Isochrony in the olivocerebellar system underlies complex spike synchrony.
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Action Potentials↗
Biomedical subjects
Rodolfo Llinás
Publications and source records attributed to Rodolfo Llinás.
The representation of polysemy: MEG evidence.
Most words in natural language are polysemous, that is, they can be used in more than one way. For example, paper can be used to refer to a substance made out of wood pulp or to a daily publication printed on that substance. Although virtually every sentence contains polysemy, there is little agreement as to how polysemy is represented in the mental lexicon. Do different uses of polysemous words involve access to a single representation or do our minds store distinct representations for each different sense? Here we investigated priming between senses with a combination of behavioral and magnetoencephalographic measures in order to test whether different senses of the same word involve identity or mere formal and semantic similarity. Our results show that polysemy effects are clearly distinct from similarity effects bilaterally. In the left hemisphere, sense-relatedness elicited shorter latencies of the M350 source, which has been hypothesized to index lexical activation. Concurrent activity in the right hemisphere, on the other hand, peaked later for sense-related than for unrelated target stimuli, suggesting competition between related senses. The obtained pattern of results supports models in which the representation of polysemy involves both representational identity and difference: Related senses connect to same abstract lexical representation, but are distinctly listed within that representation.
Adolescent↗
Olivocerebellar modulation of motor cortex ability to generate vibrissal movements in rat.
The vibrissal movements known as whisking are generated in a pulsatile, or non-continuous, fashion and comprise sequences of brief regularly spaced movements. These rhythmic timing sequences imply the existence of periodically issued motor commands. As inferior olivary (IO) neurones generate periodic synchronous discharges that could provide the underlying timing signal, this possibility was tested by determining whether the olivocerebellar system modulates motor cortex (MCtx)-triggered whisker movements in rats. Trains of current pulses were applied to MCtx, and the resulting whisker movements were recorded using a high speed video camera. The evoked movement patterns demonstrated properties consistent with the existence of an oscillatory motor driving rhythm. In particular, movement amplitude showed a bell-shaped dependence on stimulus frequency, with a peak at 11.5+/-2.3 Hz. Moreover, movement trajectories showed harmonic and subharmonic entrainment patterns within specific stimulus frequency ranges. By contrast, movements evoked by facial nerve stimulation showed no such frequency-dependent properties. To test whether the IO was the oscillator in question, IO neuronal properties were modified in vivo by intra-IO picrotoxin injection, which enhances synchronous oscillatory IO activity and reduces its natural frequency. The ensuing changes in the evoked whisker patterns were consistent with these pharmacological effects. Furthermore, in cerebellectomized rats, oscillatory modulation of MCtx-evoked movements was greatly reduced, and intra-IO picrotoxin injections did not affect the evoked movement patterns. Additionally, multielectrode recording of Purkinje cell complex spikes showed a temporal correlation of olivocerebellar activity during MCtx stimulus trains to evoked movement patterns. In sum, the results indicate that MCtx's ability to generate movements is modulated by an oscillatory signal arising in the olivocerebellar system.
Animals↗
Role of gap junctions in synchronized neuronal oscillations in the inferior olive.
Inferior olivary (IO) neurons are electrically coupled through gap junctions and generate synchronous subthreshold oscillations of their membrane potential at a frequency of 1-10 Hz. Whereas the ionic mechanisms of these oscillatory responses are well understood, their origin and ensemble properties remain controversial. Here, the role of gap junctions in generating and synchronizing IO oscillations was examined by combining intracellular recordings with high-speed voltage-sensitive dye imaging in rat brain stem slices. Single cell responses and ensemble synchronized responses of IO neurons were compared in control conditions and in the presence of 18beta-glycyrrhetinic acid (18beta-GA), a pharmacological gap junction blocker. Under our experimental conditions, 18beta-GA had no adverse effects on intrinsic electroresponsive properties of IO neurons, other than the block of gap junction-dependent dye coupling and the resulting change in cells' passive properties. Application of 18beta-GA did not abolish single cell oscillations. Pharmacologically uncoupled IO neurons continued to oscillate with a frequency and amplitude that were similar to those recorded in control conditions. However, these oscillations were no longer synchronized across a population of IO neurons. Our optical recordings did not detect any clusters of synchronous oscillatory activity in the presence of the blocker. These results indicate that gap junctions are not necessary for generating subthreshold oscillations, rather, they are required for clustering of coherent oscillatory activity in the IO. The findings support the view that oscillatory properties of single IO neurons endow the system with important reset dynamics, while gap junctions are mainly required for synchronized neuronal ensemble activity.
