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Sten Grillner

Publications and source records attributed to Sten Grillner.

At least 19 recordsLinked to original sources
PubMed2007

Descending GABAergic projections to the mesencephalic locomotor region in the lamprey Petromyzon marinus.

The mesencephalic locomotor region (MLR) plays a significant role in the control of locomotion in all vertebrate species investigated. Forebrain neurons are likely to modulate MLR activity, but little is known about their inputs. Descending GABAergic projections to the MLR were identified by double-labeling neurons using Neurobiotin injected into the MLR combined with immunofluorescence against GABA. Several GABAergic projections to the MLR were identified in the telencephalon and diencephalon. The most abundant GABAergic projection to the MLR came from the caudal portion of the medial pallium, a region that may have similarities with the amygdala of higher vertebrates. A small population of GABAergic cells projecting to the MLR was found in the striatum and the ventral portion of the lateral pallium, which could respectively correspond to the input and output components of the basal ganglia thought to be involved in the selection of motor programs. Other GABAergic projections were found to come from the thalamus and the hypothalamus, which could take part in the motivational aspect of motor behavior in lampreys. Electrophysiological experiments were also carried out to examine the effects of GABA agonists and antagonists injected into the MLR in a semi-intact lamprey preparation. The GABA agonist inhibited locomotion, whereas the GABA antagonist initiated it. These results suggest that the GABAergic projections to the MLR modulate the activity of MLR neurons, which would be inhibited by GABA at rest.

Afferent Pathways↗
PubMed2006

Biological pattern generation: the cellular and computational logic of networks in motion.

In 1900, Ramón y Cajal advanced the neuron doctrine, defining the neuron as the fundamental signaling unit of the nervous system. Over a century later, neurobiologists address the circuit doctrine: the logic of the core units of neuronal circuitry that control animal behavior. These are circuits that can be called into action for perceptual, conceptual, and motor tasks, and we now need to understand whether there are coherent and overriding principles that govern the design and function of these modules. The discovery of central motor programs has provided crucial insight into the logic of one prototypic set of neural circuits: those that generate motor patterns. In this review, I discuss the mode of operation of these pattern generator networks and consider the neural mechanisms through which they are selected and activated. In addition, I will outline the utility of computational models in analysis of the dynamic actions of these motor networks.

Animals↗
PubMed2006

Afferents of the lamprey optic tectum with special reference to the GABA input: combined tracing and immunohistochemical study.

The optic tectum in the lamprey midbrain, homologue of the superior colliculus in mammals, is important for eye movement control and orienting responses. There is, however, only limited information regarding the afferent input to the optic tectum except for that from the eyes. The objective of this study was to define specifically the gamma-aminobutyric acid (GABA)-ergic projections to the optic tectum in the river lamprey (Lampetra fluviatilis) and also to describe the tectal afferent input in general. The origin of afferents to the optic tectum was studied by using the neuronal tracer neurobiotin. Injection of neurobiotin into the optic tectum resulted in retrograde labelling of cell groups in all major subdivisions of the brain. The main areas shown to project to the optic tectum were the following: the caudoventral part of the medial pallium, the area of the ventral thalamus and dorsal thalamus, the nucleus of the posterior commissure, the torus semicircularis, the mesencephalic M5 nucleus of Schober, the mesencephalic reticular area, the ishtmic area, and the octavolateral nuclei. GABAergic projections to the optic tectum were identified by combining neurobiotin tracing and GABA immunohistochemistry. On the basis of these double-labelling experiments, it was shown that the optic tectum receives a GABAergic input from the caudoventral part of the medial pallium, the dorsal and ventral thalamus, the nucleus of M5, and the torus semicircularis. The afferent input to the optic tectum in the lamprey brain is similar to that described for other vertebrate species, which is of particular interest considering its position in phylogeny.

Afferent Pathways↗
PubMed2006

Effects of flufenamic acid on fictive locomotion, plateau potentials, calcium channels and NMDA receptors in the lamprey spinal cord.

