Neighboring Neurons Research Articles

Operant conditioning reveals task-specific responses of single neurons in a brain–machine interface

Objective. Volitional modulation of single cortical neurons holds great potential for the implementation of brain–machine interfaces (BMIs) because it can induce a rapid acquisition of arbitrary associations between machines and neural activity. It can also be used as a framework to study the limits of single-neuron control in BMIs. Approach. We tested the control of a one-dimensional actuator in two BMI tasks which differed only in the neural contingency that determined when a reward was dispensed. A thresholded activity task, commonly implemented in single-neuron BMI control, consisted of reaching or exceeding a neuron activity level, while the second task consisted of reaching and maintaining a narrow neuron activity level (i.e. windowed activity task). Main findings. Single neurons in layer V of the motor cortex of rats improved performance during both the thresholded activity and windowed activity BMI tasks. However, correct performance during the windowed activity task was accompanied by activation of neighboring neurons, not in direct control of the BMI. In contrast, only neurons in direct control of the BMI were active at the time of reward during the thresholded activity task. Significance. These results suggest that thresholded activity single-neuron BMI implementations are more appropriate compared to windowed activity BMI tasks to capitalize on the adaptability of cortical circuits to acquire novel arbitrary skills.

A cut finite element method for spatially resolved energy metabolism models in complex neuro-cell morphologies with minimal remeshing

A thorough understanding of brain metabolism is essential to tackle neurodegenerative diseases. Astrocytes are glial cells which play an important metabolic role by supplying neurons with energy. In addition, astrocytes provide scaffolding and homeostatic functions to neighboring neurons and contribute to the blood–brain barrier. Recent investigations indicate that the complex morphology of astrocytes impacts upon their function and in particular the efficiency with which these cells metabolize nutrients and provide neurons with energy, but a systematic understanding is still elusive. Modelling and simulation represent an effective framework to address this challenge and to deepen our understanding of brain energy metabolism. This requires solving a set of metabolic partial differential equations on complex domains and remains a challenge. In this paper, we propose, test and verify a simple numerical method to solve a simplified model of metabolic pathways in astrocytes. The method can deal with arbitrarily complex cell morphologies and enables the rapid and simple modification of the model equations by users also without a deep knowledge in the numerical methods involved. The results obtained with the new method (CutFEM) are as accurate as the finite element method (FEM) whilst CutFEM disentangles the cell morphology from its discretisation, enabling us to deal with arbitrarily complex morphologies in two and three dimensions.

Endocannabinoids and Dopamine Balance Basal Ganglia Output.

The entopeduncular nucleus is one of the basal ganglia's output nuclei, thereby controlling basal ganglia information processing. Entopeduncular nucleus neurons integrate GABAergic inputs from the Striatum and the globus pallidus, together with glutamatergic inputs from the subthalamic nucleus. We show that endocannabinoids and dopamine interact to modulate the long-term plasticity of all these primary afferents to the entopeduncular nucleus. Our results suggest that the interplay between dopamine and endocannabinoids determines the balance between direct pathway (striatum) and indirect pathway (globus pallidus) in entopeduncular nucleus output. Furthermore, we demonstrate that, despite the lack of axon collaterals, information is transferred between neighboring neurons in the entopeduncular nucleus via endocannabinoid diffusion. These results transform the prevailing view of the entopeduncular nucleus as a feedforward “relay” nucleus to an intricate control unit, which may play a vital role in the process of action selection.

Lysosomal Functions in Glia Associated with Neurodegeneration

Lysosomes are cellular organelles that contain various acidic digestive enzymes. Despite their small size, they have multiple functions. Lysosomes remove or recycle unnecessary cell parts. They repair damaged cellular membranes by exocytosis. Lysosomes also sense cellular energy status and transmit signals to the nucleus. Glial cells are non-neuronal cells in the nervous system and have an active role in homeostatic support for neurons. In response to dynamic cues, glia use lysosomal pathways for the secretion and uptake of regulatory molecules, which affect the physiology of neighboring neurons. Therefore, functional aberration of glial lysosomes can trigger neuronal degeneration. Here, we review lysosomal functions in oligodendrocytes, astrocytes, and microglia, with emphasis on neurodegeneration.

