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.     

Active neocortical processes during quiescent sleep

The neocortex and the thalamus constitute a unified oscillatory machine during different states of vigilance. The cortically generated slow sleep oscillation has the virtue of grouping other sleep rhythms, including those arising in the thalamus, within complex wave-sequences. Despite the coherent oscillatory activity in corticothalamic circuits, on the functional side there is dissociation between thalamus and neocortex during sleep. While dorsal thalamic neurons undergo inhibitory processes induced by prolonged spikebursts of GABAergic thalamic reticular neurons, the cortex displays, periodically, a rich spontaneous activity and preserves the capacity to process internally generated signals. Simultaneous intracellular recordings from thalamic and cortical neurons show that short-term plasticity processes occur after prolonged and rhythmic spike-bursts fired by thalamic and cortical neurons during slow-wave sleep oscillations. This may serve to support resonant phenomena and reorganize corticothalamic circuitry.     

A thalamo-cortical neural mass model for the simulation of brain rhythms during sleep

Cortico-thalamic interactions are known to play a pivotal role in many brain phenomena, including sleep, attention, memory consolidation and rhythm generation. Hence, simple mathematical models that can simulate the dialogue between the cortex and the thalamus, at a mesoscopic level, have a great cognitive value. In the present work we describe a neural mass model of a cortico-thalamic module, based on neurophysiological mechanisms. The model includes two thalamic populations (a thalamo-cortical relay cell population, TCR, and its related thalamic reticular nucleus, TRN), and a cortical column consisting of four connected populations (pyramidal neurons, excitatory interneurons, inhibitory interneurons with slow and fast kinetics). Moreover, thalamic neurons exhibit two firing modes: bursting and tonic. Finally, cortical synapses among pyramidal neurons incorporate a disfacilitation mechanism following prolonged activity. Simulations show that the model is able to mimic the different patterns of rhythmic activity in cortical and thalamic neurons (beta and alpha waves, spindles, delta waves, K-complexes, slow sleep waves) and their progressive changes from wakefulness to deep sleep, by just acting on modulatory inputs. Moreover, simulations performed by providing short sensory inputs to the TCR show that brain rhythms during sleep preserve the cortex from external perturbations, still allowing a high cortical activity necessary to drive synaptic plasticity and memory consolidation. In perspective, the present model may be used within larger cortico-thalamic networks, to gain a deeper understanding of mechanisms beneath synaptic changes during sleep, to investigate the specific role of brain rhythms, and to explore cortical synchronization achieved via thalamic influences.     

Dynamics of spontaneous activity in random networks with multiple neuron subtypes and synaptic noise

During slow-wave sleep, brain electrical activity is dominated by the slow (< 1 Hz) electroencephalogram (EEG) oscillations characterized by the periodic transitions between active (or Up) and silent (or Down) states in the membrane voltage of the cortical and thalamic neurons. Sleep slow oscillation is believed to play critical role in consolidation of recent memories. Past computational studies, based on the Hodgkin-Huxley type neuronal models, revealed possible intracellular and network mechanisms of the neuronal activity during sleep, however, they failed to explore the large-scale cortical network dynamics depending on collective behavior in the large populations of neurons. In this new study, we developed a novel class of reduced discrete time spiking neuron models for large-scale network simulations of wake and sleep dynamics. In addition to the spiking mechanism, the new model implemented nonlinearities capturing effects of the leak current, the Ca²⁺ dependent K⁺ current and the persistent Na⁺ current that were found to be critical for transitions between Up and Down states of the slow oscillation. We applied the new model to study large-scale two-dimensional cortical network activity during slow-wave sleep. Our study explained traveling wave dynamics and characteristic synchronization properties of transitions between Up and Down states of the slow oscillation as observed in vivo in recordings from cats. We further predict a critical role of synaptic noise and slow adaptive currents for spike sequence replay as found during sleep related memory consolidation.     

