How is information processed in the brain? This is one of the main and most challenging questions in Neuroscience. The established hypothesis is that information is encoded in the temporal dynamics of spikes. However, there is growing evidence that continuous signals such as Local Field Potentials (LFP) can play an important role in coding neural information. Recently, Montemurro et al. [2008] reported that the phase-of-firing code, a mechanism previously observed in the hippocampus, is used in the sensory cortices for information encoding. In the phase-of-firing code, the neurons communicate spikes with respect to the phase of continuous signals produced by population activity, such as the LFP. Using information-theoretic measures, it was shown that when the timing of spikes was measured with respect to the phase of the LFP, an extra amount of sensory information was revealed in the responses that was not available from the spike codes alone. On the one hand, it still remains to be established how widespread this novel coding mechanism is. So far it has been verified in a few sensory modalities and it is not clear whether it is a universal coding mechanism. On the other, the estimation of information from continuous signals poses serious challenges from a technical point of view. The main reason is that accurate estimations of information measures require unrealistic amount of experimental data, mostly due to the presence of correlated activity. When these measures are applied to assess the information content in continuous responses, they lead to severe biases in the results, which can affect the conclusions regarding the validity of specific neural codes. The main goal of this Thesis is to explore the universality of the phase-of-firing code by studying it in novel systems, establish the origin of this code, and to develop more effcient numerical methods to accurately quantify information encoded in continuous brain signals. In particular, in this Thesis we investigate the role of continuous signals in sensory modalities where it has not been explored so far. We verified the presence of a phase-of-firing code in both the somatosensory cortex of the rat, and the visual thalamus of mice, thus giving support to the possible universality of this coding mechanism. While the phase-of-firing code found in these systems shares common features with those found in previous studies, we also characterised important differences. In the rat whisker system it was found that high frequency bands of the LFP play a more prominent role than that observed in the visual and auditory cortices of monkeys. This is compatible with the behavioural and mechanical constraints of this system, which require a high discrimination of finely structured temporal information in the stimulus. In the case of the visual thalamus of mice, we found that the phase-of-firing code contributes significantly to the encoding of irradiance information conveyed by melanopsin photoreceptors in the retina. We also investigated the source of the phase-of-firing codes in cortex by modelling the relationship between population spikes and LFP. In particular, we studied the interplay between the effective spatial integration of information resulting from population activity and the temporal memory imprinted in the LFP as a consequence of filtering mechanisms in the neural tissue. We found that most of the information in the LFP comes from a neural neighbourhood of a radius of about 150-350 μm, and a temporal history of 200-300 msec. Finally, we developed novel practical methods for quantifying the information content of continuous signals in the brain, which yield accurate results under realistic experimental conditions. These methods are based on the projection of the statistics of the response space into a lower dimensional manifold. In particular, we modelled continuous neural responses as a hierarchy of Markov models of increasing order, and found that the structure of temporal dependencies of real LFP can be captured by the lowest orders. This helped us put a new light on the previous studies regarding the phase-of-firing code. Altogether, these results contribute an advance both at the level of understanding information coding strategies combining spike and continuous signals, and the required computational methods to quantify accurately information in experimental neural responses.

In the present study, electrophysiological and behavioral effects of compromised Gama-Aminobutyric Acid (GABAergic) transmission were investigated in adult Rhesus macaque monkeys (N=2). GABAergic transmission was perturbed in the putamen by administration of a GABAa receptor antagonist, gabazine (10 and 500 μM), via a microdialysis-local field potential (MD-LFP) probe. Resultant changes in striatal local field potentials (LFPs) were measured as an assay of synchrony. Gabazine perfusion evoked discrete large amplitude spikes in LFPs in all subjects, and the frequency and shape of individual spikes were concentration-dependent. Pre-treatment with the GABAa receptor agonist, muscimol (100 μM) blocked the gabazine-induced events, confirming a role for GABAa receptors in the effects. Behavioral manifestations of gabazine treatment were observed only at the maximum concentration. Unusual facial movements suggested aberrant electrical activity was propagated from striatum to motor cortex, perhaps via reentrant circuits. These results support a role for GABAergic transmission in segregation of striatal circuits.

