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Journal of Neural Engineering Mar 2021. Accurate inference of functional connectivity is critical for understanding brain function. Previous methods have limited ability distinguishing between direct and...
. Accurate inference of functional connectivity is critical for understanding brain function. Previous methods have limited ability distinguishing between direct and indirect connections because of inadequate scaling with dimensionality. This poor scaling performance reduces the number of nodes that can be included in conditioning. Our goal was to provide a technique that scales better and thereby enables minimization of indirect connections.. Our major contribution is a powerful model-free framework, graphical directed information (GDI), that enables pairwise directed functional connections to be conditioned on the activity of substantially more nodes in a network, producing a more accurate graph of functional connectivity that reduces indirect connections. The key technology enabling this advancement is a recent advance in the estimation of mutual information (MI), which relies on multilayer perceptrons and exploiting an alternative representation of the Kullback-Leibler divergence definition of MI. Our second major contribution is the application of this technique to both discretely valued and continuously valued time series.. GDI correctly inferred the circuitry of arbitrary Gaussian, nonlinear, and conductance-based networks. Furthermore, GDI inferred many of the connections of a model of a central pattern generator circuit in, while also reducing many indirect connections.. GDI is a general and model-free technique that can be used on a variety of scales and data types to provide accurate direct connectivity graphs and addresses the critical issue of indirect connections in neural data analysis.
Topics: Brain; Magnetic Resonance Imaging; Models, Neurological; Nerve Net; Neural Networks, Computer
PubMed: 33684898
DOI: 10.1088/1741-2552/abecc6 -
Frontiers in Computational Neuroscience 2023The dynamical properties of the brain and the dynamics of the body strongly influence one another. Their interaction generates complex adaptive behavior. While a wide...
UNLABELLED
The dynamical properties of the brain and the dynamics of the body strongly influence one another. Their interaction generates complex adaptive behavior. While a wide variety of simulation tools exist for neural dynamics or biomechanics separately, there are few options for integrated brain-body modeling. Here, we provide a tutorial to demonstrate how the widely-used NEURON simulation platform can support integrated neuromechanical modeling. As a first step toward incorporating biomechanics into a NEURON simulation, we provide a framework for integrating inputs from a "periphery" and outputs to that periphery. In other words, "body" dynamics are driven in part by "brain" variables, such as voltages or firing rates, and "brain" dynamics are influenced by "body" variables through sensory feedback. To couple the "brain" and "body" components, we use NEURON's construct to share information between "brain" and "body" modules. This approach allows separate specification of brain and body dynamics and code reuse. Though simple in concept, the use of pointers can be challenging due to a complicated syntax and several different programming options. In this paper, we present five different computational models, with increasing levels of complexity, to demonstrate the concepts of code modularity using pointers and the integration of neural and biomechanical modeling within NEURON. The models include: (1) a neuromuscular model of calcium dynamics and muscle force, (2) a neuromechanical, closed-loop model of a half-center oscillator coupled to a rudimentary motor system, (3) a closed-loop model of neural control for respiration, (4) a pedagogical model of a non-smooth "brain/body" system, and (5) a closed-loop model of feeding behavior in the sea hare that incorporates biologically-motivated non-smooth dynamics. This tutorial illustrates how NEURON can be integrated with a broad range of neuromechanical models.
CODE AVAILABLE AT
https://github.com/fietkiewicz/PointerBuilder.
PubMed: 37583894
DOI: 10.3389/fncom.2023.1143323 -
Frontiers in Physiology 2018Important insights into the selection pressures and core molecular modules contributing to the evolution of pain-related processes have come from studies of nociceptive... (Review)
Review
Important insights into the selection pressures and core molecular modules contributing to the evolution of pain-related processes have come from studies of nociceptive systems in several molluscan and arthropod species. These phyla, and the chordates that include humans, last shared a common ancestor approximately 550 million years ago. Since then, animals in these phyla have continued to be subject to traumatic injury, often from predators, which has led to similar adaptive behaviors (e.g., withdrawal, escape, recuperative behavior) and physiological responses to injury in each group. Comparisons across these taxa provide clues about the contributions of convergent evolution and of conservation of ancient adaptive mechanisms to general nociceptive and pain-related functions. Primary nociceptors have been investigated extensively in a few molluscan and arthropod species, with studies of long-lasting nociceptive sensitization in the gastropod, , and the insect, , being especially fruitful. In , nociceptive sensitization has been investigated as a model for aversive memory and for hyperalgesia. Neuromodulator-induced, activity-dependent, and axotomy-induced plasticity mechanisms have been defined in synapses, cell bodies, and axons of primary nociceptors. Studies of nociceptive sensitization in larvae have revealed numerous molecular contributors in primary nociceptors and interacting cells. Interestingly, molecular contributors examined thus far in and are largely different, but both sets overlap extensively with those in mammalian pain-related pathways. In contrast to results from and , nociceptive sensitization examined in moth larvae () disclosed central hyperactivity but no obvious peripheral sensitization of nociceptive responses. Squid () show injury-induced sensitization manifested as behavioral hypersensitivity to tactile and especially visual stimuli, and as hypersensitivity and spontaneous activity in nociceptor terminals. Temporary blockade of nociceptor activity during injury subsequently increased mortality when injured squid were exposed to fish predators, providing the first demonstration in any animal of the adaptiveness of nociceptive sensitization. Immediate responses to noxious stimulation and nociceptive sensitization have also been examined behaviorally and physiologically in a snail (), octopus (), crayfish (), hermit crab (), and shore crab (). Molluscs and arthropods have systems that suppress nociceptive responses, but whether opioid systems play antinociceptive roles in these phyla is uncertain.
