Neural Circuit Function Research Articles

An activity-dependent determinant of synapse elimination in the mammalian brain

To establish functional neural circuits in the brain, synaptic connections are refined by neural activity during development, where active connections are maintained and inactive ones are eliminated. However, the molecular signals that regulate synapse refinement remain to be elucidated. When we inactivate a subset of neurons in the mouse cingulate cortex, their callosal connections are eliminated through activity-dependent competition. Using this system, we identify JAK2 tyrosine kinase as a key regulator of inactive synapse elimination. We show that JAK2 is necessary and sufficient for elimination of inactive connections; JAK2 is activated at inactive synapses in response to signals from other active synapses; STAT1, a substrate of JAK2, mediates inactive synapse elimination; JAK2 signaling is critical for physiological refinement of synapses during normal development; and JAK2 regulates synapse refinement in multiple brain regions. We propose that JAK2 is an activity-dependent switch that serves as a determinant of inactive synapse elimination.

Multiplexing viral approaches to the study of the neuronal circuits

Neural circuits are composed of multitudes of elaborately interconnected cell types. Understanding neural circuit function requires not only cell-specific knowledge of connectivity, but the ability to record and manipulate distinct cell types independently. Recent advances in viral vectors promise the requisite specificity to perform true “circuit-breaking” experiments. However, such new avenues of multiplexed, cell-specific investigation raise new technical issues: one must ensure that both the viral vectors and their transgene payloads do not overlap with each other in both an anatomical and a functional sense. This review describes benefits and issues regarding the use of viral vectors to analyse the function of neural circuits and provides a resource for the design and implementation of such multiplexing experiments.

Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease.

Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR–GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR–GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn–mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1–mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1–mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction.

Microglia regulate synaptic development and plasticity.

Synapses are fundamental structures of neural circuits that transmit information between neurons. Thus, the process of neural circuit formation via proper synaptic connections shapes the basis of brain functions and animal behavior. Synapses continuously undergo repeated formation and elimination throughout the lifetime of an organism, reflecting the dynamics of neural circuit function. The structural transformation of synapses has been described mainly in relation to neural activity‐dependent strengthening and weakening of synaptic functions, that is, functional plasticity of synapses. An increasing number of studies have unveiled the roles of microglia, brain‐resident immune cells that survey the brain parenchyma with highly motile processes, in synapse formation and elimination as well as in regulating synaptic function. Over the past 15 years, the molecular mechanisms underlying microglia‐dependent regulation of synaptic plasticity have been thoroughly studied, and researchers have reported that the disruption of microglia‐dependent regulation causes synaptic dysfunction that leads to brain diseases. In this review, we will broadly introduce studies that report the roles of microglia in synaptic plasticity and the possible underlying molecular mechanisms.

Light Stimuli and Circadian Clock Affect Neural Development in Drosophila melanogaster.

Endogenous clocks enable organisms to adapt cellular processes, physiology, and behavior to daily variation in environmental conditions. Metabolic processes in cyanobacteria to humans are under the influence of the circadian clock, and dysregulation of the circadian clock causes metabolic disorders. In mouse and Drosophila, the circadian clock influences translation of factors involved in ribosome biogenesis and synchronizes protein synthesis. Notably, nutrition signals are mediated by the insulin receptor/target of rapamycin (InR/TOR) pathways to regulate cellular metabolism and growth. However, the role of the circadian clock in Drosophila brain development and the potential impact of clock impairment on neural circuit formation and function is less understood. Here we demonstrate that changes in light stimuli or disruption of the molecular circadian clock cause a defect in neural stem cell growth and proliferation. Moreover, we show that disturbed cell growth and proliferation are accompanied by reduced nucleolar size indicative of impaired ribosomal biogenesis. Further, we define that light and clock independently affect the InR/TOR growth regulatory pathway due to the effect on regulators of protein biosynthesis. Altogether, these data suggest that alterations in InR/TOR signaling induced by changes in light conditions or disruption of the molecular clock have an impact on growth and proliferation properties of neural stem cells in the developing Drosophila brain.

Moral & Intellectual Life of the West

From the earliest times, American ethics, the rules for the moral & intellectual life of the West, used to be founded upon the two principles of self-reliance and good neighborliness. Here we consider the underlying functions of neural brain circuits, organic structures that have evolved adaptively by Darwinian rules subject to selection pressure. In the left brain resides our self-reliant private Ego, making plans, launching initiatives. Your public Ego dwells in the right brain, looking around, meeting with your friendly neighbor. A main component is our bilateral interior cosmos, providing us with all the detailed information about our environment as well as the universe at large.

Open science takes on Parkinson's disease.