A Ca(2+)-activated, non-selective cation current (I(CAN)) has been suggested to contribute to plateau potentials in lamprey reticulospinal neurons, providing the drive for locomotor initiation. Flufenamic acid (FFA) is commonly used as a blocker of I(CAN). To explore the effects of FFA on spinal locomotor pattern generation, we induced fictive locomotion in the isolated lamprey spinal cord. Bath-applied FFA (100-200microM) caused a marked reduction of amplitude and regularity of the locomotor burst activity. We next analyzed the NMDA-induced membrane potential oscillations in single spinal neurons. The duration of depolarizing plateaus was markedly reduced when applying FFA, suggesting an involvement of I(CAN). However, in experiments with intracellular injection of the Ca(2+) chelator BAPTA, and in the presence of the K(Ca)-channel blocker apamin, no support was found for an involvement of I(CAN). We therefore explored alternative explanations of the effects of FFA. FFA reduced the size of the slow, Ca(2+)-dependent afterhyperpolarization, suggesting an influence on calcium channels. FFA also reduced the NMDA component of reticulospinal EPSPs as well as NMDA-induced depolarizing responses, demonstrating an influence on NMDA receptors. These non-selective effects of FFA can account for its influence on fictive locomotion and on membrane potential oscillations and thus, a specific involvement of the I(CAN) current in the lamprey spinal cord is not supported.

Animals↗
PubMed2006

5-HT Modulation of identified segmental premotor interneurons in the lamprey spinal cord.

Ipsilaterally projecting spinal excitatory interneurons (EINs) generate the hemisegmental rhythmic locomotor activity in lamprey, while the commissural interneurons ensure proper left-right alternation. 5-HT is a potent modulator of the locomotor rhythm and is endogenously released from the spinal cord during fictive locomotion. The effect of 5-HT was investigated for three segmental premotor interneuron types: EINs, commissural excitatory and commissural inhibitory interneurons. All three types of interneurons produced chemical postsynaptic potentials in motoneurons, but only those from EINs had an electrical component. The effect of 5-HT was studied on the slow afterhyperpolarization, involved in spike frequency regulation, and on the segmental synaptic transmission to motoneurons. 5-HT induced a reduction in the slow afterhyperpolarization and a depression of synaptic transmission in all three types of segmental interneurons. Thus 5-HT is a very potent modulator of membrane properties and synaptic transmission of last-order segmental premotor interneurons. Such modulation of locomotor network interneurons can partially account for the observed effects of 5-HT on the swimming pattern in lamprey.

Action Potentials↗
PubMed2006

Pattern of motor coordination underlying backward swimming in the lamprey.

The main form of locomotion in the lamprey (a lower vertebrate, cyclostome) is forward swimming (FS) based on periodical waves of lateral body flexion propagating from head to tail. The lamprey is also capable of backward swimming (BS). Here we describe the kinematical and electromyographic (EMG) pattern of BS, as well as the effects on this pattern exerted by different lesions of the spinal cord. The BS was evoked by tactile stimulation of a large area in the anterior part of the body. Swimming was attributed to the waves of lateral body undulations propagating from tail to head. The EMG bursts on the two sides alternated, and the EMG in more caudal segments led in phase the EMG in more rostral segments. Main kinematical characteristics of BS strongly differed from those of FS: the amplitude of undulations was much larger and their frequency lower. Also, the maintenance of the dorsal-side-up body orientation ascribed to vestibular postural reflexes (typical for FS) was not observed during BS. A complete transection of the spinal cord did not abolish the generation of forward-propagating waves rostral to the lesion. After a lateral hemisection of the spinal cord, the BS pattern persisted on both sides rostral to the lesion; caudal to the lesion, it was present on the intact side and reduced or abolished on the lesioned side. The role of the spinal cord in generation of different forms of undulatory locomotion (FS and BS) is discussed.

Animals↗
PubMed2005

Role of AMPA receptor desensitization and the side effects of a DMSO vehicle on reticulospinal EPSPs and locomotor activity.

