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Neocortical interneurons provide inhibition responsible for organizing neuronal activity into brain oscillations that subserve cognitive functions such as memory, attention, or prediction. However, the interneuronal contribution to the entrainment of neocortical oscillations within and across different cortical layers was not described. Here, using layer-specific optogenetic stimulations with micro-Light-Emitting Diode arrays, directed toward parvalbumin-expressing (PV) interneurons in non-anesthetized awake mice, we found that supragranular layer stimulations of PV neurons were most efficient at entraining supragranular local field potential (LFP) oscillations at gamma frequencies (γ: 25-80 Hz), whereas infragranular layer stimulation of PV neurons better entrained the LFP at delta (δ: 2-5 Hz) and theta (θ: 6-10 Hz) frequencies. At the level of neuronal action potential activity, we observed that supragranular neurons better followed the imposed PV stimulation rhythm than their infragranular counterparts at most frequencies when the stimulation was delivered in their respective layer. Moreover, the neuronal entrainment evoked by local stimulation could propagate across layers, though with a lesser impact when the stimulation occurs in deep layers, suggesting a direction-specific laminar propagation. These results establish a layer-based framework for oscillations to entrain the primary somatosensory cortex in awake conditions.
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Interneuronas , Parvalbúminas , Ratones , Animales , Parvalbúminas/metabolismo , Interneuronas/fisiología , Neuronas/fisiología , Encéfalo/metabolismo , Potenciales de Acción/fisiologíaRESUMEN
Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels were for the first time implicated in absence seizures (ASs) when an abnormal Ih (the current generated by these channels) was reported in neocortical layer 5 neurons of a mouse model. Genetic studies of large cohorts of children with Childhood Absence Epilepsy (where ASs are the only clinical symptom) have identified only 3 variants in HCN1 (one of the genes that code for the 4 HCN channel isoforms, HCN1-4), with one (R590Q) mutation leading to loss-of-function. Due to the multi-faceted effects that HCN channels exert on cellular excitability and neuronal network dynamics as well as their modulation by environmental factors, it has been difficult to identify the detailed mechanism by which different HCN isoforms modulate ASs. In this review, we systematically and critically analyze evidence from established AS models and normal non-epileptic animals with area- and time-selective ablation of HCN1, HCN2 and HCN4. Notably, whereas knockout of rat HCN1 and mouse HCN2 leads to the expression of ASs, the pharmacological block of all HCN channel isoforms abolishes genetically determined ASs. These seemingly contradictory results could be reconciled by taking into account the well-known opposite effects of Ih on cellular excitability and network function. Whereas existing evidence from mouse and rat AS models indicates that pan-HCN blockers may provide a novel approach for the treatment of human ASs, the development of HCN isoform-selective drugs would greatly contribute to current research on the role for these channels in ASs generation and maintenance as well as offer new potential clinical applications.
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Epilepsia Tipo Ausencia , Animales , Niño , Humanos , Ratones , Ratas , Epilepsia Tipo Ausencia/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Neuronas/metabolismo , Convulsiones/genética , Convulsiones/metabolismoRESUMEN
During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamus cooperatively engage in rhythmic activities that are exquisitely reflected in the electroencephalogram as distinctive rhythms spanning a range of frequencies from <1 Hz slow waves to 13 Hz alpha waves. In the thalamus, these diverse activities emerge through the interaction of cell-intrinsic mechanisms and local and long-range synaptic inputs. One crucial feature, however, unifies thalamic oscillations of different frequencies: repetitive burst firing driven by voltage-dependent Ca2+ spikes. Recent evidence reveals that thalamic Ca2+ spikes are inextricably linked to global somatodendritic Ca2+ transients and are essential for several forms of thalamic plasticity. Thus, we propose herein that alongside their rhythm-regulation function, thalamic oscillations of low-vigilance states have a plasticity function that, through modifications of synaptic strength and cellular excitability in local neuronal assemblies, can shape ongoing oscillations during inattention and NREM sleep and may potentially reconfigure thalamic networks for faithful information processing during attentive wakefulness.
