Biomedical subjects

Igor Timofeev

Publications and source records attributed to Igor Timofeev.

At least 19 recordsLinked to original sources

PubMed2006

Slow state transitions of sustained neural oscillations by activity-dependent modulation of intrinsic excitability.

Little is known about the dynamics and mechanisms of transitions between tonic firing and bursting in cortical networks. Here, we use a computational model of a neocortical circuit with extracellular potassium dynamics to show that activity-dependent modulation of intrinsic excitability can lead to sustained oscillations with slow transitions between two distinct firing modes: fast run (tonic spiking or fast bursts with few spikes) and slow bursting. These transitions are caused by a bistability with hysteresis in a pyramidal cell model. Balanced excitation and inhibition stabilizes a network of pyramidal cells and inhibitory interneurons in the bistable region and causes sustained periodic alternations between distinct oscillatory states. During spike-wave seizures, neocortical paroxysmal activity exhibits qualitatively similar slow transitions between fast run and bursting. We therefore predict that extracellular potassium dynamics can cause alternating episodes of fast and slow oscillatory states in both normal and epileptic neocortical networks.

Animals↗

PubMed2006

Precise long-range synchronization of activity and silence in neocortical neurons during slow-wave oscillations [corrected].

Slow-wave sleep is characterized by alternating periods of activity and silence in corticothalamic networks. Both activity and silence are stable network states, but the mechanisms of their alternation remain unknown. We show, using simultaneous multisite intracellular recordings in cats, that slow rhythm involves all neocortical neurons and that both activity and silence started almost synchronously in cells located up to 12 mm apart. Activity appeared predominantly at the area 5/7 border and spread in both anterior and posterior directions. The activity started earlier in fast-spiking cells and intrinsically bursting cells than in regular-spiking neurons. These results provide direct evidence for two mechanisms of active state generation: spread of activity from a local focus and synchronization of weaker activity, originating at multiple locations. Surprisingly, onsets of silent states were synchronized even more precisely than the onsets of activity, showing no latency bias for location or cell type. This most intriguing finding exposes a major gap in understanding the nature of state alternation. We suggest that it is the synchronous termination of activity and occurrence of silent states of the neuronal network that makes the EEG picture during slow-wave sleep so characteristic. Synchronous onset of silence in distant neurons cannot rely exclusively on properties of individual cells and synapses, such as adaptation of neuronal firing or synaptic depression; instead, it implies the existence of a network mechanism. Revealing this yet unknown large-scale mechanism, which switches network activity to silence, will aid our understanding of the origin of brain rhythms in normal function and pathology.

Action Potentials↗

PubMed2006

Detection of active and silent states in neocortical neurons from the field potential signal during slow-wave sleep.

Oscillations of the local field potentials (LFPs) or electroencephalogram (EEG) at frequencies below 1 Hz are a hallmark of the slow-wave sleep. However, the timing of the underlying cellular events, which is an alternation of active and silent states of thalamocortical network, can be assessed only approximately from the phase of slow waves. Is it possible to detect, using the LFP or EEG, the timing of each episode of cellular activity or silence? With simultaneous recordings of the LFP and intracellular activity of 2-3 neocortical cells, we show that high-gamma-range (20-100 Hz) components in the LFP have significantly higher power when cortical cells are in active states as compared with silent-state periods. Exploiting this difference we have developed a new method, which uses the LFP signal to detect episodes of activity and silence of neocortical neurons. The method allows robust, reliable, and precise detection of timing of each episode of activity and silence of the neocortical network. It works with both surface and depth EEG, and its performance is affected little by the EEG prefiltering during recording. These results open new perspectives for studying differential operation of neural networks during periods of activity and silence, which rapidly alternate on the subsecond scale.

Action Potentials↗

PubMed2006

Waking-sleep modulation of paroxysmal activities induced by partial cortical deafferentation.

We investigated the dependency of electrical seizures produced by cortical undercut upon behavioral states of vigilance in chronically implanted cats. Experiments were performed 1-12 weeks after white matter transection. Multisite field potentials and intracellular activity were recorded from suprasylvian and marginal gyri. Paroxysmal activity developed within days and consisted of spike-wave complexes at 3-4 Hz occurring during the waking state (correlated with eye movements), being enhanced during slow-wave sleep (SWS) and blocked during rapid eye movement (REM) sleep. Prolonged hyperpolarizing events were seen not only during SWS (which is the case in normal animals) but also during both waking and REM, thus resulting in bimodal distribution of the membrane potential in all 3 natural states of vigilance. The increased synchrony of field potential activity expressed by shorter time of propagation over the cortical surface and the tendency toward generalization are ascribed to changes in intrinsic neuronal properties and potential disinhibition following cortical undercut.