Animals↗
The effects of microgravity on the development of surface righting in rats.
The active interaction of neonatal animals with their environment has been shown to be a decisive factor in the postnatal development of sensory systems, which demonstrates a critical period in their maturation. The direct demonstration of such a dependence on the rearing environment has not been demonstrated for motor system function. Nor has the role of gravity in mammalian motor system development been investigated. Here we report the results of two space flight missions examining the effect of removing gravity on the development of surface righting. Since the essential stimulus that drives this synergy, gravitation, was missing, righting did not occur while the animals were in the microgravity environment. We hypothesize that this absence of contextual motor experience arrested the maturation of the motor tactics for surface righting. Such effects were permanent in rats spending 16 days (from postnatal day (P), P14 to P30), but were transient in animals spending nine days (from P15 to P24) in microgravity. Thus, active, contextual interaction with the environment during a critical period of development is necessary for the postnatal maturation of motor tactics as exemplified by surface righting, and such events must occur within a particular time period. Further, Earth's gravitational field is not assumed by the developing motor system. Rather, postnatal motor system development is appropriate to the gravitational field in which the animal is reared.
Adaptation, Physiological↗
Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease.
Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca2+) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD.
Animals↗
Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect.
Brain function is fundamentally related in the most general sense to the richness of thalamocortical interconnectivity, and in particular to the rhythmic oscillatory properties of thalamocortical loops. Such rhythmicity is involved in the genesis of cognition, in the sleep-wake cycle, and in several neurological and psychiatric disorders. The role of GABA-mediated transmission in regulating these functional states is addressed here. At the cortical level, inhibition determines the spread of cortical activation by sculpting the precise activity patterns that underlie the details of cognition and motor control. At the thalamic level, GABA-mediated inhibition modulates and resets distribution of the ongoing thalamocortical rhythmic oscillations that bind multisensory inputs into a single cognitive experience and regulate arousal levels.
Animals↗
A model of thalamocortical relay cells.
It is well established that the main intrinsic electrophysiological properties of thalamocortical relay cells, production of a low threshold burst upon release from hyperpolarized potential and production of a train of single spikes following stimulation from depolarized potentials, can be readily modelled using a single compartment. There is, however, another less well explored intrinsic electrophysiological characteristic of relay cells for which models have not yet accounted: at somatic potentials near spike threshold, relay cells produce a fast ragged high threshold oscillation in somatic voltage. Optical [Ca(2+)] imaging and pharmacological tests indicate that this oscillation correlates with a high threshold Ca(2+) current in the dendrites. Here we present the development of a new compartment model of the thalamic relay cell guided by the simultaneous constraints that it must produce the familiar regular spiking relay mode and low threshold rebound bursts which characterize these cells, as well as the less-studied fast oscillation occurring at near-threshold somatic potentials. We arrive at a model cell which is capable of the production of isolated high threshold Ca(2+) spikes in distal branch segments, driven by a rapidly inactivating intermediate threshold Ca(2+) channel. Further, the model produces the low threshold spike behaviour of the relay cell without requiring high T-current density in the distal dendritic segments. The results thus support a new picture of the dendritic tree of relay cells which may have implications for the manner in which thalamic relay cells integrate descending input from the cortex.
Action Potentials↗
Electrotonically mediated oscillatory patterns in neuronal ensembles: an in vitro voltage-dependent dye-imaging study in the inferior olive.
