An Integrative View of Mechanisms Underlying Generalized Spike-and-Wave Epileptic Seizures and Its Implication on Optimal Therapeutic Treatments

Many types of epileptic seizures are characterized by generalized spike-and-wave discharges. In the past, notable effort has been devoted to understanding seizure dynamics and various hypotheses have been proposed to explain the underlying mechanisms. In this paper, by taking an integrative view of the underlying mechanisms, we demonstrate that epileptic seizures can be generated by many different combinations of synaptic strengths and intrinsic membrane properties. This integrative view has important medical implications: the specific state of a patient characterized by a set of biophysical characteristics ultimately determines the optimal therapeutic treatment. Through the same view, we further demonstrate the potentiation effect of rational polypharmacy in the treatment of epilepsy and provide a new angle to resolve the debate on polypharmacy. Our results underscore the need for personalized medicine and demonstrate that computer modeling and simulation may play an important role in assisting the clinicians in selecting the optimal treatment on an individual basis

Slow-wave sleep : generation and propagation of slow waves, role in long-term plasticity and gating

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2012-2013.Le sommeil est connu pour réguler plusieurs fonctions importantes pour le cerveau et parmi celles-ci, il y a le blocage de l’information sensorielle par le thalamus et l’amélioration de la consolidation de la mémoire. Le sommeil à ondes lentes, en particulier, est considéré être critique pour ces deux processus. Cependant, leurs mécanismes physiologiques sont inconnus. Aussi, la marque électrophysiologique distinctive du sommeil à ondes lentes est la présence d’ondes lentes de grande amplitude dans le potentiel de champ cortical et l’alternance entre des périodes d’activités synaptiques intenses pendant lesquelles les neurones corticaux sont dépolarisés et déchargent plusieurs potentiels d’action et des périodes silencieuses pendant lesquelles aucune décharge ne survient, les neurones corticaux sont hyperpolarisés et très peu d’activités synaptiques sont observées. Tout d'abord, afin de mieux comprendre les études présentées dans ce manuscrit, une introduction générale couvrant l'architecture du système thalamocortical et ses fonctions est présentée. Celle-ci comprend une description des états de vigilance, suivie d'une description des rythmes présents dans le système thalamocortical au cours du sommeil à ondes lentes, puis par une description des différents mécanismes de plasticité synaptique, et enfin, deux hypothèses sur la façon dont le sommeil peut affecter la consolidation de la mémoire sont présentées. Puis, trois études sont présentées et ont été conçues pour caractériser les propriétés de l'oscillation lente du sommeil à ondes lentes. Dans la première étude (chapitre II), nous avons montré que les périodes d'activité (et de silence) se produisent de façon presque synchrone dans des neurones qui ont jusqu'à 12 mm de distance. Nous avons montré que l'activité était initiée en un point focal et se propageait rapidement à des sites corticaux voisins. Étonnamment, le déclenchement des états silencieux était encore plus synchronisé que le déclenchement des états actifs. L'hypothèse de travail pour la deuxième étude (chapitre III) était que les états actifs sont générés par une sommation de relâches spontanées de médiateurs. Utilisant différents enregistrements à la fois chez des animaux anesthésiés et chez d’autres non-anesthésiés, nous avons montré qu’aucune décharge neuronale ne se produit dans le néocortex pendant les états silencieux du sommeil à ondes lentes, mais certaines activités synaptiques peuvent ii être observées avant le début des états actifs, ce qui était en accord avec notre hypothèse. Nous avons également montré que les neurones de la couche V étaient les premiers à entrer dans l’état actif pour la majorité des cycles, mais ce serait ainsi uniquement pour des raisons probabilistes; ces cellules étant équipées du plus grand nombre de contacts synaptiques parmi les neurones corticaux. Nous avons également montré que le sommeil à ondes lentes et l’anesthésie à la kétamine-xylazine présentent de nombreuses similitudes. Ayant utilisé une combinaison d'enregistrements chez des animaux anesthésiés à la kétamine-xylazine et chez des animaux non-anesthésiés, et parce que l'anesthésie à la kétamine-xylazine est largement utilisée comme un modèle de sommeil à ondes lentes, nous avons