A typical Go/No-Go decision is suggested to be implemented in the brain via the activation of the direct or indirect pathway in the basal ganglia. Medium spiny neurons (MSNs) in the striatum, receiving input from cortex and projecting to the direct and indirect pathways express D1 and D2 type dopamine receptors, respectively. Recently, it has become clear that the two types of MSNs markedly differ in their mutual and recurrent connectivities as well as feedforward inhibition from FSIs. Therefore, to understand striatal function in action selection, it is of key importance to identify the role of the distinct connectivities within and between the two types of MSNs on the balance of their activity. Here, we used both a reduced firing rate model and numerical simulations of a spiking network model of the striatum to analyze the dynamic balance of spiking activities in D1 and D2 MSNs. We show that the asymmetric connectivity of the two types of MSNs renders the striatum into a threshold device, indicating the state of cortical input rates and correlations by the relative activity rates of D1 and D2 MSNs. Next, we describe how this striatal threshold can be effectively modulated by the activity of fast spiking interneurons, by the dopamine level, and by the activity of the GPe via pallidostriatal backprojections. We show that multiple mechanisms exist in the basal ganglia for biasing striatal output in favour of either the `Go' or the `No-Go' pathway. This new understanding of striatal network dynamics provides novel insights into the putative role of the striatum in various behavioral deficits in patients with Parkinson's disease, including increased reaction times, L-Dopa-induced dyskinesia, and deep brain stimulation-induced impulsivity.
Visual Abstract Significance StatementRecent findings suggest that striatal activity is organized in spatially compact neuron clusters. Here, we show that striatal projection neurons should have a nonmonotonically changing distance-dependent connectivity to obtain spatially localized activity patterns in striatum. Among the different states a striatal network can show, asynchronous-irregular and transition activity states closely resemble striatal activity in the healthy state. In contrast, strong cortical inputs as observed in Parkinson's disease drive the network into a winner-take-all state, in which the striatum loses its stimulus sensitivity. Thus, our model makes specific predictions about the spatial network connectivity in the striatum and provides new insights about how the striatum might make a transition from a healthy state to a Parkinson's disease state. The striatum is the main input nucleus of the basal ganglia. Characterizing striatal activity dynamics is crucial to understanding mechanisms underlying action selection, initiation, and execution. Here, we studied the effects of spatial network connectivity on the spatiotemporal structure of striatal activity. We show that a striatal network with nonmonotonically changing distance-dependent connectivity (according to a gamma distribution) can exhibit a wide repertoire of spatiotemporal dynamics, ranging from spatially homogeneous, asynchronous-irregular (AI) activity to a state with stable, spatially localized activity bumps, as in "winner-take-all" (WTA) dynamics. Among these regimes, the unstable activity bumps [transition activity (TA)] regime closely resembles the experimentally observed spatiotemporal activity dynamics and neuronal assemblies in the striatum. In contrast, striatal networks with monotonically decreasing distance-dependent connectivity (in a Gaussian fashion) can exhibit only an AI state. Thus, given the observation of spatially compact neuronal clusters in the striatum, our model suggests that recurrent connectivity among striatal projection neurons should vary nonmonotonically. In brain disorders such as Parkinson's disease, increased cortical inputs and high striatal firing rates are associated with a reduction in stimulus sensitivity. Consistent with this, our model suggests that strong cortical inputs drive the striatum to a WTA state, leading to low stimulus sensitivity and high variability. In contrast, the AI and TA states show high stimulus sensitivity and reliability. Thus, based on these results, we propose that in a healthy state the striatum operates in a AI/TA state and that lack of dopamine pushes it into a WTA state.
