtures of a visual comparison strategy and a statistical timing strategy. Separately, mice also have periods of task engagement and disengagement. Two-photon calcium imaging shows large strategy dependent differences in neural activity in excitatory, Sst inhibitory, and Vip inhibitory cells in response to both image changes and image omissions. In contrast, task engagement has limited effects on neural population activity. We find the diversity of neural correlates of strategy can be understood parsimoniously as increased activation of the Vip-Sst disinhibitory circuit during the visual comparison strategy which facilitates task appropriate responses.

neuroscience↗

bioRxiv2023

Cell class-specific electric field entrainment of neural activity

Electric fields affect the activity of neurons and brain circuits, yet how this interaction happens at the cellular level remains enigmatic. Lack of understanding on how to stimulate the human brain to promote or suppress specific activity patterns significantly limits basic research and clinical applications. Here we study how electric fields impact the subthreshold and spiking properties of major cortical neuronal classes. We find that cortical neurons in rodent neocortex and hippocampus as well as human cortex exhibit strong and cell class-dependent entrainment that depends on the stimulation frequency. Excitatory pyramidal neurons with their typically slower spike rate entrain to slow and fast electric fields, while inhibitory classes like Pvalb and SST with their fast spiking predominantly phase lock to fast fields. We show this spike-field entrainment is the result of two effects: non-specific membrane polarization occurring across classes and class-specific excitability properties. Importantly, these properties of spike-field and class-specific entrainment are present in cells across cortical areas and species (mouse and human). These findings open the door to the design of selective and class-specific neuromodulation technologies.

neuroscience↗

bioRxiv2022

Highly multiplexed detection of microRNAs, proteins and small molecules using barcoded molecular probes and nanopore sequencing

Currently, most blood tests in a clinical setting only investigate a handful of markers. A low-cost, rapid, and highly multiplexed platform for the quantitative detection of blood biomarkers has the potential to advance clinical diagnostics beyond the single biomarker paradigm. In this study, we perform nanopore sequencing of barcoded molecular probes that have been engineered to recognise a panel of biological targets (miRNAs, proteins, and small molecules such as neurotransmitters), allowing for highly multiplexed simultaneous detection. Our workflow is rapid, from sample preparation to results in 1 hour. We also demonstrate that the strategy can be used to detect biomarkers directly from human serum without extraction or amplification. The established method is easily adaptable, as the number and type of targets detected can be greatly expanded depending on the application required.

biophysics↗

bioRxiv2022

Cortico-thalamo-cortical interactions modulate electrically evoked EEG responses in mice

Perturbational complexity analysis predicts the presence of consciousness in volunteers and patients by stimulating the brain with brief pulses, recording electroencephalographic (EEG) responses, and computing their spatiotemporal complexity. We examined the underlying neural circuits in mice by directly stimulating cortex while recording with EEG and Neuropixels probes during wakefulness and isoflurane anesthesia. When mice are awake, stimulation of deep cortical layers reliably evokes locally a brief pulse of excitation, followed by a bi-phasic sequence of 120 ms profound off period and a rebound excitation. A similar pattern, partially attributed to burst spiking, is seen in thalamic nuclei, and is associated with a pronounced late component in the evoked EEG. We infer that cortico-thalamo-cortical interactions drive the long-lasting evoked EEG signals elicited by deep cortical stimulation during the awake state. The cortical and thalamic off period and rebound excitation, and the late component in the EEG, are reduced during running and absent during anesthesia.

neuroscience↗

bioRxiv2022

Uncovering circuit mechanisms of current sinksand sources with biophysical simulations ofprimary visual cortex