Activation of the vertebrate locomotor network is mediated by glutamatergic synaptic drive, normally initiated by the brain stem. Previous investigations have studied the role of glutamate receptors, especially NMDA receptors, in generating and regulating locomotor pattern generation. Few studies, however, have focused on the role of AMPA receptors in shaping network activity, especially with regard to their rapid desensitization. It is important to determine whether AMPA receptor desensitization plays a role in regulating neuronal network activity. We examined this question on both the network and synaptic levels in the lamprey (Lampetra fluviatilis) spinal cord using a selective and potent inhibitor of AMPA receptor desensitization, cyclothiazide (CTZ). The solvent dimethyl sulfoxide (DMSO) is commonly used to dissolve this drug, as well as many others. Unexpectedly, the vehicle alone already at 0.02%, but not at 0.01%, caused significant increases in excitatory postsynaptic potential (EPSP) amplitudes and NMDA-induced locomotor frequency. The results indicate that DMSO may have a profound influence when used > or = 0.02%, a concentration 10-50 times less than that most commonly used. Subsequently we applied CTZ concentrations < or =10 microM (DMSO < or =0.01%). CTZ (1.25-5 microM) caused an appreciable and significant increase in EPSPs mediated by non-NMDA receptors and in both AMPA- and NMDA-induced locomotor frequency, but no effects on EPSPs mediated by NMDA receptors. From the effects of CTZ it is apparent that AMPA receptor desensitization plays an important role in determining locomotor frequency and that this is likely a result of its limiting function on AMPA receptor-mediated EPSPs.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2005

Mechanisms of rhythm generation in a spinal locomotor network deprived of crossed connections: the lamprey hemicord.

The spinal network coordinating locomotion in the lamprey serves as a model system, in which it has been possible to elucidate connectivity and cellular mechanisms using the isolated spinal cord. Locomotor burst activity alternates between the left and right side of a segment through reciprocal inhibition. We have recently shown that the burst generation itself in a hemisegment does not require inhibitory mechanisms. The focus of this study is the intrinsic operation of this hemisegmental burst-generating component of the locomotor network. Brief electrical stimulation (0.3 s) of the hemicord evokes long-lasting bouts (>2 min) of bursts (2-15 Hz) in the mid to high-frequency range of locomotion. Bout release is an all-or-none phenomenon requiring a threshold intensity of stimulation and glutamatergic transmission within a population of excitatory interneurons, with axons extending over several segments. The progressive activity-dependent decrease in burst frequency that takes place during a bout is followed by a slow recovery process lasting >20 min. Intracellular recordings of single motoneurons, excitatory interneurons, and inhibitory interneurons show that locomotor bouts, in general, are accompanied by a marked depolarization. Membrane potential oscillations and spikes occur in phase with the ventral root (VR) bursts. Active motoneurons and interneurons fire one spike per VR burst, as also confirmed by axonal recordings. Thus, the reciprocal inhibition between opposite hemisegments in the intact cord not only ensures left-right alternation and lowers the locomotor frequency but also promotes a shift from single to multiple action potentials per cycle in network neurons.

Action Potentials↗
PubMed2005

Integrative neuroscience: linking levels of analyses.

If we are to understand how the brain performs different integrated functions in cellular terms, we need both to understand all relevant levels of analysis from the molecular to the behavioural and cognitive levels and to realize an integration of such levels. This is currently a major challenge for neuroscience. Most research, whether dealing with perception, action or learning, focuses on a few levels of organization, for instance the molecular level and brain imaging, and leaves other crucial areas practically untouched. To reach the level of understanding that we desire, a multi-level approach is required in which the different levels link into each other. It is possible to bridge across the different levels for one system, and this has been demonstrated, for example, in the lamprey in generation of goal-directed locomotion. It can be argued that an integrated analysis of any neural system cannot be performed without the aid of a close interaction between experiments and modelling. The dynamic processing within any neural system is such that an intuitive interpretation is rarely sufficient.

Animals↗
PubMed2005

Mechanisms for selection of basic motor programs--roles for the striatum and pallidum.