PubMed: 30123137
DOI: 10.3389/fphys.2018.01049 -
Frontiers in Neuroscience 2020Luqin is a neuropeptide that was discovered and named on account of its expression in left upper quadrant cells of the abdominal ganglion in the mollusc . Subsequently,... (Review)
Review
Luqin is a neuropeptide that was discovered and named on account of its expression in left upper quadrant cells of the abdominal ganglion in the mollusc . Subsequently, luqin-type peptides were identified as cardio-excitatory neuropeptides in other molluscs and a cognate receptor was discovered in the pond snail Phylogenetic analyses have revealed that orthologs of molluscan luqin-type neuropeptides occur in other phyla; these include neuropeptides in ecdysozoans (arthropods, nematodes) that have a C-terminal RYamide motif (RYamides) and neuropeptides in ambulacrarians (echinoderms, hemichordates) that have a C-terminal RWamide motif (RWamides). Furthermore, precursors of luqin-type neuropeptides typically have a conserved C-terminal motif containing two cysteine residues, although the functional significance of this is unknown. Consistent with the orthology of the neuropeptides and their precursors, phylogenetic and pharmacological studies have revealed that orthologous G-protein coupled receptors (GPCRs) mediate effects of luqin-type neuropeptides in spiralians, ecdysozoans, and ambulacrarians. Luqin-type signaling originated in a common ancestor of the Bilateria as a paralog of tachykinin-type signaling but, unlike tachykinin-type signaling, luqin-type signaling was lost in chordates. This may largely explain why luqin-type signaling has received less attention than many other neuropeptide signaling systems. However, insights into the physiological actions of luqin-type neuropeptides (RYamides) in ecdysozoans have been reported recently, with roles in regulation of feeding and diuresis revealed in insects and roles in regulation of feeding, egg laying, locomotion, and lifespan revealed in the nematode Furthermore, characterization of a luqin-type neuropeptide in the starfish (phylum Echinodermata) has provided the first insights into the physiological roles of luqin-type signaling in a deuterostome. In conclusion, although luqin was discovered in over 30 years ago, there is still much to be learnt about luqin-type neuropeptide signaling. This will be facilitated in the post-genomic era by the emerging opportunities for experimental studies on a variety of invertebrate taxa.
PubMed: 32132900
DOI: 10.3389/fnins.2020.00130 -
Scientific Reports Jun 2021Electric currents can produce quick, reversible control of neural activity. Externally applied electric currents have been used in inhibiting certain ganglion cells in...
Electric currents can produce quick, reversible control of neural activity. Externally applied electric currents have been used in inhibiting certain ganglion cells in clinical practices. Via electromagnetic induction, a miniature-sized magnetic coil could provide focal stimulation to the ganglion neurons. Here we report that high-frequency stimulation with the miniature coil could reversibly block ganglion cell activity in marine mollusk Aplysia californica, regardless the firing frequency of the neurons, or concentration of potassium ions around the ganglion neurons. Presence of the ganglion sheath has minimal impact on the inhibitory effects of the coil. The inhibitory effect was local to the soma, and was sufficient in blocking the neuron's functional output. Biophysical modeling confirmed that the miniature coil induced a sufficient electric field in the vicinity of the targeted soma. Using a multi-compartment model of Aplysia ganglion neuron, we found that the high-frequency magnetic stimuli altered the ion channel dynamics that were essential for the sustained firing of action potentials in the soma. Results from this study produces several critical insights to further developing the miniature coil technology for neural control by targeting ganglion cells. The miniature coil provides an interesting neural modulation strategy in clinical applications and laboratory research.