Local field potential (LFP) recordings reflect the dynamics of the current source density (CSD) in brain tissue. The synaptic, cellular and circuit contributions to current sinks and sources are ill-understood. We investigated these in mouse primary visual cortex using public Neuropixels recordings and a detailed circuit model based on simulating the Hodgkin-Huxley dynamics of numerous cortical neurons belonging to 17 cell types. The model simultaneously captured spiking and CSD responses and demonstrated a two-way dissociation: Firing rates are altered with minor effects on the CSD pattern by adjusting synaptic weights, and CSD is altered with minor effects on firing rates by adjusting synaptic placement on the dendrites. We describe how thalamocortical inputs and recurrent connections sculpt specific sinks and sources early in the visual response, whereas cortical feedback crucially alters them in later stages. Our findings show that CSD analysis provides powerful constraints for modeling beyond those from considering spikes.

neuroscience↗

bioRxiv2022

Regional and cell type-specific afferent and efferent projections of the mouse claustrum

The claustrum (CLA) is a conspicuous subcortical structure interconnected with cortical and subcortical regions. However, its regional anatomy and cell-type-specific connections in the mouse remain largely undetermined. Here, we accurately delineated the boundary of the mouse CLA and quantitatively investigated its inputs and outputs brain-wide using anterograde and retrograde viral tracing and fully reconstructed single claustral principal neurons. At a population level, the CLA reciprocally connects with all isocortical modules. It also receives inputs from at least 35 subcortical structures but sends projections back to only a few of them. We found that cell types projecting to the CLA are differentiated by cortical areas and layers. We classified single CLA principal neurons into at least 9 cell types that innervate the diverse sets of functionally linked cortical targets. Axons of interneurons within the CLA arborize along almost its entire anteroposterior extent. Together, this detailed wiring diagram of the cell-type-specific connections of the mouse CLA lays a foundation for studying its functions.

neuroscience↗

bioRxiv2022

Influence of claustrum on cortex varies by area, layer, and cell type

The claustrum is a small subcortical structure with widespread connections with disparate regions of the cortex. These far-reaching projections have led to many hypotheses concerning its function. However, we know little about how claustrum input affects neural activity in cortex, particularly beyond frontal areas. Here, using optogenetics and multi-regional Neuropixels recordings from over 15,000 neurons in awake mice, we demonstrate that the effect of claustrum input differs depending on brain area, layer, and cell type. Brief claustrum stimulation produces approximately 1 spike per claustrum neuron, which affects many fast-spiking (FS; putative inhibitory) but very few regular-spiking (RS; putative excitatory) cortical neurons. Prolonged claustrum stimulation affects many more cortical FS and RS neurons. More inhibition occurs in frontal regions and deeper layers, while more excitation occurs in posterior regions and superficial layers. These differences imply that the function of claustrum input to cortex depends on the area, supporting the idea that claustro-cortical circuits are organized into functional modules.

neuroscience↗

bioRxiv2022

A survey of neurophysiological differentiation across mouse visual brain areas and timescales

