Sensory Coding by Cerebellar Mossy Fibres through Inhibition-Driven Phase Resetting and Synchronisation

Temporal coding of spike-times using oscillatory mechanisms allied to spike-time dependent plasticity could represent a powerful mechanism for neuronal communication. However, it is unclear how temporal coding is constructed at the single neuronal level. Here we investigate a novel class of highly regular, metronome-like neurones in the rat brainstem which form a major source of cerebellar afferents. Stimulation of sensory inputs evoked brief periods of inhibition that interrupted the regular firing of these cells leading to phase-shifted spike-time advancements and delays. Alongside phase-shifting, metronome cells also behaved as band-pass filters during rhythmic sensory stimulation, with maximal spike-stimulus synchronisation at frequencies close to the idiosyncratic firing frequency of each neurone. Phase-shifting and band-pass filtering serve to temporally align ensembles of metronome cells, leading to sustained volleys of near-coincident spike-times, thereby transmitting synchronised sensory information to downstream targets in the cerebellar cortex

High frequency field potentials of the cerebellar cortex

The cerebellum plays a crucial role in motor coordination along with basal ganglia and the motor areas of the cerebral cortex. Both somatosensory and the cerebro-cerebral pathways bring in massive amounts of neural information to the cerebellum. The output of the cerebellar cortex projects to various motor cortices as well as down to the spinal cord to make its contributions to the motor function. The origin and function of the field potential oscillations in the cerebellum, especially in the high frequencies, have not been explored sufficiently. The primary objective of this study was to investigate the spatio-temporal characteristics of high frequency field potentials (150-350Hz) in the cerebellar cortex in a behavioral context. To this end, the paramedian lobule in rats was recorded using micro electro-corticogram (µ-ECoG) electrode arrays while the animal performed a lever press task using the forelimb. The phase synchrony analysis shows that the high frequency oscillations recorded at multiple points across the paramedian cortex episodically synchronize immediately before and desynchronize during the lever press. The electrode contacts were grouped according to their temporal course of phase synchrony around the time of lever press. Contact groups presented patches with slightly stronger synchrony values in the medio-lateral direction, and did not appear to form parasagittal zones. Spatiotemporal synchrony of high frequency field potentials has not been reported at such large-scales previously in the cerebellar cortex

The role of oscillation population activity in cortico-basal ganglia circuits.

The basal ganglia (BG) are a group of subcortical brain nuclei that are anatomically situated between the cortex and thalamus. Hitherto, models of basal ganglia function have been based solely on the anatomical connectivity and changes in the rate of neurons mediated by inhibitory and excitatory neurotransmitter interactions and modulated by dopamine. Depletion of striatal dopamine as occurs in Parkinson's Disease (PD) however, leads primarily to changes in the rhythmicity of basal ganglia neurons. The general aim of this thesis is to use frontal electrocorticogram (ECoG) and basal ganglia local field potential (LFP) recordings in the rat to further investigate the putative role for oscillations and synchronisation in these structures in the healthy and dopamine depleted brain. In the awake animal, lesion of the SNc lead to a dramatic increase in the power and synchronisation of P-frequency band oscillations in the cortex and subthalamic nucleus (STN) compared to the sham lesioned animal. These results are highly similar to those in human patients and provide further evidence for a direct pathophysological role for p-frequency band oscillations in PD. In the healthy, anaesthetised animal, LFPs recorded in the STN, globus pallidus (GP) and substantia nigra pars reticulata (SNr) were all found to be coherent with the ECoG. A detailed analysis of the interdependence and direction of these activities during two different brain states, prominent slow wave activity (SWA) and global activation, lead to the hypothesis that there were state dependant changes in the dominance of the cortico-subthalamic and cortico-striatal pathways. Multiple LFP recordings in the striatum and GP provided further evidence for this hypothesis, as coherence between the ECoG and GP was found to be dependent on the striatum. Together these results suggest that oscillations and synchronisation may mediate information flow in cortico-basal ganglia networks in both health and disease