Topics: Action Potentials; Animals; Aplysia; Ganglia, Invertebrate; Magnetic Fields; Neurons
PubMed: 34193906
DOI: 10.1038/s41598-021-93114-x -
Scientific Reports Oct 2020Numerous neurological dysfunctions are characterized by undesirable nerve activity. By providing reversible nerve blockage, electric stimulation with an implanted...
Numerous neurological dysfunctions are characterized by undesirable nerve activity. By providing reversible nerve blockage, electric stimulation with an implanted electrode holds promise in the treatment of these conditions. However, there are several limitations to its application, including poor bio-compatibility and decreased efficacy during chronic implantation. A magnetic coil of miniature size can mitigate some of these problems, by coating it with biocompatible material for chronic implantation. However, it is unknown if miniature coils could be effective in axonal blockage and, if so, what the underlying mechanisms are. Here we demonstrate that a submillimeter magnetic coil can reversibly block action potentials in the unmyelinated axons from the marine mollusk Aplysia californica. Using a multi-compartment model of the Aplysia axon, we demonstrate that the miniature coil causes a significant local depolarization in the axon, alters activation dynamics of the sodium channels, and prevents the traveling of the invading action potentials. With improved biocompatibility and capability of emitting high-frequency stimuli, micro coils provide an interesting alternative for electric blockage of axonal conductance in clinical settings.
Topics: Action Potentials; Animals; Aplysia; Axons; Magnetic Phenomena; Models, Neurological; Nerve Fibers, Unmyelinated; Neural Conduction
PubMed: 33093520
DOI: 10.1038/s41598-020-74891-3 -
Journal of Neurochemistry Oct 2016This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and... (Review)
Review
This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal studies in the first phase of the six-decade span of this review firmly established the cellular basis of behavior - a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long-term potentiation and long-term depression, was then discovered as being important for local circuit refinement in the context of memory formation and behavioral change and stabilization in the mammalian central nervous system. Direct demonstration of plasticity of neuronal circuit function in vivo, for example, hippocampal neurons forming place cell firing patterns, extended this concept. However, additional neurophysiologic and computational studies demonstrated that circuit development and stabilization additionally relies on non-Hebbian, homoeostatic, forms of plasticity, such as synaptic scaling and control of membrane intrinsic properties. Activity-dependent neurodevelopment was found to be associated with cell-wide adjustments in post-synaptic receptor density, and found to occur in conjunction with synaptic pruning. Pioneering cellular neurophysiologic studies demonstrated the critical roles of transmembrane signal transduction, NMDA receptor regulation, regulation of neural membrane biophysical properties, and back-propagating action potential in critical time-dependent coincidence detection in behavior-modifying circuits. Concerning the molecular mechanisms underlying these processes, regulation of gene transcription was found to serve as a bridge between experience and behavioral change, closing the 'nature versus nurture' divide. Both active DNA (de)methylation and regulation of chromatin structure have been validated as crucial regulators of gene transcription during learning. The discovery of protein synthesis dependence on the acquisition of behavioral change was an influential discovery in the neurochemistry of behavioral modification. Higher order cognitive functions such as decision making and spatial and language learning were also discovered to hinge on neural plasticity mechanisms. The role of disruption of these processes in intellectual disabilities, memory disorders, and drug addiction has recently been clarified based on modern genetic techniques, including in the human. The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life-span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as 'conceptual advances', as viewed by the author. The fifteen areas are delineated in the figure above. This article is part of the 60th Anniversary special issue.
Topics: Animals; Behavior; Brain; Humans; Learning; Long-Term Potentiation; Memory Disorders; Neuronal Plasticity
PubMed: 26875778
DOI: 10.1111/jnc.13580 -
The Journal of Neuroscience : the... Feb 2022Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of OC plasticity loci and their synergism have not been examined...
Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of OC plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of , and appetitive OC increases neuronal excitability and electrical coupling among several neurons leading to an increase in expression of ingestive behavior. Here, we used the analog of OC to investigate whether OC reduces the excitability of a neuron, B4, whose inhibitory connections decrease expression of ingestive behavior. We found OC decreased the excitability of B4. This change appeared intrinsic to B4 because it could be replicated with an analog of OC in isolated cultures of B4 neurons. In addition to changes in B4 excitability, OC decreased the strength of B4's inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the excitability of another neuron critical for feeding behavior, B8, or the B4-to-B8 inhibitory connection. A conductance-based circuit model indicated that reducing the B4-to-B51 synapse, or increasing B51 excitability, mediated the OC phenotype more effectively than did decreasing B4 excitability. We combined these modifications to examine whether they could act synergistically. Combinations including B51 synergistically enhanced feeding. Taken together, these results suggest modifications of diverse loci work synergistically to mediate OC and that some neurons are well suited to work synergistically with plasticity in other loci. The ways in which synergism of diverse plasticity loci mediate the change in motor patterns in operant conditioning (OC) are poorly understood. Here, we found that OC was in part mediated by decreasing the intrinsic excitability of a critical neuron of feeding behavior, and specifically reducing the strength of one of its inhibitory connections that targets a key decision-making neuron. A conductance-based computational model indicated that the known plasticity loci showed a surprising level of synergism to mediate the behavioral changes associated with OC. These results highlight the importance of understanding the diversity, specificity and synergy among different types of plasticity that encode memory. Also, because OC in is mediated by dopamine (DA), the present study provides insights into specific and synergistic mechanisms of DA-mediated reinforcement of behaviors.
Topics: Animals; Aplysia; Computer Simulation; Conditioning, Operant; Models, Neurological; Neuronal Plasticity; Neurons
PubMed: 34992131
DOI: 10.1523/JNEUROSCI.1722-21.2021 -
Journal of Integrative Neuroscience Dec 2020Invertebrate animal models show simple behaviors supported by neural circuits easily accessible for experimentation and yet complex enough to provide necessary...
Invertebrate animal models show simple behaviors supported by neural circuits easily accessible for experimentation and yet complex enough to provide necessary information on the cellular and molecular mechanisms that govern the vertebrate nervous system's function. The mechanisms underlying simple forms of learning have been extensively studied in the marine gastropod Aplysia californica, in which elementary non-associative learning of the behavioral habituation and sensitization type has been studied using the gill withdrawal reflex. A strong stimulus applied to the neck or tail improves the reflex response through heterosynaptic facilitation. The neurotransmitter serotonin is involved in both behavioral sensitization and dishabituation by acting through the second messenger cyclic adenosine monophosphate, protein kinase A, the phosphorylation of a K+ channel, causing its closure. This broadens the action potential profile, increases the influx of Ca2+ through voltage-gated Ca2+ channels, and enhances the neurotransmitter glutamate's release. Short-term memory is based on covalent modifications of pre-existing proteins, while long-term memory requires gene transcription, protein translation and growth of new synapses. Another simple invertebrate model is the leech Hirudo medicinalis. In nearly-intact preparations, the repetitive application of light electrical stimuli at the level of the caudal portion of the body wall can induce the habituation of swimming induction. At the same time, the stroke on the dorsal skin generates behavioral sensitization or dishabituation. Knowledge of the molecular mechanisms of activity-dependent forms of synaptic plasticity provides a basis for understanding the mechanisms underlying learning, memory, other forms of brain plasticity, and pathological conditions and suggests potential therapeutic interventions.
Topics: Animals; Aplysia; Behavior, Animal; Gene Expression; Habituation, Psychophysiologic; Hirudo medicinalis; Learning; Memory; Neuronal Plasticity; Reflex; Serotonin; Synaptic Transmission
PubMed: 33378841
DOI: 10.31083/j.jin.2020.04.318 -
Biomolecules Jul 2021It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by...
It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by enzymes of the NAD salvage pathway. Thereby, vacor is transformed into the NAD analog vacor adenine dinucleotide (VAD), a molecule that causes cell toxicity. Therefore, vacor may potentially be exploited to kill cancer cells. In this study, we have developed efficient enzymatic and chemical procedures to produce vacor analogs of NAD and nicotinamide riboside (NR). VAD was readily generated by a base-exchange reaction, replacing the nicotinamide moiety of NAD by vacor, catalyzed by ADP ribosyl cyclase. Additionally, we present the chemical synthesis of the nucleoside version of vacor, vacor riboside (VR). Similar to the physiological NAD precursor, NR, VR was converted to the corresponding mononucleotide (VMN) by nicotinamide riboside kinases (NRKs). This conversion is quantitative and very efficient. Consequently, phosphorylation of VR by NRKs represents a valuable alternative to produce the vacor analog of NMN, compared to its generation from vacor by nicotinamide phosphoribosyltransferase (NamPT).
Topics: ADP-ribosyl Cyclase; Animals; Antineoplastic Agents; Aplysia; Cell Proliferation; HEK293 Cells; Humans; NAD; Niacinamide; Phenylurea Compounds; Phosphotransferases (Alcohol Group Acceptor); Pyridinium Compounds
PubMed: 34356669
DOI: 10.3390/biom11071044