effectué des mesures quantitatives des différences entre les deux groupes d'enregistrements (chapitre IV). Nous avons trouvé que l'oscillation lente était beaucoup plus rythmique sous anesthésie et elle était aussi plus cohérente entre des sites d’enregistrements distants en comparaison aux enregistrements de sommeil naturel. Sous anesthésie, les ondes lentes avaient également une amplitude plus grande et une durée plus longue par rapport au sommeil à ondes lentes. Toutefois, les ondes fuseaux (spindles) et gamma étaient également affectées par l'anesthésie. Dans l'étude suivante (Chapitre V), nous avons investigué le rôle du sommeil à ondes lentes dans la formation de la plasticité à long terme dans le système thalamocortical. À l’aide de stimulations pré-thalamiques de la voie somatosensorielle ascendante (fibres du lemnisque médial) chez des animaux non-anesthésiés, nous avons montré que le potentiel évoqué enregistré dans le cortex somatosensoriel était augmenté dans une période d’éveil suivant un épisode de sommeil à ondes lentes par rapport à l’épisode d’éveil précédent et cette augmentation était de longue durée. Nous avons également montré que le sommeil paradoxal ne jouait pas un rôle important dans cette augmentation d'amplitude des réponses évoquées. À l’aide d'enregistrements in vitro en mode cellule-entière, nous avons caractérisé le mécanisme derrière cette augmentation et ce mécanisme est compatible avec la forme classique de potentiation à long terme, car il nécessitait une activation à la fois les récepteurs NMDA et des récepteurs AMPA, ainsi que la présence de calcium dans le neurone post-synaptique. iii La dernière étude incluse dans cette thèse (chapitre VI) a été conçue pour caractériser un possible mécanisme physiologique de blocage sensoriel thalamique survenant pendant le sommeil. Les ondes fuseaux sont caractérisées par la présence de potentiels d’action calcique à seuil bas et le calcium joue un rôle essentiel dans la transmission synaptique. En utilisant plusieurs techniques expérimentales, nous avons vérifié l'hypothèse que ces potentiels d’action calciques pourraient causer un appauvrissement local de calcium dans l'espace extracellulaire ce qui affecterait la transmission synaptique. Nous avons montré que les canaux calciques responsables des potentiels d’action calciques étaient localisés aux synapses et que, de fait, une diminution locale de la concentration extracellulaire de calcium se produit au cours d’un potentiel d’action calcique à seuil bas spontané ou provoqué, ce qui était suffisant pour nuire à la transmission synaptique. Nous concluons que l'oscillation lente est initiée en un point focal et se propage ensuite aux aires corticales voisines de façon presque synchrone, même pour des cellules séparées par jusqu'à 12 mm de distance. Les états actifs de cette oscillation proviennent d’une sommation de relâches spontanées de neuromédiateurs (indépendantes des potentiels d’action) et cette sommation peut survenir dans tous neurones corticaux. Cependant, l’état actif est généré plus souvent dans les neurones pyramidaux de couche V simplement pour des raisons probabilistes. Les deux types d’expériences (kétamine-xylazine et sommeil à ondes lentes) ont montré plusieurs propriétés similaires, mais aussi quelques différences quantitatives. Nous concluons également que l'oscillation lente joue un rôle essentiel dans l'induction de plasticité à long terme qui contribue très probablement à la consolidation de la mémoire. Les ondes fuseaux, un autre type d’ondes présentes pendant le sommeil à ondes lentes, contribuent au blocage thalamique de l'information sensorielle.Sleep is known to mediate several major functions in the brain and among them are the gating of sensory information during sleep and the sleep-related improvement in memory consolidation. Slow-wave sleep in particular is thought to be critical for both of these processes. However, their physiological mechanisms are unknown. Also, the electrophysiological hallmark of slow-wave sleep is the presence of large amplitude slow waves in the cortical local field potential and the alternation of periods of intense synaptic activity in which cortical neurons are depolarized and fire action potentials and periods of silence in which no firing occurs, cortical neurons are hyperpolarized, and very little synaptic activities are observed. First, in order to better understand the studies presented in this manuscript, a general introduction covering the thalamocortical system architecture and function is presented, which includes a description of the states of vigilance, followed by a description