Made available in DSpace on 2014-12-17T15:29:22Z (GMT). No. of bitstreams: 1 SergioACO_TESE.pdf: 4589227 bytes, checksum: 062baf399b5377e444d02b747586f12b (MD5) Previous issue date: 2014-03-31 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Desde os descobrimentos pioneiros de Hubel e Wiesel acumulou-se uma vasta literatura descrevendo as respostas neuronais do c?rtex visual prim?rio (V1) a diferentes est?mulos visuais. Estes est?mulos consistem principalmente em barras em movimento, pontos ou grades, que s?o ?teis para explorar as respostas dentro do campo receptivo cl?ssico (CRF do ingl?s classical receptive field) a caracter?sticas b?sicas dos est?mulos visuais como a orienta??o, dire??o de movimento, contraste, entre outras. Entretanto, nas ?ltimas duas d?cadas, tornou-se cada vez mais evidente que a atividade de neur?nios em V1 pode ser modulada por est?mulos fora do CRF. Desta forma, ?reas visuais prim?rias poderiam estar envolvidas em fun??es visuais mais complexas como, por exemplo, a separa??o de um objeto ou figura do seu fundo (segrega??o figura-fundo) e assume-se que as conex?es intr?nsecas de longo alcance em V1, assim como as conex?es de ?reas visuais superiores, est?o ativamente envolvidas neste processo. Sua poss?vel fun??o foi inferida a partir da an?lise das varia??es das respostas induzidas por um est?mulo localizado fora do CRF de neur?nios individuais. Mesmo sendo muito prov?vel que estas conex?es tenham tamb?m um impacto tanto na atividade conjunta de neur?nios envolvidos no processamento da figura quanto no potencial de campo, estas quest?es permanecem pouco estudadas. Visando examinar a modula??o do contexto visual nessas atividades, coletamos potenciais de a??o e potenciais de campo em paralelo de at? 48 eletrodos implantados na ?rea visual prim?ria de gatos anestesiados. Estimulamos com grades compostas e cenas naturais, focando-nos na atividade de neur?nios cujo CRF estava situado na figura. Da mesma forma, visando examinar a influ?ncia das conex?es laterais, o sinal proveniente da ?rea visual isot?pica e contralateral foi removido atrav?s da desativa??o revers?vel por resfriamento. Fizemos isso devido a: i) as conex?es laterais intr?nsecas n?o podem ser facilmente manipuladas sem afetar diretamente os sinais que est?o sendo medidos, ii) as conex?es inter-hemisf?ricas compartilham as principais caracter?sticas anat?micas com a rede lateral intr?nseca e podem ser vistas como uma continua??o funcional das mesmas entre os dois hemisf?rios e iii) o resfriamento desativa as conex?es de forma causal e revers?vel, silenciando temporariamente seu sinal, permitindo conclus?es diretas a respeito da sua contribui??o. Nossos resultados demonstram que o mecanismo de segmenta??o figurafundo se reflete nas taxas de disparo de neur?nios individuais, assim como na pot?ncia do potencial de campo e na rela??o entre sua fase e os padr?es de disparo produzidos pela popula??o. Al?m disso, as conex?es laterais inter-hemisf?ricas modulam estas vari?veis dependendo da estimula??o feita fora do CRF. Observamos tamb?m uma influ?ncia deste circuito lateral na coer?ncia entre potenciais de campo entre eletrodos distantes. Em conclus?o, nossos resultados d?o suporte ? ideia de um mecanismo complexo de segmenta??o figura-fundo atuando desde as ?reas visuais prim?rias em diferentes escalas de frequ?ncia. Esse mecanismo parece envolver grupos de neur?nios ativos sincronicamente e dependentes da fase do potencial de campo. Nossos resultados tamb?m s?o compat?veis com a hip?tese que conex?es laterais de longo alcance tamb?m fazem parte deste mecanismo / Since Hubel and Wiesel s pioneer finding a vast body of literature has accumulated describing neuronal responses in the primary visual cortex (V1) to different visual stimuli. These stimuli mainly consisted of moving bars, dots or gratings which served to explore the responses to basic visual features such as orientation, direction of motion or contrast, among others, within a classical receptive field (CRF). However, in the last two decades it became increasingly evident that the activity of V1 neurons can be modulated by stimulation outside their CRF. Thus, early visual areas might be already involved in more complex visual tasks like, for example, the segmentation of an object or a figure from its (back)-ground. It is assumed that intrinsic long-range horizontal connections within V1 as well as feedback connections from higher visual areas are actively involved in the figure-ground segmentation process. Their possible role has been inferred from the analysis of the spike rate variations induced by stimuli placed outside the CRF of single neurons. Although it is very likely that those connections also have an impact on the joined activity of neurons involved in processing the figure and on their local field potentials (LFP), these issues remain understudied. In order to examine the context-dependent modulation of those activities, we recorded spikes and LFPs in parallel from up to 48 electrodes in the primary visual cortex of anesthetized cats. We stimulated with composite grating