The Aligning Science Across Parkinson’s (ASAP) initiative was set up to improve understanding of the biology underlying the onset and progression of Parkinson’s disease. With an emphasis on open science and collaboration, we have assembled a research network led by nearly 100 investigators to explore the pathology of Parkinson’s disease, and this network will soon expand to include researchers working on relevant (dys)-functional neural circuits. We have also contributed to large-scale genetics and patient cohort initiatives related to the disease. We hope that these actions, and others planned for the future, will deepen our knowledge of the molecular mechanisms underlying the origin and evolution of Parkinson’s disease and, ultimately, contribute to the development of novel therapies.

A Functional Spiking Neural Network of Ultra Compact Neurons.

We demonstrate that recently introduced ultra-compact neurons (UCN) with a minimal number of components can be interconnected to implement a functional spiking neural network. For concreteness we focus on the Jeffress model, which is a classic neuro-computational model proposed in the 40’s to explain the sound directionality detection by animals and humans. In addition, we introduce a long-axon neuron, whose architecture is inspired by the Hodgkin-Huxley axon delay-line and where the UCNs implement the nodes of Ranvier. We then interconnect two of those neurons to an output layer of UCNs, which detect coincidences between spikes propagating down the long-axons. This functional spiking neural neuron circuit with biological relevance is built from identical UCN blocks, which are simple enough to be made with off-the-shelf electronic components. Our work realizes a new, accessible and affordable physical model platform, where neuroscientists can construct arbitrary mid-size spiking neuronal networks in a lego-block like fashion that work in continuous time. This should enable them to address in a novel experimental manner fundamental questions about the nature of the neural code and to test predictions from mathematical models and algorithms of basic neurobiology research. The present work aims at opening a new experimental field of basic research in Spiking Neural Networks to a potentially large community, which is at the crossroads of neurobiology, dynamical systems, theoretical neuroscience, condensed matter physics, neuromorphic engineering, artificial intelligence, and complex systems.

Establishment and Maintenance of Neural Circuit Architecture.

The ability to sense the world, process information, and navigate the environment depends on the assembly and continuous function of neural circuits in the brain. Within the past two decades, new technologies have rapidly advanced our understanding of how neural circuits are wired during development and how they are stably maintained, often for years. Electron microscopy reconstructions of model organism connectomes have provided a map of the stereotyped (and variable) connections in the brain; advanced light microscopy techniques have enabled direct observation of the cellular dynamics that underlie circuit construction and maintenance; transcriptomic and proteomic surveys of both developing and mature neurons have provided insights into the molecular and genetic programs governing circuit establishment and maintenance; and advanced genetic techniques have allowed for high-throughput discovery of wiring regulators. These tools have empowered scientists to rapidly generate and test hypotheses about how circuits establish and maintain connectivity. Thus, the set of principles governing circuit formation and maintenance have been expanded. These principles are discussed in this review.

Auditory Brainstem Deficits from Early Treatment with a CSF1R Inhibitor Largely Recover with Microglial Repopulation.

Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB) was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R). Defective pruning of calyces of Held and significant reduction of the mature astrocyte marker glial fibrillary acidic protein (GFAP) were observed after hearing onset. Here, we investigated the time course required for microglia to populate the mouse MNTB after cessation of CSF1R inhibitor treatment. We then examined whether defects seen after microglial depletion were rectified by microglial repopulation. We found that microglia returned to control levels at four weeks of age (18 d postcessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at four weeks and GFAP expression recovered by seven weeks. We further investigated the effects of microglia elimination and repopulation on auditory function using auditory brainstem recordings (ABRs). Temporary microglial depletion significantly elevated auditory thresholds in response to 4. 8, and 12 kHz at four weeks. Treatment significantly affected latencies, interpeak latencies, and amplitudes of all the ABR peaks in response to many of the frequencies tested. These effects largely recovered by seven weeks. These findings highlight the functions of microglia in the formation of auditory neural circuits early in development. Further, the results suggest that microglia retain their developmental functions beyond the period of circuit refinement.

Developmental synaptic regulator, TWEAK/Fn14 signaling, is a determinant of synaptic function in models of stroke and neurodegeneration

Identifying molecular mediators of neural circuit development and/or function that contribute to circuit dysfunction when aberrantly reengaged in neurological disorders is of high importance. The role of the TWEAK/Fn14 pathway, which was recently reported to be a microglial/neuronal axis mediating synaptic refinement in experience-dependent visual development, has not been explored in synaptic function within the mature central nervous system. By combining electrophysiological and phosphoproteomic approaches, we show that TWEAK acutely dampens basal synaptic transmission and plasticity through neuronal Fn14 and impacts the phosphorylation state of pre- and postsynaptic proteins in adult mouse hippocampal slices. Importantly, this is relevant in two models featuring synaptic deficits. Blocking TWEAK/Fn14 signaling augments synaptic function in hippocampal slices from amyloid-beta-overexpressing mice. After stroke, genetic or pharmacological inhibition of TWEAK/Fn14 signaling augments basal synaptic transmission and normalizes plasticity. Our data support a glial/neuronal axis that critically modifies synaptic physiology and pathophysiology in different contexts in the mature brain and may be a therapeutic target for improving neurophysiological outcomes.

