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Koch, C.

Publications and source records attributed to Koch, C..

10 recordsLinked to original sources
bioRxiv2018

High-density extracellular probes reveal dendritic backpropagation and facilitate neuron classification

Different neuron types serve distinct roles in neural processing. Extracellular electrical recordings are extensively used to study brain function but are typically blind to cell identity. Morpho-electric properties of neurons measured on spatially dense electrode arrays might be useful for distinguishing neuron types. Here we used Neuropixels probes to record from cortical and subcortical regions of the mouse brain. Extracellular waveforms of each neuron were detected across many channels and showed distinct spatiotemporal profiles among brain regions. Classification of neurons by brain region was improved with multi-channel compared to single-channel waveforms. In visual cortex, waveform clustering identified the canonical regular spiking (RS) and fast spiking (FS) classes, but also uncovered a subclass of RS units with unidirectional backpropagating action potentials (BAPs). Moreover, BAPs were observed in many hippocampal RS cells. Overall, waveform analysis of spikes from high-density probes aids neuron identification and can reveal dendritic backpropagation.

neuroscience↗
bioRxiv2018

A robust ex vivo experimental platform for molecular-genetic dissection of adult human neocortical cell types and circuits

The powerful suite of available genetic tools is driving tremendous progress in understanding mouse brain cell types and circuits. However, the degree of conservation in human remains largely unknown in large part due to the lack of such tools and healthy tissue preparations. To close this gap, we describe a robust and stable adult human neurosurgically-derived ex vivo acute and cultured neocortical brain slice system optimized for rapid molecular-genetic manipulation. Surprisingly, acute human brain slices exhibited exceptional viability, and neuronal intrinsic membrane properties could be assayed for at least three days. Maintaining adult human slices in culture under sterile conditions further enabled the application of viral tools to drive rapid expression of exogenous transgenes. Widespread neuron-specific labeling was achieved as early as two days post infection with HSV-1 vectors, with virally-transduced neurons exhibiting membrane properties largely comparable to uninfected neurons over this short timeframe. Finally, we demonstrate the suitability of this culture paradigm for optical manipulation and monitoring of neuronal activity using genetically encoded probes, opening a path for applying modern molecular-genetic tools to study human brain circuit function.

neuroscience↗
bioRxiv2018

h-channels contribute to divergent electrophysiological properties of supragranular pyramidal neurons in human versus mouse cerebral cortex

Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single cell/nucleus RNA sequencing revealed ubiquitous HCN1-subunit expression in excitatory neurons in human, but not mouse supragranular layers. Using patch-clamp recordings, we found stronger h-channel-related membrane properties in supragranular pyramidal neurons in human temporal cortex, compared to mouse supragranular pyramidal neurons in temporal association area. The magnitude of these differences depended upon cortical depth and was largest in pyramidal neurons in deep L3. Additionally, pharmacologically blocking h-channels produced a larger change in membrane properties in human compared to mouse neurons. Finally, using biophysical modeling, we provided evidence that h-channels promote the transfer of theta frequencies from dendrite-to-soma in human L3 pyramidal neurons. Thus, h-channels contribute to between-species differences in a fundamental neuronal property.

neuroscience↗
bioRxiv2018

Sparse recurrent excitatory connectivity in the cortical microcircuit of the adult mouse and human

Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, the Allen Institute is engaged in a pipeline project using multipatch electrophysiology, supplemented with 2-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell types and layers we sampled, with the most sparse connections in layers 5 and 6. Almost all mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons; however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits.

neuroscience↗
bioRxiv2018

The organization of intracortical connections by layer and cell class in the mouse brain

