@article{Girardi2023,
title = {Cultured Vagal Afferent Neurons as Sensors for Intestinal Effector Molecules},
author = {Gregory Girardi and Danielle Zumpano and Noah Goshi and Helen Raybould and Erkin Seker},
url = {https://www.mdpi.com/2079-6374/13/6/601},
doi = {10.3390/bios13060601},
year = {2023},
date = {2023-05-31},
journal = {biosensors},
abstract = {The gut–brain axis embodies the bi-directional communication between the gastrointestinal tract and the central nervous system (CNS), where vagal afferent neurons (VANs) serve as sensors for a variety of gut-derived signals. The gut is colonized by a large and diverse population of microorganisms that communicate via small (effector) molecules, which also act on the VAN terminals situated in the gut viscera and consequently influence many CNS processes. However, the convoluted in vivo environment makes it difficult to study the causative impact of the effector molecules on VAN activation or desensitization. Here, we report on a VAN culture and its proof-of-principle demonstration as a cell-based sensor to monitor the influence of gastrointestinal effector molecules on neuronal behavior. We initially compared the effect of surface coatings (poly-L-lysine vs. Matrigel) and culture media composition (serum vs. growth factor supplement) on neurite growth as a surrogate of VAN regeneration following tissue harvesting, where the Matrigel coating, but not the media composition, played a significant role in the increased neurite growth. We then used both live-cell calcium imaging and extracellular electrophysiological recordings to show that the VANs responded to classical effector molecules of endogenous and exogenous origin (cholecystokinin serotonin and capsaicin) in a complex fashion. We expect this study to enable platforms for screening various effector molecules and their influence on VAN activity, assessed by their information-rich electrophysiological fingerprints.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Bartram2023b,
title = {Parallel reconstruction of the excitatory and inhibitory inputs received by single neurons reveals the synaptic basis of recurrent spiking},
author = {Julian Bartram and Felix Franke and Sreedhar Saseendran Kumar and Alessio Paolo Buccino and Xiaohan Xue and Tobias Gänswein and Manuel Schröter and Taehoon Kim and Krishna Chaitanya Kasuba and Andreas Hierlemann},
url = {https://elifesciences.org/reviewed-preprints/86820},
doi = {10.7554/eLife.86820},
year = {2023},
date = {2023-05-17},
journal = {eLife},
abstract = {Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. Yet, the precise relationship between the synaptic input patterns and the spiking output of individual neurons remains largely unresolved. Here, we developed, validated and applied a novel in vitro experimental platform and analytical procedures that provide – for individual neurons – simultaneous excitatory and inhibitory synaptic activity estimates during recurrent network activity. Our approach combines whole-network high-density microelectrode array (HD-MEA) recordings from rat neuronal cultures with patch clamping and enables a comprehensive mapping and characterization of active incoming connections to single postsynaptic neurons. We found that, during network states with excitation(E)-inhibition(I) balance, postsynaptic spiking coincided precisely with the maxima of fast fluctuations in the input E/I ratio. These spike-associated E/I ratio escalations were largely due to a rapid bidirectional change in synaptic inhibition that was modulated by the network-activity level. Our approach also uncovered the underlying circuit architecture and we show that individual neurons received a few key inhibitory connections – often from special hub neurons – that were instrumental in controlling postsynaptic spiking. Balanced network theory predicts dynamical regimes governed by small and rapid input fluctuation and featuring a fast neuronal responsiveness. Our findings – obtained in self-organized neuronal cultures – suggest that the emergence of these favorable regimes and associated network architectures is an inherent property of cortical networks in general.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Duru2023,
title = {Investigation of the input-output relationship of engineered neural networks using high-density microelectrode arrays},
author = {Jens Duru and Benedikt Maurer and Ciara Giles Doran and Robert Jelitto and Joël Küchler and Stephan J. Ihle and Tobias Ruff and Robert John and Barbara Genocchi and János Vörös},
url = {https://www.ssrn.com/abstract=4427959},
