Neuronal Network Function Research Articles

Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations invitro.

SummaryMicro-electrode arrays (MEAs) are increasingly used to characterize neuronal network activity of human induced pluripotent stem cell (hiPSC)-derived neurons. Despite their gain in popularity, MEA recordings from hiPSC-derived neuronal networks are not always used to their full potential in respect to experimental design, execution, and data analysis. Therefore, we benchmarked the robustness of MEA-derived neuronal activity patterns from ten healthy individual control lines, and uncover comparable network phenotypes. To achieve standardization, we provide recommendations on experimental design and analysis. With such standardization, MEAs can be used as a reliable platform to distinguish (disease-specific) network phenotypes. In conclusion, we show that MEAs are a powerful and robust tool to uncover functional neuronal network phenotypes from hiPSC-derived neuronal networks, and provide an important resource to advance the hiPSC field toward the use of MEAs for disease phenotyping and drug discovery.

Improved Method for Efficient Generation of Functional Neurons from Murine Neural Progenitor Cells.

Neuronal culture was used to investigate neuronal function in physiological and pathological conditions. Despite its inevitability, primary neuronal culture remained a gold standard method that requires laborious preparation, intensive training, and animal resources. To circumvent the shortfalls of primary neuronal preparations and efficiently give rise to functional neurons, we combine a neural stem cell culture method with a direct cell type-conversion approach. The lucidity of this method enables the efficient preparation of functional neurons from mouse neural progenitor cells on demand. We demonstrate that induced neurons (NPC-iNs) by this method make synaptic connections, elicit neuronal activity-dependent cellular responses, and develop functional neuronal networks. This method will provide a concise platform for functional neuronal assessments. This indeed offers a perspective for using these characterized neuronal networks for investigating plasticity mechanisms, drug screening assays, and probing the molecular and biophysical basis of neurodevelopmental and neurodegenerative diseases.

SyNC, a Computationally Extensive and Realistic Neural Net to Identify Relative Impacts of Synaptopathy Mechanisms on Glutamatergic Neurons and Their Networks in Autism and Complex Neurological Disorders.

Synaptic function and experience-dependent plasticity across multiple synapses are dependent on the types of neurons interacting as well as the intricate mechanisms that operate at the molecular level of the synapse. To understand the complexity of information processing at synaptic networks will rely in part on effective computational models. Such models should also evaluate disruptions to synaptic function by multiple mechanisms. By co-development of algorithms alongside hardware, real time analysis metrics can be co-prioritized along with biological complexity. The hippocampus is implicated in autism spectrum disorders (ASD) and within this region glutamatergic neurons constitute 90% of the neurons integral to the functioning of neuronal networks. Here we generate a computational model referred to as ASD interrogator (ASDint) and corresponding hardware to enable in silicon analysis of multiple ASD mechanisms affecting glutamatergic neuron synapses. The hardware architecture Synaptic Neuronal Circuit, SyNC, is a novel GPU accelerator or neural net, that extends discovery by acting as a biologically relevant realistic neuron synapse in real time. Co-developed ASDint and SyNC expand spiking neural network models of plasticity to comparative analysis of retrograde messengers. The SyNC model is realized in an ASIC architecture, which enables the ability to compute increasingly complex scenarios without sacrificing area efficiency of the model. Here we apply the ASDint model to analyse neuronal circuitry dysfunctions associated with autism spectral disorder (ASD) synaptopathies and their effects on the synaptic learning parameter and demonstrate SyNC on an ideal ASDint scenario. Our work highlights the value of secondary pathways in regard to evaluating complex ASD synaptopathy mechanisms. By comparing the degree of variation in the synaptic learning parameter to the response obtained from simulations of the ideal scenario we determine the potency and time of the effect of a particular evaluated mechanism. Hence simulations of such scenarios in even a small neuronal network now allows us to identify relative impacts of changed parameters and their effect on synaptic function. Based on this, we can estimate the minimum fraction of a neuron exhibiting a particular dysfunction scenario required to lead to complete failure of a neural network to coordinate pre-synaptic and post-synaptic outputs.

