Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction

https://www.nature.com/articles/s41598-018-29331-

Respiration-coupled rhythms in prefrontal cortex: beyond if, to when, how, and why

Published in final edited form as: Brain Struct Funct. 2018 January ; 223(1): 11–16. doi:10.1007/s00429-017-1587-8.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794025

A biophysical model of striatal microcircuits suggests gamma and beta oscillations interleaved at delta/theta frequencies mediate periodicity in motor control

Striatal oscillatory activity is associated with movement, reward, and decision-making, and observed in several interacting frequency bands. Local field potential recordings in rodent striatum show dopamine- and reward-dependent transitions between two states: a "spontaneous" state involving β (∼15-30 Hz) and low γ (∼40-60 Hz), and a state involving θ (∼4-8 Hz) and high γ (∼60-100 Hz) in response to dopaminergic agonism and reward. The mechanisms underlying these rhythmic dynamics, their interactions, and their functional consequences are not well understood. In this paper, we propose a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms, as well as their modulation by dopamine. Building on previous modeling and experimental work suggesting that striatal projection neurons (SPNs) are capable of generating β oscillations, we show that networks of striatal fast-spiking interneurons (FSIs) are capable of generating δ/θ (ie, 2 to 6 Hz) and γ rhythms. Under simulated low dopaminergic tone our model FSI network produces low γ band oscillations, while under high dopaminergic tone the FSI network produces high γ band activity nested within a δ/θ oscillation. SPN networks produce β rhythms in both conditions, but under high dopaminergic tone, this β oscillation is interrupted by δ/θ-periodic bursts of γ-frequency FSI inhibition. Thus, in the high dopamine state, packets of FSI γ and SPN β alternate at a δ/θ timescale. In addition to a mechanistic explanation for previously observed rhythmic interactions and transitions, our model suggests a hypothesis as to how the relationship between dopamine and rhythmicity impacts motor function. We hypothesize that high dopamine-induced periodic FSI γ-rhythmic inhibition enables switching between β-rhythmic SPN cell assemblies representing the currently active motor program, and thus that dopamine facilitates movement in part by allowing for rapid, periodic shifts in motor program execution.R01 MH114877 - NIMH NIH HHSPublished versio

A biophysical model of striatal microcircuits suggests delta/theta - rhythmically interleaved gamma and beta oscillations mediate periodicity in motor control

First author draf

Interacting rhythms enhance sensitivity of target detection in a fronto-parietal computational model of visual attention

Even during sustained attention, enhanced processing of attended stimuli waxes and wanes rhythmically, with periods of enhanced and relatively diminished visual processing (and subsequent target detection) alternating at 4 or 8 Hz in a sustained visual attention task. These alternating attentional states occur alongside alternating dynamical states, in which lateral intraparietal cortex (LIP), the frontal eye field (FEF), and the mediodorsal pulvinar exhibit different activity and functional connectivity at α, β, and γ frequencies—rhythms associated with visual processing, working memory, and motor suppression. To assess whether and how these multiple interacting rhythms contribute to periodicity in attention, we propose a detailed computational model of FEF and LIP, which reproduced the rhythmic dynamics and behavioral consequences of observed attentional states when driven by θ-rhythmic inputs simulating experimentally-observed pulvinar activity. This model reveals that the frequencies and mechanisms of the observed rhythms allow for peak sensitivity in visual target detection while maintaining functional flexibility.https://www.biorxiv.org/content/10.1101/2021.02.18.431872v