Adaptation, Physiological↗

PubMed2005

Increased propensity to seizures after chronic cortical deafferentation in vivo.

Cortical injury may lead to clinical seizures. We investigated the changing patterns of the sleeplike slow oscillation and its tendency to develop into paroxysmal activity consisting of spike-wave (SW) complexes at 2-4 Hz after partial deafferentation of the suprasylvian gyrus. Experiments were carried out in anesthetized cats, at different time intervals (wk 1 to wk 5, W1-W5) after cortical undercut. Multisite field potentials and single or dual intracellular recordings from the whole extent of the deafferented gyrus were used. The field components of the slow oscillation increased in amplitudes and were transformed into paroxysmal patterns, expressed by increased firing rates and tendency to neuronal bursting. The incidence of SW seizures was higher with transition from semiacute (W1) to chronic (W2-W5) stages after cortical undercut. The propagation delay of low-frequency activities decreased from W1 to W5, during both the slow oscillation and seizures. The initiation of seizures took place in territories contiguous to the relatively intact cortex (area 5 in the anterior part of the gyrus), as shown by cross-correlations of field potentials from different sites and simultaneous intracellular recordings from the anterior and posterior parts of the gyrus. The increased amplitudes of both slow oscillation and SW seizures, and their enhanced synchrony expressed by shorter time of propagation, are ascribed to increased neuronal and network excitability after cortical undercut.

Action Potentials↗

PubMed2005

Role of network dynamics in shaping spike timing reliability.

We study the reliability of cortical neuron responses to periodically modulated synaptic stimuli. Simple map-based models of two different types of cortical neurons are constructed to replicate the intrinsic resonances of reliability found in experimental data and to explore the effects of those resonance properties on collective behavior in a cortical network model containing excitatory and inhibitory cells. We show that network interactions can enhance the frequency range of reliable responses and that the latter can be controlled by the strength of synaptic connections. The underlying dynamical mechanisms of reliability enhancement are discussed.

Action Potentials↗

PubMed2005

Synaptic plasticity in local cortical network in vivo and its modulation by the level of neuronal activity.

Neocortical neurons maintain high firing rates across all behavioral states of vigilance but the discharge patterns vary during different types of brain oscillations, which are assumed to play an important role in information processing and memory consolidation. In the present study, we report that trains of stimuli applied to local neocortical networks of cats, at frequencies that mimic endogenous brain rhythms, produced depression or potentiation of postsynaptic potentials, which lasted for several minutes. This form of synaptic plasticity was not mediated through NMDA receptors since it persisted after blockade of these receptors, but was strongly modulated by the level of background neuronal activity. Using different preparations in vivo, we found that increased background neuronal activity decreased the probability of plastic changes but enhanced the probability of potentiation over depression. Conversely, when the level of background neuronal activity was low, plasticity was observed in all neurons, but mainly depression was induced. Our results demonstrate that high levels of neuronal activity in the cortical network promote potentiation and insure the stability of synaptic connections.

Anesthesia↗

PubMed2005

Modulation of synaptic transmission in neocortex by network activities.

Neocortical neurons integrate inputs from thousands of presynaptic neurons that fire in vivo with frequencies that can reach 20 Hz. An important issue in understanding cortical integration is to determine the actual impact of presynaptic firing on postsynaptic neuron in the context of an active network. We used dual intracellular recordings from synaptically connected neurons or microstimulation to study the properties of spontaneous and evoked single-axon excitatory postsynaptic potentials (EPSPs) in vivo, in barbiturate or ketamine-xylazine anaesthetized cats. We found that active states of the cortical network were associated with higher variability and decrease in amplitude and duration of the EPSPs owing to a shunting effect. Moreover, the number of apparent failures markedly increased during active states as compared with silent states. Single-axon EPSPs in vivo showed mainly paired-pulse facilitation, and the paired-pulse ratio increased during active states as compare to silent states, suggesting a decrease in release probability during active states. Raising extracellular Ca(2+) concentration to 2.5-3.0 mm by reverse microdialysis reduced the number of apparent failures and significantly increased the mean amplitude of individual synaptic potentials. Quantitative analysis of spontaneous synaptic activity suggested that the proportion of presynaptic activity that impact at the soma of a cortical neuron in vivo was low because of a high failure rate, a shunting effect and probably dendritic filtering. We conclude that during active states of cortical network, the efficacy of synaptic transmission in individual synapses is low, thus safe transmission of information requires synchronized activity of a large population of presynaptic neurons.