Proteomic Characterization of Human Neural Stem Cells and Their Secretome During in vitro Differentiation.

Cell therapies represent a promising approach to slow down the progression of currently untreatable neurodegenerative diseases (e.g., Alzheimer's and Parkinson's disease or amyotrophic lateral sclerosis), as well as to support the reconstruction of functional neural circuits after spinal cord injuries. In such therapies, the grafted cells could either functionally integrate into the damaged tissue, partially replacing dead or damaged cells, modulate inflammatory reaction, reduce tissue damage, or support neuronal survival by secretion of cytokines, growth, and trophic factors. Comprehensive characterization of cells and their proliferative potential, differentiation status, and population purity before transplantation is crucial to preventing safety risks, e.g., a tumorous growth due to the proliferation of undifferentiated stem cells. We characterized changes in the proteome and secretome of human neural stem cells (NSCs) during their spontaneous (EGF/FGF2 withdrawal) differentiation and differentiation with trophic support by BDNF/GDNF supplementation. We used LC-MS/MS in SWATH-MS mode for global cellular proteome profiling and quantified almost three thousand cellular proteins. Our analysis identified substantial protein differences in the early stages of NSC differentiation with more than a third of all the proteins regulated (including known neuronal and NSC multipotency markers) and revealed that the BDNF/GDNF support affected more the later stages of the NSC differentiation. Among the pathways identified as activated during both spontaneous and BDNF/GDNF differentiation were the HIF-1 signaling pathway, Wnt signaling pathway, and VEGF signaling pathway. Our follow-up secretome analysis using Luminex multiplex immunoassay revealed significant changes in the secretion of VEGF and IL-6 during NSC differentiation. Our results further demonstrated an increased expression of neuropilin-1 as well as catenin β-1, both known to participate in the regulation of VEGF signaling, and showed that VEGF-A isoform 121 (VEGF121), in particular, induces proliferation and supports survival of differentiating cells.

Circumventing neural damage in a C.elegans chemosensory circuit using genetically engineered synapses.

Neuronal loss can considerably diminish neural circuit function, impairing normal behavior by disrupting information flow in the circuit. Here, we use genetically engineered electrical synapses to reroute the flow of information in a C.elegans damaged chemosensory circuit in order to restore organism behavior. We impaired chemotaxis by removing one pair of interneurons from the circuit then artificially coupled two other adjacent neuron pairs by ectopically expressing the gap junction protein, connexin, in them. This restored chemotaxis in the animals. We expected to observe linear and direct information flow between the connexin-coupled neurons in the recovered circuit but also revealed the formation of new potent left-right lateral electrical connections within the connexin-expressing neuron pairs. Our analysis suggests that these additional electrical synapses help restore circuit function by amplifying weakened neuronal signals in the damaged circuit in addition to emulating the wild-type circuit. A record of this paper's transparent peer review process is included in the Supplemental Information.

Scrap and Build for Functional Neural Circuits: Spatiotemporal Regulation of Dendrite Degeneration and Regeneration in Neural Development and Disease.

Dendrites are cellular structures essential for the integration of neuronal information. These elegant but complex structures are highly patterned across the nervous system but vary tremendously in their size and fine architecture, each designed to best serve specific computations within their networks. Recent in vivo imaging studies reveal that the development of mature dendrite arbors in many cases involves extensive remodeling achieved through a precisely orchestrated interplay of growth, degeneration, and regeneration of dendritic branches. Both degeneration and regeneration of dendritic branches involve precise spatiotemporal regulation for the proper wiring of functional networks. In particular, dendrite degeneration must be targeted in a compartmentalized manner to avoid neuronal death. Dysregulation of these developmental processes, in particular dendrite degeneration, is associated with certain types of pathology, injury, and aging. In this article, we review recent progress in our understanding of dendrite degeneration and regeneration, focusing on molecular and cellular mechanisms underlying spatiotemporal control of dendrite remodeling in neural development. We further discuss how developmental dendrite degeneration and regeneration are molecularly and functionally related to dendrite remodeling in pathology, disease, and aging.