and natural scene stimuli focusing on populations of neurons whose CRFs were situated on the foreground figure. In addition, in order to examine the influence of horizontal connections we removed the inter-hemispheric input of the isotopic contralateral visual areas by means of reversible cooling deactivation. We did so because i) the intrinsic horizontal connections cannot be easily manipulated without directly affecting the measured signals, ii) because inter-hemispheric connections share the major anatomical features with the intrinsic lateral network and can be seen as a functional continuation of the latter across the two hemispheres and iii) because cooling causally and reversibly deactivates input connections by temporarily silencing the sending neurons and thus enables direct conclusions on their contribution. Our results demonstrate that the figure-ground segmentation mechanism is reflected in the spike rate of single neurons, as well as in their LFP power and its phase-relationship to the spike patterns produced by the population. In addition "lateral" inter-hemispheric connections modulate spike rates and LFP power depending on the stimulation of the neurons CRF surround. Further, we observe an influence of this lateral circuit on field- field coherences between remote recording sites. In conclusion, our findings support the idea of complex figure-ground segmentation mechanism acting already in early visual areas on different time scales. This mechanism seems to involve groups of neurons firing synchronously and dependent on the LFP s phase. Our results are also compatible with the hypothesis that long-range lateral connections contribute to that mechanism

The last decade has seen a surge in the development of Brain-Machine Interfaces (BMI) as assistive neural devices for paralysis patients. Current BMI research typically involves a subject performing movements by controlling a robotic prosthesis. The neural signal that we consider for analysis is the Local Field Potential (LFP). The LFP is a low frequency neural signal recorded from intra-cortical electrodes, and has been recognized as one containing movement information. This thesis investigates hand-movement prediction using LFP data as input. In Chapter 1, we give an overview of Brain Machine Interfaces. In Chapter 2, we review the necessary concepts in time series analysis and pattern recognition. In the final chapter, we discuss classification accuracies when considering Summed power and Coherence as feature vectors.

The hippocampal CA1 is crucial for myriad types of learning and memory. It is theorized to provide a spatiotemporal framework for the encoding of relevant information during learning, allowing an individual to create a cognitive map of its environment and experiences. To probe CA1 network dynamics that underlie such complex cognitive function, in this work we used recently developed cellular optical imaging techniques that provide high spatial and temporal resolutions. Genetically-encoded calcium indicators offer the ability to record intracellular calcium dynamics, a proxy of neural activity, from hundreds of cells in behaving animals with single cell resolution in genetically-defined cell types. In complement, recently developed genetically-encoded voltage indicators have enabled direct recording of transmembrane voltage of individual genetically-defined cells in behaving animals. The work presented here uses the genetically-encoded calcium indicator GCaMP6f and the genetically-encoded voltage indicator SomArchon to interrogate the activities of individual hippocampal CA1 neurons and their relationship to the dynamics of the broader network during behavior. First, we provide the first in vivo, real-time evidence that two unique populations of CA1 cells encode trace conditioning and extinction learning, two distinct phases of hippocampal-dependent learning. The population of cells responsible for the representation of extinction learning emerges within one session of extinction training. Second, we perform calcium imaging in a mouse model containing a total knockout of NEXMIF, a gene causative of autism spectrum disorder. We reveal that loss of NEXMIF causes over-synchronization of the CA1 circuit, particularly during locomotion, impairing the information encoding capacity of the network. Finally, we conduct voltage imaging of CA1 pyramidal cells and parvalbumin (PV)-positive interneurons, with simultaneous recording of local field potential (LFP), to characterize how cellular-level membrane dynamics and spiking relate to network-level LFP. We demonstrate that in PV neurons, membrane potential oscillations in the theta frequency range show consistent synchrony with LFP theta oscillations and organize spike timing of the PV population relative to LFP theta, indicating that PV interneurons orchestrate theta rhythmicity in the CA1 network. In summary, this dissertation utilizes genetically-encoded optical reporters of neural activity, providing critical insights into the function of the CA1 as a flexible, diverse network of individual neurons.

