Effects of weak electric fields on long-term synaptic plasticity

Transcranial direct current stimulation (tDCS) is a technique where a weak direct electrical current is applied to the scalp with the goal of stimulating the brain. There is tremendous interest in the use of tDCS for treating brain disorders and improving brain function. However, the effects of tDCS have been highly variable across studies, leading to a debate over its efficacy. A major challenge is therefore to design tDCS protocols that yield predictable effects, which will require a better understanding of its basic mechanisms of action. One commonly discussed mechanism is that tDCS may alter synaptic plasticity, but the biophysics that support this interaction between tDCS and synaptic plasticity remain unclear. This dissertation is centered around a fundamental hypothesis; that tDCS can modulate the brain’s ongoing endogenous synaptic plasticity by altering the voltage dynamics in postsynaptic neurons. In chapters 1 and 2, I discuss how this hypothesis is built on decades of research characterizing effects of weak electric fields on neuronal membrane potential and the dependence of synaptic plasticity on membrane potential. In chapters 3 and 4, several experimental predictions of this theory are tested using a canonical model system for studying synaptic plasticity, the hippocampal brain slice. The theory accounts for the dependence of DCS effects on the temporal pattern of synaptic inputs and their location along a dendritic arbor, which may be sources of unexplained variability in human tDCS studies. An essential part of the proposed theory is that the effects of tDCS are mediated by the same cellular machinery that implements Hebbian synaptic plasticity. In chapter 4, we show that the effects of DCS therefore exhibit Hebbian properties, such as pathway specificity and associativity, whose role in associative learning has been studied extensively. These results suggest that tDCS can enhance associative learning and remain functionally specific by interacting with endogenous plasticity mechanisms. We further propose that clinical tDCS should be paired with tasks that induce plasticity to harness this phenomenon. In chapters 4 and 5, I present a computational model that incorporates established biophysical mechanisms for neuronal voltage dynamics, Hebbian synaptic plasticity, and membrane polarization due to weak electric fields. The model is in good agreement with our experimental results, demonstrating their consistency with the proposed theory. The model is then used to predict effects of tDCS with new synaptic input patterns and propose future brain slice experiments. The remaining chapters, 6 through 8, discuss the advances made by this work and important limitations. The theory and accompanying model provide a principled method for predicting effects on synaptic plasticity when tDCS is applied during training. However, it does not account for several observed effects of tDCS, such as on plasticity that is induced after stimulation has ended. Integrating the present theory with other potential mechanisms is therefore an important area for future research. Nonetheless, this work establishes a mechanistic framework for interpreting the effects of tDCS on synaptic plasticity and should aid in the design of tDCS protocols to facilitate associative learning

Modification of synaptic-input clustering by intrinsic excitability plasticity on cerebellar Purkinje cell dendrites

小脳神経細胞の樹状突起で新規の学習原理を発見 --小脳プルキンエ細胞の樹状突起では、樹状突起の興奮性が入力の伝搬を決める--. 京都大学プレスリリース. 2019-11-26.Dendrites filtering neuron's excitement. 京都大学プレスリリース. 2019-12-09.The role of dendrites in the integration of widespread synaptic activity has been studied in experiments and theories (Johnston et al., 1996; Magee, 2007). However, whether the conduction of synaptic currents from dendrites to the soma depends on excitability of those dendritic branches is unclear. How modulation of the branch excitability affects the conduction of synaptic inputs and their selection on dendrites is also elusive. Here, I performed simultaneous voltage-clamp recordings from the soma and dendrites of single cerebellar Purkinje neurons in male Sprague-Dawley rats and analyzed the relationship between spontaneous excitatory postsynaptic currents (EPSCs) on both sides. I found that EPSCs on distal dendrites have a salient discordance in amplitude, compared to those on the soma. Furthermore, individual ratios of the EPSC concurrently recorded on the soma and dendrites were not unique, but discrete, suggesting the occurrence of various attenuations in different paths of dendritic branches to the soma. The obtained data and simulations indicate several distinct groups (4.5 ± 0.3, n = 22 somato-dendritic recordings) of co-occurred synaptic inputs in Purkinje cell dendrites. This clustering of synaptic currents was suggested to emerge at farther distances than the secondary bifurcations. Finally, ratios of the co-EPSCs were uniformly distributed after either intrinsic plasticity induction or SK-channel blockade. Overall, results suggest that in Purkinje cells the excitability along the dendrite processes modulates the conduction of EPSCs and makes active inputs heterogeneous through SK channel activity, intrinsic plasticity and dendritic branching. These properties of dendrites may confer branch-specific computational power to neurons

Neural Field Model of VSD Optical Imaging Signals

In this report we propose a solution to the direct problem of VSD optical imaging based on a neural field model of a cortical area and reproduce optical signals observed in various mammals cortices. We first present a biophysical approach to neural fields and show that these easily integrate the biological knowledge on cortical structure, especially horizontal and vertical connectivity patterns. After having introduced the reader to VSD optical imaging, we propose a biophysical formula expressing the optical imaging signal in terms of the activity of the field. Then, we simulate optical signals that have been observed by experimentalists. We have chosen two experimental sets: the line-motion illusion in the visual cortex of mammals (jancke, chavane, et al. 2004} and the spread of activity in the rat barrel cortex (petersen, grinvald, et al. 2003). We begin with a structural description of both areas, with a focus on horizontal connectivity. Finally we simulate the corresponding neural field equations and extract the optical signal using the direct problem formula developed in the preceding sections. We have been able to reproduce the main experimental results with these models

Modulation of Network Oscillations by Brain Stimulation

Finding new and effective treatments for mental illness represents one of the largest challenges of our time due the large number of people affected. Despite long and careful study there have been few recent breakthroughs in pharmacological treatments of mental illness. To address this, the National Institute of Mental Health (NIMH) has recently begun to focus on the investigation of network level correlates of mental illnesses. Patients with mental illness often exhibit aberrant neural oscillatory activity, thus making the network level a promising scale for the identification of measureable neural correlates of mental illnesses. At the network level, neural activity is primarily in the form of cortical oscillations which may be recorded noninvasively with electroencephalography (EEG). Such EEG oscillations are the result of synchronized activity from many cells in the neocortex. However the exact mechanisms of how oscillations arise and spread throughout the brain remain unknown. Non-invasive brain stimulation is a promising treatment modality because it specifically targets activity of brain networks. Unlike pharmacological treatments, stimulation with electric and magnetic fields directly targets electrical activity of many cells in a network. In particular, transcranial alternating current stimulation appears to be especially suited for targeting oscillations in brain networks. Despite the promise of these brain stimulation techniques, the underlying mechanisms remain unknown. The studies presented in this dissertation address two critical gaps in the treatment of mental illnesses. (1) How does rhythmic network activity arise from cellular and synaptic components? And (2) how does brain stimulation interact with ongoing network activity? Only by understanding how network activity arises and how it interacts with brain stimulation we may begin to design brain stimulation paradigms for treatment of mental illness.Doctor of Philosoph

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 localization, regulation and function of synaptopodin and the cisternal organelle in the axon initial segment during murine visual system development

Activity-dependent development of neurons during critical periods of plasticity is a hallmark feature of visual system maturation. Synaptopodin (synpo) is an actin-associated protein and an essential component of the cisternal organelle (CO), localized in the axon initial segment (AIS). The CO is a putative Ca2+ store and potentially plays a role in Ca2+ current regulation of the AIS. The CO is the structural correlate of the spine apparatus in dendritic spines, which is a dynamic structure and exhibits striking plasticity depending on synpo expression. The AIS undergoes activity-dependent plasticity during visual cortex development, yet, how this plasticity is regulated remains to be elucidated. Furthermore, the structure of the AIS in retinal ganglion cells (RGCs) and its ability to undergo plasticity during retinal development is largely unknown. Therefore, the current thesis investigates the putative role of the CO in AIS structural plasticity in the murine visual system. For this purpose, the developmental regulation of synpo/CO expression in AIS was examined utilizing semi-quantitative immunofluorescence. Confocal microscopy and self-programmed macros were utilized to analyze synpo/CO cluster remodeling in AIS in the visual cortex and the retina. Activity-dependent regulation of synpo/CO expression was tested by performing visual deprivation experiments. The impact of synpo/CO expression on AIS maturation under normal and visual deprivation conditions was investigated in wildtype and synpo KO mice. The precise subcellular localization of synpo/CO in retinal AIS was determined applying super resolution microscopy. It was found that synpo/CO expression is dynamically regulated in an activity-dependent manner in a subset of visual cortex neurons and RGCs during visual system development. Dark-rearing of mice resulted in a significant increase in size and number of synpo/CO clusters in the AIS. Furthermore, a correlation between synpo/CO and structural AIS length maturation was found in the visual cortex. Visual deprivation led to the maintenance of elongated AIS with juvenile characteristics in adult wildtype, and to AIS shortening in synpo KO mice. This indicates a potential role for synpo/CO in AIS structural maturation. Super resolution analysis of retinal AIS revealed gaps in the AIS scaffold where synpo/CO clusters are located. In summary, the present thesis highlights that synpo/CO expression is regulated in an activity-dependent manner during visual system development and that the presence of synpo/CO influences structural AIS plasticity in the visual cortex