Information diversity in individual auditory cortical neurons is associated with functionally distinct coordinated neuronal ensembles

Neuronal activity in auditory cortex is often highly synchronous between neighboring neurons. Such coordinated activity is thought to be crucial for information processing. We determined the functional properties of coordinated neuronal ensembles (cNEs) within primary auditory cortical (AI) columns relative to the contributing neurons. Nearly half of AI cNEs showed robust spectro-temporal receptive fields whereas the remaining cNEs showed little or no acoustic feature selectivity. cNEs can therefore capture either specific, time-locked information of spectro-temporal stimulus features or reflect stimulus-unspecific, less-time specific processing aspects. By contrast, we show that individual neurons can represent both of those aspects through membership in multiple cNEs with either high or absent feature selectivity. These associations produce functionally heterogeneous spikes identifiable by instantaneous association with different cNEs. This demonstrates that single neuron spike trains can sequentially convey multiple aspects that contribute to cortical processing, including stimulus-specific and unspecific information.

REST Protects Dopaminergic Neurons from Mitochondrial and α-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model.

Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared with neighboring protected SN GABAergic neurons, which correlated with the accumulation of α-synuclein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient induced pluripotent stem cell-derived dopaminergic neurons carrying the SNCA-Triplication mutation, which accumulated α-synuclein oligomers and mitochondrial damage, and displayed REST target gene dysregulation. Furthermore, CRISPR-mediated REST KO induced mitochondrial dysfunction and impaired mitophagy in vitro Conversely, REST overexpression attenuated mitochondrial toxicity and mitochondrial morphology disruption through the transcription factor PGC-1α. Finally, decreased α-synuclein oligomer accumulation and mitochondrial dysfunction in mice correlated with nuclear REST and PGC-1α in protected SN GABAergic neurons compared with vulnerable dopaminergic neurons. Our findings show that increased levels of α-synuclein oligomers cause dopaminergic neuronal-specific dysfunction through mitochondrial toxicity, which can be attenuated by REST in an early model of Parkinsonian pathology. These findings highlight REST as a mediator of dopaminergic vulnerability in PD.SIGNIFICANCE STATEMENT Understanding early Parkinsonian pathophysiology through studies of advanced preclinical models is fundamental to the translation of disease-modifying therapies. Here we show disease-relevant levels of α-synuclein expression in mice leads to accumulation of α-synuclein oligomers in the absence of overt aggregation, and mitochondrial dysfunction in dopaminergic neurons lacking the RE1 Silencing Transcription Factor. Our findings identify the mechanism of action of RE1 Silencing Transcription Factor and PGC-1α as mediators of dopaminergic vulnerability in α-synuclein BAC-transgenic mice and induced pluripotent stem cell-derived dopaminergic cultures, highlighting their potential as therapeutic targets.

Tetrode Recording in the Xenopus laevis Visual System Using Multichannel Glass Electrodes.

The Xenopus tadpole visual system shows an extraordinary extent of developmental and visual experience-dependent plasticity, establishing sophisticated neuronal response properties that guide essential survival behaviors. The external development and access to the developing visual circuit of Xenopus tadpoles make them an excellent experimental system in which to elucidate plastic changes in neuronal properties and their capacity to encode information about the visual scene. The temporal structure of neural activity encodes a significant amount of information, access to which requires recording methods with high temporal resolution. Conversely, elucidating changes in the temporal structure of neural activity requires recording over extended periods. It is challenging to maintain patch-clamp recordings over extended periods and Ca2+ imaging has limited temporal resolution. Extracellular recordings have been used in other systems for extended recording; however, spike amplitudes in the developing Xenopus visual circuit are not large enough to be captured by distant electrodes. Here we describe a juxtacellular tetrode recording method for continuous long-term recordings from neurons in intact tadpoles, which can also be exposed to diverse visual stimulation protocols. Electrode position in the tectum is stabilized by the large contact area in the tissue. Contamination of the signal from neighboring neurons is minimized by the tight contact between the glass capillaries and the dense arrangement of neurons in the tectum. This recording method enables analysis of developmental and visual experience-dependent plastic changes in neuronal response properties at higher temporal resolution and over longer periods than current methods.