Local field potentials (LFPs), extracellular potentials that reflect localized electrical activity, have long been used as a window to understand the behavioural dependence and mechanistic aspects of brain physiology. A principal premise that has driven the interpretation of LFPs is that they largely reflect the synaptic drive that impinges on neurons located in the vicinity of the recording microelectrode. An implicit, yet critical, assumption that led to the emergence of this premise is that dendrites, the structures onto which most synaptic inputs project, are purely passive compartments. However, there is a growing body of evidence demonstrating that dendrites express a plethora of active conductance, like voltage-gated ion channels, several of which are active in the subthreshold regime. These subthreshold-activated ion channels and their intra-neuronal localization profiles play widely acknowledged regulatory roles in the physiology, plasticity and pathophysiology of synapses and neurons. Despite this, the implications for the existence of these subthreshold conductances on constituent oscillatory patterns in LFPs and on the phase of neuronal spiking with reference to oscillating LFPs have surprisingly remained unexplored. The aim of this thesis is to examine if there exists a role of subthreshold conductances in regulating LFPs and the phase of spikes with reference to these LFPs. To address this, we chose to study LFPs and spikes from the CA1 region of the rat hippocampus, with hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels forming the specific subthreshold conductance of focus. The reasons behind these choices were manifold. First, CA1 pyramidal neurons are arranged in a laminar open-field configuration, making the interpretation of the source-sink formation in this region relatively tractable. Second, the dendrites of these neurons are endowed with a multitude of subthreshold conductances whose expression profiles, physiology and plasticity have been characterized in great detail. Third, this brain region has been implicated in coding for episodic and spatial memories. The phase of the spikes of the CA1 pyramidal neurons, with reference to the LFP, is believed to serve as a code that can be used to decode the location of the animal. Given that the most dominant LFP pattern seen in the CA1 region during such active exploration (and possibly encoding of spatial memories) consists of oscillations in the 4–10 Hz theta frequency band, we decided to focus our study on theta-frequency LFPs. Finally, consistent with the choice of the specific band of LFP frequencies, we focused on HCN channels because of their predominantly dendritic expression and their ability to bestow resonance and impedance phase lead, both in the theta-frequency range, on CA1 pyramidal neurons. In exploring the role of HCN channels on LFPs, we used a multi-compartmental morphologically realistic CA1 pyramidal neuron model and introduced an HCN channel conductance gradient that was constrained with several experimental measurements. This neuron was driven by dendritic excitatory synapses and perisomatic inhibitory synapses, both theta-modulated with a phase difference of +60º between their arrivals timings. We increased the excitatory synaptic conductance with distance from the soma to account for the fact that irrespective of the location of the synapse in the dendrites, the unitary excitatory post-synaptic potential remains the same at the soma. Employing these model configurations, we generated 25 different synaptic distributions on the same neuronal morphology to account for the input variability and for each of these models, we recorded transmembrane currents from all the compartments, for 8–10 cycles of the theta-modulated inputs. To model LFPs using the forward modelling scheme of line source approximation, we designed a cylindrical neuropil of 40 µm height and 100 µm radius and inserted a virtual linear electrode with 7 contact points distributed on the probe at the canter of the neuropil such that we could compute the LFP at all the strata of the CA1 region. Accounting for the volume of the neuropil and the density of neurons in this region, we took 440 instances of the morphology, rotated them at uniformly distributed angles, and distributed the somata of these model neurons within the neuropil. Each of these 440 neurons received transmembrane currents from one of the 25 models picked uniformly. With a