of the rhythms present in the thalamocortical system during slow-wave sleep, then by a description of the mechanisms of synaptic plasticity, and finally two hypotheses about how sleep might affect the consolidation of memory are presented. Then, three studies are presented and were designed to characterize the properties of the sleep slow oscillation. In the first study (Chapter II), we showed that periods of activity (and silence) occur almost synchronously in neurons that are separated by up to 12 mm. The activity was initiated in a focal point and rapidly propagated to neighboring sites. Surprisingly, the onsets of silent states were even more synchronous than onsets of active states. The working hypothesis for the second study (Chapter III) was that active states are generated by a summation of spontaneous mediator releases. Using different recordings in both anesthetized and non-anesthetized animals, we showed that no neuronal firing occurs in the neocortex during silent states of slow-wave sleep but some synaptic activities might be observed prior to the onset of active states, which was in agreement with our hypothesis. We also showed that layer V neurons were leading the onset of active states in most of the cycles but this would be due to probabilistic reasons; these cells being equipped with the most numerous synaptic contacts among cortical neurons. We also showed that slow-wave sleep and ketamine-xylazine shares many similarities. v Having used a combination of recordings in ketamine-xylazine anesthetized and non-anesthetized animals, and because ketamine-xylazine anesthesia is extensively used as a model of slow-wave sleep, we made quantitative measurements of the differences between the two groups of recordings (Chapter IV). We found that the slow oscillation was much more rhythmic under anesthesia and it was also more coherent between distant sites as compared to recordings during slow-wave sleep. Under anesthesia, slow waves were also of larger amplitude and had a longer duration as compared to slow-wave sleep. However, spindles and gamma were also affected by the anesthesia. In the following study (Chapter V), we investigated the role of slow-wave sleep in the formation of long-term plasticity in the thalamocortical system. Using pre-thalamic stimulations of the ascending somatosensory pathway (medial lemniscus fibers) in non-anesthetized animals, we showed that evoked potential recorded in the somatosensory cortex were enhanced in a wake period following a slow-wave sleep episode as compared to the previous wake episode and this enhancement was long-lasting. We also showed that rapid eye movement sleep did not play a significant role in this enhancement of response amplitude. Using whole-cell recordings in vitro, we characterized the mechanism behind this enhancement and it was compatible with the classical form of long-term potentiation, because it required an activation of both NMDA and AMPA receptors as well as the presence of calcium in the postsynaptic neuron. The last study included in this thesis (Chapter VI) was designed to characterise a possible physiological mechanism of thalamic sensory gating occurring during sleep. Spindles are characterized by the presence of low-threshold calcium spikes and calcium plays a critical role in the synaptic transmission. Using several experimental techniques, we verified the hypothesis that these calcium spikes would cause a local depletion of calcium in the extracellular space which would impair synaptic transmission. We showed that calcium channels responsible for calcium spikes were co-localized with synapses and that indeed, local extracellular calcium depletion occurred during spontaneous or induced low-threshold calcium spike, which was sufficient to impair synaptic transmission. We conclude that slow oscillation originate at a focal point and then propagate to neighboring cortical areas being almost synchronous even in cells located up to 12 mm vi apart. Active states of this oscillation originate from a summation of spike-independent mediator releases that might occur in any cortical neurons, but happens more often in layer V pyramidal neurons simply due to probabilistic reasons. Both experiments in ketamine-xylazine anesthesia and non-anesthetized animals showed several similar properties, but also some quantitative differences. We also conclude that slow oscillation plays a critical role in the induction of long-term plasticity, which very likely contributes to memory consolidation. Spindles, another oscillation present in slow-wave sleep, contribute to the thalamic gating of information