Neurophysiological differentiation (ND), a metric that quantifies the number of distinct activity states that the brain or its part visits over a period of time, has been used as a correlate of meaningfulness or subjective perception of visual stimuli. ND has largely been studied in non-invasive human whole-brain recordings where spatial resolution is limited. However, it is likely that perception is supported by discrete populations of spiking neurons rather than the whole brain. Therefore, in this study, we use Neuropixels recordings from the mouse brain to characterize the ND metric within neural populations recorded at single-cell resolution in localized regions. Using the spiking activity of thousands of simultaneously recorded neurons spanning 6 visual cortical areas as well as the visual thalamus, we show that the ND of stimulus-evoked activity of the entire visual cortex is higher for naturalistic stimuli relative to artificial ones. This finding holds in most individual areas throughout the visual hierarchy as well. For animals performing an image change detection task, ND of the entire visual cortex (though not individual areas) is higher for successful detection compared to failed trials, consistent with the assumed perception of the stimulus. Analysis of spiking activity allows us to characterize the ND metric across a wide range of timescales from 10s of milliseconds to a few seconds. This analysis reveals that although ND of activity of single neurons is often maximized at an optimal timescale around 100 ms, the optimum shifts to under 5 ms for ND of neuronal ensembles. Finally, we find that the ND of activations in convolutional neural networks (CNNs) trained on an image classification task shows distinct trends relative to the mouse visual system: ND is often higher for less naturalistic stimuli and varies by orders of magnitude across the hierarchy, compared to modest variation in the mouse brain. Together, these results suggest that ND computed on cellular-level neural recordings can be a useful tool highlighting cell populations that may be involved in subjective perception. SummaryAdvances in our understanding on neural coding has revealed that information about visual stimuli is represented across several brain regions. However, availability of information does not imply that it is necessarily utilized by the brain, much less that it is subjectively perceived. Since percepts originate in neural activity, distinct percepts must be associated with distinct states of neural activity, at least within the brain region that supports the percepts. Thus, one approach developed in this direction is to quantify the number of distinct states that the activity of the brain goes through, called neurophysiological differentiation (ND). ND of the entire brain has been shown to reflect subjective reports of visual stimulus meaningfulness. But what specific subpopulations within the brain could be supporting conscious perception, and what is the correct timescale on which states should be quantified? In this study, we analyze ND of spiking neural activity in the mouse visual cortex recorded using Neuropixels probes, allowing us to characterize the ND metric across a wide range of timescales all the way down from 5 ms to a few seconds. It also allows us to understand the ND of neural activity of different ensembles of neurons, from individual thalamic or cortical ensembles to those spanning across multiple visual areas in the mouse brain.

neuroscience↗

bioRxiv2021

Backward masking in mice requires visual cortex

Visual masking is used to infer the timescale of conscious perception in humans; yet the underlying circuit mechanisms are not understood. Here we describe a two-alternative choice backward masking task in mice and humans, in which the location of a briefly presented grating is effectively masked within a 50 ms window after stimulus onset. Importantly, human subjects reported reduced perceptual visibility during masking that closely corresponded with behavior deficits. In mice, optogenetic silencing of visual cortex reduces performance over a similar time course as masking. However, response rates and accuracy do not match masking, demonstrating that cortical silencing and masking are distinct phenomena. Spiking responses recorded in primary visual cortex (V1) are consistent with masked behavior when quantified over long, but not short, time windows, indicating masking involves further downstream processing. Behavioral performance can be quantitatively recapitulated by a dual accumulator model constrained by V1 activity. The model and the animals performance for the earliest decisions imply that the initial spike arriving from the periphery can trigger a correct response, but subsequent V1 spikes, evoked by the mask, degrade performance for longer decisions. To test the necessity of visual cortex for backward masking, we optogenetically silenced mask-evoked cortical activity which fully restored discrimination of target location. Together, these results demonstrate that mice, like humans, are susceptible to backward visual masking and that visual cortex has a crucial role in this process.

neuroscience↗

bioRxiv2021

L-DOPA enhances hippocampal directionsignals in younger and older adults

Previous studies indicate a role of dopamine in hippocampus-dependent spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a DA precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved in the hippocampus and the retrosplenial cortex following L-DOPA administration. This suggests that DA enhances the specificity of neural representations of walking direction in these areas. In the hippocampus these results were found in both age groups, while in the RSC they were only observed in younger adults. Taken together, our study provides evidence for a mechanistic link between DA and the specificity of neural responses during spatial navigation. Significance StatementThe sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someones true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.

neuroscience↗

bioRxiv2021

CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

CD19-targeted CAR therapies have successfully treated B cell leukemias and lymphomas, but many responders later relapse or experience toxicities. CAR intracellular domains (ICDs) are key to converting antigen recognition into anti-tumor effector functions. Despite the many possible immune signaling domain combinations that could be included in CARs, almost all CARs currently rely upon CD3{zeta}, CD28, and/or 4-1BB signaling. To explore the signaling potential of CAR ICDs, we generated a library of 700,000 CD19 CAR molecules with diverse signaling domains and developed a high throughput screening platform to enable optimization of CAR signaling for anti-tumor functions. Our strategy identifies CARs with novel signaling domain combinations that elicit distinct T cell behaviors from a clinically available CAR, including enhanced proliferation and persistence, lower exhaustion, potent cytotoxicity in an in vitro tumor rechallenge condition, and comparable tumor control in vivo. This approach is readily adaptable to numerous disease models, cell types, and selection conditions, making it a promising tool for rapidly improving adoptive cell therapies and expanding their utility to new disease indications.