passive model, where we did not introduce HCN channels, we expectedly observed the formation of a source-sink structure that expressed as a progressive phase shift spanning different strata, owing to the perisomatic inhibitory currents coupled with the dendritic excitatory currents. On introducing a somatodendritic gradient of HCN conductance with identical input conditions, we observed a phase lead in the LFPs across all the layers, with the magnitude of the lead increasing with distance from the soma in a manner that was correlated with the increase in HCN conductance. Next, we computed spike phases, for each of the 25 neuron models, with reference to the stratum pyramidale (SP) LFP for model configurations with and without HCN channels. We found that the spikes showed a phase lag in the presence of a gradient of HCN channels when compared to the spike phases measured from the passive neuron models. Finally, we computed the coherence of spikes across all the 25 passive or 25 active (with HCN channels) neuron models and found that the presence of HCN channels greatly enhanced spike phase coherence across neurons. Together, these results demonstrate that the presence of HCN channels introduces a lead in the theta-frequency LFP phase, a lag in the associated spike phase, and a significant enhancement of spike phase coherence. Exploring the robustness of these findings to the model configuration, we first found these conclusions to be robust to increases in neuropil size (400-µm diameter neuropil with 1797 neurons, and 1-mm diameter neuropil with 11297 neurons). Next, we introduced heterogeneities in the population of neurons (in terms of morphology as well as passive and active properties) that formed the neuropil, and found our conclusions to be invariant to such degeneracy in the underlying neuronal population. It has been observed that under certain pathological conditions like epilepsy, an entire population of CA1 neurons can undergo intrinsic plasticity, such as global (i.e., across the entire neuronal topograph) downregulation of HCN channels. To assess the impact of such up/downregulation on LFPs, we respectively increased/decreased HCN channel conductance globally in our model neurons, and found the magnitude of the lead in the LFP phase to progressively increase with HCN-channel conductance. Similarly, the magnitude of the spike-phase lag and the spike phase coherence also progressively increased as functions of HCN-channel conductance. Although such population-level global intrinsic plasticity is observed under pathological conditions, a more physiological scenario would be when a single neuron, in the process of encoding new inputs (such as encoding spatial or episodic memories), undergoes intrinsic plasticity. To assess this, we increased or decreased HCN-channel conductance specifically in a single neuron placed closest to the electrode, while leaving the HCN expression in other neurons of the neuropil at the baseline level. Expectedly, we did not find significant changes in LFP amplitude or phase, but we did find a significant lag in the spike phase preference of the neuron that underwent an upregulation of HCN conductance. Another physiological scenario is when the rat experiences a reward or exhibits anxiety-like behaviour, which can lead to changes in hormonal or neuromodulator concentrations. These changes, functioning through the activation of G-protein coupled receptors and the consequent elevation of cytosolic cyclic adenosine monophosphate (cAMP) concentrations, could shift the half-maximal activation voltage ( V1/2 ) of HCN channels to a more depolarized potential. Would such a shift in V1/2 impact LFPs and spike phases in a manner similar to that observed with increasing the conductance of HCN channels? Assessing this within our modeling framework, we found that shifting the V1/2 by +5 mV resulted in an increased lead in the LFP phase, an increased lag in the spike phase and an enhanced spike phase coherence compared to the case with a hyperpolarized V1/2 . What are the biophysical mechanisms that underlie these robust changes observed in LFPs and spike phases observed as a consequence of these several ways of increasing the current through HCN channels? We reasoned that our observations could be explained by one of the two distinct changes conferred on CA1 pyramidal neuron physiology by the presence of HCN channels. First, in the presence of HCN channels, the voltage response of CA1 