Insulin signaling mediates neurodegeneration in glioma.

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is one of the most aggressive and frequent primary brain tumors. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here, we describe in a Drosophila model how glioblastoma cells produce ImpL2, an antagonist of the insulin pathway, which targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue synapse loss and to delay the premature death caused by glioma. Therefore, signals from glioblastoma to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies.

Combined kinesin-1 and kinesin-3 activity drives axonal trafficking of TrkB receptors in Rab6 carriers.

SummaryNeurons depend on proper localization of neurotrophic receptors in their distal processes for their function. The Trk family of neurotrophin receptors controls neuronal survival, differentiation, and remodeling and are well known to function as retrograde signal carriers transported from the distal axon toward the cell body. However, the mechanism driving anterograde trafficking of Trk receptors into the axon is not well established. We used microfluidic compartmental devices and inducible secretion assay to systematically investigate the retrograde and anterograde trafficking routes of TrkB receptor along the axon in rat hippocampal neurons. We show that newly synthesized TrkB receptors traffic through the secretory pathway and are directly delivered into axon. We found that these TrkB carriers associate and are regulated by Rab6. Furthermore, the combined activity of kinesin-1 and kinesin-3 is needed for the formation of axon-bound TrkB secretory carriers and their effective entry and processive anterograde transport beyond the proximal axon.

Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory

Astrocytes metabolically interact with neighboring neurons by providing multiple substances to neurons. How astrocytes regulate neural functions via altering the neuronal metabolic state remains elusive. Here, we demonstrate that astrocytic ApoE vectors a variety of microRNAs (miRNAs), and these miRNAs specifically silence genes involved in neuronal cholesterol biosynthesis, ultimately accounting for accumulation of the pathway-initiating substrate acetyl-CoA. Consequently, histone acetylation is promoted, and transcription is activated in neurons. Functionally, we demonstrate that ApoE-mediated neuronal histone acetylation leads to increased H3K27ac enrichment in the promoters of multiple neuronal immediate early genes and subsequently to enhanced memory consolidation in mice. Importantly, human ApoE4 vectors lower levels of miRNAs than ApoE3 and therefore is less capable of metabolic and epigenetic regulation in neurons. Collectively, our findings define an astrocytic ApoE-mediated neuronal epigenetic mechanism as a novel means through which astrocytes modulate brain connectivity and function.

A Bioinspired Neural Network-Based Approach for Cooperative Coverage Planning of UAVs

This paper describes a bioinspired neural-network-based approach to solve a coverage planning problem for a fleet of unmanned aerial vehicles exploring critical areas. The main goal is to fully cover the map, maintaining a uniform distribution of the fleet on the map, and avoiding collisions between vehicles and other obstacles. This specific task is suitable for surveillance applications, where the uniform distribution of the fleet in the map permits them to reach any position on the map as fast as possible in emergency scenarios. To solve this problem, a bioinspired neural network structure is adopted. Specifically, the neural network consists of a grid of neurons, where each neuron has a local cost and has a local connection only with neighbor neurons. The cost of each neuron influences the cost of its neighbors, generating an attractive contribution to unvisited neurons. We introduce several controls and precautions to minimize the risk of collisions and optimize coverage planning. Then, preliminary simulations are performed in different scenarios by testing the algorithm in four maps and with fleets consisting of 3 to 10 vehicles. Results confirm the ability of the proposed approach to manage and coordinate the fleet providing the full coverage of the map in every tested scenario, avoiding collisions between vehicles, and uniformly distributing the fleet on the map.

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

WGEVIA: A Graph Level Embedding Method for Microcircuit Data.

Functional microcircuits are useful for studying interactions among neural dynamics of neighboring neurons during cognition and emotion. A functional microcircuit is a group of neurons that are spatially close, and that exhibit synchronized neural activities. For computational analysis, functional microcircuits are represented by graphs, which pose special challenges when applied as input to machine learning algorithms. Graph embedding, which involves the conversion of graph data into low dimensional vector spaces, is a general method for addressing these challenges. In this paper, we discuss limitations of conventional graph embedding methods that make them ill-suited to the study of functional microcircuits. We then develop a novel graph embedding framework, called Weighted Graph Embedding with Vertex Identity Awareness (WGEVIA), that overcomes these limitations. Additionally, we introduce a dataset, called the five vertices dataset, that helps in assessing how well graph embedding methods are suited to functional microcircuit analysis. We demonstrate the utility of WGEVIA through extensive experiments involving real and simulated microcircuit data.