Breathing coordinates cortico-hippocampal dynamics in mice during offline states

Network dynamics have been proposed as a mechanistic substrate for the information transfer across cortical and hippocampal circuits. However, little is known about the mechanisms that synchronize and coordinate these processes across widespread brain regions during offline states. Here we address the hypothesis that breathing acts as an oscillatory pacemaker, persistently coupling distributed brain circuit dynamics. Using large-scale recordings from a number of cortical and subcortical brain regions in behaving mice, we uncover the presence of an intracerebral respiratory corollary discharge, that modulates neural activity across these circuits. During offline states, the respiratory modulation underlies the coupling of hippocampal sharp-wave ripples and cortical DOWN/UP state transitions, which mediates systems memory consolidation. These results highlight breathing, a perennial brain rhythm, as an oscillatory scaffold for the functional coordination of the limbic circuit that~supports the segregation and integration of information flow across neuronal networks during offline states

Lasting EEG/MEG aftereffects on human brain oscillations after rhythmic transcranial brain stimulation: Level of control over oscillatory network activity

A number of rhythmic protocols have emerged for non-invasive brain stimulation (NIBS) in humans, including transcranial alternating current stimulation (tACS), oscillatory transcranial direct current stimulation (otDCS) and repetitive (also called rhythmic) transcranial magnetic stimulation (rTMS). With these techniques, it is possible to match the frequency of the externally applied electromagnetic fields to the intrinsic frequency of oscillatory neural population activity ("frequency-tuning"). Mounting evidence suggests that by this means tACS, otDCS, and rTMS can entrain brain oscillations and promote associated functions in a frequency-specific manner, in particular during (i.e. online to) stimulation. Here, we focus instead on the changes in oscillatory brain activity that persist after the end of stimulation. Understanding such aftereffects in healthy participants is an important step for developing these techniques into potentially useful clinical tools for the treatment of specific patient groups. Reviewing the electrophysiological evidence in healthy participants, we find aftereffects on brain oscillations to be a common outcome following tACS/otDCS and rTMS. However, we did not find a consistent, predictable pattern of aftereffects across studies, which is in contrast to the relative homogeneity of reported online effects. This indicates that aftereffects are partially dissociated from online, frequency-specific (entrainment) effects during tACS/otDCS and rTMS. We outline possible accounts and future directions for a better understanding of the link between online entrainment and offline aftereffects, which will be key for developing more targeted interventions into oscillatory brain activity