Functional neuronal networks reveal emotional processing differences in children with ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder that, in addition to inattention, excessive activity, or impulsivity, makes it difficult for children to process facial emotions and thus to interact with their peers. Here we analyze neuronal networks of children with this disorder by means of the phase-locking value (PLV) method. In particular, we determine the level of phase synchronization between 62 EEG channels of 22 healthy boys and 22 boys with ADHD, recorder whilst observing facial emotions of anger, happiness, neutrality, and sadness. We construct neuronal networks based on the gamma sub-band, which according to previous studies, shows the highest response to emotional stimuli. We find that the functional connectivity of the frontal and occipital lobes in the ADHD group is significantly (P-value < 0.01) higher than in the healthy group. More functional connectivity in these lobes shows more phase synchronization between the neurons of these brain regions, representing some problems in the brain emotional processing center in the ADHD group. The shortest path lengths in these lobes are also significantly (P-value < 0.01) higher in the ADHD group than in the healthy group. This result indicates less efficiency of information transmission and segregation in occipital and frontal lobes of ADHD neuronal networks, responsible for visual and emotional processing in the brain, respectively. We hope that our approach will help obtain further insights into ADHD with methods of network science.

Astrocytic Ca2+ Signaling in Epilepsy.

Epilepsy is one of the most common neurological disorders – estimated to affect at least 65 million worldwide. Most of the epilepsy research has so far focused on how to dampen neuronal discharges and to explain how changes in intrinsic neuronal activity or network function cause seizures. As a result, pharmacological therapy has largely been limited to symptomatic treatment targeted at neurons. Given the expanding spectrum of functions ascribed to the non-neuronal constituents of the brain, in both physiological brain function and in brain disorders, it is natural to closely consider the roles of astrocytes in epilepsy. It is now widely accepted that astrocytes are key controllers of the composition of the extracellular fluids, and may directly interact with neurons by releasing gliotransmitters. A central tenet is that astrocytic intracellular Ca2+ signals promote release of such signaling substances, either through synaptic or non-synaptic mechanisms. Accruing evidence suggests that astrocytic Ca2+ signals play important roles in both seizures and epilepsy, and this review aims to highlight the current knowledge of the roles of this central astrocytic signaling mechanism in ictogenesis and epileptogenesis.

Culture of Rat Primary Cortical Cells for Microelectrode Array (MEA) Recordings to Screen for Acute and Developmental Neurotoxicity.

Neurotoxicity testing of chemicals, drug candidates, and environmental pollutants still relies on extensive in vivo studies that are very costly, time-consuming, and ethically debated due to the large number of animals typically used. Currently, rat primary cortical cultures are widely used for in vitro neurotoxicity studies, as they closely resemble the in vitro brain with respect to the diversity of cell types, their physiological functions, and the pathological processes that they undergo. Common in vitro assays for neurotoxicity screening often focus on very target-specific endpoints such as morphological, biochemical, or electrophysiological changes, and such narrow focus can hamper translation and interpretation. Microelectrode array (MEA) recordings provide a non-invasive platform for extracellular recording of electrical activity of cultured neuronal cells, thereby enabling the evaluation of changes in neuronal (network) function as a sensitive and integrated endpoint for neurotoxicity screening. Here, we describe an in vitro approach for assessing changes in neuronal network function as a measure for neurotoxicity, using rat primary cortical cultures grown on MEAs. We provide a detailed protocol for the culture of rat primary cortical cells, and describe several experimental procedures to address acute, subchronic, and chronic exposure scenarios. We additionally describe the steps for processing and analyzing MEA and cell viability data. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Isolation and culture of rat primary cortical cells on 48-well MEA plates Support Protocol 1: Pretreatment and washing of 48-well MEA plates before first use or for re-use Support Protocol 2: Coating of 48-well MEA plates with 0.1% PEI solution Basic Protocol 2: MEA measurements during acute exposure Alternate Protocol 1: MEA measurements during subchronic exposure Alternate Protocol 2: MEA measurements during chronic exposure Support Protocol 3: Determination of cell viability after MEA experiments Basic Protocol 3: MEA data processing Basic Protocol 4: Analyzing MEA experiments after acute and subchronic exposure Alternate Protocol 3: Analyzing MEA experiments after chronic exposure.