Thalamic T-type Ca2+ channels and NREM sleep

T-type Ca2+ channels play a number of different and pivotal roles in almost every type of neuronal oscillation expressed by thalamic neurones during non-rapid eye movement (NREM) sleep, including those underlying sleep theta waves, the K-complex and the slow (<1 Hz) sleep rhythm, sleep spindles and delta waves. In particular, the transient opening of T channels not only gives rise to the 'classical' low threshold Ca2+ potentials, and associated high frequency burst of action potentials, that are characteristically present during sleep spindles and delta waves, but also contributes to the high threshold bursts that underlie the thalamic generation of sleep theta rhythms. The persistent opening of a small fraction of T channels, i.e. I(Twindow), is responsible for the large amplitude and long lasting depolarization, or UP state, of the slow (<1 Hz) sleep oscillation in thalamic neurones. These cellular findings are in part matched by the wake-sleep phenotype of global and thalamic-selective CaV3.1 knockout mice that show a decreased amount of total NREM sleep time. T-type Ca2+ channels, therefore, constitute the single most crucial voltage-dependent conductance that permeates all activities of thalamic neurones during NREM sleep. Since I(Twindow) and high threshold bursts are not restricted to thalamic neurones, the cellular neurophysiology of T channels should now move away from the simplistic, though historically significant, view of these channels as being responsible only for low threshold Ca2+ potentials.     

Nucleus reticularis thalami participates in sleep spindles, not in beta rhythms concomitant with attention in cat.

In the awake cat, characteristic electrocortical synchronized oscillations (beta rhythms) can develop on the parietal cortex in specific behavioural situations such as during attentive fixation of a target. These activities differ from other synchronized rhythms which accompany slow sleep ("spindles") and are more widespread. It is shown here through single unit recording from the thalamic nucleus reticularis (RET), that the latter structure participates in spindles (as already postulated by other authors), but not in the beta rhythms which seem to depend on a more restricted thalamic focus in the posterior thalamic nucleus. These data thus support the idea that RET plays a role in slow-wave sleep but not in the cognitive operations involved in focussing attention.     

Hippocampal memory consolidation during sleep: a comparison of mammals and birds

The transition from wakefulness to sleep is marked by pronounced changes in brain activity. The brain rhythms that characterize the two main types of mammalian sleep, slow‐wave sleep (SWS) and rapid eye movement (REM) sleep, are thought to be involved in the functions of sleep. In particular, recent theories suggest that the synchronous slow‐oscillation of neocortical neuronal membrane potentials, the defining feature of SWS, is involved in processing information acquired during wakefulness. According to the Standard Model of memory consolidation, during wakefulness the hippocampus receives input from neocortical regions involved in the initial encoding of an experience and binds this information into a coherent memory trace that is then transferred to the neocortex during SWS where it is stored and integrated within preexisting memory traces. Evidence suggests that this process selectively involves direct connections from the hippocampus to the prefrontal cortex (PFC), a multimodal, high‐order association region implicated in coordinating the storage and recall of remote memories in the neocortex. The slow‐oscillation is thought to orchestrate the transfer of information from the hippocampus by temporally coupling hippocampal sharp‐wave/ripples (SWRs) and thalamocortical spindles. SWRs are synchronous bursts of hippocampal activity, during which waking neuronal firing patterns are reactivated in the hippocampus and neocortex in a coordinated manner. Thalamocortical spindles are brief 7–14 Hz oscillations that may facilitate the encoding of information reactivated during SWRs. By temporally coupling the readout of information from the hippocampus with conditions conducive to encoding in the neocortex, the slow‐oscillation is thought to mediate the transfer of information from the hippocampus to the neocortex. Although several lines of evidence are consistent with this function for mammalian SWS, it is unclear whether SWS serves a similar function in birds, the only taxonomic group other than mammals to exhibit SWS and REM sleep. Based on our review of research on avian sleep, neuroanatomy, and memory, although involved in some forms of memory consolidation, avian sleep does not appear to be involved in transferring hippocampal memories to other brain regions. Despite exhibiting the slow‐oscillation, SWRs and spindles have not been found in birds. Moreover, although birds independently evolved a brain region—the caudolateral nidopallium (NCL)—involved in performing high‐order cognitive functions similar to those performed by the PFC, direct connections between the NCL and hippocampus have not been found in birds, and evidence for the transfer of information from the hippocampus to the NCL or other extra‐hippocampal regions is lacking. Although based on the absence of evidence for various traits, collectively, these findings suggest that unlike mammalian SWS, avian SWS may not be involved in transferring memories from the hippocampus. Furthermore, it suggests that the slow‐oscillation, the defining feature of mammalian and avian SWS, may serve a more general function independent of that related to coordinating the transfer of information from the hippocampus to the PFC in mammals. Given that SWS is homeostatically regulated (a process intimately related to the slow‐oscillation) in mammals and birds, functional hypotheses linked to this process may apply to both taxonomic groups.     