doi = {DOI: 10.2139/ssrn.4427959},
year = {2023},
date = {2023-04-24},
journal = {SSRN},
abstract = {Bottom-up neuroscience utilizes small, engineered biological neural networks to study neuronal activity in systems of reduced complexity. We present a platform that establishes up to six independent networks formed by primary rat neurons on planar complementary metal–oxide–semiconductor (CMOS) microelectrode arrays (MEAs). We introduce an approach that allows repetitive stimulation and recording of network activity at any of the over 700 electrodes underlying a network. We demonstrate that the continuous application of a repetitive super-threshold stimulus yields a reproducible network answer within a 15 ms post-stimulus window. This response can be tracked with high spatiotemporal resolution across the whole extent of the network. Moreover, we show that the location of the stimulation plays a significant role in the networks’ early response to the stimulus. By applying a stimulation pattern to all network-underlying electrodes in sequence, the sensitivity of the whole network to the stimulus can be visualized. We demonstrate that microchannels reduce the voltage stimulation threshold and induce the strongest network response. By varying the stimulation amplitude and frequency we reveal discrete network transition points. Finally, we introduce vector fields to follow stimulation-induced spike propagation pathways within the network. Overall we show that our defined neural networks on CMOS MEAs enable us to elicit highly reproducible activity patterns that can be precisely modulated by stimulation amplitude, stimulation frequency and the site of stimulation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Xu2023,
title = {Generation of functional posterior spinal motor neurons from hPSCs-derived human spinal cord neural progenitor cells},
author = {He Jax Xu and Yao Yao and Fenyong Yao and Jiehui Chen and Meishi Li and Xianfa Yang and Sheng Li and Fangru Lu and Ping Hu and Shuijin He and Guangdun Peng and Naihe Jing},
url = {https://cellregeneration.springeropen.com/articles/10.1186/s13619-023-00159-6},
doi = {10.1186/s13619-023-00159-6},
year = {2023},
date = {2023-03-23},
journal = {Cell Regeneration},
abstract = {Spinal motor neurons deficiency results in a series of devastating disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal cord injury (SCI). These disorders are currently incurable, while human pluripotent stem cells (hPSCs)-derived spinal motor neurons are promising but suffered from inappropriate regional identity and functional immaturity for the study and treatment of posterior spinal cord related injuries. In this study, we have established human spinal cord neural progenitor cells (hSCNPCs) via hPSCs differentiated neuromesodermal progenitors (NMPs) and demonstrated the hSCNPCs can be continuously expanded up to 40 passages. hSCNPCs can be rapidly differentiated into posterior spinal motor neurons with high efficiency. The functional maturity has been examined in detail. Moreover, a co-culture scheme which is compatible for both neural and muscular differentiation is developed to mimic the neuromuscular junction (NMJ) formation in vitro. Together, these studies highlight the potential avenues for generating clinically relevant spinal motor neurons and modeling neuromuscular diseases through our defined hSCNPCs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Cai2023,
title = {Brain Organoid Computing for Artificial Intelligence},
author = {Hongwei Cai and Zheng Ao and Chunhui Tian and Zhuhao Wu and Hongcheng Liu and Jason Tchieu and Mingxia Gu and Ken Mackie and and Feng Guo},
url = {https://www.biorxiv.org/content/10.1101/2023.02.28.530502v1},
doi = {10.1101/2023.02.28.530502},
year = {2023},
date = {2023-03-01},
journal = {bioRxiv},
abstract = {Brain-inspired hardware emulates the structure and working principles of a biological brain and may address the hardware bottleneck for fast-growing artificial intelligence (AI). Current brain-inspired silicon chips are promising but still limit their power to fully mimic brain function for AI computing. Here, we develop Brainoware, living AI hardware that harnesses the computation power of 3D biological neural networks in a brain organoid. Brain-like 3D in vitro cultures compute by receiving and sending information via a multielectrode array. Applying spatiotemporal electrical stimulation, this approach not only exhibits nonlinear dynamics and fading memory properties but also learns from training data. Further experiments demonstrate real-world applications in solving non-linear equations. This approach may provide new insights into AI hardware.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Qian2023,
title = {Multiplex epigenome editing of MECP2 to rescue Rett syndrome neurons},
author = {Junming Qian and Xiaonan Guan and Bing Xie and Chuanyun Xu and Jacqueline Niu and Xin Tang and Charles H. Li and Henry M. Colecraft and Rudolf Jaenisch and X. Shawn Liu},
url = {https://www.science.org/doi/10.1126/scitranslmed.add4666},
doi = {10.1126/scitranslmed.add4666},
year = {2023},
date = {2023-01-18},
journal = {Science Translational Medicine},
abstract = {Rettsyndrome(RTT)isanX-linkedneurodevelopmental disorder caused byloss-of-function heterozygous mutationsofmethyl CpG-binding protein2(MECP2) ontheXchromosome inyoungfemales. Reactivationofthe silent wild-type MECP2 allelefromtheinactiveXchromosome (Xi)represents apromising therapeutic opportunity forfemale patients withRTT.Here,weapplied amultiple xepigenome editing approachtoreactivate MECP2 fromXiinRTThuman embryonicstemcells(hESCs) andderivedneurons.Demethyla tionofthe MECP2 promoter bydCas9-T et1withtarget single-guide RNAreactivatedMECP2 fromXiinRTThESCs without detectable off-target effects atthetranscriptional level.Neuronsderivedfrommethyla tion-edited RTThESCs maintained MECP2 reactivationandreversedthesmaller somasizeandelectrophysiological abnormalities, twohallmarks ofRTT.InRTTneurons,insulationofthemethyla tion-edited MECP2 locusbydCpf1-CT CF (acatalytically deadCpf1fusedwithCCCTC-binding factor)withtarget CRISPR RNAenhanced MECP2 reactivationandrescued RTT-relatedneuronaldefects, providing aproof-of-concept studyforepigenome editing to treatRTTandpotentially otherdominant X-linkeddiseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Bartram2023,
title = {Parallel reconstruction of the excitatory and inhibitory inputs received by single neurons reveals the synaptic basis of recurrent spiking},
author = {Julian Bartram and Felix Franke and Sreedhar Saseendran Kumar and Alessio Paolo Buccino and Xiaohan Xue and Tobias Gänswein and Manuel Schröter and Taehoon Kim and Krishna Chaitanya Kasuba and Andreas Hierlemann},
url = {https://www.biorxiv.org/content/10.1101/2023.01.06.523018v2},
doi = {https://doi.org/10.1101/2023.01.06.523018},
year = {2023},
date = {2023-01-08},
journal = {bioRxiv},
abstract = {Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. However, the precise relationship between synaptic input patterns and spiking output of individual neurons remains unresolved during spontaneous network activity. Here, using whole-network high-density microelectrode array (HD-MEA) recordings and patch clamping, we developed a novel experimental approach and analytical tools that provide a comprehensive long-term input-output characterization of individual neurons in cortical cell cultures. We found that, during in vivo-like network activity with excitation(E)-inhibition(I) balance, postsynaptic spiking coincided with the maxima of rapid, network state-dependent fluctuations in the input E/I ratio. Our approach also uncovered the underlying circuit architecture and we identified a few key inhibitory inputs – often from special hub neurons – that were instrumental in mediating these E/I ratio changes. Balanced network theory predicts dynamical regimes governed by input fluctuation and featuring a fast neuronal responsiveness. Our findings – obtained in self-organized neuronal cultures – suggest that the emergence of these favorable regimes and associated network architectures is an inherent property of all cortical networks.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Han2022,
title = {A functional neuron maturation device provides convenient application on microelectrode array for neural network measurement},
author = {Xiaobo Han and Naoki Matsuda and Yuto Ishibashi and Aoi Odawara and Sayuri Takahashi and Norie Tooi and Koshi Kinoshita and Ikuro Suzuki },
url = {https://biomaterialsres.biomedcentral.com/articles/10.1186/s40824-022-00324-z},
doi = {https://doi.org/10.1186/s40824-022-00324-z},
year = {2022},
date = {2022-12-20},
journal = {Biomaterials Research},
abstract = {Background
Microelectrode array (MEA) systems are valuable for in vitro assessment of neurotoxicity and drug efficiency. However, several difficulties such as protracted functional maturation and high experimental costs hinder the use of MEA analysis requiring human induced pluripotent stem cells (hiPSCs). Neural network functional parameters are also needed for in vitro to in vivo extrapolation.