DynaSim: a MATLAB toolbox for neural modeling and simulation

[EN] DynaSim is an open-source MATLAB/GNU Octave toolbox for rapid prototyping of neural models and batch simulation management. It is designed to speed up and simplify the process of generating, sharing, and exploring network models of neurons with one or more compartments. Models can be specified by equations directly (similar to XPP or the Brian simulator) or by lists of predefined or custom model components. The higher-level specification supports arbitrarily complex population models and networks of interconnected populations. DynaSim also includes a large set of features that simplify exploring model dynamics over parameter spaces, running simulations in parallel using both multicore processors and high-performance computer clusters, and analyzing and plotting large numbers of simulated data sets in parallel. It also includes a graphical user interface (DynaSim GUI) that supports full functionality without requiring user programming. The software has been implemented in MATLAB to enable advanced neural modeling using MATLAB, given its popularity and a growing interest in modeling neural systems. The design of DynaSim incorporates a novel schema for model specification to facilitate future interoperability with other specifications (e.g., NeuroML, SBML), simulators (e.g., NEURON, Brian, NEST), and web-based applications (e.g., Geppetto) outside MATLAB. DynaSim is freely available at http://dynasimtoolbox.org. This tool promises to reduce barriers for investigating dynamics in large neural models, facilitate collaborative modeling, and complement other tools being developed in the neuroinformatics community.This material is based upon research supported by the U.S. Army Research Office under award number ARO W911NF-12-R-0012-02, the U.S. Office of Naval Research under award number ONR MURI N00014-16-1-2832, and the National Science Foundation under award number NSF DMS-1042134 (Cognitive Rhythms Collaborative: A Discovery Network)Sherfey, JS.; Soplata, AE.; Ardid-Ramírez, JS.; Roberts, EA.; Stanley, DA.; Pittman-Polletta, BR.; Kopell, NJ. (2018). DynaSim: a MATLAB toolbox for neural modeling and simulation. Frontiers in Neuroinformatics. 12:1-15. https://doi.org/10.3389/fninf.2018.00010S11512Bokil, H., Andrews, P., Kulkarni, J. E., Mehta, S., & Mitra, P. P. (2010). Chronux: A platform for analyzing neural signals. Journal of Neuroscience Methods, 192(1), 146-151. doi:10.1016/j.jneumeth.2010.06.020Brette, R., Rudolph, M., Carnevale, T., Hines, M., Beeman, D., Bower, J. M., … Destexhe, A. (2007). Simulation of networks of spiking neurons: A review of tools and strategies. Journal of Computational Neuroscience, 23(3), 349-398. doi:10.1007/s10827-007-0038-6Börgers, C., & Kopell, N. (2005). Effects of Noisy Drive on Rhythms in Networks of Excitatory and Inhibitory Neurons. Neural Computation, 17(3), 557-608. doi:10.1162/0899766053019908Ching, S., Cimenser, A., Purdon, P. L., Brown, E. N., & Kopell, N. J. (2010). Thalamocortical model for a propofol-induced  -rhythm associated with loss of consciousness. Proceedings of the National Academy of Sciences, 107(52), 22665-22670. doi:10.1073/pnas.1017069108Delorme, A., & Makeig, S. (2004). EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. Journal of Neuroscience Methods, 134(1), 9-21. doi:10.1016/j.jneumeth.2003.10.009Durstewitz, D., Seamans, J. K., & Sejnowski, T. J. (2000). Neurocomputational models of working memory. Nature Neuroscience, 3(S11), 1184-1191. doi:10.1038/81460EatonJ. W. BatemanD. HaubergS. WehbringR. GNU Octave Version 4.2.0 Manual: A High-Level Interactive Language for Numerical Computations2016Ermentrout, B. (2002). Simulating, Analyzing, and Animating Dynamical Systems. doi:10.1137/1.9780898718195FitzHugh, R. (1955). Mathematical models of threshold phenomena in the nerve membrane. The Bulletin of Mathematical Biophysics, 17(4), 257-278. doi:10.1007/bf02477753Gewaltig, M.-O., & Diesmann, M. (2007). NEST (NEural Simulation Tool). Scholarpedia, 2(4), 1430. doi:10.4249/scholarpedia.1430Gleeson, P., Crook, S., Cannon, R. C., Hines, M. L., Billings, G. O., Farinella, M., … Silver, R. A. (2010). NeuroML: A Language for Describing Data Driven Models of Neurons and Networks with a High Degree of Biological Detail. PLoS Computational Biology, 6(6), e1000815. doi:10.1371/journal.pcbi.1000815Goodman, D. (2008). Brian: a simulator for spiking neural networks in Python. Frontiers in Neuroinformatics, 2. doi:10.3389/neuro.11.005.2008Goodman, D. F. M. (2009). The Brian simulator. Frontiers in Neuroscience, 3(2), 192-197. doi:10.3389/neuro.01.026.2009Hines, M. L., & Carnevale, N. T. (1997). The NEURON Simulation Environment. Neural Computation, 9(6), 1179-1209. doi:10.1162/neco.1997.9.6.1179Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of Physiology, 117(4), 500-544. doi:10.1113/jphysiol.1952.sp004764Hucka, M., Finney, A., Sauro, H. M., Bolouri, H., Doyle, J. C., Kitano, H., … Wang. (2003). The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics, 19(4), 524-531. doi:10.1093/bioinformatics/btg015Izhikevich, E. M. (2003). Simple model of spiking neurons. IEEE Transactions on Neural Networks, 14(6), 1569-1572. doi:10.1109/tnn.2003.820440Kopell, N., Ermentrout, G. B., Whittington, M. A., & Traub, R. D. (2000). Gamma rhythms and beta rhythms have different synchronization properties. Proceedings of the National Academy of Sciences, 97(4), 1867-1872. doi:10.1073/pnas.97.4.1867Kramer, M. A., Roopun, A. K., Carracedo, L. M., Traub, R. D., Whittington, M. A., & Kopell, N. J. (2008). Rhythm Generation through Period Concatenation in Rat Somatosensory Cortex. PLoS Computational Biology, 4(9), e1000169. doi:10.1371/journal.pcbi.1000169Lorenz, E. N. (1963). Deterministic Nonperiodic Flow. Journal of the Atmospheric Sciences, 20(2), 130-141. doi:10.1175/1520-0469(1963)0202.0.co;2Markram, H., Meier, K., Lippert, T., Grillner, S., Frackowiak, R., Dehaene, S., … Saria, A. (2011). Introducing the Human Brain Project. Procedia Computer Science, 7, 39-42. doi:10.1016/j.procs.2011.12.015McDougal, R. A., Morse, T. M., Carnevale, T., Marenco, L., Wang, R., Migliore, M., … Hines, M. L. (2016). Twenty years of ModelDB and beyond: building essential modeling tools for the future of neuroscience. Journal of Computational Neuroscience, 42(1), 1-10. doi:10.1007/s10827-016-0623-7Meng, L., Kramer, M. A., Middleton, S. J., Whittington, M. A., & Eden, U. T. (2014). A Unified Approach to Linking Experimental, Statistical and Computational Analysis of Spike Train Data. PLoS ONE, 9(1), e85269. doi:10.1371/journal.pone.0085269Morris, C., & Lecar, H. (1981). Voltage oscillations in the barnacle giant muscle fiber. 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Fractal Patterns of Neural Activity Exist within the Suprachiasmatic Nucleus and Require Extrinsic Network Interactions