The mammalian cortex is a laminar structure composed of many cell types densely interconnected in complex ways. Recent systematic efforts to map the mouse mesoscale connectome provide comprehensive projection data on interareal connections, but not at the level of specific cell classes or layers within cortical areas. We present here a significant expansion of the Allen Mouse Brain Connectivity Atlas, with [~]1,000 new axonal projection mapping experiments across nearly all isocortical areas in 49 Cre driver lines. Using 13 lines selective for cortical layer-specific projection neuron classes, we identify the differential contribution of each layer/class to the overall intracortical connectivity patterns. We find layer 5 (L5) projection neurons account for essentially all intracortical outputs. L2/3, L4, and L6 neurons contact a subset of the L5 cortical targets. We also describe the most common axon lamination patterns in cortical targets. Most patterns are consistent with previous anatomical rules used to determine hierarchical position between cortical areas (feedforward, feedback), with notable exceptions. While diverse target lamination patterns arise from every source layer/class, L2/3 and L4 neurons are primarily associated with feedforward type projection patterns and L6 with feedback. L5 has both feedforward and feedback projection patterns. Finally, network analyses revealed a modular organization of the intracortical connectome. By labeling interareal and intermodule connections as feedforward or feedback, we present an integrated view of the intracortical connectome as a hierarchical network.

neuroscience↗
bioRxiv2018

Visual physiology of the Layer 4 cortical circuit in silico

Despite advances in experimental techniques and accumulation of large datasets concerning the composition and properties of the cortex, quantitative modeling of cortical circuits under in-vivo-like conditions remains challenging. Here we report and publicly release a biophysically detailed circuit model of layer 4 in the mouse primary visual cortex, receiving thalamo-cortical visual inputs. The 45,000-neuron model was subjected to a battery of visual stimuli, and results were compared to published work and new in vivo experiments. Simulations reproduced a variety of observations, including effects of optogenetic perturbations. Critical to the agreement between responses in silico and in vivo were the rules of functional synaptic connectivity between neurons. Interestingly, after extreme simplification the model still performed satisfactorily on many measurements, although quantitative agreement with experiments suffered. These results emphasize the importance of functional rules of cortical wiring and enable a next generation of data-driven models of in vivo neural activity and computations.\n\nAUTHOR SUMMARYHow can we capture the incredible complexity of brain circuits in quantitative models, and what can such models teach us about mechanisms underlying brain activity? To answer these questions, we set out to build extensive, bio-realistic models of brain circuitry employing systematic datasets on brain structure and function. Here we report the first modeling results of this project, focusing on the layer 4 of the primary visual cortex (V1) of the mouse. Our simulations reproduced a variety of experimental observations in a large battery of visual stimuli. The results elucidated circuit mechanisms determining patters of neuronal activity in layer 4 - in particular, the roles of feedforward thalamic inputs and specific patterns of intracortical connectivity in producing tuning of neuronal responses to the orientation of motion. Simplification of neuronal models led to specific deficiencies in reproducing experimental data, giving insights into how biological details contribute to various aspects of brain activity. To enable future development of more sophisticated models, we make the software code, the model, and simulation results publicly available.

neuroscience↗
bioRxiv2017

Metagenomic signature of natural strongyle infection in susceptible and resistant horses