Neuronal oscillations: from single-unit activity to emergent dynamics and back

L’objectiu principal d’aquesta tesi és avançar en la comprensió del processament d’informació en xarxes neuronals en presència d’oscil lacions subumbrals. La majoria de neurones propaguen la seva activitat elèctrica a través de sinapsis químiques que són activades, exclusivament, quan el corrent elèctric que les travessa supera un cert llindar. És per aquest motiu que les descàrregues ràpides i intenses produïdes al soma neuronal, els anomenats potencials d’acció, són considerades la unitat bàsica d’informació neuronal, és a dir, el senyal mínim i necessari per a iniciar la comunicació entre dues neurones. El codi neuronal és entès, doncs, com un llenguatge binari que expressa qualsevol missatge (estímul sensorial, memòries, etc.) en un tren de potencials d’acció. Tanmateix, cap funció cognitiva rau en la dinàmica d’una única neurona. Circuits de milers de neurones connectades entre sí donen lloc a determinats ritmes, palesos en registres d’activitat colectiva com els electroencefalogrames (EEG) o els potencials de camp local (LFP). Si els potencials d’acció de cada cèl lula, desencadenats per fluctuacions estocàstiques de les corrents sinàptiques, no assolissin un cert grau de sincronia, no apareixeria aquesta periodicitat a nivell de xarxa. Per tal de poder entendre si aquests ritmes intervenen en el codi neuronal hem estudiat tres situacions. Primer, en el Capítol 2, hem mostrat com una cadena oberta de neurones amb un potencial de membrana intrínsecament oscil latori filtra un senyal periòdic arribant per un dels extrems. La resposta de cada neurona (pulsar o no pulsar) depèn de la seva fase, de forma que cada una d’elles rep un missatge filtrat per la precedent. A més, cada potencial d’acció presinàptic provoca un canvi de fase en la neurona postsinàptica que depèn de la seva posició en l’espai de fases. Els períodes d’entrada capaços de sincronitzar les oscil lacions subumbrals són aquells que mantenen la fase d’arribada dels potencials d’acció fixa al llarg de la cadena. Per tal de què el missatge arribi intacte a la darrera neurona cal, a més a més, que aquesta fase permeti la descàrrega del voltatge transmembrana. En segon cas, hem estudiat una xarxa neuronal amb connexions tant a veïns propers com de llarg abast, on les oscil lacions subumbrals emergeixen de l’activitat col lectiva reflectida en els corrents sinàptics (o equivalentment en el LFP). Les neurones inhibidores aporten un ritme a l’excitabilitat de la xarxa, és a dir, que els episodis en què la inhibició és baixa, la probabilitat d’una descàrrega global de la població neuronal és alta. En el Capítol 3 mostrem com aquest ritme implica l’aparició d’una bretxa en la freqüència de descàrrega de les neurones: o bé polsen espaiadament en el temps o bé en ràfegues d’elevada intensitat. La fase del LFP determina l’estat de la xarxa neuronal codificant l’activitat de la població: els mínims indiquen la descàrrega simultània de moltes neurones que, ocasionalment, han superat el llindar d’excitabilitat degut a un decreixement global de la inhibició, mentre que els màxims indiquen la coexistència de ràfegues en diferents punts de la xarxa degut a decreixements locals de la inhibició en estats globals d’excitació. Aquesta dinàmica és possible gràcies al domini de la inhibició sobre l’excitació. En el Capítol 4 considerem acoblament entre dues xarxes neuronals per tal d’estudiar la interacció entre ritmes diferents. Les oscil lacions indiquen recurrència en la sincronització de l’activitat col lectiva, de manera que durant aquestes finestres temporals una població optimitza el seu impacte en una xarxa diana. Quan el ritme de la població receptora i el de l’emissora difereixen significativament, l’eficiència en la comunicació decreix, ja que les fases de màxima resposta de cada senyal LFP no mantenen una diferència constant entre elles. Finalment, en el Capítol 5 hem estudiat com les oscil lacions col lectives pròpies de l’estat de son donen lloc al fenomen de coherència estocàstica. Per a una intensitat òptima del soroll, modulat per l’excitabilitat de la xarxa, el LFP assoleix una regularitat màxima donant lloc a un període refractari de la població neuronal. En resum, aquesta Tesi mostra escenaris d’interacció entre els potencials d’acció, característics de la dinàmica de neurones individuals, i les oscil lacions subumbrals, fruit de l’acoblament entre les cèl lules i ubiqües en la dinàmica de poblacions neuronals. Els resultats obtinguts aporten funcionalitat a aquests ritmes emergents, agents sincronitzadors i moduladors de les descàrregues neuronals i reguladors de la comunicació entre xarxes neuronals.The main objective of this thesis is to better understand information processing in neuronal networks in the presence of subthreshold oscillations. Most neurons propagate their electrical activity via chemical synapses, which are only activated when the electric current that passes through them surpasses a certain threshold. Therefore, fast and intense discharges produced at the neuronal soma (the action potentials or spikes) are considered the basic unit of neuronal information. The neuronal code is understood, then, as a binary language that expresses any message (sensory stimulus, memories, etc.) in a train of action potentials. Circuits of thousands of interconnected neurons give rise to certain rhythms, revealed in collective activity measures such as electroencephalograms (EEG) and local field potentials (LFP). Synchronization of action potentials of each cell, triggered by stochastic fluctuations of the synaptic currents, cause this periodicity at the network level.To understand whether these rhythms are involved in the neuronal code we studied three situations. First, in Chapter 2, we showed how an open chain of neurons with an intrinsically oscillatory membrane potential filters a periodic signal coming from one of its ends. The response of each neuron (to spike or not) depends on its phase, so that each cell receives a message filtered by the preceding one. Each presynaptic action potential causes a phase change in the postsynaptic neuron, which depends on its position in the phase space. Those incoming periods that are able to synchronize the subthreshold oscillations, keep the phase of arrival of action potentials fixed along the chain. The original message reaches intact the last neuron provided that this phase allows the discharge of the transmembrane voltage.I the second case, we studied a neuronal network with connections to both long range and close neighbors, in which the subthreshold oscillations emerge from the collective activity apparent in the synaptic currents. The inhibitory neurons provide a rhythm to the excitability of the network. When inhibition is low, the likelihood of a global discharge of the neuronal population is high. In Chapter 3 we show how this rhythm causes a gap in the discharge frequency of neurons: either they pulse single spikes or they fire bursts of high intensity. The LFP phase determines the state of the neuronal network, coding the activity of the population: its minima indicate the simultaneous discharge of many neurons, while its maxima indicate the coexistence of bursts due to local decreases of inhibition at global states of excitation. In Chapter 4 we consider coupling between two neural networks in order to study the interaction between different rhythms. The oscillations indicate recurrence in the synchronization of collective activity, so that during these time windows a population optimizes its impact on a target network. When the rhythm of the emitter and receiver population differ significantly, the communication efficiency decreases as the phases of maximum response of each LFP signal do not maintain a constant difference between them.Finally, in Chapter 5 we studied how oscillations typical of the collective sleep state give rise to stochastic coherence. For an optimal noise intensity, modulated by the excitability of the network, the LFP reaches a maximal regularity leading to a refractory period of the neuronal population.In summary, this Thesis shows scenarios of interaction between action potentials, characteristics of the dynamics of individual neurons, and the subthreshold oscillations, outcome of the coupling between the cells and ubiquitous in the dynamics of neuronal populations . The results obtained provide functionality to these emerging rhythms, triggers of synchronization and modulator agents of the neuronal discharges and regulators of the communication between neuronal networks