Intrinsic and synaptic membrane properties of neurons in the thalamic reticular nucleus

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2004-2005Le noyau réticulaire thalamique (RE) est une structure qui engendre des fuseaux, une oscillation bioélectrique de marque pendant les stades précoces du sommeil. De multiples propriétés neuronales, intrinsèques et synaptiques, sont impliquées dans la génération, la propagation, le maintien et la terminaison des ondes en fuseaux. D’un autre côté, ce rythme constitue un état spécial de l’activité du réseau qui est généré par le réseau lui-même et affecte les propriétés cellulaires du noyau RE. Cette étude se concentre sur ces sujets: comment les propriétés cellulaires et les propriétés du réseau sont inter-reliées et interagissent pour engendrer les ondes fuseaux dans les neurones du RE et leurs cibles, les neurones thalamocorticaux. La présente thèse fournit de nouvelles évidences montrant le rôle fondamental joué par les neurones du noyau RE dans la genèse des ondes en fuseaux, dû aux synapses chimiques établies par ces neurones. La propagation et la synchronisation de l’activité sont modulées par les synapses électriques entre les neurones réticulaires thalamiques, mais aussi par les composantes dépolarisantes secondaires des réponses synaptiques évoquées par le cortex. De plus, la forme générale et la terminaison des oscillations thalamiques sont probablement contrôlées en grande partie par les neurones du RE, lesquels expriment une conductance intrinsèque leurs procurant une membrane avec un comportement bistable. Finalement, les oscillations thalamiques en fuseaux sont aussi capables de moduler les propriétés membranaires et l’activité des neurones individuels du RE.The thalamic reticular nucleus (RE) is a key structure related to spindles, a hallmark bioelectrical oscillation during early stages of sleep. Multiple neuronal properties, both intrinsic and synaptic, are implicated in the generation, propagation, maintenance and termination of spindle waves. On the other hand, this rhythm constitutes a special state of network activity, which is generated within, and affects single-cell properties of the RE nucleus. This study is focused on these topics: how cellular and network properties are interrelated and interact to generate spindle waves in the pacemaking RE neurons and their targets, thalamocortical neurons. The present thesis provides new evidence showing the fundamental role played by the RE nucleus in the generation of spindle waves, due to chemical synapses established by its neurons. The propagation and synchronization of activity is modulated by electrical synapses between thalamic reticular neurons, but also by the secondary depolarizing component of cortically-evoked synaptic responses. Additionally, the general shaping and probably the termination of thalamic oscillations could be controlled to a great extent by RE neurons, which express an intrinsic conductance endowing them with membrane bistable behaviour. Finally, thalamic spindle oscillations are also able to modulate the membrane properties and activities of individual RE neurons

The Dynamic Brain in Action: Cortical Oscillations and Coordination Dynamics

Cortical oscillations are electrical activities with rhythmic and/or repetitive nature generated spontaneously and in response to stimuli. Study of cortical oscillations has become an area of converging interests since the last two decades and has deepened our understanding of its physiological basis across different behavioral states. Experimental and modeling work has taught us that there is a wide diversity of cellular and circuit mechanisms underlying the generation of cortical rhythms. A wildly diverse set of functions has pertained to synchronous oscillations but their significance in cognition should be better appraised in the more general framework of correlation between spike times of neurons. Oscillations are the core mechanism in adjusting neuronal interactions and shaping temporal coordination of neural activity. In the first part of this thesis, we review essential feature of cortical oscillations in membrane potentials and local field potentials recorded from turtle ex vivo preparation. Then we develop a simple computational model that reproduces the observed features. This modeling investigation suggests a plausible underlying mechanism for rhythmogenesis through cellular and circuit properties. The second part of the thesis is about temporal coordination dynamics quantified by signal and noise correlations. Here, again, we present a computational model to show how temporal coordination and synchronous oscillations can be sewn together. More importantly, what biophysical ingrediants are necessary for a network to reproduce the observed coordination dynamics