Table of contentsA1 Functional advantages of cell-type heterogeneity in neural circuitsTatyana O. SharpeeA2 Mesoscopic modeling of propagating waves in visual cortexAlain DestexheA3 Dynamics and biomarkers of mental disordersMitsuo KawatoF1 Precise recruitment of spiking output at theta frequencies requires dendritic h-channels in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneuronsVladislav Sekulić, Frances K. SkinnerF2 Kernel methods in reconstruction of current sources from extracellular potentials for single cells and the whole brainsDaniel K. Wójcik, Chaitanya Chintaluri, Dorottya Cserpán, Zoltán SomogyváriF3 The synchronized periods depend on intracellular transcriptional repression mechanisms in circadian clocks.Jae Kyoung Kim, Zachary P. Kilpatrick, Matthew R. Bennett, Kresimir JosićO1 Assessing irregularity and coordination of spiking-bursting rhythms in central pattern generatorsIrene Elices, David Arroyo, Rafael Levi, Francisco B. Rodriguez, Pablo VaronaO2 Regulation of top-down processing by cortically-projecting parvalbumin positive neurons in basal forebrainEunjin Hwang, Bowon Kim, Hio-Been Han, Tae Kim, James T. McKenna, Ritchie E. Brown, Robert W. McCarley, Jee Hyun ChoiO3 Modeling auditory stream segregation, build-up and bistabilityJames Rankin, Pamela Osborn Popp, John RinzelO4 Strong competition between tonotopic neural ensembles explains pitch-related dynamics of auditory cortex evoked fieldsAlejandro Tabas, André Rupp, Emili Balaguer-BallesterO5 A simple model of retinal response to multi-electrode stimulationMatias I. Maturana, David B. Grayden, Shaun L. Cloherty, Tatiana Kameneva, Michael R. Ibbotson, Hamish MeffinO6 Noise correlations in V4 area correlate with behavioral performance in visual discrimination taskVeronika Koren, Timm Lochmann, Valentin Dragoi, Klaus ObermayerO7 Input-location dependent gain modulation in cerebellar nucleus neuronsMaria Psarrou, Maria Schilstra, Neil Davey, Benjamin Torben-Nielsen, Volker SteuberO8 Analytic solution of cable energy function for cortical axons and dendritesHuiwen Ju, Jiao Yu, Michael L. Hines, Liang Chen, Yuguo YuO9 C. elegans interactome: interactive visualization of Caenorhabditis elegans worm neuronal networkJimin Kim, Will Leahy, Eli ShlizermanO10 Is the model any good? Objective criteria for computational neuroscience model selectionJustas Birgiolas, Richard C. Gerkin, Sharon M. CrookO11 Cooperation and competition of gamma oscillation mechanismsAtthaphon Viriyopase, Raoul-Martin Memmesheimer, Stan GielenO12 A discrete structure of the brain wavesYuri Dabaghian, Justin DeVito, Luca PerottiO13 Direction-specific silencing of the Drosophila gaze stabilization systemAnmo J. Kim, Lisa M. Fenk, Cheng Lyu, Gaby MaimonO14 What does the fruit fly think about values? A model of olfactory associative learningChang Zhao, Yves Widmer, Simon Sprecher,Walter SennO15 Effects of ionic diffusion on power spectra of local field potentials (LFP)Geir Halnes, Tuomo Mäki-Marttunen, Daniel Keller, Klas H. Pettersen,Ole A. Andreassen...
The excess of 15-30 Hz (β-band) oscillations in the basal ganglia is one of the key signatures of Parkinson's disease (PD). The STN-GPe network is integral to generation and modulation of β band oscillations in basal ganglia. However, the role of changes in the firing rates and spike bursting of STN and GPe neurons in shaping these oscillations has remained unclear. In order to uncouple their effects, we studied the dynamics of STN-GPe network using numerical simulations. In particular, we used a neuron model, in which firing rates and spike bursting can be independently controlled. Using this model, we found that while STN firing rate is predictive of oscillations, GPe firing rate is not. The effect of spike bursting in STN and GPe neurons was state-dependent. That is, only when the network was operating in a state close to the border of oscillatory and non-oscillatory regimes, spike bursting had a qualitative effect on the β band oscillations. In these network states, an increase in GPe bursting enhanced the oscillations whereas an equivalent proportion of spike bursting in STN suppressed the oscillations. These results provide new insights into the mechanisms underlying the transient β bursts and how duration and power of β band oscillations may be controlled by an interplay of GPe and STN firing rates and spike bursts.