Spatiotemporal profiles of ensemble subthreshold neuronal oscillation were studied in brainstem slices using high-speed voltage-sensitive dye imaging. After local electrical stimuli, the overall voltage profile demonstrated coherent oscillatory waves that spread over the inferior olive (IO). These oscillations were also observed in concurrently obtained intracellular recordings from IO neurons. Over the first few seconds after the stimuli, the optically recorded oscillations clustered into coherent groups comprising hundreds of neurons. Statistical analysis of the spatial profiles of these clusters revealed size fluctuation around stable core regions that were surrounded by a rim the diameter of which varied in time during the oscillation period. The neuronal ensemble oscillations were calcium derived and had an average frequency range of 1-7 Hz. This rhythmic response demonstrated a different spatiotemporal distribution in the presence of picrotoxin, which induced the merging of neuronal clusters into larger areas of coherent activity. The possibility that such clustering is a consequence of intrinsic oscillations in ensembles of coupled neurons was tested using mathematical modeling.
Action Potentials↗
Modeling inferior olive neuron dynamics.
A model for the study of the dynamic properties of inferior olive neuron is presented. The model, a dynamical system, comprises two autonomous components of minimal complexity that are capable of reproducing the large gamut of experimentally observed inferior olive neuron dynamics. The two autonomous parts are responsible for largely different aspects of the dynamic profile of the model. These include subthreshold oscillations and different modes (high and low threshold) of action potential generation.
Action Potentials↗
Residual cerebral activity and behavioural fragments can remain in the persistently vegetative brain.
This report identifies evidence of partially functional cerebral regions in catastrophically injured brains. To study five patients in a persistent vegetative state (PVS) with different behavioural features, we employed [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET), MRI and magnetoencephalographic (MEG) responses to sensory stimulation. Each patient's brain expressed a unique metabolic pattern. In three of the five patients, co-registered PET/MRI correlate islands of relatively preserved brain metabolism with isolated fragments of behaviour. Two patients had suffered anoxic injuries and demonstrated marked decreases in overall cerebral metabolism to 30-40% of normal. Two other patients with non-anoxic, multifocal brain injuries demonstrated several isolated brain regions with relatively higher metabolic rates, that ranged up to 50-80% of normal. Nevertheless, their global metabolic rates remained <50% of normal. MEG recordings from three PVS patients provide clear evidence for the absence, abnormality or reduction of evoked responses. Despite major abnormalities, however, these data also provide evidence for localized residual activity at the cortical level. Each patient partially preserved restricted sensory representations, as evidenced by slow evoked magnetic fields and gamma band activity. In two patients, these activations correlate with isolated behavioural patterns and metabolic activity. Remaining active regions identified in the three PVS patients with behavioural fragments appear to consist of segregated corticothalamic networks that retain connectivity and partial functional integrity. A single patient who suffered severe injury to the tegmental mesencephalon and paramedian thalamus showed widely preserved cortical metabolism, and a global average metabolic rate of 65% of normal. The relatively high preservation of cortical metabolism in this patient defines the first functional correlate of clinical- pathological reports associating permanent unconsciousness with structural damage to these regions. The specific patterns of preserved metabolic activity identified in these patients do not appear to represent random survivals of a few neuronal islands; rather they reflect novel evidence of the modular nature of individual functional networks that underlie conscious brain function. The variations in cerebral metabolism in chronic PVS patients indicate that some cerebral regions can retain partial function in catastrophically injured brains.
Adult↗
A New Approach to the Analysis of Multidimensional Neuronal Activity: Markov Random Fields.
How can information hidden in a spatial configuration of neuronal activity be addressed? The Markov Random Field method for the analysis of the spatial component of a multidimensional neuronal process is introduced and after simulations is applied to experimental data on rat at olivocerebellar activity. Using this method it was determined, for the first time, that the activity demonstrates dynamic coupling and may have different fine spatial substructures. The results obtained support the view that the inferior olive serves as a movement organizing centre that controls motor activity by means of spatially as well as temporally organized patterns of coherent activity. Copyright 1997 Elsevier Science Ltd.
Journal Article↗