Impact of intrinsic properties and synaptic factors on the activity of neocortical networks in vivo.

To investigate the relative impact of intrinsic and synaptic factors in the maintenance of the membrane potential of cat neocortical neurons in various states of the network, we performed intracellular recordings in vivo. Experiments were done in the intact cortex and in isolated neocortical slabs of anesthetized animals, and in naturally sleeping and awake cats. There are at least four different electrophysiological cell classes in the neocortex. The responses of different neuronal classes to direct depolarization result in significantly different responses in postsynaptic cells. The activity patterns observed in the intact cortex of anesthetized cats depended mostly on the type of anesthesia. The intracellular activity in small neocortical slabs was composed of silent periods, lasting for tens of seconds, during which only small depolarizing potentials (SDPs, presumed miniature synaptic potentials) were present, and relatively short-lasting (a few hundred milliseconds) active periods. Our data suggest that minis might be amplified by intrinsically-bursting neurons and that the persistent Na+ current brings neurons to firing threshold, thus triggering active periods. The active periods in neurons were composed of the summation of synaptic events and intrinsic depolarizing currents. In chronically-implanted cats, slow-wave sleep was characterized by active (depolarizing) and silent (hyperpolarizing) periods. The silent periods were absent in awake cats. We propose that both intrinsic and synaptic factors are responsible for the transition from silent to active states found in naturally sleeping cats and that synaptic depression might be responsible for the termination of active states during sleep. In view of the unexpected high firing rates of neocortical neurons during the depolarizing epochs in slow-wave sleep, we suggest that cortical neurons are implicated in short-term plasticity processes during this state, in which the brain is disconnected from the outside world, and that memory traces acquired during wakefulness may be consolidated during sleep.     

Modeling the contribution of lamina 5 neuronal and network dynamics to low frequency EEG phenomena

The Electroencephalogram (EEG) is an important clinical and research tool in neurophysiology. With the advent of recording techniques, new evidence is emerging on the neuronal populations and wiring in the neocortex. A main challenge is to relate the EEG generation mechanisms to the underlying circuitry of the neocortex. In this paper, we look at the principal intrinsic properties of neocortical cells in layer 5 and their network behavior in simplified simulation models to explain the emergence of several important EEG phenomena such as the alpha rhythms, slow-wave sleep oscillations, and a form of cortical seizure. The models also predict the ability of layer 5 cells to produce a resonance-like neuronal recruitment known as the augmenting response. While previous models point to deeper brain structures, such as the thalamus, as the origin of many EEG rhythms (spindles), the current model suggests that the cortical circuitry itself has intrinsic oscillatory dynamics which could account for a wide variety of EEG phenomena.Electronic Supplementary Material Supplementary material is available for this article at Sensorimotor Control Project- MIT Harvard NeuroEngineering Research Collaborative.     

Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans

Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5–1.0Hz) and thalamic spindles (12–15Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission.     

Slow Oscillation Amplitudes and Up-State Lengths Relate to Memory Improvement

There is growing evidence of the active involvement of sleep in memory consolidation. Besides hippocampal sharp wave-ripple complexes and sleep spindles, slow oscillations appear to play a key role in the process of sleep-associated memory consolidation. Furthermore, slow oscillation amplitude and spectral power increase during the night after learning declarative and procedural memory tasks. However, it is unresolved whether learning-induced changes specifically alter characteristics of individual slow oscillations, such as the slow oscillation up-state length and amplitude, which are believed to be important for neuronal replay. 24 subjects (12 men) aged between 20 and 30 years participated in a randomized, within-subject, multicenter study. Subjects slept on three occasions for a whole night in the sleep laboratory with full polysomnography. Whereas the first night only served for adaptation purposes, the two remaining nights were preceded by a declarative word-pair task or by a non-learning control task. Slow oscillations were detected in non-rapid eye movement sleep over electrode Fz. Results indicate positive correlations between the length of the up-state as well as the amplitude of both slow oscillation phases and changes in memory performance from pre to post sleep. We speculate that the prolonged slow oscillation up-state length might extend the timeframe for the transfer of initial hippocampal to long-term cortical memory representations, whereas the increase in slow oscillation amplitudes possibly reflects changes in the net synaptic strength of cortical networks.     