The classical model of basal ganglia has been refined in recent years with discoveries of subpopulations within a nucleus and previously unknown projections. One such discovery is the presence of subpopulations of arkypallidal and prototypical neurons in external globus pallidus, which was previously considered to be a primarily homogeneous nucleus. Developing a computational model of these multiple interconnected nuclei is challenging, because the strengths of the connections are largely unknown. We therefore use a genetic algorithm to search for the unknown connectivity parameters in a firing rate model. We apply a binary cost function derived from empirical firing rate and phase relationship data for the physiological and Parkinsonian conditions. Our approach generates ensembles of over 1,000 configurations, or homologies, for each condition, with broad distributions for many of the parameter values and overlap between the two conditions. However, the resulting effective weights of connections from or to prototypical and arkypallidal neurons are consistent with the experimental data. We investigate the significance of the weight variability by manipulating the parameters individually and cumulatively, and conclude that the correlation observed between the parameters is necessary for generating the dynamics of the two conditions. We then investigate the response of the networks to a transient cortical stimulus, and demonstrate that networks classified as physiological effectively suppress activity in the internal globus pallidus, and are not susceptible to oscillations, whereas parkinsonian networks show the opposite tendency. Thus, we conclude that the rates and phase relationships observed in the globus pallidus are predictive of experimentally observed higher level dynamical features of the physiological and parkinsonian basal ganglia, and that the multiplicity of solutions generated by our method may well be indicative of a natural diversity in basal ganglia networks. We propose that our approach of generating and analyzing an ensemble of multiple solutions to an underdetermined network model provides greater confidence in its predictions than those derived from a unique solution, and that projecting such homologous networks on a lower dimensional space of sensibly chosen dynamical features gives a better chance than a purely structural analysis at understanding complex pathologies such as Parkinson's disease.
The cerebellar cortex encodes sensorimotor adaptation during skilled locomotor behaviors, however the precise relationship between synaptic connectivity and behavior is unclear. We studied synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs) in murine acute cerebellar slices using photostimulation of caged glutamate combined with patch-clamp in developing or after mice adapted to different locomotor contexts. By translating individual maps into graph network entities, we found that synaptic maps in juvenile animals undergo critical period characterized by dissolution of their structure followed by the re-establishment of a patchy functional organization in adults. Although, in adapted mice, subdivisions in anatomical microzones do not fully account for the observed spatial map organization in relation to behavior, we can discriminate locomotor contexts with high accuracy. We also demonstrate that the variability observed in connectivity maps directly accounts for motor behavior traits at the individual level. Our findings suggest that, beyond general motor contexts, GC-PC networks also encode internal models underlying individual-specific motor adaptation.
The basal ganglia have been hypothesized to be involved in action selection, i.e. resolving competition between simultaneously activated motor programs. It has been shown that the direct pathway facilitates action execution whereas the indirect pathway inhibits it. However, as the pathways are both active during an action, it remains unclear whether their role is co-operative or competitive. In order to investigate this issue, we developed a striatal model consisting of D1 and D2 medium spiny neurons (MSNs) and interfaced it to a simulated robot moving in an environment. We demonstrate that this model is able to reproduce key behavioral features of several experiments involving optogenetic manipulation of the striatum, such as freezing and ambulation. We then investigate the interaction of D1- and D2-MSNs. We find that their fundamental relationship is co-operative within a channel and competitive between channels; this turns out to be crucial for action selection. However, individual pairs of D1- and D2-MSNs may exhibit predominantly competition or co-operation depending on their distance, and D1- and D2-MSNs population activity can alternate between co-operation and competition modes during a stimulation. Additionally, our results show that D2-D2 connectivity between channels is necessary for effective resolution of competition; in its absence, a conflict of two motor programs typically results in neither being selected.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.