Methods
In the present study, we produced a cost effective nanofiber culture platform, the SCAD device, for long-term culture of hiPSC-derived neurons and primary peripheral neurons. The notable advantage of SCAD device is convenient application on multiple MEA systems for neuron functional analysis.

Results
We showed that the SCAD device could promote functional maturation of cultured hiPSC-derived neurons, and neurons responded appropriately to convulsant agents. Furthermore, we successfully analyzed parameters for in vitro to in vivo extrapolation, i.e., low-frequency components and synaptic propagation velocity of the signal, potentially reflecting neural network functions from neurons cultured on SCAD device. Finally, we measured the axonal conduction velocity of peripheral neurons. Conclusions: Neurons cultured on SCAD devices might constitute a reliable in vitro platform to investigate neuron functions, drug efficacy and toxicity, and neuropathological mechanisms by MEA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{McSweeney2022b,
title = {CASK loss of function differentially regulates neuronal maturation and synaptic function in human induced cortical excitatory neurons},
author = {Danny McSweeney and Rafael Gabriel and Kang Jin and Zhiping P. Pang and Bruce Aronow and and ChangHui Pak},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(22)01459-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004222014596%3Fshowall%3Dtrue},
doi = {https://doi.org/10.1016/j.isci.2022.105187},
year = {2022},
date = {2022-10-21},
journal = {iScience},
abstract = {Loss-of-function (LOF) mutations in CASK cause severe developmental pheno- types, including microcephaly with pontine and cerebellar hypoplasia, X-linked in- tellectual disability, and autism. Unraveling the pathological mechanisms of CASK-related disorders has been challenging owing to limited human cellular models to study the dynamic roles of this molecule during neuronal maturation and synapse development. Here, we investigate cell-autonomous functions of CASK in cortical excitatory induced neurons (iNs) generated from CASK knockout (KO) isogenic human embryonic stem cells (hESCs) using gene expression, mor- phometrics, and electrophysiology. While immature CASK KO iNs show robust neuronal outgrowth, mature CASK KO iNs display severe defects in syn- aptic transmission and synchronized network activity without compromising neuronal morphology and synapse numbers. In the developing human cortical excitatory neurons, CASK functions to promote both structural integrity and establishment of cortical excitatory neuronal networks. These results lay the foundation for future studies identifying suppressors of such phenotypes rele- vant to human patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Kagan2022,
title = {In vitro neurons learn and exhibit sentience when embodied in a simulated game-world},
author = {Brett J. Kagan and Andy C. Kitchen and Nhi T. Tran and Forough Habibollahi and Moein Khajehnejad and Bradyn J. Parker and Anjali Bhat and Ben Rollo and Adeel Razi and Karl J. Friston},
url = {https://www.cell.com/neuron/fulltext/S0896-6273(22)00806-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627322008066%3Fshowall%3Dtrue#articleInformation},
doi = {https://doi.org/10.1016/j.neuron.2022.09.001},
year = {2022},
date = {2022-10-12},
journal = {Neuron},
abstract = {Integrating neurons into digital systems may enable performance infeasible with silicon alone. Here, we develop DishBrain, a system that harnesses the inherent adaptive computation of neurons in a structured environment. In vitro neural networks from human or rodent origins are integrated with in silico computing via a high-density multielectrode array. Through electrophysiological stimulation and recording, cultures are embedded in a simulated game-world, mimicking the arcade game ‘‘Pong.’’ Applying implications from the theory of active inference via the free energy principle, we find apparent learning within five minutes of real-time gameplay not observed in control conditions. Further experiments demonstrate the importance of closed-loop structured feedback in eliciting learning over time. Cultures display the ability to self-organize activity in a goal-directed manner in response to sparse sensory information about the consequences of their actions, which we term synthetic biological intelligence. Future applications may provide further insights into the cellular correlates of intelligence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Habibey2022,
title = {Long-term morphological and functional dynamics of human stem cell-derived neuronal networks on high-density micro-electrode arrays},
author = {Rouhollah Habibey and Johannes Striebel and Felix Schmieder and Jürgen Czarske and Volker Busskamp},
url = {https://www.frontiersin.org/articles/10.3389/fnins.2022.951964/full},