Action Potentials↗

PubMed2004

Neuronal mechanisms mediating the variability of somatosensory evoked potentials during sleep oscillations in cats.

The slow oscillation (SO) generated within the corticothalamic system is composed of active and silent states. The studies of response variability during active versus silent network states within thalamocortical system of human and animals provided inconsistent results. To investigate this inconsistency, we used electrophysiological recordings from the main structures of the somatosensory system in anaesthetized cats. Stimulation of the median nerve (MN) elicited cortical responses during all phases of SO. Cortical responses to stimulation of the medial lemniscus (ML) were virtually absent during silent periods. At the ventral-posterior lateral (VPL) level, ML stimuli elicited either EPSPs in isolation or EPSPs crowned by spikes, as a function of membrane potential. Response to MN stimuli elicited compound synaptic responses and spiked at any physiological level of membrane potential. The responses of dorsal column nuclei neurones to MN stimuli were of similar latency, but the latencies of antidromic responses to ML stimuli were variable. Thus, the variable conductance velocity of ascending prethalamic axons was the most likely cause of the barrages of synaptic events in VPL neurones mediating their firing at different level of the membrane potential. We conclude that the preserved ability of the somatosensory system to transmit the peripheral stimuli to the cerebral cortex during all the phases of sleep slow oscillation is based on the functional properties of the medial lemniscus and on the intrinsic properties of the thalamocortical cells. However the reduced firing ability of the cortical neurones during the silent state may contribute to impair sensory processing during sleep.

Animals↗

PubMed2004

Homeostatic synaptic plasticity can explain post-traumatic epileptogenesis in chronically isolated neocortex.

Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1-3 cm/s and consisted of large (10-15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis.

Action Potentials↗

PubMed2004

Membrane bistability in thalamic reticular neurons during spindle oscillations.

The thalamic reticular (RE) nucleus is a major source of inhibition in the thalamus. It plays a crucial role in regulating the excitability of thalamocortical networks and in generating some sleep rhythms. Current-clamp intracellular recordings of RE neurons in cats under barbiturate anesthesia revealed the presence of membrane bistability in approximately 20% of neurons. Bistability consisted of two alternate membrane potentials, separated by approximately 17-20 mV. While non-bistable (common) RE neurons fired rhythmic spike-bursts during spindles, bistable RE neurons fired tonically, with burst modulation, throughout spindle sequences. Bistability was strongly voltage dependent and only expressed under resting conditions (i.e. no current injection). The transition from the silent to the active state was a regenerative event that could be activated by brief depolarization, whereas brief hyperpolarizations could switch the membrane potential from the active to the silent state. These effects outlasted the current pulses. Corticothalamic stimulation could also switch the membrane potential from silent to active states. Addition of QX-314 in the recording micropipette either abolished or disrupted membrane bistability, suggesting I(Na(p)) to be responsible for its generation. Thalamocortical cells presented various patterns of spindling that reflected the membrane bistability in RE neurons. Finally, experimental data and computer simulations predicted a role for RE neurons' membrane bistability in inducing various patterns of spindling in target thalamocortical cells. We conclude that membrane bistability of RE neurons is an intrinsic property, likely generated by I(Na(p)) and modulated by cortical influences, as well as a factor that determines different patterns of spindle rhythms in thalamocortical neurons.

Action Potentials↗

PubMed2004

Prolonged hyperpolarizing potentials precede spindle oscillations in the thalamic reticular nucleus.

