The Decade of the Dendritic NMDA Spike

In the field of cortical cellular physiology, much effort has been invested in understanding thick apical drites of pyramidal neurons and the regenerative sodium and calcium spikes that take place in the apical trunk. Here we focus on thin dendrites of pyramidal cells (basal, oblique, and tuft dendrites), and we discuss one relatively novel form of an electrical signal (“NMDA spike”) that is specific for these branches. Basal, oblique, and apical tuft dendrites receive a high density of glutamatergic synaptic contacts. Synchronous activation of 10–50 neighboring glutamatergic synapses triggers a local dendritic regenerative potential, NMDA spike/plateau, which is characterized by significant local amplitude (40–50 mV) and an extraordinary duration (up to several hundred milliseconds). The NMDA plateau potential, when it is initiated in an apical tuft dendrite, is able to maintain a good portion of that tuft in a sustained depolarized state. However, if NMDA-dominated plateau potentials originate in proximal segments of basal dendrites, they regularly bring the neuronal cell body into a sustained depolarized state, which resembles a cortical up state. At each dendritic initiation site (basal, oblique, and tuft) an NMDA spike creates favorable conditions for causal interactions of active synaptic inputs, including the spatial or temporal binding of information, as well as processes of short-term and long-term synaptic modifications (e.g., long-term potentiation or long-term depression). Because of their strong amplitudes and durations, local dendritic NMDA spikes make up the cellular substrate for multisite independent subunit computations that enrich the computational power and repertoire of cortical pyramidal cells. We propose that NMDA spikes are likely to play significant roles in cortical information processing in awake animals (spatiotemporal binding, working memory) and during slow-wave sleep (neuronal up states, consolidation of memories

A New Principle for Information Storage in an Enzymatic Pathway Model

Strong experimental evidence indicates that protein kinase and phosphatase (KP) cycles are critical to both the induction and maintenance of activity-dependent modifications in neurons. However, their contribution to information storage remains controversial, despite impressive modeling efforts. For instance, plasticity models based on KP cycles do not account for the maintenance of plastic modifications. Moreover, bistable KP cycle models that display memory fail to capture essential features of information storage: rapid onset, bidirectional control, graded amplitude, and finite lifetimes. Here, we show in a biophysical model that upstream activation of KP cycles, a ubiquitous mechanism, is sufficient to provide information storage with realistic induction and maintenance properties: plastic modifications are rapid, bidirectional, and graded, with finite lifetimes that are compatible with animal and human memory. The maintenance of plastic modifications relies on negligible reaction rates in basal conditions and thus depends on enzyme nonlinearity and activation properties of the activity-dependent KP cycle. Moreover, we show that information coding and memory maintenance are robust to stochastic fluctuations inherent to the molecular nature of activity-dependent KP cycle operation. This model provides a new principle for information storage where plasticity and memory emerge from a single dynamic process whose rate is controlled by neuronal activity. This principle strongly departs from the long-standing view that memory reflects stable steady states in biological systems, and offers a new perspective on memory in animals and humans

Dendritic Slow Dynamics Enables Localized Cortical Activity to Switch between Mobile and Immobile Modes with Noisy Background Input

Mounting lines of evidence suggest the significant computational ability of a single neuron empowered by active dendritic dynamics. This motivates us to study what functionality can be acquired by a network of such neurons. The present paper studies how such rich single-neuron dendritic dynamics affects the network dynamics, a question which has scarcely been specifically studied to date. We simulate neurons with active dendrites networked locally like cortical pyramidal neurons, and find that naturally arising localized activity – called a bump – can be in two distinct modes, mobile or immobile. The mode can be switched back and forth by transient input to the cortical network. Interestingly, this functionality arises only if each neuron is equipped with the observed slow dendritic dynamics and with in vivo-like noisy background input. If the bump activity is considered to indicate a point of attention in the sensory areas or to indicate a representation of memory in the storage areas of the cortex, this would imply that the flexible mode switching would be of great potential use for the brain as an information processing device. We derive these conclusions using a natural extension of the conventional field model, which is defined by combining two distinct fields, one representing the somatic population and the other representing the dendritic population. With this tool, we analyze the spatial distribution of the degree of after-spike adaptation and explain how we can understand the presence of the two distinct modes and switching between the modes. We also discuss the possible functional impact of this mode-switching ability

Dendritic spikes control synaptic plasticity and somatic output in cerebellar Purkinje cells.