The nervous system contains a toolbox of motor programs in the brainstem and spinal cord--that is, neuronal networks designed to handle the basic motor repertoire required for survival, including locomotion, posture, eye movements, breathing, chewing, swallowing and expression of emotions. The neural mechanisms responsible for selecting which motor program should be recruited at a given instant are the focus of this review. Motor programs are kept under tonic inhibition by GABAergic pallidal neurons (the output nuclei of the basal ganglia). The motor programs can be relieved from pallidal inhibition through activation of striatal neurons at the input stage of the basal ganglia. It is argued that the striatum has a prominent role in selecting which motor program should be called into action.

Animals↗
PubMed2005

Microcircuits in action--from CPGs to neocortex.

To understand the interface between global brain function and molecular neuroscience--that is, the microcircuit level--a major challenge. Such understanding is prerequisite if we are to account for neural function in cellular terms. Very few vertebrate microcircuits are yet understood because their analysis is demanding technically. In this review of the TINS Microcircuits Special Feature, we attempt to shed light on the problem by comparing the operation of four types of microcircuit, to identify common molecular and cellular components. Central pattern generator (CPG) networks underlying rhythmic movements and hippocampal microcircuits that generate gamma and theta rhythms are compared with the neocortical microcircuits used in cognitive tasks and a cerebellar network. The long-term goal is to identify the components of a molecular and synaptic tool kit for the design of different microcircuits.

Animals↗
PubMed2005

Synaptic pathways in neural microcircuits.

The functions performed by different neural microcircuits depend on the anatomical and physiological properties of the various synaptic pathways connecting neurons. Neural microcircuits across various species and brain regions are similar in terms of their repertoire of neurotransmitters, their synaptic kinetics, their short-term and long-term plasticity, and the target-specificity of their synaptic connections. However, microcircuits can be fundamentally different in terms of the precise recurrent design used to achieve a specific functionality. In this review, which is part of the TINS Microcircuits Special Feature, we compare the connectivity designs in spinal, hippocampal, neocortical and cerebellar microcircuits, and discuss the different computational challenges that each microcircuit faces.

Animals↗
PubMed2004

The spinal GABAergic system is a strong modulator of burst frequency in the lamprey locomotor network.

The spinal network coordinating locomotion is comprised of a core of glutamate and glycine interneurons. This network is modulated by several transmitter systems including spinal GABA interneurons. The purpose of this study is to explore the contribution of GABAergic neurons to the regulation of locomotor burst frequency in the lamprey model. Using gabazine, a competitive GABAA antagonist more specific than bicuculline, the goal was to provide a detailed analysis of the influence of an endogenous activation of GABAA receptors on fictive locomotion, as well as their possible interaction with GABAB and involvement of GABAC receptors. During N-methyl-D-aspartate (NMDA)-induced fictive locomotion (ventral root recordings in the isolated spinal cord), gabazine (0.1-100 microM) significantly increased the burst rate up to twofold, without changes in regularity or "burst quality." Gabazine had a proportionately greater effect at higher initial burst rates. Picrotoxin (1-7.5 microM), a less selective GABAA antagonist, also produced a pronounced increase in frequency, but at higher concentrations, the rhythm deteriorated, likely due to the unspecific effects on glycine receptors. The selective GABAB antagonist CGP55845 also increased the frequency, and this effect was markedly enhanced when combined with the GABAA antagonist gabazine. The GABAC antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) had no effect on locomotor bursting. Thus the spinal GABA system does play a prominent role in burst frequency regulation in that it reduces the burst frequency by < or =50%, presumably due to presynaptic and soma-dendritic effects documented previously. It is not required for burst generation, but acts as a powerful modulator.

Algorithms↗
PubMed2004

Muscle twitches during sleep shape the precise muscles of the withdrawal reflex.

Very precise nociceptive skin reflexes that withdraw the skin from a harmful stimulus are formed through an experience-dependent mechanism that develops around two weeks after birth in rodents. Tactile input paves the way for the nociceptive reflex, and nociceptive stimuli are not required for the reflex to be formed. Petersson et al. show that the tactile input produced during muscle twitches occurring during sleep are essential for this process to develop.

