Our main aim is to understand the cellular bases of motor behaviour with a focus on the mechanisms underlying selection of behavior and the neural bases of in particular locomotion.
This requires a detailed knowledge of which nerve cells take part, how they talk to each other through synaptic interaction and an understanding of the intrinsic function of these networks.
Essentially our research extends from ion channels and synapses to network mechanisms and behaviour utilising a multitude of techniques from patch clamp, tract tracing and cellular imaging to modelling and studies of behaviour. We utilise preferentially the lamprey as model organism.
We have been able to successfully model, based on detailed cellular knowledge, the networks responsible for the command and pattern generating systems for locomotion including steering and posture.
Our work continues with several foci including the role of the pallium/cortex, basal ganglia for selection of different patterns of motor behaviour, optic tectum for steering and eye motor coordination, the physiological role of different modulator systems acting through the spinal networks, and different ion channel subtypes contributing to neuronal function.
Our recent findings have shown that the lamprey forebrain has all components of the mammalian forebrain – a finding that has radically changed the view on the evolutionary origin of the vertebrate forebrain. The basic organisation had evolved 560 rather than 300 million years ago as previously believed.
The projects are supported by The Swedish Research Council, EU (Human Brain Project) and Karolinska Institutet.
The lamprey pallium/cortex is three-layered with an inner and outer granular layer and a molecular layer. The GABAergic cells are most abundant in the inner granular layer. Phylogenetically, a layered pallium/cortex has been demonstrated in mammals, birds, reptiles and the lamprey.
Visual, somatosensory and motor areas in the dorsal pallium and olfactory representation in the ventral pallium are a general and common schema of vertebrate pallial organisation.
a. Summarising schematic of the lamprey dorsal pallium, showing retinotopic visual areas, somatosensory areas and motor areas, as well as the retinal, trigeminal and dorsal column nucleus afferents relayed via distinct subpopulations of thalamic neurons.
b. The olfactory system in lamprey resembles that of mammals in many respects with a dual efferent system conveyed via tufted- and mitral-like cells. The latter target the olfactory cortex located in the ventral pallium, whereas the former target a separate limited region, the dmtn (dorsomedial telencephalic nucleus). The mitral-like (magenta) and tufted-like (blue) cells display different morphology.
The organisation of the basal ganglia including the dopamine system is virtually identical throughout vertebrate phylogeny – from lamprey to primates. This applies to the overall neural organisation, transmitters, peptides, synaptic connectivity and expression of ion channels.
The striatum consists of GABAergic neurons as do globus pallidus externa (GPe), globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr). SNr and GPi represent the output level of the basal ganglia, which project via different subpopulations of neurons to the optic tectum (superior colliculus), the mesencephalic (MLR) and diencephalic (DLR) locomotor command regions and additional brainstem motor centres, and also back to thalamus with efference copies of information sent to the brainstem. The indirect loop is represented by the GPe, the subthalamic nucleus (STN) and the output level (SNr/GPi) — the net effect being an enhancement of activity in these nuclei. The striatal neurons of the direct pathway to SNr/GPi express the dopamine D1 receptor (D1) and substance P (SP), while the indirect pathway neurons in striatum express the dopamine D2 receptor (D2) and enkephalin (Enk). Also indicated is the dopamine input from the substantia nigra pars compacta (SNc, green) to striatum and brainstem centres.
The optic tectum contains motor circuits for the control of eye and orienting/evasive movements and receives visual input arranged in a retinotopic map. The optic tectum is controlled from both the basal ganglia and cortex/pallium. We have used an isolated eye-brain preparation to allow for a detailed analysis.
The mechanisms underlying the operation of the forebrain and midbrain in action selection are being investigated through detailed modelling based on experimental data, on the systems level as well as on the cellular and subcellular levels.
Locomotor network of the lamprey. Left: Schematic representation of the forebrain, brainstem and spinal components of the neural circuitry generates rhythmic locomotor activity. Middle: Neuron model simulation using Hodgkin-Huxley formalism of the action potential with fast and slow afterhyperpolarisation (AHP) and synaptic properties. Right: Network model simulation of rhythmic, alternating activity in the spinal segmental network.