pyramidal neurons shows a phase lead with reference to a sinusoidal current input (inductive phase lead) in the theta frequency range. Second, HCN channels regulate the excitability of these cells by decreasing the input resistance and impedance amplitude. To delineate the differential role of the inductive changes vs. changes in excitability, we replaced HCN channels by a faster variant (HCNFast) such that neuronal excitability remained the same while abolishing the inductive phase lead in the theta band. On doing so, we found that the lead in the LFP phase and the lag in the spike phase brought about by HCN channels was partially reversed when HCN conductance values were low. However the reversal was not substantial when HCN conductance values were high, suggesting that the inductive phase component dominates at lower HCN channel conductances, whereas the excitability component plays a critical role at higher HCN conductances. Akin to intrinsic plasticity mentioned above, under certain pathological conditions, an entire population of neurons can undergo scaling of their excitatory or inhibitory synapses. In assessing the implications for such synaptic plasticity, we first found that our conclusions on the roles of HCN channels in introducing a lead in the LFP phase, a lag in the spike phase and an enhancement of spike phase coherence were invariant to the specific values of synaptic conductances, or the phase difference between excitatory and inhibitory theta-modulated inputs. While these observations further established the robustness of the changes brought about by HCN channels to LFPs and associated spikes, we next asked whether synaptic plasticity, mediated by changes in subthreshold synaptic conductances, could itself bring about changes in the LFP and spike phase. Expectedly, we found that scaling up of excitatory synapses introduced a mild lag in the LFP phase and a lead in the spike phase, whereas scaling up of inhibitory synapses introduced a lead in the LFP phase and a lag in the spike phase. Finally, we observed a critical role of the arrival phase of inhibition with reference to excitation in altering both, the stratum pyramidale LFP and associated spike phases, with the magnitude of change in both the LFP and the spike phase roughly following the magnitude of the shift in the excitatory-inhibitory phase difference. However, in contrast to changes observed with HCN-channel plasticity, there was no significant change in spike phase coherence with any of the three forms of synaptic changes explored. Together, our results identify definite roles for HCN channels and synaptic receptors in phase-coding schemas and in the formation and dynamic reconfiguration of neuronal cell assemblies and present a clear case for the incorporation of subthreshold-activated ion channels, their gradients, and their plasticity into the computation of LFPs. Given the rich expression of several subthreshold ion channels — including HCN, A-type potassium and T-type calcium — in neuronal dendrites, future work could focus on the impact of subthreshold channels on LFPs recorded in different brain regions under different behavioral states. This thesis is organized into seven chapters. Chapter 1 provides the motivations for the study, introduces the aim of the study and poses the specific questions asked in our endeavor to understand the role of subthreshold conductances in regulating LFPs and spike phases. Chapter 2 discusses the physiological foundations and relevant literature that places the questions posed in the first chapter in the context of the aim of the thesis, with an emphasis on the literature on HCN channels. In chapter 3, we introduce the computational and theoretical foundations required to model neurons and to compute LFPs. In chapter 4, we look at the consequences of the presence of a non-uniform density of somatodendritic HCN channels on LFPs and spike phase and test the robustness of the effects observed. In chapter 5, we present our assessment of the impact of intrinsic plasticity/modulation of HCN channels on LFPs and spike phases, also exploring the biophysical mechanisms underlying such an impact. In chapter 6, we test if the observed effects still hold under synaptic plasticity, and assess the regulation of LFPs and spike phases by synaptic changes. In chapter 7, we summarize and conclude the results presented in the preceding chapters and provide some potential directions for future studies.