doi = {10.3389/fnins.2022.951964},
year = {2022},
date = {2022-10-04},
journal = {Frontiers in Neuroscience},
abstract = {Comprehensive electrophysiological characterizations of human induced pluripotent stem cell (hiPSC)-derived neuronal networks are essential to determine to what extent these in vitro models recapitulate the functional features of in vivo neuronal circuits. High-density micro-electrode arrays (HD-MEAs) offer non-invasive recording with the best spatial and temporal resolution possible to date. For 3 months, we tracked the morphology and activity features of developing networks derived from a transgenic hiPSC line in which neurogenesis is inducible by neurogenic transcription factor overexpression. Our morphological data revealed large-scale structural changes from homogeneously distributed neurons in the first month to the formation of neuronal clusters over time. This led to a constant shift in position of neuronal cells and clusters on HD-MEAs and corresponding changes in spatial distribution of the network activity maps. Network activity appeared as scarce action potentials (APs), evolved as local bursts with longer duration and changed to network-wide synchronized bursts with higher frequencies but shorter duration over time, resembling the emerging burst features found in the developing human brain. Instantaneous firing rate data indicated that the fraction of fast spiking neurons (150–600 Hz) increases sharply after 63 days post induction (dpi). Inhibition of glutamatergic synapses erased burst features from network activity profiles and confirmed the presence of mature excitatory neurotransmission. The application of GABAergic receptor antagonists profoundly changed the bursting profile of the network at 120 dpi. This indicated a GABAergic switch from excitatory to inhibitory neurotransmission during circuit development and maturation. Our results suggested that an emerging GABAergic system at older culture ages is involved in regulating spontaneous network bursts. In conclusion, our data showed that long-term and continuous microscopy and electrophysiology readouts are crucial for a meaningful characterization of morphological and functional maturation in stem cell-derived human networks. Most importantly, assessing the level and duration of functional maturation is key to subject these human neuronal circuits on HD-MEAs for basic and biomedical applications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Kumar2022,
title = {Tracking axon initial segment plasticity using high-density microelectrode arrays: A computational study},
author = {Sreedhar S. Kumar and Tobias Gänswein and Alessio P. Buccino and Xiaohan Xue and Julian Bartram and Vishalini Emmenegger and Andreas Hierlemann},
url = {https://www.frontiersin.org/articles/10.3389/fninf.2022.957255/full},
doi = {10.3389/fninf.2022.957255},
year = {2022},
date = {2022-10-03},
journal = {Frontiers in Neuroinformatics},
abstract = {Despite being composed of highly plastic neurons with extensive positive feedback, the nervous system maintains stable overall function. To keep activity within bounds, it relies on a set of negative feedback mechanisms that can induce stabilizing adjustments and that are collectively termed “homeostatic plasticity.” Recently, a highly excitable microdomain, located at the proximal end of the axon—the axon initial segment (AIS)—was found to exhibit structural modifications in response to activity perturbations. Though AIS plasticity appears to serve a homeostatic purpose, many aspects governing its expression and its functional role in regulating neuronal excitability remain elusive. A central challenge in studying the phenomenon is the rich heterogeneity of its expression (distal/proximal relocation, shortening, lengthening) and the variability of its functional role. A potential solution is to track AISs of a large number of neurons over time and attempt to induce structural plasticity in them. To this end, a promising approach is to use extracellular electrophysiological readouts to track a large number of neurons at high spatiotemporal resolution by means of high-density microelectrode arrays (HD-MEAs). However, an analysis framework that reliably identifies specific activity signatures that uniquely map on to underlying microstructural changes is missing. In this study, we assessed the feasibility of such a task and used the distal relocation of the AIS as an exemplary problem. We used sophisticated computational models to systematically explore the relationship between incremental changes in AIS positions and the specific consequences observed in simulated extracellular field potentials. An ensemble of feature changes in the extracellular fields that reliably characterize AIS plasticity was identified. We trained models that could detect these signatures with remarkable accuracy. Based on these findings, we propose a hybrid analysis framework that could potentially enable high-throughput experimental studies of activity-dependent AIS plasticity using HD-MEAs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Lee2022,