Characterization of multiscale logic operations in the neural circuits

Background: Ever since the seminal work by McCulloch and Pitts, the theory of neural computation and its philosophical foundation known as 'computationalism' have been central to brain-inspired artificial intelligence (AI) technologies. The present study describes neural dynamics and neural coding approaches to understand the mechanisms of neural computation. The primary focus is to characterize the multiscale nature of logic computations in the brain, which might occur at a single neuron level, between neighboring neurons via synaptic transmission, and at the neural circuit level. Results: For this, we begin the analysis with simple neuron models to account for basic Boolean logic operations at a single neuron level and then move on to the phenomenological neuron models to explain the neural computation from the viewpoints of neural dynamics and neural coding. The roles of synaptic transmission in neural computation are investigated using biologically realistic multi-compartment neuron models: two representative computational entities, CA1 pyramidal neuron in the hippocampus and Purkinje fiber in the cerebellum, are analyzed in the information-theoretic framework. We then construct two-dimensional mutual information maps, which demonstrate that the synaptic transmission can process not only basic AND/OR Boolean logic operations but also the linearly non-separable XOR function. Finally, we provide an overview of the evolutionary algorithm and discuss its benefits in automated neural circuit design for logic operations. Conclusions: This study provides a comprehensive perspective on the multiscale logic operations in the brain from both neural dynamics and neural coding viewpoints. It should thus be beneficial for understanding computational principles of the brain and may help design biologically plausible neuron models for AI devices.

Delayed Treatment with Human Dental Pulp Stem Cells Accelerates Functional Recovery and Modifies Responses of Peri-Infarct Astrocytes Following Photothrombotic Stroke in Rats

Dental pulp contains multipotent mesenchymal stem cells that improve outcomes when administered early after temporary middle cerebral artery occlusion in rats. To further assess the therapeutic potential of these cells, we tested whether functional recovery following stroke induced by photothrombosis could be modified by a delayed treatment that was initiated after the infarct attained maximal volume. Photothrombosis induces permanent focal ischemia resulting in tissue changes that better reflect key aspects of the many human strokes in which early restoration of blood flow does not occur. Human dental pulp stem cells (approximately 400 × 103 viable cells) or vehicle were injected into the infarct and adjacent brain tissue of Sprague-Dawley rats at 3 days after the induction of unilateral photothrombotic stroke in the sensorimotor cortex. Forepaw function was tested up to 28 days after stroke. Cellular changes in peri-infarct tissue at 28 days were assessed using immunohistochemistry. Rats treated with the stem cells showed faster recovery compared with vehicle-treated animals in a test of forelimb placing in response to vibrissae stimulation and in first attempt success in a skilled forelimb reaching test. Total success in the skilled reaching test and forepaw use during exploration in a Perspex cylinder were not significantly different between the 2 groups. At 28 days after stroke, rats treated with the stem cells showed decreased immunolabeling for glial fibrillary acidic protein in tissue up to 1 mm from the infarct, suggesting decreased reactive astrogliosis. Synaptophysin, a marker of synapses, and collagen IV, a marker of capillaries, were not significantly altered at this time by the stem-cell treatment. These results indicate that dental pulp stem cells can accelerate recovery without modifying initial infarct formation. Decreases in reactive astrogliosis in peri-infarct tissue could have contributed to the change by promoting adaptive responses in neighboring neurons.

Electrolyte-gated transistors for neuromorphic applications

Von Neumann computers are currently failing to follow Moore’s law and are limited by the von Neumann bottleneck. To enhance computing performance, neuromorphic computing systems that can simulate the function of the human brain are being developed. Artificial synapses are essential electronic devices for neuromorphic architectures, which have the ability to perform signal processing and storage between neighboring artificial neurons. In recent years, electrolyte-gated transistors (EGTs) have been seen as promising devices in imitating synaptic dynamic plasticity and neuromorphic applications. Among the various electronic devices, EGT-based artificial synapses offer the benefits of good stability, ultra-high linearity and repeated cyclic symmetry, and can be constructed from a variety of materials. They also spatially separate “read” and “write” operations. In this article, we provide a review of the recent progress and major trends in the field of electrolyte-gated transistors for neuromorphic applications. We introduce the operation mechanisms of electric-double-layer and the structure of EGT-based artificial synapses. Then, we review different types of channels and electrolyte materials for EGT-based artificial synapses. Finally, we review the potential applications in biological functions.