Prefrontal rhythms for cognitive control

Goal-directed behavior requires flexible selection among action plans and updating behavioral strategies when they fail to achieve desired goals. Lateral prefrontal cortex (LPFC) is implicated in the execution of behavior-guiding rule-based cognitive control while anterior cingulate cortex (ACC) is implicated in monitoring processes and updating rules. Rule-based cognitive control requires selective processing while process monitoring benefits from combinatorial processing. I used a combination of computational and experimental methods to investigate how network oscillations and neuronal heterogeneity contribute to cognitive control through their effects on selective versus combinatorial processing modes in LPFC and ACC. First, I adapted an existing LPFC model to explore input frequency- and coherence-based output selection mechanisms for flexible routing of rate-coded signals. I show that the oscillatory states of input encoding populations can exhibit a stronger influence over downstream competition than their activity levels. This enables an output driven by a weaker resonant input signal to suppress lower-frequency competing responses to stronger, less resonant (though possibly higher-frequency) input signals. While signals are encoded in population firing rates, output selection and signal routing can be governed independently by the frequency and coherence of oscillatory inputs and their correspondence with output resonant properties. Flexible response selection and gating can be achieved by oscillatory state control mechanisms operating on input encoding populations. These dynamic mechanisms enable experimentally-observed LPFC beta and gamma oscillations to flexibly govern the selection and gating of rate-coded signals for downstream read-out. Furthermore, I demonstrate how differential drives to distinct interneuron populations can switch working memory representations between asynchronous and oscillatory states that support rule-based selection. Next, I analyzed physiological data from the LeBeau laboratory and built a de novo model constrained by the biological data. Experimental data demonstrated that fast network oscillations at both the beta- and gamma frequency bands could be elicited in vitro in ACC and neurons exhibited a wide range of intrinsic properties. Computational modeling of the ACC network revealed that the frequency of network oscillation generated was dependent upon the time course of inhibition. Principal cell heterogeneity broadened the range of frequencies generated by the model network. In addition, with different frequency inputs to two neuronal assemblies, heterogeneity decreased competition and increased spike coherence between the networks thus conferring a combinatorial advantage to the network. These findings suggest that oscillating neuronal populations can support either response selection (routing), or combination, depending on the interplay between the kinetics of synaptic inhibition and the degree of heterogeneity of principal cell intrinsic conductances. Such differences may support functional differences between the roles of LPFC and ACC in cognitive control

Brain State Dependent Activity in the Lateral Geniculate Nucleus

Brain state dependent thalamocortical (TC) activity plays and important role in sensory coding, oscillations and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state dependent spontaneous and visually evoked activity of LGN neurons in awake behaving animals remains controversial. In awake head-restrained mice, using a combination of pupillometry, extracellular and intracellular recordings from morphologically and physiologically identified LGN neurons we show that TC neurons and putative local interneurons are inversely related to arousal forming two complementary coalitions with TC cells being positively correlates with wakefulness, while local interneuron activity is negatively correlated. Additionally, the orientation tuning of visually evoked thalamic cell responses is altered during various brain states. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback by GABAA agonist muscimol applied on the dural surface significantly diminishes the correlation between brain states and thalamic neuronal activity. Additional investigations show that by photostimulating GABAergic axons (expressing Channelrhodopsin-2 in a Cre-dependent manner) that project from the lateral hypothalamus (LH) to the dorsal raphe nucleus (DRN), neurons in the DRN increase their action potential output, presumably through disinhibition. Taken together our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal dependent brain states in awake mice and this fact might have important functional implications

A model for cerebral cortical neuron group electric activity and its implications for cerebral function

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2002.Includes bibliographical references (p. 245-265).The electroencephalogram, or EEG, is a recording of the field potential generated by the electric activity of neuronal populations of the brain. Its utility has long been recognized as a monitor which reflects the vigilance states of the brain, such as arousal, drowsiness, and sleep stages. Moreover, it is used to detect pathological conditions such as seizures, to calibrate drug action during anesthesia, and to understand cognitive task signatures in healthy and abnormal subjects. Being an aggregate measure of neural activity, understanding the neural origins of EEG oscillations has been limited. With the advent of recording techniques, however, and as an influx of experimental evidence on cellular and network properties of the neocortex has become available, a closer look into the neuronal mechanisms for EEG generation is warranted. Accordingly, we introduce an effective neuronal skeleton circuit at a neuronal group level which could reproduce basic EEG-observable slow ( 3mm). The effective circuit makes use of the dynamic properties of the layer 5 network to explain intra-cortically generated augmenting responses, restful alpha, slow wave (< 1Hz) oscillations, and disinhibition-induced seizures. Based on recent cellular evidence, we propose a hierarchical binding mechanism in tufted layer 5 cells which acts as a controlled gate between local cortical activity and inputs arriving from distant cortical areas. This gate is manifested by the switch in output firing patterns in tufted(cont.) layer 5 cells between burst firing and regular spiking, with specific implications on local functional connectivity. This hypothesized mechanism provides an explanation of different alpha band (10Hz) oscillations observed recently under cognitive states. In particular, evoked alpha rhythms, which occur transiently after an input stimulus, could account for initial reogranization of local neural activity based on (mis)match between driving inputs and modulatory feedback of higher order cortical structures, or internal expectations. Emitted alpha rhythms, on the other hand, is an example of extreme attention where dominance of higher order control inputs could drive reorganization of local cortical activity. Finally, the model makes predictions on the role of burst firing patterns in tufted layer 5 cells in redefining local cortical dynamics, based on internal representations, as a prelude to high frequency oscillations observed in various sensory systems during cognition.by Fadi Nabih Karameh.Ph.D

Properties and function of somatostatin-containing inhibitory interneurons in the somatosensory cortex of the mouse

GABAergic inhibitory interneurons play a pivotal role in balancing neuronal activity in the neocortex. They can be classified into different classes according to their variable morphological, electrophysiological, and neurochemical properties, including two major groups: parvalbumin-containing (PV+), fast-spiking (FS) cells and somatostatin-containing (SOM+) cells. Using transgenic mice, we identified two subgroups, distinct by all criteria, of SOM+ cells in the somatosensory (barrel) cortex of the mouse, one (called X94) in layer 4 and 5B, and the other one (X98) in deep layers (Ma et al., 2006). We found that X98 cells were calbindin-expressing (CB+), infragranular, layer 1--targeting Martinotti cells, and had a propensity to fire low-threshold calcium spikes, whereas X94 cells did not express CB, targeted mostly layer 4, discharged in stuttering pattern and with quasi fast-spiking properties. In the barrel cortex, it was previously shown that SOM+ cells mediate disynaptic inhibition in supragranular and infragranular layers. However, the roles of layer 4 SOM+ cells remain largely unknown. We used dual whole-cell recording to elucidate the synaptic circuits in layer 4 and the function of layer 4 SOM+ cells during cortical network activities. We found that layer 4 X94 SOM+ cells received strongly facilitating excitatory input and generated relatively slow rising inhibitory postsynaptic currents (IPSCs) compared to those evoked by FS cells. Strikingly, our data showed that SOM+ cells mediated strong synaptic inhibition of FS cells with connection probability greater than 90% in layer 4, but received very little reciprocal inhibition from FS cells, and no reciprocal inhibition from other SOM+ cells. Moreover, 100% of recorded SOM+-SOM+ cell pairs were electrically coupled with higher coupling ratio compared to that of electrically coupled FS cell pairs. In order to examine the functions of SOM+ cells, we applied 0 Mg2+ artificial cerebrospinal fluid (ACSF) to induce episodes of cortical network activity and observed that, during episodes of network activity, SOM+ cells fired robustly and synchronously, and produced strong inhibition of regular-spiking (RS) excitatory cells and inhibitory FS cells, especially the latter. Taken together, our data reveal that SOM+ cells in the barrel cortex can be sub-divided into different subtypes, and that layer 4 SOM+ cells exert a powerful inhibitory effect during high frequency network activity

A Distinct Class of Slow ( approximately 0.2-2 Hz) Intrinsically Bursting Layer 5 Pyramidal Neurons Determines UP/DOWN State Dynamics in the Neocortex

During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at approximately 0.2-2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca(2+) medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states