title = {Repeated and On-Demand Intracellular Recordings of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells},
author = {Jihyun Lee and Tobias Gänswein and Hasan Ulusan and Vishalini Emmenegger and Ardan M. Saguner and Firat Duru and and Andreas Hierlemann},
url = {https://pubs.acs.org/doi/10.1021/acssensors.2c01678},
doi = {https://doi.org/10.1021/acssensors.2c01678},
year = {2022},
date = {2022-09-27},
journal = {ACS Sensors},
abstract = {Pharmaceutical compounds may have cardiotoxic properties, triggering potentially life-threatening arrhythmi- as. To investigate proarrhythmic effects of drugs, the patch clamp technique has been used as the gold standard for charac- terizing the electrophysiology of cardiomyocytes in vitro. However, the applicability of this technology for drug screening is limited, as it is complex to use and features low throughput. Recent studies have demonstrated that 3D-nanostructured electrodes enable to obtain intracellular signals from many cardiomyocytes in parallel; however, the tedious electrode fab- rication and limited measurement duration still remain major issues for cardiotoxicity testing. Here, we demonstrate how porous Pt-black electrodes, arranged in high-density microelectrode arrays, can be used to record intracellular-like signals of cardiomyocytes at large-scale repeatedly over an extended period of time. The developed technique, which yields highly parallelized electroporations by using stimulation voltages around 1 Volt peak-to-peak amplitude, enabled intracellular-like recordings at high success rates without causing significant alteration in key electrophysiological features. In a proof of concept study, we investigated electrophysiological modulations induced by two clinically applied drugs, nifedipine and quinidine. As the obtained results were in good agreement with previously published data, we are confident that the devel- oped technique has the potential to be routinely used in in vitro platforms for cardiotoxicity screening.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Al-Absi2022,
title = {Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus},
author = {Abdel-Rahman Al-Absi and Sakeerthi Kethees Thambiappaa and Ahmad Raza Khanc and Simon Glerup and Connie Sanchez and Anne M. Landau and Jens R. Nyengaard},
url = {https://www.sciencedirect.com/science/article/pii/S1044743122000756?via%3Dihub},
doi = {https://doi.org/10.1016/j.mcn.2022.103769},
year = {2022},
date = {2022-08-18},
journal = {Molecular and Cellular Neuroscience},
abstract = {The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome.
We investigated the putative deficit of GABAA receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [3H]muscimol tracer revealed a significant reduction in GABAA receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67+ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electro- physiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABAA receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice.
Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABAA receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Buccino2022,
title = {A multi-modal fitting approach to construct single-neuron models with patch clamp and high-density microelectrode arrays},
author = {Buccino, Alessio Paolo; Damart, Tanguy; Bartram, Julian; Mandge, Darshan; Xue, Xiaohan; Zbili, Mickael; Gänswein, Tobias; Jaquier, Aurélien; Emmenegger, Vishalini; Markram, Henry; Hierlemann, Andreas; Van Geit, Werner.},
doi = {https://doi.org/10.1101/2022.08.03.502468},
year = {2022},
date = {2022-08-11},
journal = {bioRxiv},
abstract = {In computational neuroscience, multicompartment models are among the most biophysically realistic representations of single neurons. Constructing such models usually involves the use of the patch-clamp technique to record somatic voltage signals under different experimental conditions. The experimental data are then used to fit the many parameters of the model. While patching of the soma is currently the gold-standard approach to build multicompartment models, several studies have also evidenced a richness of dynamics in dendritic and axonal sections. Recording from the soma alone makes it hard to observe and correctly parameterize the activity of non-somatic compartments.

In order to provide a richer set of data as input to multicompartment models, we here investigate the combination of somatic patch-clamp recordings with recordings of high-density micro-electrode arrays (HD-MEAs). HD-MEAs enable the observation of extracellular potentials and neural activity of neuronal compartments at sub-cellular resolution.

