Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

GABAB receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABAB receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABAB receptors. Here, we investigate the impact of GABAB receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABAB receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 μM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABAB receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABAB receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABAB receptors regulated neuronal output in different ways. Activation of somatic GABAB receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABAB receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABAB receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABAB receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABAB receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.NHMR

Simulations of Neocortical Columnar Oscillations

The intentionof this thesis is to examine the role of the neocortical local drcuit in supporting synchronisatLon and fast (gamma) oscUlation. The aim is to include stereotypical features of the local neocortex in model simulations of cortical activity. Modelling is hmitedby scale in number and detail. Model features include three neurontypes(RS, FS and IB) andsynapses with three time courses takenfrom reportedtri-phasic PSPs (fEPSP, flPSP andsIPSP). Cell types and synapses are distributedin a two layer model. The contribution of the layers to columnactivity is investigated. The upperlayer has a tendancy towardspredse synchronisation and can dominate the activity producing synchronisation and oscillation in the whole column. This is attributed to the stronger inhibitory circuit in the upperlayer. The lower layer achieves a less precise synchronisatiorv this is attributed to a lower level of inhibition and the intraburst duration of IB neurons. The significance of this difference in the temporal properties of the two layers is discussed in relation to existing theories andmodels of local cortical function. Following a further consideration of local cortical physiology a new model of cortical functioning is proposed. The key features of this model include: the generation of local oscillations in a vertical interlarninar reciprocal circuit; the apical dendrite providing a sharp coincidence detection functionbetweenthe layers; slow axonal lateral propagationprovidinga time delay network; apical dendrites of bursting cells (CH and IB) providing coincidence detectionbetweenmputs 6:0m distant areas (layer 1 inputs) and local activity; bursting cell innervationof intemeurons, linking the local oscillation cy de to coinddence detection. This moddis termed an'intrinsically osdllating time coding networld (lOTCN). Specific predictions are made concerning the functiorungof the local circuit m neocortex, and the connectivity of CH neurons

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

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

Phase synchronization of coupled bursting neurons and the generalized Kuramoto model

Bursting neurons fire rapid sequences of action potential spikes followed by a quiescent period. The basic dynamical mechanism of bursting is the slow currents that modulate a fast spiking activity caused by rapid ionic currents. Minimal models of bursting neurons must include both effects. We considered one of these models and its relation with a generalized Kuramoto model, thanks to the definition of a geometrical phase for bursting and a corresponding frequency. We considered neuronal networks with different connection topologies and investigated the transition from a non-synchronized to a partially phase-synchronized state as the coupling strength is varied. The numerically determined critical coupling strength value for this transition to occur is compared with theoretical results valid for the generalized Kuramoto model.Comment: 31 pages, 5 figure

Comparing Epileptiform Behavior of Mesoscale Detailed Models and Population Models of Neocortex

Two models of the neocortex are developed to study normal and pathologic neuronal activity. One model contains a detailed description of a neocortical microcolumn represented by 656 neurons, including superficial and deep pyramidal cells, four types of inhibitory neurons, and realistic synaptic contacts. Simulations show that neurons of a given type exhibit similar, synchronized behavior in this detailed model. This observation is captured by a population model that describes the activity of large neuronal populations with two differential equations with two delays. Both models appear to have similar sensitivity to variations of total network excitation. Analysis of the population model reveals the presence of multistability, which was also observed in various simulations of the detailed model

Bursting neurons signal input slope

Brief bursts of high-frequency action potentials represent a common firing mode of pyramidal neurons, and there are indications that they represent a special neural code. It is therefore of interest to determine whether there are particular spatial and temporal features of neuronal inputs that trigger bursts. Recent work on pyramidal cells indicates that bursts can be initiated by a specific spatial arrangement of inputs in which there is coincident proximal and distal dendritic excitation (Larkum et al., 1999). Here we have used a computational model of an important class of bursting neurons to investigate whether there are special temporal features of inputs that trigger bursts. We find that when a model pyramidal neuron receives sinusoidally or randomly varying inputs, bursts occur preferentially on the positive slope of the input signal. We further find that the number of spikes per burst can signal the magnitude of the slope in a graded manner. We show how these computations can be understood in terms of the biophysical mechanism of burst generation. There are several examples in the literature suggesting that bursts indeed occur preferentially on positive slopes (Guido et al., 1992; Gabbiani et al., 1996). Our results suggest that this selectivity could be a simple consequence of the biophysics of burst generation. Our observations also raise the possibility that neurons use a burst duration code useful for rapid information transmission. This possibility could be further examined experimentally by looking for correlations between burst duration and stimulus variables

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