Hippocampal ripples and memory consolidation

During slow wave sleep and quiet wakefulness, the hippocampus generates high frequency field oscillations (ripples) during which pyramidal neurons replay previous waking activity in a temporally compressed manner. As a result, reactivated firing patterns occur within shorter time windows propitious for synaptic plasticity within the hippocampal network and in downstream neocortical structures. This is consistent with the long-held view that ripples participate in strengthening and reorganizing memory traces, possibly by mediating information transfer to neocortical areas. Recent studies have confirmed that ripples and associated neuronal reactivations play a causal role in memory consolidation during sleep and rest. However, further research will be necessary to better understand the neurophysiological mechanisms of memory consolidation, in particular the selection of reactivated assemblies, and the functional specificity of awake ripples.     

Transcranial electrical currents to probe EEG brain rhythms and memory consolidation during sleep in humans

Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (～0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8-12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25-45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies.     

Regional slow waves and spindles in human sleep

The most prominent EEG events in sleep are slow waves, reflecting a slow (<1 Hz) oscillation between up and down states in cortical neurons. It is unknown whether slow oscillations are synchronous across the majority or the minority of brain regions--are they a global or local phenomenon? To examine this, we recorded simultaneously scalp EEG, intracerebral EEG, and unit firing in multiple brain regions of neurosurgical patients. We find that most sleep slow waves and the underlying active and inactive neuronal states occur locally. Thus, especially in late sleep, some regions can be active while others are silent. We also find that slow waves can propagate, usually from medial prefrontal cortex to the medial temporal lobe and hippocampus. Sleep spindles, the other hallmark of NREM sleep EEG, are likewise predominantly local. Thus, intracerebral communication during sleep is constrained because slow and spindle oscillations often occur out-of-phase in different brain regions.     

Cellular mechanisms of the slow (<1 Hz) oscillation in thalamocortical neurons in vitro

The slow (<1 Hz) rhythm is a defining feature of the electroencephalogram during sleep. Since cortical circuits can generate this rhythm in isolation, it is assumed that the accompanying slow oscillation in thalamocortical (TC) neurons is largely a passive reflection of neocortical activity. Here we show, however, that by activating the metabotropic glutamate receptor (mGluR), mGluR1a, cortical inputs can recruit intricate cellular mechanisms that enable the generation of an intrinsic slow oscillation in TC neurons in vitro with identical properties to those observed in vivo. These mechanisms rely on the "window" component of the T-type Ca(2+) current and a Ca(2+)-activated, nonselective cation current. These results suggest an active role for the thalamus in shaping the slow (<1 Hz) sleep rhythm.     

Gap junctions modulate seizures in a mean-field model of general anesthesia for the cortex

During slow-wave sleep, general anesthesia, and generalized seizures, there is an absence of consciousness. These states are characterized by low-frequency large-amplitude traveling waves in scalp electroencephalogram. Therefore the oscillatory state might be an indication of failure to form coherent neuronal assemblies necessary for consciousness. A generalized seizure event is a pathological brain state that is the clearest manifestation of waves of synchronized neuronal activity. Since gap junctions provide a direct electrical connection between adjoining neurons, thus enhancing synchronous behavior, reducing gap-junction conductance should suppress seizures; however there is no clear experimental evidence for this. Here we report theoretical predictions for a physiologically-based cortical model that describes the general anesthetic phase transition from consciousness to coma, and includes both chemical synaptic and direct electrotonic synapses. The model dynamics exhibits both Hopf (temporal) and Turing (spatial) instabilities; the Hopf instability corresponds to the slow (≲8 Hz) oscillatory states similar to those seen in slow-wave sleep, general anesthesia, and seizures. We argue that a delicately balanced interplay between Hopf and Turing modes provides a canonical mechanism for the default non-cognitive rest state of the brain. We show that the Turing mode, set by gap-junction diffusion, is generally protective against entering oscillatory modes; and that weakening the Turing mode by reducing gap conduction can release an uncontrolled Hopf oscillation and hence an increased propensity for seizure and simultaneously an increased sensitivity to GABAergic anesthesia.     