TLR2- and TLR3-activated microglia induce different levels of neuronal network dysfunction in a context-dependent manner

Recognition of pathogen- or damage-associated molecular patterns (PAMPs, DAMPs) by innate Toll-like receptors (TLRs) is central to the activation of microglia (brain macrophages) in many CNS diseases. Notably, TLR-mediated microglial activation is complex and modulated by additional exogenous and endogenous immunological signals. The impact of different microglial reactive phenotypes on electrical activity and neurotransmission is widely unknown, however. We explored the effects of TLR ligands on microglia and neuronal network function in rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortical tissue lacking adaptive immunity. Single exposure of slice cultures to TLR2 or TLR3 ligands [PGN, poly(I:C)] for 2–3 days induced moderate microglial activation featuring IL-6 and TNF-α release and only mild alterations of fast neuronal gamma band oscillations (30–70 Hz) that are fundamental to higher cognitive functions, such as perception, memory and behavior. Paired exposure to TLR3/TLR2 or TLR3/TLR4 ligands (LPS) induced nitric oxide (NO) release, enhanced TNF-α release, and associated with advanced network dysfunction, including slowing to the beta frequency band (12–30 Hz) and neural bursts (hyperexcitability). Paired exposure to a TLR ligand and the leukocyte cytokine IFN-γ enhanced NO release and associated with severe network dysfunction, albeit sensitive parvalbumin- and somatostatin-positive inhibitory interneurons were preserved. Notably, the neuronal disturbance was prevented by either microglial depletion or pharmacological inhibition of oxidant-producing enzymes, inducible NO synthase (iNOS) and NADPH oxidase. In conclusion, TLR-activated microglia can induce different levels of neuronal network dysfunction, in which severe dysfunction is mainly caused by reactive oxygen and nitrogen species rather than proinflammatory cytokines. Our findings provide a mechanistic insight into microglial activation and functional neuronal network impairment, with relevance to neuroinflammation and neurodegeneration observed in, e.g., meningoencephalitis, multiple sclerosis and Alzheimer’s disease.

Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function

Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.

Neuronal replacement: Concepts, achievements, and call for caution.

Regenerative approaches have made such a great progress, now aiming toward replacing the exact neurons lost upon injury or neurodegeneration. Transplantation and direct reprogramming approaches benefit from identification of molecular programs for neuronal subtype specification, allowing engineering of more precise neuronal subtypes. Disentangling subtype diversity from dynamic transcriptional states presents a challenge now. Adequate identity and connectivity is a prerequisite to restore neuronal network function, which is achieved by transplanted neurons generating the correct output and input, depending on the location and injury condition. Direct neuronal reprogramming of local glial cells has also made great progress in achieving high efficiency of conversion, with adequate output connectivity now aiming toward the goal of replacing neurons in a noninvasive approach.

Microglia provide structural resolution to injured dendrites after severe seizures

SUMMARYAlthough an imbalance between neuronal excitation and inhibition underlies seizures, clinical approaches that target these mechanisms are insufficient in containing seizures in patients with epilepsy, raising the need for alternative approaches. Brain-resident microglia contribute to the development and stability of neuronal structure and functional networks that are perturbed during seizures. However, the extent of microglial contributions in response to seizures in vivo remain to be elucidated. Using two-photon in vivo imaging to visualize microglial dynamics, we show that severe seizures induce formation of microglial process pouches that target but rarely engulf beaded neuronal dendrites. Microglial process pouches are stable for hours, although they often shrink in size. We further find that microglial process pouches are associated with a better structural resolution of beaded dendrites. These findings provide evidence for the structural resolution of injured dendrites by microglia as a form of neuroprotection.

FMRP attenuates activity dependent modifications in the mitochondrial proteome

Homeostatic plasticity is necessary for the construction and maintenance of functional neuronal networks, but principal molecular mechanisms required for or modified by homeostatic plasticity are not well understood. We recently reported that homeostatic plasticity induced by activity deprivation is dysregulated in cortical neurons from Fragile X Mental Retardation protein (FMRP) knockout mice (Bulow et al. in Cell Rep 26: 1378-1388 e1373, 2019). These findings led us to hypothesize that identifying proteins sensitive to activity deprivation and/or FMRP expression could reveal pathways required for or modified by homeostatic plasticity. Here, we report an unbiased quantitative mass spectrometry used to quantify steady-state proteome changes following chronic activity deprivation in wild type and Fmr1−/y cortical neurons. Proteome hits responsive to both activity deprivation and the Fmr1−/y genotype were significantly annotated to mitochondria. We found an increased number of mitochondria annotated proteins whose expression was sensitive to activity deprivation in Fmr1−/y cortical neurons as compared to wild type neurons. These findings support a novel role of FMRP in attenuating mitochondrial proteome modifications induced by activity deprivation.

Built to Last: Functional and Structural Mechanisms in the Moth Olfactory Network Mitigate Effects of Neural Injury.

Most organisms suffer neuronal damage throughout their lives, which can impair performance of core behaviors. Their neural circuits need to maintain function despite injury, which in particular requires preserving key system outputs. In this work, we explore whether and how certain structural and functional neuronal network motifs act as injury mitigation mechanisms. Specifically, we examine how (i) Hebbian learning, (ii) high levels of noise, and (iii) parallel inhibitory and excitatory connections contribute to the robustness of the olfactory system in the Manduca sexta moth. We simulate injuries on a detailed computational model of the moth olfactory network calibrated to data. The injuries are modeled on focal axonal swellings, a ubiquitous form of axonal pathology observed in traumatic brain injuries and other brain disorders. Axonal swellings effectively compromise spike train propagation along the axon, reducing the effective neural firing rate delivered to downstream neurons. All three of the network motifs examined significantly mitigate the effects of injury on readout neurons, either by reducing injury’s impact on readout neuron responses or by restoring these responses to pre-injury levels. These motifs may thus be partially explained by their value as adaptive mechanisms to minimize the functional effects of neural injury. More generally, robustness to injury is a vital design principle to consider when analyzing neural systems.

The glucocorticoid receptor specific modulator CORT108297 reduces brain pathology following status epilepticus

ObjectiveGlucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297. MethodsMice were treated with either C108297 or vehicle for 10 days beginning one day after pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were assessed to determine whether hypothalamic-pituitary-adrenal axis hyperreactivity could be controlled. Status epilepticus-induced pathology was assessed by quantifying ectopic hippocampal granule cell density, microglial density, astrocyte density and mossy cell loss. Neuronal network function was examined indirectly by determining the density of Fos immunoreactive neurons following restraint stress. ResultsTreatment with C108297 attenuated corticosterone hypersecretion after status epilepticus. Treatment also decreased the density of hilar ectopic granule cells and reduced microglial proliferation. Mossy cell loss, on the other hand, was not prevented in treated mice. C108297 altered the cellular distribution of Fos protein but did not restore the normal pattern of expression. InterpretationResults demonstrate that baseline corticosterone levels can be normalized with C108297, and implicate glucocorticoid signaling in the development of structural changes following status epilepticus. These findings support the further development of glucocorticoid receptor modulators as novel therapeutics for the prevention of brain pathology following status epilepticus.

Reactive astrocytes as treatment targets in Alzheimer's disease-Systematic review of studies using the APPswePS1dE9 mouse model.

Astrocytes regulate synaptic communication and are essential for proper brain functioning. In Alzheimer's disease (AD) astrocytes become reactive, which is characterized by an increased expression of intermediate filament proteins and cellular hypertrophy. Reactive astrocytes are found in close association with amyloid‐beta (Aβ) deposits. Synaptic communication and neuronal network function could be directly modulated by reactive astrocytes, potentially contributing to cognitive decline in AD. In this review, we focus on reactive astrocytes as treatment targets in AD in the APPswePS1dE9 AD mouse model, a widely used model to study amyloidosis and gliosis. We first give an overview of the model; that is, how it was generated, which cells express the transgenes, and the effect of its genetic background on Aβ pathology. Subsequently, to determine whether modifying reactive astrocytes in AD could influence pathogenesis and cognition, we review studies using this mouse model in which interventions were directly targeted at reactive astrocytes or had an indirect effect on reactive astrocytes. Overall, studies specifically targeting astrocytes to reduce astrogliosis showed beneficial effects on cognition, which indicates that targeting astrocytes should be included in developing novel therapies for AD.

Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation

BackgroundHuman induced pluripotent stem cells (iPSC) have opened new avenues for regenerative medicine. Consequently, iPSC-derived motor neurons have emerged as potentially viable therapies for spinal cord injuries and neurodegenerative disorders including Amyotrophic Lateral Sclerosis. However, direct clinical application of iPSC bears in itself the risk of tumorigenesis and other unforeseeable genetic or epigenetic abnormalities.ResultsEmploying RNA-seq technology, we identified and characterized gene regulatory networks triggered by in vitro chemical reprogramming of iPSC into cells with the molecular features of motor neurons (MNs) whose function in vivo is to innervate effector organs. We present meta-transcriptome signatures of 5 cell types: iPSCs, neural stem cells, motor neuron progenitors, early motor neurons, and mature motor neurons. In strict response to the chemical stimuli, along the MN differentiation axis we observed temporal downregulation of tumor growth factor-β signaling pathway and consistent activation of sonic hedgehog, Wnt/β-catenin, and Notch signaling. Together with gene networks defining neuronal differentiation (neurogenin 2, microtubule-associated protein 2, Pax6, and neuropilin-1), we observed steady accumulation of motor neuron-specific regulatory genes, including Islet-1 and homeobox protein HB9. Interestingly, transcriptome profiling of the differentiation process showed that Ca2+ signaling through cAMP and LPC was downregulated during the conversion of the iPSC to neural stem cells and key regulatory gene activity of the pathway remained inhibited until later stages of motor neuron formation. Pathways shaping the neuronal development and function were well-represented in the early motor neuron cells including, neuroactive ligand-receptor interactions, axon guidance, and the cholinergic synapse formation. A notable hallmark of our in vitro motor neuron maturation in monoculture was the activation of genes encoding G-coupled muscarinic acetylcholine receptors and downregulation of the ionotropic nicotinic acetylcholine receptors expression. We observed the formation of functional neuronal networks as spontaneous oscillations in the extracellular action potentials recorded on multi-electrode array chip after 20 days of differentiation.ConclusionsDetailed transcriptome profile of each developmental step from iPSC to motor neuron driven by chemical induction provides the guidelines to novel therapeutic approaches in the re-construction efforts of muscle innervation.

Multi-scale network imaging in a mouse model of amyloidosis

The adult neocortex is not hard-wired but instead retains the capacity to reorganise across multiple spatial scales long into adulthood. Plastic reorganisation occurs at the level of mesoscopic sensory maps, functional neuronal assemblies and synaptic ensembles and is thought to be a critical feature of neuronal network function. Here, we describe a series of approaches that use calcium imaging to measure network reorganisation across multiple spatial scales in vivo. At the mesoscopic level, we demonstrate that sensory activity can be measured in animals undergoing longitudinal behavioural assessment involving automated touchscreen tasks. At the cellular level, we show that network dynamics can be longitudinally measured at both stable and transient functional assemblies. At the level of single synapses, we show that functional subcellular calcium imaging approaches can be used to measure synaptic ensembles of dendritic spines in vivo. Finally, we demonstrate that all three levels of imaging can be spatially related to local pathology in a preclinical rodent model of amyloidosis. We propose that multi-scale in vivo calcium imaging can be used to measure parallel plasticity processes operating across multiple spatial scales in both the healthy brain and preclinical models of disease.

In Vitro Development of Human iPSC-Derived Functional Neuronal Networks on Laser-Fabricated 3D Scaffolds.