Cortical transcriptome analysis after spinal cord injury reveals the regenerative mechanism of central nervous system in CRMP2 knock-in mice.

Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2 (CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function after spinal cord injury (SCI). We aimed to reveal the intracellular mechanism in axotomized neurons in the CRMP2 knock-in (CRMP2KI) mouse model by performing transcriptome analysis in mouse sensorimotor cortex using micro-dissection punching system. Prior to that, we analyzed the structural pathophysiology in axotomized or neighboring neurons after SCI and found that somatic atrophy and dendritic spine reduction in sensorimotor cortex were suppressed in CRMP2KI mice. Further analysis of the transcriptome has aided in the identification of four hemoglobin genes Hba-a1, Hba-a2, Hbb-bs, and Hbb-bt that are significantly upregulated in wild-type mice with concomitant upregulation of genes involved in the oxidative phosphorylation and ribosomal pathways after SCI. However, we observed substantial upregulation in channel activity genes and downregulation of genes regulating vesicles, synaptic function, glial cell differentiation in CRMP2KI mice. Moreover, the transcriptome profile of CRMP2KI mice has been discussed wherein energy metabolism and neuronal pathways were found to be differentially regulated. Our results showed that CRMP2KI mice displayed improved SCI pathophysiology not only via microtubule stabilization in neurons, but also possibly via the whole metabolic system in the central nervous system, response changes in glial cells, and synapses. Taken together, we reveal new insights on SCI pathophysiology and the regenerative mechanism of central nervous system by the inhibition of CRMP2 phosphorylation at Ser522. All these experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee at Waseda University, Japan (2017-A027 approved on March 21, 2017; 2018-A003 approved on March 25, 2018; 2019-A026 approved on March 25, 2019).

Curvature-processing domains in primate V4.

Neurons in primate V4 exhibit various types of selectivity for contour shapes, including curves, angles, and simple shapes. How are these neurons organized in V4 remains unclear. Using intrinsic signal optical imaging and two-photon calcium imaging, we observed submillimeter functional domains in V4 that contained neurons preferring curved contours over rectilinear ones. These curvature domains had similar sizes and response amplitudes as orientation domains but tended to separate from these regions. Within the curvature domains, neurons that preferred circles or curve orientations clustered further into finer scale subdomains. Nevertheless, individual neurons also had a wide range of contour selectivity, and neighboring neurons exhibited a substantial diversity in shape tuning besides their common shape preferences. In strong contrast to V4, V1 and V2 did not have such contour-shape-related domains. These findings highlight the importance and complexity of curvature processing in visual object recognition and the key functional role of V4 in this process.

How Do Cortical Excitatory Neurons Terminate Their Migration at the Right Place? Critical Roles of Environmental Elements.

Interactions between neurons and their environment are crucial for proper termination of neuronal migration during brain development. In this review, we first introduce the migration behavior of cortical excitatory neurons from neurogenesis to migration termination, focusing on morphological and behavioral changes. We then describe possible requirements for environmental elements, including extracellular matrix proteins and Cajal–Retzius cells in the marginal zone, radial glial cells, and neighboring neurons, to ensure proper migration termination of these neurons at their final destinations. The requirements appear to be highly linked to sequential and/or concurrent changes in adhesiveness of migrating neurons and their surroundings, which allow the neurons to reach their final positions, detach from substrates, and establish stable laminar structures.

Information-Limiting Correlations in Neural Populations: The Devil Is in the Details

Neurons are noisy. Neuronal activity varies in response to repetitions of the same stimulus. Neuronal noise is ubiquitous in the brain and is often correlated among neighboring neurons, which means that stimulus-independent fluctuations in neuronal activity can affect entire populations of cells ([