The thalamic reticular (RE) nucleus is a key structure in the generation of spindles, a hallmark bioelectrical oscillation during early stages of sleep. Intracellular recordings of RE neurons in vivo revealed the presence of prolonged hyperpolarizing potentials preceding spindles in a subgroup (30%) of neurons. These hyperpolarizations (6-10 mV) lasted for 200-300 ms and were present just before the onset of spontaneously occurring spindle waves. Corticothalamic volleys also were effective in generating such hyperpolarizations followed by spindles in RE neurons. A drop of up to 40% in the apparent input resistance (R(in)) was associated with these hyperpolarizing potentials, suggesting an active process rather than disfacilitation. Accordingly, the reversal potential was approximately -100 mV for both spontaneous and cortically elicited hyperpolarizations, consistent with the activation of slow K(+) conductances. QX-314 in the recording pipettes decreased both the amplitude and incidence of prolonged hyperpolarizations, suggesting the participation of G protein-dependent K(+) currents in the generation of hyperpolarizations. Simultaneous extracellular and intracellular recordings in the RE nucleus demonstrated that some RE neurons discharged during the hyperpolarizations and, thus, may be implicated in their generation. The prolonged hyperpolarizations preceding spindles may play a role in the transition from tonic to bursting firing of RE neurons within a range of membrane potential (-60 to -65 mV) at which they set favorable conditions for the generation of low-threshold spike bursts that initiate spindle sequences. These data are further arguments for the generation of spindles within the thalamic RE nucleus.

Action Potentials↗

PubMed2004

Contribution of intrinsic neuronal factors in the generation of cortically driven electrographic seizures.

Some electrographic seizures are generated intracortically. The cellular and ionic bases of cortically generated spontaneous seizures are not fully understood. Here we investigated spontaneously occurring seizures consisting of spike-wave complexes intermingled with fast runs in ketamine-xylazine anesthetized cats, using dual intracellular recordings in which one pipette contained a control solution and another pipette contained blockers of K(+), Na(+), or Ca(2+) currents. We show that closely located neocortical neurons display virtually identical fluctuations of the membrane potential during electrographic seizures, thus directly demonstrating a high degree of focal synchrony during paroxysmal activity. In addition to synaptic drives, the persistent Na(+) current [I(Na(p))] and probably the high-threshold Ca(2+) current contributed to the generation of paroxysmal depolarizing shifts (PDSs) during cortically driven seizures. Ca(2+)-activated K(+) current [I(K(Ca))] took also part in the control of the amplitude and duration of PDSs. The hyperpolarizing components of seizures largely depended on Cs(+)-sensitive K(+) currents. I(K(Ca)) played a significant, while not exclusive, role in the mediation of hyperpolarizing potentials related to EEG "waves" during spike-wave seizures. We conclude that intrinsic cellular factors have significant role in the generation of depolarizing and hyperpolarizing components of seizures.

Action Potentials↗

PubMed2004

Experimental evidence and modeling studies support a synchronizing role for electrical coupling in the cat thalamic reticular neurons in vivo.

Thalamic reticular (RE) neurons are crucially implicated in brain rhythms. Here, we report that RE neurons of adult cats, recorded and stained intracellularly in vivo, displayed spontaneously occurring spikelets, which are characteristic of central neurons that are coupled electrotonically via gap junctions. Spikelets occurred spontaneously during spindles, an oscillation in which RE neurons play a leading role, as well as during interspindle lulls. They were significantly different from excitatory postsynaptic potentials and also distinct from fast prepotentials that are presumably dendritic spikes generated synaptically. Spikelets were strongly reduced by halothane, a blocker of gap junctions. Multi-site extracellular recordings performed before, during and after administration of halothane demonstrated a role for electrical coupling in the synchronization of spindling activity within the RE nucleus. Finally, computational models of RE neurons predicted that gap junctions between these neurons could mediate the spread of low-frequency activity at great distances. These experimental and modeling data suggest that electrotonic coupling within the RE nucleus plays an important role in the generation and synchronization of low-frequency (spindling) activities in the thalamus.

Action Potentials↗

PubMed2004

Synaptic enhancement induced through callosal pathways in cat association cortex.

The corpus callosum plays a major role in synchronizing neocortical activities in the two hemispheres. We investigated the changes in callosally elicited excitatory postsynaptic potentials (EPSPs) of neurons from cortical association areas 5 and 7 of cats under barbiturate or ketamine-xylazine anesthesia. Single pulses to callosal pathway evoked control EPSPs; pulse-trains were subsequently applied at different frequencies to homotopic sites in the contralateral cortex, as conditioning stimulation; thereafter, the single pulses were applied again to test changes in synaptic responsiveness by comparing the amplitudes of control and conditioned EPSPs. In 41 of 42 neurons recorded under barbiturate anesthesia, all frequencies of conditioning callosal stimuli induced short-term (5-30 min) enhancement of test EPSPs elicited by single stimuli. Neurons tested with successive conditioning pulse-trains at different frequencies displayed stronger enhancement with high-frequency (40-100 Hz) than with low-frequency (10-20 Hz) rhythmic pulse-trains; >100 Hz, the potentiation saturated. In a neuronal sample, microdialysis of an N-methyl-D-aspartate (NMDA) receptor blocker in barbiturate-treated cats suppressed this potentiation, and potentiation of callosally evoked EPSPs was not detected in neurons recorded under ketamine-xylazine anesthesia, thus indicating that EPSPs' potentiation implicates, at least partially, NMDA receptors. These data suggest that callosal activities occurring within low-frequency and fast-frequency oscillations play a role in cortical synaptic plasticity.