PERTURBING THE NEURONAL NETWORK DYNAMICS IN THE HIGHER-ORDER THALAMO-CORTICAL NETWORK

Understanding the brain’s dynamics and its role in cognitive functions will open up new avenues for the treatment of psychiatric illnesses. Oscillations reveal rhythmic features in the dynamics that are associated with different mental states and cognitive processes. One cognitive function of transdiagnostic importance is sustained attention. Sustained attention is the ability to focus our cognitive resources to process unpredictable information for an extended period of time. Temporary loss of sustained attention could lead to accidents while driving, and long-term sustained attention deficit is linked to many psychiatric disorders. Sustained visual attention requires an active engagement of higher-order visual circuitry to maintain a mental state for processing unpredictable visual inputs. The coordinated activity of groups of neurons in such circuitry gives rise to cortico-thalamo-cortical oscillations, which are crucial for mediating top-down control signals and bottom-up information transduction. Through its widespread interconnection with the cortex, the higher-order visual thalamus is ideally positioned to serve such a role by coordinating cortico-cortical synchrony that supports attentional engagement. However, the causal mechanisms underlying the oscillatory synchronization in the posterior visual thalamo-cortical network as well as their function during sustained attention remains unknown. Thus, basic science and translational work with causal perturbation is needed to shine a light on the role of these oscillatory dynamics in neuronal processing and behavior. The studies in this dissertation attempted to address this question by targeting the higher-order thalamo-cortical visual system and combining multiple causal perturbation tools (eg. optogenetics and transcranial brain stimulation), simultaneous multisite electrophysiological recordings, and a sustained attention task. Through a logical process of target identification, engagement, and validation, our work contributes to understanding: 1. how does the higher-order visual thalamus causally coordinate thalamo-cortical communications to enhance attentional behavior, and 2. how does transcranial alternating current stimulation affect single-neuron activity as well as long-range circuit dynamics in this network? Taken together, this work provides causal evidence underlying the mechanism of brain stimulations and its effect on behavior, which ultimately could inform the broader scientific community on how to rationally refine targeted circuit-based therapeutics for treating cognitive deficits.Doctor of Philosoph

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

Techniques for imaging small impedance changes in the human head due to neuronal depolarisation

A new imaging modality is being developed, which may be capable of imaging small impedance changes in the human head due to neuronal depolarization. One way to do this would be by imaging the impedance changes associated with ion channels opening in neuronal membranes in the brain during activity. The results of previous modelling and experimental studies indicated that impedance changes between 0.6%and 1.7% locally in brain grey matter when recorded at DC. This reduces by a further of 10% if measured at the surface of the head, due to distance and the effect of the resistive skull. In principle, this could be measured using Electrical Impedance Tomography (ElT) but it is close to its threshold of detectability. With the inherent limitation in the use of electrodes, this work proposed two new schemes. The first is a magnetic measurement scheme based on recording the magnetic field with Superconducting Quantum Interference Devices (SQUIDs), used in Magnetoencephalography (MEG) as a result of a non-invasive injection of current into the head. This scheme assumes that the skull does not attenuate the magnetic field. The second scheme takes into consideration that the human skull is irregular in shape, with less and varying conductivity as compared to other head tissues. Therefore, a key issue is to know through which electrodes current can be injected in order to obtain high percentage changes in surface potential when there is local conductivity change in the head. This model will enable the prediction of the current density distribution at specific regions in the brain with respect to the varying skull and local conductivities. In the magnetic study, the head was modelled as concentric spheres, and realistic head shapes to mimic the scalp, skull, Cerebrospinal Auid (CSF) and brain using the Finite Element Method (FEM). An impedance change of 1 % in a 2cm-radius spherical volume depicting the physiological change in the brain was modelled as the region of depolarisation. The magnetic field, 1 cm away from the scalp, was estimated on injecting a constant current of 100 µA into the head from diametrically opposed electrodes. However, in the second scheme, only the realistic FEM of the head was used, which included a specific region of interest; the primary visual cortex (V1). The simulated physiological change was the variation in conductivity of V1 when neurons were assumed to be firing during a visual evoked response. A near DC current of 100 µA was driven through possible pairs of 31 electrodes using ElT techniques. For a fixed skull conductivity, the resulting surface potentials were calculated when the whole head remained unperturbed, or when the conductivity of V1 changed by 0.6%, 1 %, and 1.6%. The results of the magnetic measurement predicted that standing magnetic field was about 10pT and the field changed by about 3fT (0.03%) on depolarization. For the second scheme, the greatest mean current density through V1 was 0.020 ± 0.005 µAmm-2, and occurred with injection through two electrodes positioned near the occipital cortex. The corresponding maximum change in potential from baseline was 0.02%. Saline tank experiments confirmed the accuracy of the estimated standing potentials. As the noise density in a typical MEG system in the frequency band is about 7fT/√Hz, it places the change at the limit of detectability due to low signal to noise ratio. This is therefore similar to electrical recording, as in conventional ElT systems, but there may be advantages to MEG in that the magnetic field direcdy traverses the skull and instrumentation errors from the electrode-skin interface will be obviated. This has enabled the estimation of electrode positions most likely to permit recording of changes in human experiments and suggests that the changes, although tiny, may just be discernible from noise