Memory impairment and alterations in prefrontal cortex gamma band activity following methamphetamine sensitization

RATIONALE: Repeated methamphetamine (MA) use leads to increases in the incentive motivational properties of the drug as well as cognitive impairments. These behavioral alterations persist for some time following abstinence, and neuroadaptations in the structure and function of the prefrontal cortex (PFC) are particularly important for their expression. However, there is a weak understanding of the changes in neural firing and oscillatory activity in the PFC evoked by repeated drug use, thus complicating the development of novel treatment strategies for addiction. OBJECTIVES: The purpose of the current study was to assess changes in cognitive and brain function following MA sensitization. METHODS: Sensitization was induced in rats, then temporal and recognition memory were assessed after 1 or 30 days of abstinence. Electrophysiological recordings from the medial PFC were also acquired from rats whereupon simultaneous measures of oscillatory and spiking activity were examined. RESULTS: Impaired temporal memory was observed after 1 and 30 days of abstinence. However, recognition memory was only impaired after 1 day of abstinence. An injection of MA profoundly decreased neuronal firing rate and the anesthesia-induced slow oscillation (SO) in both sensitized (SENS) and control (CTRL) rats. Strong correlations were observed between the SO and gamma band power, which was altered in SENS animals. A decrease in the number of neurons phase-locked to the gamma oscillation was also observed in SENS animals. CONCLUSIONS: The changes observed in PFC function may play an integral role in the expression of the altered behavioral phenotype evoked by MA sensitization