Cette thèse a pour objectif de contribuer à la modélisation, à la simulation et à l’analyse des signaux contenant des potentiels d’action extracellulaires (EAPs), tels que mesurés in-vivo par des microélectrodes implantées dans le cerveau. Les modèles actuels pour la simulation des EAPs consistent soit en des modèles compartimentaux très détaillés et lourds en calcul, soit en des modèles dipolaires jugés trop simplistes. Dans un premier temps, une approche de simulation des EAPs se situant entre ces deux extrêmes est proposée, où la somme des contributions des compartiments du neurone est traitée comme une convolution, appliquée aux courants membranaires d’un seul compartiment actif. L'analyse des EAPs passe par une étape de classification des potentiels d'action détectés dans le signal enregistré, qui consiste à discriminer les formes de potentiels d’action et ainsi à identifier l'activité de neurones uniques. Dans cette thèse, une nouvelle approche basée sur l’inférence bayésienne est développée permettant l'extraction et la classification simultanées des EAPs. La méthode est appliquée à des signaux générés à l'aide de l'approche de simulation proposée plus haut, confirmant la qualité de la méthode de classification introduite et illustrant la capacité de la méthode de simulation à générer des EAPs réalistes de formes diverses et discriminables. Nous avons enrichi une modélisation de l’activité hippocampique réalisée dans l’équipe permettant de reproduire des oscillations dans ces bandes fréquentielles spécifiques en introduisant les EAPs, ceci afin d’évaluer les contributions de l'activité synaptique et celle des potentiels d’action à certaines bandes de fréquence des signaux enregistrés. Finalement, une étude sur signaux réels enregistrés dans le cadre de l'étude de la perception des visages chez l'homme a été menée, illustrant les performances de la méthode de spike sorting proposée dans un cadre réel et ouvrant la discussion sur les perspectives qu'offrent ces travaux de thèse pour l'étude de questions neuroscientifiques basées sur l'analyse de signaux multi-échelle. / The objective of this thesis is to contribute to the modelling, simulation and analysis of signals containing extracellular action potentials (EAPs), as measured in vivo by microelectrodes implanted in the brain. Current models for the EAPs simulation consist either of very detailed and computationally heavy compartmental models or dipole models considered too simplistic. An EAP simulation approach between these two extremes is proposed, where the sum of the contributions of the neuron compartments is treated as a convolution, applied to the membrane currents of a single active compartment. The analysis of EAPs involves a step of classifying the action potentials detected in the recorded signal, which consists in discriminating the forms of action potentials and thus identifying the activity of single neurons In this thesis, a new approach based on Bayesian inference is developed allowing the simultaneous extraction and classification of EAPs. The method is applied to signals generated using the simulation approach proposed above, confirming the quality of the sorting method introduced and illustrating the ability of the simulation method to generate realistic EAPs of various and discriminatory forms. We modified a model of hippocampal activity previously proposed in our team, able to reproduce oscillations in specific frequency bands, by including the EAPs model, which allowed to evaluate the contributions of synaptic activity and that of action potentials the recorded signals. Finally, a study on real signals recorded as part of the study of face perception in humans is conducted, illustrating the performance of the proposed spike sorting method in a real setting and opening the discussion on the perspectives offered by this thesis work for the study of neuroscientific questions based on multiscale signal analysis.

Infant vocalisations are uniquely salient sounds in the environment. They universally attract attention and compel the listener to respond with speed and care. They provide a wealth of information to parents about their infant’s needs and affective state. There is a scientific consensus that early parenting has a profound impact on child development. In particular, the sensitivity with which parents respond to their infant’s communicative cues has been shown to affect cognitive and socio-emotional outcomes. The mechanisms underlying such sensitivity are not well understood. In this thesis, adults’ sensitivity to infant cues will be considered in terms of two components, the ‘promptness’ and ‘appropriateness’ of responses, as originally conceptualised by Bell and Ainsworth (1972). Promptness of responses is considered in terms of adults’ ability to move with speed and effort after listening to infant vocalisations. Appropriateness, on the other hand, is considered in terms of adults’ ability to differentiate between functionally significant parameters in infant vocalisations. The effect of modifiable environmental factors on the promptness and appropriateness of responses is also investigated. Finally, a focused investigation of the brain basis of responses to infant vocalisations is presented. Overall, findings demonstrated that infant vocalisations undergo privileged, specialised processing in the adult brain. After hearing an infant cry, adults with and without depression were found to move with greater coordination and effort. Adults were also found to be attuned to subtle parameters in infant cries. This sensitivity was shown to be affected by two participant-level factors, depression and previous musical training. Furthermore, this sensitivity could be enhanced through intervention, as evidenced by findings from short-term, perceptual discrimination training. The notion of privileged processing of infant vocalisations is further supported by evidence of early discrimination of infant sounds in a survival-related subcortical brain structure. Future directions for this work include directly relating current experimental measures of adults’ responses to infant cues with parental sensitivity to infant communication during dynamic interactions. Translating current findings into applied settings would require an investigation of the effects of factors such as musical and perceptual training on sensitivity to infant cues in at-risk populations, such as mothers and fathers with depression. Lastly, an increased understanding of the brain basis of adults’ sensitivity to infant cues will provide insight into our greatest challenge: parenting our young.