Network simulation of 10,000 neurons. (A) The activity of the network is shown in the form of a raster plot (Bottom) and spike histogram (Top). (B) Example traces of each cell type in the network are shown. The network is driven with cortical and thalamic input and modulated by dopamine, as indicated at the Top of the figure and the shaded areas (in A and B, respectively). The three inputs represent 1) baseline activation of cortical and thalamic input (thal+crtx baseline), 2) a cortical command signal (crtx cmd), during which the cortical activation is increased (given to all cells except the ChINs), and 3) a dopaminergic modulation signal that acts on conductances in accordance.
Both spinal and hypothalamic cerebrospinal fluid-contacting (CSF-c) neurons serve as pH sensors, thereby providing a novel homeostatic module for the regulation of pH in the CNS. In the spinal cord, acidic pH is mediated by the ASIC3 and alkaline pH via PKD2L1 channels, whereas in hypothalamus the acidic response is mediated via ASIC3 and alkaline pH via connexin hemichannels.
A GPU-based computational framework that bridges neuron simulation and artificial intelligence.
Zhang Y, He G, Ma L, Liu X, Hjorth JJJ, Kozlov A, He Y, Zhang S, Kotaleski JH, Tian Y, Grillner S, Du K, Huang T
Nat Commun 2023 Sep;14(1):5798
The Basal Ganglia Downstream Control of Action - An Evolutionarily Conserved Strategy.
Frost-Nylén J, Thompson WS, Robertson B, Grillner S
Curr Neuropharmacol 2023 Aug;():
Conserved subcortical processing in visuo-vestibular gaze control.
Wibble T, Pansell T, Grillner S, Pérez-Fernández J
Nat Commun 2022 08;13(1):4699
ExSTED microscopy reveals contrasting functions of dopamine and somatostatin CSF-c neurons along the lamprey central canal.
Jalalvand E, Alvelid J, Coceano G, Edwards S, Robertson B, Grillner S, Testa I
Elife 2022 02;11():
The neural bases of vertebrate motor behaviour through the lens of evolution.
Suryanarayana SM, Robertson B, Grillner S
Philos Trans R Soc Lond B Biol Sci 2022 02;377(1844):20200521
Dopaminergic and Cholinergic Modulation of Large Scale Networks in silico Using Snudda.
Frost Nylen J, Hjorth JJJ, Grillner S, Hellgren Kotaleski J
Front Neural Circuits 2021 ;15():748989
Evolution of the vertebrate motor system - from forebrain to spinal cord.
Grillner S
Curr Opin Neurobiol 2021 12;71():11-18
The Lamprey Forebrain - Evolutionary Implications.
Suryanarayana SM, Pérez-Fernández J, Robertson B, Grillner S
Brain Behav Evol 2021 Jun;():1-16
The tectum/superior colliculus as the vertebrate solution for spatial sensory integration and action.
Isa T, Marquez-Legorreta E, Grillner S, Scott EK
Curr Biol 2021 06;31(11):R741-R762
The CPGs for Limbed Locomotion-Facts and Fiction.
Grillner S, Kozlov A
Int J Mol Sci 2021 May;22(11):
Basal ganglia reign through downstream control of motor centers in midbrain and brain stem while updating cortex with efference copy information.
Grillner S, Thompson WS
Neuron 2021 05;109(10):1587-1589
Olfaction in Lamprey Pallium Revisited-Dual Projections of Mitral and Tufted Cells.
Suryanarayana SM, Pérez-Fernández J, Robertson B, Grillner S
Cell Rep 2021 Jan;34(1):108596
Basal Ganglia-A Motion Perspective.
Grillner S, Robertson B, Kotaleski JH
Compr Physiol 2020 09;10(4):1241-1275
Reciprocal interaction between striatal cholinergic and low-threshold spiking interneurons - A computational study.
Frost Nylén J, Carannante I, Grillner S, Hellgren Kotaleski J
Eur J Neurosci 2021 Apr;53(7):2135-2148
The microcircuits of striatum in silico.
Hjorth JJJ, Kozlov A, Carannante I, Frost Nylén J, Lindroos R, Johansson Y, Tokarska A, Dorst MC, Suryanarayana SM, Silberberg G, Hellgren Kotaleski J, Grillner S
Proc Natl Acad Sci U S A 2020 04;117(17):9554-9565
The evolutionary origin of visual and somatosensory representation in the vertebrate pallium.
Suryanarayana SM, Pérez-Fernández J, Robertson B, Grillner S
Nat Ecol Evol 2020 Apr;4(4):639-651
Current Principles of Motor Control, with Special Reference to Vertebrate Locomotion.