2-Amino-5-phosphonovalerate↗

PubMed2004

Synaptic interactions between thalamic and cortical inputs onto cortical neurons in vivo.

To study the interactions between thalamic and cortical inputs onto neocortical neurons, we used paired-pulse stimulation (PPS) of thalamic and cortical inputs as well as PPS of two cortical or two thalamic inputs that converged, at different time intervals, onto intracellularly recorded cortical and thalamocortical neurons in anesthetized cats. PPS of homosynaptic cortico-cortical pathways produced facilitation, depression, or no significant effects in cortical pathways, whereas cortical responses to thalamocortical inputs were mostly facilitated at both short and long intervals. By contrast, heterosynaptic interactions between either cortical and thalamic, or thalamic and cortical, inputs generally produced decreases in the peak amplitudes and depolarization area of evoked excitatory postsynaptic potentials (EPSPs), with maximal effect at approximately 10 ms and lasting from 60 to 100 ms. All neurons tested with thalamic followed by cortical stimuli showed a decrease in the apparent input resistance (R(in)), the time course of which paralleled that of decreased responses, suggesting that shunting is the factor accounting for EPSP's decrease. Only half of neurons tested with cortical followed by thalamic stimuli displayed changes in R(in). Spike shunting in the thalamus may account for those cases in which decreased synaptic responsiveness of cortical neurons was not associated with decreased R(in) because thalamocortical neurons showed decreased firing probability during cortical stimulation. These results suggest a short-lasting but strong shunting between thalamocortical and cortical inputs onto cortical neurons.

Action Potentials↗

PubMed2003

Neuronal plasticity in thalamocortical networks during sleep and waking oscillations.

Spontaneous brain oscillations during states of vigilance are associated with neuronal plasticity due to rhythmic spike bursts and spike trains fired by thalamic and neocortical neurons during low-frequency rhythms that characterize slow-wave sleep and fast rhythms occurring during waking and REM sleep. Intracellular recordings from thalamic and related cortical neurons in vivo demonstrate that, during natural slow-wave sleep oscillations or their experimental models, both thalamic and cortical neurons progressively enhance their responsiveness. This potentiation lasts for several minutes after the end of oscillatory periods. Cortical neurons display self-sustained activity, similar to responses evoked during previous epochs of stimulation, despite the fact that thalamic neurons remain under a powerful hyperpolarizing pressure. These data suggest that, far from being a quiescent state during which the cortex and subcortical structures are globally inhibited, slow-wave sleep may consolidate memory traces acquired during wakefulness in corticothalamic networks. Similar phenomena occur as a consequence of fast oscillations during brain-activated states.

Animals↗

PubMed2003

Hyperexcitability of intact neurons underlies acute development of trauma-related electrographic seizures in cats in vivo.

Cortical trauma can lead to development of electrographic paroxysmal activities. Current views of trauma-induced epileptogenesis suggest that chronic neuronal hyperexcitability and extensive morphological reorganization of the traumatized cortex are required for the generation of electrographic seizures. However, the mechanisms responsible for the initiation of electrographic seizures shortly after cortical injury are poorly understood. Here we show that, in the experimental model of partially deafferented (undercut) cortex, an increase in intrinsic and synaptic excitability of neurons in areas adjacent to the undercut cortex is sufficient for the generation of electrographic paroxysmal activity within few hours after partial cortical deafferentation. Locally increased and spatially restricted neuronal excitability arose from the increased incidence of intrinsically bursting neurons, enhanced intrinsic and synaptic neuronal responsiveness, and slight disinhibition. These mechanisms only operate in neurons located in the vicinity of partially deafferented sites because, after the cortical injury, partially deafferented neurons are mostly silent and hypoexcitable. Our results suggest that trauma-induced electrographic seizures first arise in cortical fields that are closest to the site of injury and such seizures do not require long-term neuronal reorganization.

Animals↗