The mammalian central circadian pacemaker (the suprachiasmatic nucleus, SCN) contains thousands of neurons that are coupled through a complex network of interactions. In addition to the established role of the SCN in generating rhythms of ∼24 hours in many physiological functions, the SCN was recently shown to be necessary for normal self-similar/fractal organization of motor activity and heart rate over a wide range of time scales—from minutes to 24 hours. To test whether the neural network within the SCN is sufficient to generate such fractal patterns, we studied multi-unit neural activity of in vivo and in vitro SCNs in rodents. In vivo SCN-neural activity exhibited fractal patterns that are virtually identical in mice and rats and are similar to those in motor activity at time scales from minutes up to 10 hours. In addition, these patterns remained unchanged when the main afferent signal to the SCN, namely light, was removed. However, the fractal patterns of SCN-neural activity are not autonomous within the SCN as these patterns completely broke down in the isolated in vitro SCN despite persistence of circadian rhythmicity. Thus, SCN-neural activity is fractal in the intact organism and these fractal patterns require network interactions between the SCN and extra-SCN nodes. Such a fractal control network could underlie the fractal regulation observed in many physiological functions that involve the SCN, including motor control and heart rate regulation

Differential contributions of synaptic and intrinsic inhibitory currents to speech segmentation via flexible phase-locking in neural oscillators