immunology↗

bioRxiv2021

Integrative biology defines novel biomarkers of resistance to strongylid infection in horses

The widespread failure of anthelmintic drugs against nematodes of veterinary interest requires novel control strategies. Selective treatment of the most susceptible individuals could reduce drug selection pressure but requires appropriate biomarkers of the intrinsic susceptibility potential. To date, this has been missing in livestock species. Here, we selected Welsh ponies with divergent intrinsic susceptibility to cyathostomin infection and found that their potential was sustained across a 10-year time window. Using this unique set of individuals, we monitored variations in their blood cell populations, plasma metabolites and faecal microbiota over a grazing season to isolate core differences between their respective responses under worm-free or natural infection conditions. Our analyses identified the concomitant rise in plasmatic phenylalanine level and faecal Prevotella abundance and the reduction in circulating monocyte counts as biomarkers of the need for drug treatment. This biological signal was replicated in other independent populations. We also unravelled an immunometabolic network encompassing plasmatic beta-hydroxybutyrate level, short-chain fatty acid producing bacteria and circulating neutrophils that forms the discriminant baseline between susceptible and resistant individuals. Altogether our observations open new perspectives on the susceptibility of equids to cyathostomin infection and leave scope for both new biomarkers of infection and nutritional intervention.

systems biology↗

bioRxiv2021

Anterior claustrum cells are responsive during behavior but not passive sensory stimulation

The claustrum is uniquely positioned to communicate with almost all higher-order cortical areas through widespread and reciprocal anatomical projections, yet the in vivo functional properties of claustrum neurons are not well understood. Here we use microendoscope imaging in mice to measure activity in populations of genetically-labelled Gnb4+ claustrum neurons. We find that only a small fraction of cells in the anterior claustrum are responsive to visual or auditory stimuli when delivered under passive yet wakeful conditions. In contrast, during a visual behavioral task, the majority of cells in the anterior claustrum are strongly modulated, with separate and spatially intermingled cell populations showing either increases or decreases in activity relative to spontaneous levels. Our results suggest that the Gnb4+ cells in the anterior claustrum do not represent passively presented sensory stimuli; rather, these cells are strongly engaged during behavior associated with sensory-motor transformations.

neuroscience↗

bioRxiv2021

Memory CD8+ T cells mediate early pathogen-specific protection through localized delivery of chemokines and IFNγ to clusters of inflammatory monocytes

While cognate antigen drives clonal expansion of memory CD8+ T cells to achieve sterilizing immunity in immunized hosts, not much is known on how cognate antigen contributes to early mechanisms of protection before clonal expansion occurs. Herein, using distinct models of immunization, we establish that cognate antigen recognition by CD8+ TM cells on dendritic cells initiates their rapid and coordinated production of a burst of CCL3, CCL4 and XCL1 chemokines under the transcriptional control of IRF4. Using intravital microscopy imaging and in vivo monoclonal antibody labelling, we reveal that memory CD8+ T cells undergo antigen-mediated arrest in splenic red pulp clusters of CCR2+ monocytes where they locally deliver both IFN{gamma}- and chemokine-potentiating microbicidal activities to achieve early protection. Thus, rapid and effective memory CD8+ T cell responses require a complex series of spatially and temporally coordinated stepwise molecular and cellular events that quickly restrict microbial pathogen growth and optimize the local delivery of effector molecules before clonal expansion occurs.

immunology↗

bioRxiv2020

Measuring stimulus-evoked neurophysiological differentiation in distinct populations of neurons in mouse visual cortex