Gastrointestinal strongyles are a major threat to horses' health and welfare. Given that strongyles inhabit the same niche as the gut microbiota, they may interact with each other. These beneficial or detrimental interactions are unknown in horses and could partly explain contrasted susceptibility to infection between individuals. To address these questions, an experimental pasture trial with 20 worm-free female Welsh ponies (10 susceptible (S) and 10 resistant (R) to parasite infection) was implemented for five months. Fecal egg counts (FEC), hematological and biochemical data, body weight and gut microbiota composition were studied in each individual after 0, 24, 43, 92 and 132 grazing days.\n\nThe predicted R ponies exhibited lower FEC after 92 and 132 grazing days, and showed higher levels of circulating monocytes and eosinophils, while S ponies developed lymphocytosis by the end of the trial. Although the overall microbiota diversity remained similar between the two groups, R and S ponies exhibited sustained differential abundances in Clostridium XIVa, Ruminococcus, Acetivibrio and unclassified Lachnospiracea at day 0. These bacteria may hence contribute to the intrinsic pony resistance towards strongyle infection. Moreover, Paludibacter, Campylobacter, Bacillus, Pseudomonas, Clostridium III, Acetivibrio, members of the unclassified Eubacteriaceae and Ruminococcaceae and fungi loads were increased in infected S ponies, suggesting that strongyle and fungi may contribute to each others success in the ecological niche of the equine intestines. In contrast, butyrate-producing bacteria such as Ruminococcus, Clostridium XIVa and members of the Lachnospiraceae family decreased in S relative to R ponies. Additionally, these gut microbiota alterations induced changes in several immunological pathways in S ponies, including pathogen sensing, lipid metabolism, and activation of signal transduction that are critical for the regulation of immune system and energy homeostasis. These observations shed light on a putative implication of the gut microbiota in the intrinsic resistance to strongyle infection.\n\nOverall, this longitudinal study provides a foundation to better understand the mechanisms that underpin the relationship between host susceptibility to strongyle infection, immune response and gut microbiota under natural conditions in horses and should contribute to the development of novel biomarkers of strongyle susceptibility and provide additional control options.

systems biology↗
bioRxiv2017

Generalized Leaky Integrate-And-Fire Models Classify Multiple Neuron Types

In the mammalian neocortex, there is a high diversity of neuronal types. To facilitate construction of system models with multiple cell types, we generate a database of point models associated with the Allen Cell Types Database. We construct a series of generalized integrate-and-fire (GLIF) models of increasing complexity aiming to reproduce the spiking behaviors of the recorded neurons. We test the performance of these GLIF models on data from 771 neurons from 14 transgenic lines, with increasing model performance for more complex models. To answer how complex a model needs to be to reproduce the number of electrophysiological cell types, we perform unsupervised clustering on the parameters extracted from these models. The number of clusters is smaller for individual model types, but when combining all GLIF parameters 18 clusters are obtained, while 11 clusters are obtained using 16 electrophysiological features. Therefore, these low dimensional models have the capacity to characterize the diversity of cell types without the need for a priori defined features.

neuroscience↗
bioRxiv2017

Neural precursors of decisions that matter--an ERP study of deliberate and arbitrary choice

The readiness potential (RP)--a key ERP correlate of upcoming action--is known to precede subjects reports of their decision to move. Some view this as evidence against a causal role for consciousness in human decision-making and thus against free-will. Yet those studies focused on arbitrary decisions--purposeless, unreasoned, and without consequences. It remains unknown to what degree the RP generalizes to deliberate, more ecological decisions. We directly compared deliberate and arbitrary decision-making during a $1000-donation task to non-profit organizations. While we found the expected RPs for arbitrary decisions, they were strikingly absent for deliberate ones. Our results and drift-diffusion model are congruent with the RP representing accumulation of noisy, random fluctuations that drive arbitrary--but not deliberate--decisions. They further point to different neural mechanisms underlying deliberate and arbitrary decisions, challenging the generalizability of studies that argue for no causal role for consciousness in decision-making to real-life decisions.\n\nSignificance StatementThe extent of human free will has been debated for millennia. Previous studies demonstrated that neural precursors of action--especially the readiness potential--precede subjects reports of deciding to move. Some viewed this as evidence against free-will. However, these experiments focused on arbitrary decisions--e.g., randomly raising the left or right hand. We directly compared deliberate (actual $1000 donations to NPOs) and arbitrary decisions, and found readiness potentials before arbitrary decisions, but--critically--not before deliberate decisions. This supports the interpretation of readiness potentials as byproducts of accumulation of random fluctuations in arbitrary but not deliberate decisions and points to different neural mechanisms underlying deliberate and arbitrary choice. Hence, it challenges the generalizability of previous results from arbitrary to deliberate decisions.

neuroscience↗