Current hypotheses suggest that speech segmentation-the initial division and grouping of the speech stream into candidate phrases, syllables, and phonemes for further linguistic processing-is executed by a hierarchy of oscillators in auditory cortex. Theta (∼3-12 Hz) rhythms play a key role by phase-locking to recurring acoustic features marking syllable boundaries. Reliable synchronization to quasi-rhythmic inputs, whose variable frequency can dip below cortical theta frequencies (down to ∼1 Hz), requires "flexible" theta oscillators whose underlying neuronal mechanisms remain unknown. Using biophysical computational models, we found that the flexibility of phase-locking in neural oscillators depended on the types of hyperpolarizing currents that paced them. Simulated cortical theta oscillators flexibly phase-locked to slow inputs when these inputs caused both (i) spiking and (ii) the subsequent buildup of outward current sufficient to delay further spiking until the next input. The greatest flexibility in phase-locking arose from a synergistic interaction between intrinsic currents that was not replicated by synaptic currents at similar timescales. Flexibility in phase-locking enabled improved entrainment to speech input, optimal at mid-vocalic channels, which in turn supported syllabic-timescale segmentation through identification of vocalic nuclei. Our results suggest that synaptic and intrinsic inhibition contribute to frequency-restricted and -flexible phase-locking in neural oscillators, respectively. Their differential deployment may enable neural oscillators to play diverse roles, from reliable internal clocking to adaptive segmentation of quasi-regular sensory inputs like speech.Wellcome Trust; P50 MH109429 - NIMH NIH HHS; R01 MH111439 - NIMH NIH HHS; 098353 - Wellcome TrustPublished versio

Differential contributions of synaptic and intrinsic inhibitory currents to speech segmentation via flexible phase-locking in neural oscillators

Now published in PLOS Computational Biology doi: 10.1371/journal.pcbi.1008783.Current hypotheses suggest that speech segmentation – the initial division and grouping of the speech stream into candidate phrases, syllables, and phonemes for further linguistic processing – is executed by a hierarchy of oscillators in auditory cortex. Theta (~3-12 Hz) rhythms play a key role by phase-locking to recurring acoustic features marking syllable boundaries. Reliable synchronization to quasi-rhythmic inputs, whose variable frequency can dip below cortical theta frequencies (down to ~1 Hz), requires “flexible” theta oscillators whose underlying neuronal mechanisms remain unknown. Using biophysical computational models, we found that the flexibility of phase-locking in neural oscillators depended on the types of hyperpolarizing currents that paced them. Simulated cortical theta oscillators flexibly phase-locked to slow inputs when these inputs caused both (i) spiking and (ii) the subsequent buildup of outward current sufficient to delay further spiking until the next input. The greatest flexibility in phase-locking arose from a synergistic interaction between intrinsic currents that was not replicated by synaptic currents at similar timescales. Flexibility in phase-locking enabled improved entrainment to speech input, optimal at mid-vocalic channels, which in turn supported syllabic-timescale segmentation through identification of vocalic nuclei. Our results suggest that synaptic and intrinsic inhibition contribute to frequency-restricted and -flexible phase-locking in neural oscillators, respectively. Their differential deployment may enable neural oscillators to play diverse roles, from reliable internal clocking to adaptive segmentation of quasi-regular sensory inputs like speech. Author summary: Oscillatory activity in auditory cortex is believed to play an important role in auditory and speech processing. One suggested function of these rhythms is to divide the speech stream into candidate phonemes, syllables, words, and phrases, to be matched with learned linguistic templates. This requires brain rhythms to flexibly synchronize with regular acoustic features of the speech stream. How neuronal circuits implement this task remains unknown. In this study, we explored the contribution of inhibitory currents to flexible phase-locking in neuronal theta oscillators, believed to perform initial syllabic segmentation. We found that a combination of specific intrinsic inhibitory currents at multiple timescales, present in a large class of cortical neurons, enabled exceptionally flexible phase-locking, which could be used to precisely segment speech by identifying vowels at mid-syllable. This suggests that the cells exhibiting these currents are a key component in the brain’s auditory and speech processing architecture.https://journals.plos.org/ploscompbiol/article/peerReview?id=10.1371/journal.pcbi.100878