Grillner S, El Manira A
Physiol. Rev. 2020 01;100(1):271-320
The role of the optic tectum for visually evoked orienting and evasive movements.
Suzuki DG, Pérez-Fernández J, Wibble T, Kardamakis AA, Grillner S
Proc. Natl. Acad. Sci. U.S.A. 2019 07;116(30):15272-15281
Individual Dopaminergic Neurons of Lamprey SNc/VTA Project to Both the Striatum and Optic Tectum but Restrict Co-release of Glutamate to Striatum Only.
von Twickel A, Kowatschew D, Saltürk M, Schauer M, Robertson B, Korsching S, et al
Curr. Biol. 2019 Feb;29(4):677-685.e6
Roles for globus pallidus externa revealed in a computational model of action selection in the basal ganglia.
Suryanarayana SM, Hellgren Kotaleski J, Grillner S, Gurney KN
Neural Netw 2019 Jan;109():113-136
Cerebrospinal Fluid-Contacting Neurons Sense pH Changes and Motion in the Hypothalamus.
Jalalvand E, Robertson B, Tostivint H, Löw P, Wallén P, Grillner S
J. Neurosci. 2018 Aug;38(35):7713-7724
Evolution: Vertebrate Limb Control over 420 Million Years.
Grillner S
Curr. Biol. 2018 02;28(4):R162-R164
The stepwise development of the lamprey visual system and its evolutionary implications.
Suzuki DG, Grillner S
Biol Rev Camb Philos Soc 2018 08;93(3):1461-1477
Direct Dopaminergic Projections from the SNc Modulate Visuomotor Transformation in the Lamprey Tectum.
Pérez-Fernández J, Kardamakis AA, Suzuki DG, Robertson B, Grillner S
Neuron 2017 Nov;96(4):910-924.e5
The Lamprey Pallium Provides a Blueprint of the Mammalian Layered Cortex.
Suryanarayana SM, Robertson B, Wallén P, Grillner S
Curr. Biol. 2017 Nov;27(21):3264-3277.e5
The pretectal connectome in lamprey.
Capantini L, von Twickel A, Robertson B, Grillner S
J. Comp. Neurol. 2017 Mar;525(4):753-772
The Basal Ganglia Over 500 Million Years.
Grillner S, Robertson B
Curr. Biol. 2016 10;26(20):R1088-R1100
Spatiotemporal interplay between multisensory excitation and recruited inhibition in the lamprey optic tectum.
Kardamakis AA, Pérez-Fernández J, Grillner S
Elife 2016 09;5():
The Spinal Cord Has an Intrinsic System for the Control of pH.
Jalalvand E, Robertson B, Tostivint H, Wallén P, Grillner S
Curr. Biol. 2016 05;26(10):1346-51
Ciliated neurons lining the central canal sense both fluid movement and pH through ASIC3.
Jalalvand E, Robertson B, Wallén P, Grillner S
Nat Commun 2016 Jan;7():10002
Tectal microcircuit generating visual selection commands on gaze-controlling neurons.
Kardamakis AA, Saitoh K, Grillner S
Proc. Natl. Acad. Sci. U.S.A. 2015 Apr;112(15):E1956-65
Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression.
Pérez-Fernández J, Stephenson-Jones M, Suryanarayana SM, Robertson B, Grillner S
J. Comp. Neurol. 2014 Dec;522(17):3775-94
Megascience efforts and the brain.
Grillner S
Neuron 2014 Jun;82(6):1209-11
Gating of steering signals through phasic modulation of reticulospinal neurons during locomotion.
Kozlov AK, Kardamakis AA, Hellgren Kotaleski J, Grillner S
Proc. Natl. Acad. Sci. U.S.A. 2014 Mar;111(9):3591-6
Independent circuits in the basal ganglia for the evaluation and selection of actions.
Stephenson-Jones M, Kardamakis AA, Robertson B, Grillner S
Proc. Natl. Acad. Sci. U.S.A. 2013 Sep;110(38):E3670-9
Evolutionary conservation of the basal ganglia as a common vertebrate mechanism for action selection.
Stephenson-Jones M, Samuelsson E, Ericsson J, Robertson B, Grillner S
Curr. Biol. 2011 Jul;21(13):1081-91
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Department of Neuroscience
Attn: Sten Grillner
Karolinska Institutet, SE-171 77 Stockholm
Karolinska Institutet, Biomedicum, 4B
Solnavägen 9, SE-171 65 Solna
Tomtebodavägen 16, SE-171 65 Solna