睡眠2期脑电信号产生的生理机制模型仿真研究

目前慢波睡眠生理机制研究已有的理论及动物实验结果显示,慢波睡眠中,皮层-丘脑系统神经元存在三种不同节律的振荡:慢振荡(<1 HZ)、δ振荡(1-4Hz)和纺锤振荡(7-14Hz)。这些神经元电活动在皮层水平广泛同步化,产生慢波睡眠脑电。提出了能分别产生这三种节律的三种神经元环路模型,并将之组合简化成一个七细胞环路模型。由这样的大量环路组成的网络模型在合适的突触连接参数范围内,能在皮层处产生人类慢波睡眠脑电2期的完整波形。这一结果说明了如何将动物实验观察到的睡眠生理机制的结果与人自然睡眠活动的脑电结果联系起来,并提示脑信息处理中由微观神经元群放电特征整合为脑的宏观功能状态的主要环节。     

In vivo electrophysiological evidences for cortical neuron-glia interactions during slow (<1 Hz) and paroxysmal sleep oscillations.

The cortical activity results from complex interactions within networks of neurons and glial cells. The dialogue signals consist of neurotransmitters and various ions, which cross through the extracellular space. Slow (<1 Hz) sleep oscillations were first disclosed and investigated at the neuronal level where they consist of an alternation of the membrane potential between a depolarized and a hyperpolarized state. However, neuronal properties alone could not account for the mechanisms underlying the oscillatory nature of the sleeping cortex. Here I will show the behavior of glial cells during the slow sleep oscillation and its relationship with the variation of the neuronal membrane potential (pairs of neurons and glia recorded simultaneously and intracellularly) suggesting that, in contrast with previous assumptions, glial cells are not idle followers of neuronal activity. I will equally present measurements of the extracellular concentration of K(+) and Ca(2+), ions known to modulate the neuronal excitability. They are also part of the ionic flux that is spatially buffered by glial cells. The timing of the spatial buffering during the slow oscillation suggests that, during normal oscillatory activity, K(+) ions are cleared from active spots and released in the near vicinity, where they modulate the excitability of the neuronal membrane and contribute to maintain the depolarizing phase of the oscillation. Ca(2+) ions undergo a periodic variation of their extracellular concentration, which modulates the synaptic efficacy. The depolarizing phase of the slow oscillation is associated with a gradual depletion of the extracellular Ca(2+) promoting a progressive disfacilitation in the network. This functional synaptic neuronal disconnection is responsible for the ending of the depolarizing phase of the slow oscillation and the onset of a phasic hyperpolarization during which the neuronal network is silent and the intra- and extracellular ionic concentrations return to normal values. Spike-wave seizures often develop during sleep from the slow oscillation. Here I will show how the increased gap junction communication substantiates the facility of the glial syncytium to spatially buffer K(+) ions that were uptaken during the spike-wave seizures, and therefore contributing to the long-range recruitment of cortical territories. Similar mechanisms as those described during the slow oscillation promote the periodic (2-3 Hz) recurrence of spike-wave complexes.     

Dynamics of neuronal activity in the lateral preoptic area of hypothalamus in the course of sleep-waking cycle

Frequency and patterns of activity of 106 neurons in the lateral preoptic area of unanesthetized cats were studied under conditions of indolent head fixation. It was shown that this structure contains two somnogenic neuronal populations with different functions. Neurons increasing their discharge frequency during transition from active to quiet wakefulness and subsequent sleep development to the point of phasic stage of paradoxical sleep development are considered as elements of an anti-waking system, which is involved in the mechanisms of sleep onset and deepening by means of inactivation of the arousal system. Neurons displaying the highest firing rates during light slow-wave sleep and synchronization of discharges with sleep spindles are considered as elements of a slow-wave sleep network.     

Interplay between Short- and Long-Term Plasticity in Cell-Assembly Formation

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes.