Persistence and storage of activity patterns in spiking recurrent cortical networks: modulation of sigmoid signals by after-hyperpolarization currents and acetylcholine

Many cortical networks contain recurrent architectures that transform input patterns before storing them in short-term memory (STM). Theorems in the 1970's showed how feedback signal functions in rate-based recurrent on-center off-surround networks control this process. A sigmoid signal function induces a quenching threshold below which inputs are suppressed as noise and above which they are contrast-enhanced before pattern storage. This article describes how changes in feedback signaling, neuromodulation, and recurrent connectivity may alter pattern processing in recurrent on-center off-surround networks of spiking neurons. In spiking neurons, fast, medium, and slow after-hyperpolarization (AHP) currents control sigmoid signal threshold and slope. Modulation of AHP currents by acetylcholine (ACh) can change sigmoid shape and, with it, network dynamics. For example, decreasing signal function threshold and increasing slope can lengthen the persistence of a partially contrast-enhanced pattern, increase the number of active cells stored in STM, or, if connectivity is distance-dependent, cause cell activities to cluster. These results clarify how cholinergic modulation by the basal forebrain may alter the vigilance of category learning circuits, and thus their sensitivity to predictive mismatches, thereby controlling whether learned categories code concrete or abstract features, as predicted by Adaptive Resonance Theory. The analysis includes global, distance-dependent, and interneuron-mediated circuits. With an appropriate degree of recurrent excitation and inhibition, spiking networks maintain a partially contrast-enhanced pattern for 800 ms or longer after stimuli offset, then resolve to no stored pattern, or to winner-take-all (WTA) stored patterns with one or multiple winners. Strengthening inhibition prolongs a partially contrast-enhanced pattern by slowing the transition to stability, while strengthening excitation causes more winners when the network stabilizes

Acetylcholine neuromodulation in normal and abnormal learning and memory: vigilance control in waking, sleep, autism, amnesia, and Alzheimer's disease

This article provides a unified mechanistic neural explanation of how learning, recognition, and cognition break down during Alzheimer's disease, medial temporal amnesia, and autism. It also clarifies whey there are often sleep disturbances during these disorders. A key mechanism is how acetylcholine modules vigilance control in cortical layer

Modelling emergent rhythmic activity in the cerebal cortex

A la portada consta: IDIBAPS Institut d'Investigacions Biomèdiques August Pi i SunyerThe brain, a natural adaptive system, can generate a rich dynamic repertoire of spontaneous activity even in the absence of stimulation. The spatiotemporal pattern of this spontaneous activity is determined by the brain state, which can range from highly synchronized to desynchronized states. During slow wave sleep, for example, the cortex operates in synchrony, defined by low-frequency fluctuations, known as slow oscillations (<1Hz). Conversely, during wakefulness, the cortex is characterized mainly by desynchronized activity, where low-frequency fluctuations are suppressed. Thus, an inherent property of the cerebral cortex is to transit between different states characterized by distinct spatiotemporal complexity patterns, varying in a large spectrum between synchronized and desynchronized activity. All these complex emergent patterns are the product of the interaction between tens of billions of neurons endowed with diverse ionic channels with complex biophysical properties. Nevertheless, what are the mechanisms behind these transitions? In this thesis, we sought to understand the mechanisms and properties behind slow oscillations, their modulation and their transitions towards wakefulness by employing experimental data analysis and computational models. We reveal the relevance of specific ionic channels and synaptic properties to maintaining the cortical state and also get out of it, and its spatiotemporal dynamics. Using a mean-field model, we also propose bridging neuronal spiking dynamics to a population description.El cerebro, un sistema adaptativo natural, es capaz de generar un amplio repertorio dinámico de actividad espontánea, incluso en ausencia de estímulos. La patrón espacio-temporal de esta actividad espontánea viene determinada por el estado cerebral, el cual puede variar de estados altamente sincronizados hasta estados muy desincronizados. Cuando en el sueño se entra en la fase de ondas lentas, por ejemplo, la corteza opera en sincronía, cuya actividad es definida por fluctuaciones de baja frecuencia, conocidas como oscilaciones lentas (<1Hz). En cambio, durante la vigilia, el córtex se caracteriza principalmente por tener una actividad desincronizada, donde las fluctuaciones de baja frecuencia desaparecen. Por lo tanto, una propiedad inherente de la corteza cerebral es transitar entre diferentes estados caracterizados por distintos patrones de complejidad espacio-temporal, los cuales se sitúan dentro del amplio espectro marcado por la actividad sincronizada y la desincronizada. Estos patrones emergentes son el producto de la interacción entre decenas de miles de millones de neuronas dotadas de múltiples y distintos canales iónicos con complejas propiedades biofísicas. Sin embargo, ¿cuáles son los mecanismos que regulan estas transiciones? En esta tesis tratamos de entender los mecanismos, propiedades y sus transiciones hacia la vigilia, que están detrás de las oscilaciones lentas a través del uso y análisis de datos experimentales y modelos computacionales. En ella describimos la importancia de los canales iónicos específicos y sus propiedades sinápticas tanto para mantener el estado cortical como para salir de él, estudiando así su dinámica espacio-temporal. Además, mediante el uso de un modelo de campo medio, proponemos establecer un puente que pueda describir la dinámica de disparos neuronales con una descripción general de la población neuronal.Postprint (published version

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

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

Dynamics and precursor signs for phase transitions in neural systems

This thesis investigates neural state transitions associated with sleep, seizure and anaesthesia. The aim is to address the question: How does a brain traverse the critical threshold between distinct cortical states, both healthy and pathological? Specifically we are interested in sub-threshold neural behaviour immediately prior to state transition. We use theoretical neural modelling (single spiking neurons, a network of these, and a mean-field continuum limit) and in vitro experiments to address this question. Dynamically realistic equations of motion for thalamic relay neuron, reticular nuclei, cortical pyramidal and cortical interneuron in different vigilance states are developed, based on the Izhikevich spiking neuron model. A network of cortical neurons is assembled to examine the behaviour of the gamma-producing cortical network and its transition to lower frequencies due to effect of anaesthesia. Then a three-neuron model for the thalamocortical loop for sleep spindles is presented. Numerical simulations of these networks confirms spiking consistent with reported in vivo measurement results, and provides supporting evidence for precursor indicators of imminent phase transition due to occurrence of individual spindles. To complement the spiking neuron networks, we study the Wilson–Cowan neural mass equations describing homogeneous cortical columns and a 1D spatial cluster of such columns. The abstract representation of cortical tissue by a pair of coupled integro-differential equations permits thorough linear stability, phase plane and bifurcation analyses. This model shows a rich set of spatial and temporal bifurcations marking the boundary to state transitions: saddle-node, Hopf, Turing, and mixed Hopf–Turing. Close to state transition, white-noise-induced subthreshold fluctuations show clear signs of critical slowing down with prolongation and strengthening of autocorrelations, both in time and space, irrespective of bifurcation type. Attempts at in vitro capture of these predicted leading indicators form the last part of the thesis. We recorded local field potentials (LFPs) from cortical and hippocampal slices of mouse brain. State transition is marked by the emergence and cessation of spontaneous seizure-like events (SLEs) induced by bathing the slices in an artificial cerebral spinal fluid containing no magnesium ions. Phase-plane analysis of the LFP time-series suggests that distinct bifurcation classes can be responsible for state change to seizure. Increased variance and growth of spectral power at low frequencies (f < 15 Hz) was observed in LFP recordings prior to initiation of some SLEs. In addition we demonstrated prolongation of electrically evoked potentials in cortical tissue, while forwarding the slice to a seizing regime. The results offer the possibility of capturing leading temporal indicators prior to seizure generation, with potential consequences for understanding epileptogenesis. Guided by dynamical systems theory this thesis captures evidence for precursor signs of phase transitions in neural systems using mathematical and computer-based modelling as well as in vitro experiments

Properties and Functions of Ih in Hippocampal Area CA3 Interneurons

Ih is an important contributor to the subthreshold membrane properties of various mammalian neurons, including interneurons. Here I characterize the properties of Ih in a subpopulation of hippocampal area CA3 interneurons with somata in stratum radiatum and stratum lacunosom moleculare. As shown in previous studies, Ih in these cells has sigmoidal voltage dependence of activation with kinetics characterized by two exponential components for both channel activation and deactivation. Interestingly, the activation and deactivation kinetics were most aptly described by distinct functions of voltage. These results were incorporated into a novel biophysical model of Ih that was applied in single compartment model simulations and dynamic clamp experiments. Finally, I assessed the functional consequences of Ih by examining the effects of this current on subthreshold temporal summation of mossy fiber EPSPs as well as frequency dependent neuronal responses. My results show that Ih decreases temporal summation of mossy fiber EPSPs but does not impart resonance in CA3 interneurons at potentials where Ih is active

Computational Study of the Mechanisms Underlying Oscillation in Neuronal Locomotor Circuits

In this thesis we model two very different movement-related neuronal circuits, both of which produce oscillatory patterns of activity. In one case we study oscillatory activity in the basal ganglia under both normal and Parkinsonian conditions. First, we used a detailed Hodgkin-Huxley type spiking model to investigate the activity patterns that arise when oscillatory cortical input is transmitted to the globus pallidus via the subthalamic nucleus. Our model reproduced a result from rodent studies which shows that two anti-phase oscillatory groups of pallidal neurons appear under Parkinsonian conditions. Secondly, we used a population model of the basal ganglia to study whether oscillations could be locally generated. The basal ganglia are thought to be organised into multiple parallel channels. In our model, isolated channels could not generate oscillations, but if the lateral inhibition between channels is sufficiently strong then the network can act as a rhythm-generating ``pacemaker'' circuit. This was particularly true when we used a set of connection strength parameters that represent the basal ganglia under Parkinsonian conditions. Since many things are not known about the anatomy and electrophysiology of the basal ganglia, we also studied oscillatory activity in another, much simpler, movement-related neuronal system: the spinal cord of the Xenopus tadpole. We built a computational model of the spinal cord containing approximately 1,500 biologically realistic Hodgkin-Huxley neurons, with synaptic connectivity derived from a computational model of axon growth. The model produced physiological swimming behaviour and was used to investigate which aspects of axon growth and neuron dynamics are behaviourally important. We found that the oscillatory attractor associated with swimming was remarkably stable, which suggests that, surprisingly, many features of axonal growth and synapse formation are not necessary for swimming to emerge. We also studied how the same spinal cord network can generate a different oscillatory pattern in which neurons on both sides of the body fire synchronously. Our results here suggest that under normal conditions the synchronous state is unstable or weakly stable, but that even small increases in spike transmission delays act to stabilise it. Finally, we found that although the basal ganglia and the tadpole spinal cord are very different systems, the underlying mechanism by which they can produce oscillations may be remarkably similar. Insights from the tadpole model allow us to predict how the basal ganglia model may be capable of producing multiple patterns of oscillatory activity