Animals↗
PubMed2004

Innate versus learned movements--a false dichotomy?

It is argued that the nervous systems of vertebrates are equipped with a "motor infrastructure," which enables them to perform the full extent of the motor repertoire characteristic of their particular species. In the human, it extends from the networks/circuits underlying locomotion and feeding to sound production in speech and arm-hand-finger coordination. Contrary to current opinion, these diverse motor patterns should be labeled as voluntary, because they can be recruited at will. Moreover, most, if not all, of the motor patterns available at birth are subject to maturation and are modified substantially through learning. We thus argue that the all-too-common distinction between learned and innate movements is based on a fundamental misconception about the neural control of the vertebrate motor system.

Animals↗
PubMed2003

Endogenous dopaminergic modulation of the lamprey spinal locomotor network.

The lamprey spinal cord contains three dopaminergic systems. The most extensive is the ventromedial plexus in which dopamine is co-localized with 5-HT and tachykinins. In this study we have investigated the effects of endogenously released dopamine on NMDA-induced spinal activity, and for comparison applied dopamine exogenously. The dopamine reuptake blocker bupropion increases the levels of extracellular dopamine in the spinal cord. Bath application of bupropion during ongoing NMDA-induced network activity (around 2 Hz) resulted in an initial increase of the burst rate followed by a transitional phase with the fast rhythm superimposed on a much slower ventral root burst activity (below 0.25 Hz). Finally only the slow rhythm was observed. The same response pattern with regard to the fast and slow rhythms was observed when dopamine was slowly perfused over the spinal cord, resulting in a gradual build-up of dopamine concentration. At low constant dopamine concentrations, however, an increased burst frequency was maintained, but at somewhat higher concentrations the fast burst rate instead was decreased. The degree of modulation of fictive locomotion by dopamine was also tested at low and high NMDA concentrations. Dopamine was found to exert stronger effects at low NMDA concentrations. With high NMDA concentrations dopamine did not induce the transition phase or the slow ventral root bursting. The slow alternating ventral root bursts, induced by bupropion, shifted to synchronized activity when glycinergic synaptic transmission was blocked with strychnine, testifying that the alternation depended on a crossed glycinergic action as previously shown for the fast rhythm.

Animals↗
PubMed2003

Fast and slow locomotor burst generation in the hemispinal cord of the lamprey.

A fundamental question in vertebrate locomotion is whether distinct spinal networks exist that are capable of generating rhythmic output for each group of muscle synergists. In many vertebrates including the lamprey, it has been claimed that burst activity depends on reciprocal inhibition between antagonists. This question was addressed in the isolated lamprey spinal cord in which the left and right sides of each myotome display rhythmic alternating activity. We sectioned the spinal cord along the midline and tested whether rhythmic motor activity could be induced in the hemicord with bath-applied D-glutamate or N-methyl-D-aspartate (NMDA) as in the intact spinal cord or by brief trains of electrical stimuli. Fast rhythmic bursting (2-12 Hz), coordinated across ventral roots, was observed with all three methods. Furthermore, to diminish gradually the crossed glycinergic inhibition, a progressive surgical lesioning of axons crossing the midline was implemented. This resulted in a gradual increase in burst frequency, linking firmly the fast hemicord rhythm [6.6 +/- 1.7 (SD) Hz] to fictive swimming in the intact cord (2.4 +/- 0.7 Hz). Ipsilateral glycinergic inhibition was not required for the hemicord burst pattern generation, suggesting that an interaction between excitatory glutamatergic neurons suffices to produce the unilateral burst pattern. In NMDA, burst activity at a much lower rate (0.1-0.4 Hz) was also encountered, which required the voltage-dependent properties of NMDA receptors in contrast to the fast rhythm. Swimming is thus produced by pairs of unilateral burst generating networks with reciprocal inhibitory connections that not only ensure left/right alternation but also downregulate frequency.

Action Potentials↗