The activity of networks subserving memory and learning in the hippocampus is under the control of GABAergic interneurons. In order to test the contribution of distinct cell types, I have recorded extracellularly, labelled, and identified different types of interneuron in area CA3 of the hippocampus, a region implicated in the generation of gamma and theta oscillations, and the initiation of sharp-waves. I present here a detailed analysis of the spike timing of parvalbumin-positive (PV) basket and physiologically identified pyramidal cells in area CA3, relative to various network states recorded in area CA3 and CA1 simultaneously. Additionally, I have shown by detailed analysis that five classes of previously recorded and identified CA1 interneuron fired with cell type specific firing patterns relative to local gamma oscillations. In CA3, PV basket cells fired phase locked to theta and gamma oscillations recorded in CA1 as well as in CA3, and increased their firing rates during CA1 sharp-waves. Pyramidal cells in CA3 were also phase-locked, but fired at phases different from basket cells. During theta oscillations, CA3 pyramidal and PV basket cells were phase locked to both CA1 and CA3 theta equally, suggesting a wide coherence of these oscillations; in contrast, cells fired more strongly phase-locked to gamma oscillations in CA3 than in CA1, suggesting a specific role for CA3 in the generation of this rhythm. In contrast to theta and gamma oscillations, CA3 basket cells were phase-locked to ripples in area CA3 but not in CA1. Overall, my results show that the spike timing of several types of interneuron in CA1, and PV basket cells in CA3, is correlated in a cell- and area-specific manner with the generation of particular states of synchronous activity.

The goal of this thesis is to investigate the functional role of the cortical column architecture within some of the existing brain coding theories. Here I focus on the hierarchical models of predictive coding and the 'phase of firing' coding hypothesis. Using an oddball paradigm consisting of a sequence of identical sounds interspersed with rare, unexpected sounds, one can observe a difference between the scalp potentials evoked by oddball and common sounds. This difference has been linked to predictive coding and novelty detection, and Stimulus Specific Adaptation (SSA) has been suggested as a likely substrate at the single neuron level. In order to simultaneously constrain hierarchical models of predictive coding, and so as to investigate the contributions that neural processing within the different cytoarchitectonic layers of the primary auditory cortex (A1) may make to SSA, I simultaneously recorded multi-unit activity and current source density (CSD) profiles across all layers in A1 of the rat in response to standard and oddball tones. Our results suggest that SSA arises at the level of the thalamocortical synapse and is further enhanced in the supragranular layers. The phase of low-frequency Local Field Potentials (LFPs) in primary sensory cortices carries stimulus related information and disambiguates the information about different stimuli evoking similar spike rates. However, it is yet unclear how these informative LFP phase values arise within the laminar organization of cortical columns. To address this issue, I performed CSD recordings in the area A1 of anaesthetized rats during the presentation of complex naturalistic sounds. Information theoretic analysis revealed that most LFP phase information originates from discrete CSD events consisting of strong granular-superficial-layer dipoles, likely triggered by bursts of thalamocortical activation. These events, which occur at rates of 2-4 Hz, reliably reset LFP phases at times of strong network excitation. They therefore provide a useful reference frame to measure neural activity with respect to salient times of stimulus history. CSD events display a diverse, stimulus-dependent morphology: these reflect the outcomes of cortical computations which result in varying extents of activation of infragranular output layers.