Despite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis--quantifying distinct patterns of neurophysiological activity--is an "inside out" approach that addresses this question. We used two-photon calcium imaging in mice to systematically survey stimulus-evoked neurophysiological differentiation in excitatory populations across 3 cortical layers (L2/3, L4, and L5) in each of 5 visual cortical areas (primary, lateral, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater neurophysiological differentiation than scrambled stimuli specifically in L2/3 of the anterolateral and anteromedial areas, and that this effect is modulated by arousal state and locomotion. Contrariwise, decoding performance was far above chance and did not vary substantially across areas and layers. Differentiation also differed within the unscrambled stimulus set, suggesting that differentiation analysis may be used to probe the ethological relevance of individual stimuli.

neuroscience↗

bioRxiv2020

Single-cell RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates and humans

Abundant anatomical and physiological evidence supports the presence of at least three distinct types of relay glutamatergic neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex. Relay neuron diversity has also been described in the mouse dLGN (also known as LGd). Different types of relay neurons in mice, humans and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to other cellular properties and differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of relay neurons in the primate dLGN, magnocellular neurons, parvocellular neurons, and two cell types expressing canonical marker genes for koniocellular neurons. Surprisingly, despite extensive documented morphological and physiological differences between magno- and parvocellular neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. We also detected strong donor-specific gene expression signatures in both macaque and human relay neurons. Likewise, the dominant feature of relay neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to striking differences in morphology and cortical projection targets. Finally, we align cellular expression profiles across species and find homologous types of relay neurons in macaque and human, and distinct relay neurons in mouse.

neuroscience↗

bioRxiv2020

Signature morpho-electric, transcriptomic, and dendritic properties of extratelencephalic-projecting human layer 5 neocortical pyramidal neurons

In the neocortex, subcerebral axonal projections originate largely from layer 5 (L5) extratelencephalic-projecting (ET) neurons. The highly distinctive morpho-electric properties of these neurons have mainly been described in rodents, where ET neurons can be labeled by retrograde tracers or transgenic lines. Similar labeling strategies are not possible in the human neocortex, rendering the translational relevance of findings in rodents unclear. We leveraged the recent discovery of a transcriptomically-defined L5 ET neuron type to study the properties of human L5 ET neurons in neocortical brain slices derived from neurosurgeries. Patch-seq recordings, where transcriptome, physiology and morphology are assayed from the same cell, revealed many conserved morpho-electric properties of human and rodent L5 ET neurons. Divergent properties were also apparent but were often smaller than differences between cell types within these two species. These data suggest a conserved function of L5 ET neurons in the neocortical hierarchy, but also highlight marked phenotypic divergence possibly related to functional specialization of human neocortex.

neuroscience↗

bioRxiv2020

Removing independent noise in systems neuroscience data using DeepInterpolation

Progress in nearly every scientific discipline is hindered by the presence of independent noise in spatiotemporally structured datasets. Three widespread technologies for measuring neural activity--calcium imaging, extracellular electrophysiology, and fMRI--all operate in domains in which shot noise and/or thermal noise deteriorate the quality of measured physiological signals. Current denoising approaches sacrifice spatial and/or temporal resolution to increase the Signal-to-Noise Ratio of weak neuronal events, leading to missed opportunities for scientific discovery. Here, we introduce DeepInterpolation, a general-purpose denoising algorithm that trains a spatio-temporal nonlinear interpolation model using only noisy samples from the original raw data. Applying DeepInterpolation to in vivo two-photon Ca2+ imaging yields up to 6 times more segmented neuronal segments with a 15 fold increase in single pixel SNR, uncovering network dynamics at the single-trial level. In extracellular electrophysiology recordings, DeepInterpolation recovered 25% more high-quality spiking units compared to a standard data analysis pipeline. On fMRI datasets, DeepInterpolation increased the SNR of individual voxels 1.6-fold. All these improvements were attained without sacrificing spatial or temporal resolution. DeepInterpolation could well have a similar impact in other domains for which independent noise is present in experimental data.

neuroscience↗