Neural progenitor cells generated from human induced pluripotent stem cells (hiPSCs) are the forefront of ″brain-on-chip″ investigations. Viable and functional hiPSC-derived neuronal networks are shaping powerful in vitro models for evaluating the normal and abnormal formation of cortical circuits, understanding the underlying disease mechanisms, and investigating the response to drugs. They therefore represent a desirable instrument for both the scientific community and the pharmacological industry. However, culture conditions required for the full functional maturation of individual neurons and networks are still unidentified. It has been recognized that three-dimensional (3D) culture conditions can better emulate in vivo neuronal tissue development compared to 2D cultures and thus provide a more desirable in vitro approach. In this paper, we present the design and implementation of a 3D scaffold platform that supports and promotes intricate neuronal network development. 3D scaffolds were produced through direct laser writing by two-photon polymerization (2PP), a high-resolution 3D laser microstructuring technology, using the biocompatible and nondegradable photoreactive resin Dental LT Clear (DClear). Neurons developed and interconnected on a 3D environment shaped by vertically stacked scaffold layers. The developed networks could support different cell types. Starting at the day 50 of 3D culture, neuronal progenitor cells could develop into cortical projection neurons (CNPs) of all six layers, different types of inhibitory neurons, and glia. Additionally and in contrast to 2D conditions, 3D scaffolds supported the long-term culturing of neuronal networks over the course of 120 days. Network health and functionality were probed through calcium imaging, which revealed a strong spontaneous neuronal activity that combined individual and collective events. Taken together, our results highlight advanced microstructured 3D scaffolds as a reliable platform for the 3D in vitro modeling of neuronal functions.

Empirically constrained network models for contrast-dependent modulation of gamma rhythm in V1

Gamma oscillations are thought to play a key role in neuronal network function and neuronal communication, yet the underlying generating mechanisms have not been fully elucidated to date. At least partly, this may be due to the fact that even in simple network models of interconnected inhibitory (I) and excitatory (E) neurons, many parameters remain unknown and are set based on practical considerations or by convention. Here, we mitigate this problem by requiring PING (Pyramidal Interneuron Network Gamma) models to simultaneously satisfy a broad set of criteria for realistic behaviour based on empirical data spanning both the single unit (spikes) and local population (LFP) levels while unknown parameters are varied. By doing so, we were able to constrain the parameter ranges and select empirically valid models. The derived model constraints implied weak rather than strong PING as the generating mechanism for gamma, connectivity between E and I neurons within specific bounds, and variations of the external input to E but not I neurons. Constrained models showed valid behaviours, including gamma frequency increases with contrast and power saturation or decay at high contrasts. Using an empirically-validated model we studied the route to gamma instability at high contrasts. This involved increased heterogeneity of E neurons with increasing input triggering a breakdown of I neuron pacemaker function. Further, we illustrate the model's capacity to resolve disputes in the literature concerning gamma oscillation properties and GABA conductance proxies. We propose that the models derived in our study will be useful for other modelling studies, and that our approach to the empirical constraining of PING models can be expanded when richer empirical datasets become available. As local gamma networks are the building blocks of larger networks that aim to understand complex cognition through their interactions, there is considerable value in improving our models of these building blocks.

Chronic vs acute manipulations reveal degeneracy in a thermosensory neuron network.

Degenerate networks can drive similar circuit outputs. Via acute manipulation of individual neurons, we previously identified circuit components that are necessary and sufficient to drive starvation-dependent plasticity in C. elegans thermotaxis behavior. Here we find that when these components are instead silenced chronically, degenerate mechanisms compensate to drive this behavior. Our results indicate that degeneracy in neuronal network function can be revealed under specific experimental conditions.

A functional spiking neuronal network for tactile sensing pathway to process edge orientation

To obtain deeper insights into the tactile processing pathway from a population-level point of view, we have modeled three stages of the tactile pathway from the periphery to the cortex in response to indentation and scanned edge stimuli at different orientations. Three stages in the tactile pathway are, (1) the first-order neurons which innervate the cutaneous mechanoreceptors, (2) the cuneate nucleus in the midbrain and (3) the cortical neurons of the somatosensory area. In the proposed network, the first layer mimics the spiking patterns generated by the primary afferents. These afferents have complex skin receptive fields. In the second layer, the role of lateral inhibition on projection neurons in the cuneate nucleus is investigated. The third layer acts as a biomimetic decoder consisting of pyramidal and cortical interneurons that correspond to heterogeneous receptive fields with excitatory and inhibitory sub-regions on the skin. In this way, the activity of pyramidal neurons is tuned to the specific edge orientations. By modifying afferent receptive field size, it is observed that the larger receptive fields convey more information about edge orientation in the first spikes of cortical neurons when edge orientation stimuli move across the patch of skin. In addition, the proposed spiking neural model can detect edge orientation at any location on the simulated mechanoreceptor grid with high accuracy. The results of this research advance our knowledge about tactile information processing and can be employed in prosthetic and bio-robotic applications.