Organ-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways

The vagus nerve supports diverse autonomic functions and behaviors important for health and survival. To understand how specific components of the vagus contribute to behaviors and long-term physiological effects, it is critical to modulate their activity with anatomical specificity in awake, freely behaving conditions using reliable methods. Here, we introduce an organ-specific scalable, multimodal, wireless optoelectronic device for precise and chronic optogenetic manipulations in vivo. When combined with an advanced, coil-antenna system and a multiplexing strategy for powering 8 individual homecages using a single RF transmitter, the proposed wireless telemetry enables low cost, high-throughput, and precise functional mapping of peripheral neural circuits, including long-term behavioral and physiological measurements. Deployment of these technologies reveals an unexpected role for stomach, non-stretch vagal sensory fibers in suppressing appetite and demonstrates the durability of the miniature wireless device inside harsh gastric conditions.

Optogenetics in Caenorhabditis elegans.

With a compact neural circuit consisting of entirely mapped 302 neurons, Caenorhabditis elegans plays an important role in the development and application of optogenetics. Optogenetics in C. elegans offers the opportunity that drastically changes experimental designs with increasing accessibility for neural activity and various cellular processes, thereby accelerating the studies on the functions of neural circuits and multicellular systems. Combining optogenetics with other approaches such as electrophysiology increases the resolution of elucidation. In particular, technologies like patterned illumination specifically developed in combination with optogenetics provide new tools to interrogate neural functions. In this chapter, we introduce the reasons to use optogenetics in C. elegans, and discuss the technical issues raised, especially for C. elegans by revisiting our chapter in the first edition of this book. Throughout the chapter, we review early and recent milestone works using optogenetics to investigate a variety of biological systems including neural and behavioral regulation.

Functional Connectome Analysis of the Striatum with Optogenetics.

Neural circuit function is determined not only by anatomical connections but also by the strength and nature of the connections, that is functional or physiological connectivity. To elucidate functional connectivity, selective stimulation of presynaptic terminals of an identified neuronal population is crucial. However, in the central nervous system, intermingled input fibers make selective electrical stimulation impossible. With optogenetics, this becomes possible, and enables the comprehensive study of functional synaptic connections between an identified population of neurons and defined postsynaptic targets to determine the functional connectome. By stimulating convergent synaptic inputs impinging on individual postsynaptic neurons, low frequency and small amplitude synaptic connections can be detected. Further, the optogenetic approach enables the measurement of cotransmission and its relative strength. Recently, optogenetic methods have been more widely used to study synaptic connectivity and revealed novel synaptic connections and revised connectivity of known projections. In this chapter, I focus on functional synaptic connectivity in the striatum, the main input structure of the basal ganglia, involved in the motivated behavior, cognition, and motor control, and its disruption in a range of neuropsychiatric disorders.

Neuroplastic Effect of Exercise Through Astrocytes Activation and Cellular Crosstalk.

Physical exercise is an effective therapy for neurorehabilitation. Exercise has been shown to induce remodeling and proliferation of astrocyte. Astrocytes potentially affect the recruitment and function of neurons; they could intensify responses of neurons and bring more neurons for the process of neuroplasticity. Interactions between astrocytes, microglia and neurons modulate neuroplasticity and, subsequently, neural circuit function. These cellular interactions promote the number and function of synapses, neurogenesis, and cerebrovascular remodeling. However, the roles and crosstalk of astrocytes with neurons and microglia and any subsequent neuroplastic effects have not been studied extensively in exercise-induced settings. This article discusses the impact of physical exercise on astrocyte proliferation and highlights the interplay between astrocytes, microglia and neurons. The crosstalk between these cells may enhance neuroplasticity, leading to the neuroplastic effects of exercise.

Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive–behavioural therapy for eating disorders

IntroductionAnorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality...

Dynamic regulation of oxytocin neuronal circuits in the sequential processes of prosocial behavior in rodent models.

:The expression of positive social (i.e., prosocial) behavior is governed by a multitude of sensory and cognitive abilities to identify and recognize key features of potential social partners, elucidate social and individual status, and maintain appropriate behaviors. Oxytocin (OT) is a neuropeptide that has been implicated as a major player in regulating prosocial behavior, and much of its role in social situations has been uncovered. As social behavior inherently comprises sequential processes related to multimodal assessments of interactive features, a comprehensive approach to understanding the functions of OT in these prosocial behavior sequences is required. Here, the author discusses recent evidence illustrating the functioning of OT neural circuits in the processing of multimodal components of social behavior, including the detection/recognition of social cues via the olfactory bulb through olfactory cortices, evaluation of social features via the circuits of the paraventricular nucleus of the hypothalamus to the medial amygdala, and maintenance of prosocial behaviors via the circuits of the ventral tegmental area to the nucleus accumbens. A review of rodent studies with an emphasis on mice and rats is also provided to investigate the effects of OT in interaction with other neurotransmitters, such as serotonin and dopamine, to characterize the neuromodulatory mechanisms that mediate the sequences of prosocial engagements. The review further highlights OT function as a temporal dynamic of specific neural circuits.