Neurons receive the vast majority of their input onto their dendrites. Dendrites express a plethora of voltage-gated channels. Regenerative, local events in dendrites and their role in the information transformation in single neurons are, however, poorly understood. This thesis investigates the basic properties and functional roles of dendritic spikes in cerebellar Purkinje cells using whole-cell patch clamp recordings from the dendrites and soma of rat Purkinje cells in brain slices. I show that parallel fibre (PF) evoked dendritic spikes are mediated by calcium channels, depend on membrane potential and stimulus intensity and are highly localized to the spiny branches receiving the synaptic input. A determining factor in the localization and spread of dendritic calcium spikes is the activation of large-conductance, calcium dependent potassium (BK) channels. I provide a strong link between dendritic spikes and the endocannabinoid dependent short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE). Gating the dendritic spikes using stimulus intensity or membrane potential, I show that the threshold of DSE is identical to that of the dendritic spikes and the extent of DSE depends on the number of dendritic spikes. Blocking BK channels increases the spatial spread of dendritic spikes and enables current injection or climbing fibre (CF) evoked dendritic spikes to suppress PF inputs via DSE. By monitoring dendritic spikes during strong PF stimulation-induced long-term depression (LTD), I also provide a link between long-term synaptic plasticity and dendritic excitability. By showing that blocking CB1 cannabinoid receptors reduces the intensity requirement for LTD, I provide a connection between the short- and long-term changes in PF strength triggered by dendritic spikes I also investigate the effect dendritic spikes have on somatic action potential output. Contrary to pyramidal cells, where dendritic spikes boost the output of the neuron, the average Purkinje cell output becomes independent from the output strength for inputs triggering dendritic spikes. However, the temporal pattern of the output is strongly affected by dendritic spikes. I show that this phenomenon depends on BK channel activation resulting in a pause in somatic firing following dendritic spikes. In summary, I present a description of PF evoked local dendritic spikes and demonstrate their functional role in controlling the synaptic input and action potential output of cerebellar Purkinje cells

Friction effects on collective mechanisms of short term memory

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, June 2004.Includes bibliographical references (p. 61).Short term memory is often correlated with persistent changes in neuronal firing rates in response to transient inputs. This thesis models the persistent maintenance of an analog eye position signal by an oculomotor neural integrator receiving transient eye movement commands. We show analytically how using neurons with multiple bistable dendritic compartments can enhance the robustness of eye fixations to mistuning while reproducing the observed linear relationship between neuronal firing rates and eye position. We calculate the network dynamics and tolerance to mistuning. Finally, we demonstrate that dendritic bistability can improve robustness in a biophysically realistic network of conductance based neurons.by Joseph H. Levine.M.Eng

Location-Dependent Effects of Inhibition on Local Spiking in Pyramidal Neuron Dendrites

Cortical computations are critically dependent on interactions between pyramidal neurons (PNs) and a menagerie of inhibitory interneuron types. A key feature distinguishing interneuron types is the spatial distribution of their synaptic contacts onto PNs, but the location-dependent effects of inhibition are mostly unknown, especially under conditions involving active dendritic responses. We studied the effect of somatic vs. dendritic inhibition on local spike generation in basal dendrites of layer 5 PNs both in neocortical slices and in simple and detailed compartmental models, with equivalent results: somatic inhibition divisively suppressed the amplitude of dendritic spikes recorded at the soma while minimally affecting dendritic spike thresholds. In contrast, distal dendritic inhibition raised dendritic spike thresholds while minimally affecting their amplitudes. On-the-path dendritic inhibition modulated both the gain and threshold of dendritic spikes depending on its distance from the spike initiation zone. Our findings suggest that cortical circuits could assign different mixtures of gain vs. threshold inhibition to different neural pathways, and thus tailor their local computations, by managing their relative activation of soma- vs. dendrite-targeting interneurons

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

Computational modeling of prefrontal cortex circuits

Dissertation presented to obtain the Ph.D degree in BiologyThe most outstanding feature of the human brain is its ability to perform highly complex cognitive tasks and one key region of the brain involved in these elaborated tasks is the prefrontal cortex. However, little is known about the basic neuronal processes that sustain these capacities. This dissertation describes the computational study of the biophysical properties of neurons in the prefrontal cortex that underlie complex cognitive processes with special emphasis in working memory, the ability to keep information online in the brain for a short period of time while processing incoming external stimuli.(...

Pathophysiological mechanisms of absence epilepsy: a computational modelling study

A typical absence is a non-convulsive epileptic seizure that is a sole symptom of childhood absence epilepsy (CAE). It is characterised by a generalised hyper-synchronous activity (2.5-5 Hz) of neurons in the thalamocortical network that manifests as a spike and slow-wave discharge (SWD) in the electroencephalogram. Although CAE is not a benign form of epilepsy, its physiological basis is not well understood. In an attempt to make progress regarding the mechanism of SWDs, I built a large-scale computational model of the thalamocortical network that replicated key cellular and network electric oscillatory behaviours. Model simulation indicated that there are multiple pathological pathways leading to SWDs. They fell into three categories depending on their network-level effects. Moreover, all SWDs had the same physiological mechanism of generation irrespective of their underlying pathology. They were initiated by an increase in NRT cell bursting prior to the SWD onset. SWDs critically depended on the T-type Ca2+ current (IT) mediated firing in NRT and higher-order thalamocortical relay cells (TCHO), as well as GABAB synaptic receptor-mediated IPSPs in TCHO cells. On the other hand, first-order thalamocortical cells were inhibited during SWDs and did not actively participate in their generation. These cells, however, could promote or disrupt SWD generation if they were hyperpolarised or depolarised, respectively. Importantly, only a minority of active TC cells with a small proportion of them bursting were necessary to ensure the SWD generation. In terms of their relationship to other brain rhythms, simulated SWDs were a product of NRT sleep spindle (6.5-14 Hz) and cortical δ (1-4 Hz) pacemakers and had their oscillation frequency settle between the preferred oscillation frequencies of the two pacemakers with the actual value depending on the cortical bursting intensity. These modelling results are discussed in terms of their implications for understanding CAE and its future research and treatment