In this work, we introduce a novel framework to combine patch-clamp and HD-MEA data to construct multicompartment models. We first validate our method on a ground-truth model with known parameters and show that the use of features extracted from extracellular signals, in addition to intracellular ones, yields models enabling better fits than using intracellular features alone. We also demonstrate our procedure using experimental data by constructing cell models from in vitro cell cultures.

The proposed multi-modal fitting procedure has the potential to augment the modeling efforts of the computational neuroscience community and to provide the field with neuronal models that are more realistic and can be better validated.

Author Summary Multicompartment models are one of the most biophysically detailed representations of single neurons. The vast majority of these models are built using experimental data from somatic recordings. However, neurons are much more than just their soma and one needs recordings from distal neurites to build an accurate model. In this article, we combine the patch-clamp technique with extracellular high-density microelectrode arrays (HD-MEAs) to compensate this shortcoming. In fact, HD-MEAs readouts allow one to record the neuronal signal in the entire axonal arbor. We show that the proposed multi-modal strategy is superior to the use of patch clamp alone using an existing model as ground-truth. Finally, we show an application of this strategy on experimental data from cultured neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Xue2022b,
title = {Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking},
author = {Xiaohan Xue and Alessio Paolo Buccino and Sreedhar Saseendran Kumar and Andreas Hierlemann and Julian Bartram},
doi = {https://doi.org/10.1088/1741-2552/ac8765},
year = {2022},
date = {2022-08-11},
journal = {Journal of Neural Engineering},
abstract = {Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays (HD-MEAs). We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. The proposed approach offers unique advantages as i) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, ii) it provides precise information of presynaptic spiking, and iii) postsynaptic spine Ca2+ signals and, finally, iv) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Idrees2022,
title = {Suppression without inhibition: how retinal computation contributes to saccadic suppression},
author = {Saad Idrees and Matthias-Philipp Baumann and Maria M. Korympidou and Timm Schubert and Alexandra Kling and Katrin Franke and Ziad M. Hafed and Felix Franke and Thomas A. Münch },
url = {https://www.nature.com/articles/s42003-022-03526-2},
year = {2022},
date = {2022-07-12},
journal = {Communications Biology},
abstract = {Visual perception remains stable across saccadic eye movements, despite the concurrent strongly disruptive visual flow. This stability is partially associated with a reduction in visual sensitivity, known as saccadic suppression, which already starts in the retina with reduced ganglion cell sensitivity. However, the retinal circuit mechanisms giving rise to such sup- pression remain unknown. Here, we describe these mechanisms using electrophysiology in mouse, pig, and macaque retina, 2-photon calcium imaging, computational modeling, and human psychophysics. We find that sequential stimuli, like those that naturally occur during saccades, trigger three independent suppressive mechanisms in the retina. The main mechanism is triggered by contrast-reversing sequential stimuli and originates within the receptive field center of ganglion cells. It does not involve inhibition or other known sup- pressive mechanisms like saturation or adaptation. Instead, it relies on temporal filtering of the inherently slow response of cone photoreceptors coupled with downstream non- linearities. Two further mechanisms of suppression are present predominantly in ON ganglion cells and originate in the receptive field surround, highlighting another disparity between ON and OFF ganglion cells. The mechanisms uncovered here likely play a role in shaping the retinal output following eye movements and other natural viewing conditions where sequential stimulation is ubiquitous.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Schroter2022,
title = {Functional imaging of brain organoids using high-density microelectrode arrays},
author = {Schröter, Manuel; Wang, Congwei; Terrigno, Marco; Hornauer, Philipp; Huang, Ziqiang; Jagasia, Ravi; Hierlemann, Andreas},
url = {https://link.springer.com/article/10.1557/s43577-022-00282-w},
year = {2022},
date = {2022-06-30},
journal = {MRS Bulletin},