Diurnal influences on electrophysiological oscillations and coupling in the dorsal striatum and cerebellar cortex of the anesthetized rat

Circadian rhythms modulate behavioral processes over a 24h period through clock gene expression. What is largely unknown is how these molecular influences shape neural activity in different brain areas. The clock gene Per2 is rhythmically expressed in the striatum and the cerebellum and its expression is linked with daily fluctuations in extracellular dopamine levels and D2 receptor activity. Electrophysiologically, dopamine depletion enhances striatal local field potential (LFP) oscillations. We investigated if LFP oscillations and synchrony were influenced by time of day, potentially via dopamine mechanisms. To assess the presence of a diurnal effect, oscillatory power and coherence were examined in the striatum and cerebellum of rats under urethane anesthesia at four different times of day (ZT1, 7, 13 and 19 – indicating number of hours after lights turned on in a 12h:12h light-dark cycle). We also investigated the diurnal response to systemic raclopride, a D2 receptor antagonist. Time of day affected the proportion of LFP oscillations within the 0-3 Hz band and the 3-8 Hz band. In both the striatum and the cerebellum, slow oscillations were strongest at ZT1 and weakest at ZT13. A 3-8 Hz oscillation was present when the slow oscillation was lowest, with peak 3-8 Hz activity occurring at ZT13. Raclopride enhanced the slow oscillations, and had the greatest effect at ZT13. Within the striatum and with the cerebellum, 0-3 Hz coherence was greatest at ZT1, when the slow oscillations were strongest. Coherence was also affected the most by raclopride at ZT13. Our results suggest that neural oscillations in the cerebellum and striatum, and the synchrony between these areas, are modulated by time of day, and that these changes are influenced by dopamine manipulation. This may provide insight into how circadian gene transcription patterns influence network electrophysiology. Future experiments will address how these network alterations are linked with behavior

Neural Mechanisms of Sensory Integration: Frequency Domain Analysis of Spike and Field Potential Activity During Arm Position Maintenance with and Without Visual Feedback

abstract: Understanding where our bodies are in space is imperative for motor control, particularly for actions such as goal-directed reaching. Multisensory integration is crucial for reducing uncertainty in arm position estimates. This dissertation examines time and frequency-domain correlates of visual-proprioceptive integration during an arm-position maintenance task. Neural recordings were obtained from two different cortical areas as non-human primates performed a center-out reaching task in a virtual reality environment. Following a reach, animals maintained the end-point position of their arm under unimodal (proprioception only) and bimodal (proprioception and vision) conditions. In both areas, time domain and multi-taper spectral analysis methods were used to quantify changes in the spiking, local field potential (LFP), and spike-field coherence during arm-position maintenance. In both areas, individual neurons were classified based on the spectrum of their spiking patterns. A large proportion of cells in the SPL that exhibited sensory condition-specific oscillatory spiking in the beta (13-30Hz) frequency band. Cells in the IPL typically had a more diverse mix of oscillatory and refractory spiking patterns during the task in response to changing sensory condition. Contrary to the assumptions made in many modelling studies, none of the cells exhibited Poisson-spiking statistics in SPL or IPL. Evoked LFPs in both areas exhibited greater effects of target location than visual condition, though the evoked responses in the preferred reach direction were generally suppressed in the bimodal condition relative to the unimodal condition. Significant effects of target location on evoked responses were observed during the movement period of the task well. In the frequency domain, LFP power in both cortical areas was enhanced in the beta band during the position estimation epoch of the task, indicating that LFP beta oscillations may be important for maintaining the ongoing state. This was particularly evident at the population level, with clear increase in alpha and beta power. Differences in spectral power between conditions also became apparent at the population level, with power during bimodal trials being suppressed relative to unimodal. The spike-field coherence showed confounding results in both the SPL and IPL, with no clear correlation between incidence of beta oscillations and significant beta coherence.Dissertation/ThesisDoctoral Dissertation Biomedical Engineering 201