abstract = {Studies have provided evidence that human cerebral organoids (hCOs) recapitulate fundamental milestones of early brain development, but many important questions regarding their functionality and electrophysiological properties persist. High-density microelectrode arrays (HD-MEAs) represent an attractive analysis platform to perform functional studies of neuronal networks at the cellular and network scale. Here, we use HD-MEAs to derive large-scale electrophysiological recordings from sliced hCOs. We record the activity of hCO slices over several weeks and probe observed neuronal dynamics pharmacologically. Moreover, we present results on how the obtained recordings can be spike-sorted and subsequently studied across scales. For example, we show how to track single neurons across several days on the HD-MEA and how to infer axonal action potential velocities. We also infer putative functional connectivity from hCO recordings. The introduced methodology will contribute to a better understanding of developing neuronal networks in brain organoids and provide new means for their functional characterization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Xu2022,
title = {Generation of functional posterior spinal motor neurons from hPSCs-derived human spinal cord neural progenitor cells},
author = {Jax H. Xu and Yao Yao and Fenyong Yao and Jiehui Chen and Meishi Li and Xianfa and Yang and Sheng Li and Fangru Lu and Ping Hu and Shuijin He and Guangdun Peng and Naihe Jing},
url = {https://www.biorxiv.org/content/10.1101/2022.06.26.495599v1},
doi = {https://doi.org/10.1101/2022.06.26.495599},
year = {2022},
date = {2022-06-27},
journal = {BioRxiv},
abstract = {Spinal motor neurons deficiency results in a series of devastating disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal cord injury (SCI). These disorders are currently incurable, while human pluripotent stem cells (hPSCs)-derived spinal motor neurons are promising but suffered from low-efficiency, functional immaturity and lacks of posterior cellular identity. In this study, we have established human spinal cord neural progenitor cells (hSCNPCs) via hPSCs differentiated neuromesodermal progenitors (NMPs) and demonstrated the hSCNPCs can be continuously expanded up to 40 passages. hSCNPCs can be rapidly differentiated into posterior spinal motor neurons with high efficiency. The functional maturity has been examined in detail. Moreover, a co-culture scheme which is compatible for both neural and muscular differentiation is developed to mimic the neuromuscular junction (NMJ) formation in vitro. Together, these studies highlight the potential avenues for generating clinically relevant spinal motor neurons and modeling neuromuscular diseases through our defined hSCNPCs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Sommer2022,
title = {Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor Neurons},
author = {Sommer, Daniel ; Rajkumar, Sandeep; Seidel, Mira; Aly, Amr; Ludolph, Albert; Ho, Ritchie; Boeckers, Tobias; Catanese, Alberto.},
url = {https://www.frontiersin.org/articles/10.3389/fnmol.2022.894230/full},
year = {2022},
date = {2022-06-14},
journal = {Frontiers in Molecular Neuroscience},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by dysfunction and loss of upper and lower motor neurons (MN). Despite several studies identifying drastic alterations affecting synaptic composition and functionality in different experimental models, the specific contribution of impaired activity to the neurodegenerative processes observed in ALS-related MN remains controversial. In particular, contrasting lines of evidence have shown both hyper- as well as hypoexcitability as driving pathomechanisms characterizing this specific neuronal population. In this study, we combined high definition multielectrode array (HD-MEA) techniques with transcriptomic analysis to longitudinally monitor and untangle the activity-dependent alterations arising in human C9orf72-mutant MN. We found a time-dependent reduction of neuronal activity in ALSC9orf72 cultures occurring as synaptic contacts undergo maturation and matched by a significant loss of mutant MN upon aging. Notably, ALS-related neurons displayed reduced network synchronicity most pronounced at later stages of culture, suggesting synaptic imbalance. In concordance with the HD-MEA data, transcriptomic analysis revealed an early up-regulation of synaptic terms in ALSC9orf72 MN, whose expression was decreased in aged cultures. In addition, treatment of older mutant cells with Apamin, a K+ channel blocker previously shown to be neuroprotective in ALS, rescued the time-dependent loss of firing properties observed in ALSC9orf72 MN as well as the expression of maturity-related synaptic genes. All in all, this study broadens the understanding of how impaired synaptic activity contributes to MN degeneration in ALS by correlating electrophysiological alterations to aging-dependent transcriptional programs.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}