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Nivel de Alerta/fisiología , Plasticidad Neuronal/fisiología , Sueño de Onda Lenta/fisiología , Tálamo/fisiología , Animales , HumanosRESUMEN
OBJECTIVE: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. METHODS: We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical Layer 5/6 and thalamocortical neurons, respectively. RESULTS: Oral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small-amplitude 4-7-Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. SIGNIFICANCE: These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.
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Anticonvulsivantes/uso terapéutico , Canales Catiónicos Regulados por Nucleótidos Cíclicos/antagonistas & inhibidores , Ivabradina/uso terapéutico , Convulsiones/prevención & control , Animales , Anticonvulsivantes/farmacología , Corteza Cerebral , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Ivabradina/farmacología , Masculino , Microinyecciones , Red Nerviosa , Neuronas/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Ratas , Ratas Wistar , Convulsiones/genética , Corteza Somatosensorial , Núcleos Talámicos VentralesRESUMEN
Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.
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Convulsiones/fisiopatología , Convulsiones/terapia , Adolescente , Animales , Niño , Comorbilidad , HumanosRESUMEN
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the Ih current they generate contribute to the pathophysiological mechanisms of absence seizures (ASs), but their precise role in neocortical and thalamic neuronal populations, the main components of the network underlying AS generation, remains controversial. In diverse genetic AS models, Ih amplitude is smaller in neocortical neurons and either larger or unchanged in thalamocortical (TC) neurons compared with nonepileptic strains. A lower expression of neocortical HCN subtype 1 channels is present in genetic AS-prone rats, and HCN subtype 2 knock-out mice exhibit ASs. Furthermore, whereas many studies have characterized Ih contribution to "absence-like" paroxysmal activity in vitro, no data are available on the specific role of cortical and thalamic HCN channels in behavioral seizures. Here, we show that the pharmacological block of HCN channels with the antagonist ZD7288 applied via reverse microdialysis in the ventrobasal thalamus (VB) of freely moving male Genetic Absence Epilepsy Rats from Strasbourg decreases TC neuron firing and abolishes spontaneous ASs. A similar effect is observed on γ-hydroxybutyric acid-elicited ASs in normal male Wistar rats. Moreover, thalamic knockdown of HCN channels via virally delivered shRNA into the VB of male Stargazer mice, another genetic AS model, decreases spontaneous ASs and Ih-dependent electrophysiological properties of VB TC neurons. These findings provide the first evidence that block of TC neuron HCN channels prevents ASs and suggest that any potential anti-absence therapy that targets HCN channels should carefully consider the opposite role for cortical and thalamic Ih in the modulation of absence seizures.SIGNIFICANCE STATEMENT Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the fine-tuning of cellular and network excitability and have been suggested to be a key element of the pathophysiological mechanism underlying absence seizures. However, the precise contribution of HCN channels in neocortical and thalamic neuronal populations to these nonconvulsive seizures is still controversial. In the present study, pharmacological block and genetic suppression of HCN channels in thalamocortical neurons in the ventrobasal thalamic nucleus leads to a marked reduction in absence seizures in one pharmacological and two genetic rodent models of absence seizures. These results provide the first evidence that block of TC neuron HCN channels prevents absence seizures.
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Epilepsia Tipo Ausencia/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/antagonistas & inhibidores , Neuronas/metabolismo , Pirimidinas/farmacología , Núcleos Talámicos Ventrales/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Epilepsia Tipo Ausencia/fisiopatología , Ratones , Neuronas/efectos de los fármacos , Ratas , Núcleos Talámicos Ventrales/efectos de los fármacosRESUMEN
This article reports on the development, i.e., the design, fabrication, and validation of an implantable optical neural probes designed for in vivo experiments relying on optogenetics. The probes comprise an array of ten bare light-emitting diode (LED) chips emitting at a wavelength of 460 nm and integrated along a flexible polyimide-based substrate stiffened using a micromachined ladder-like silicon structure. The resulting mechanical stiffness of the slender, 250-µm-wide, 65-µm-thick, and 5- and 8-mm-long probe shank facilitates its implantation into neural tissue. The LEDs are encapsulated by a fluropolymer coating protecting the implant against the physiological conditions in the brain. The electrical interface to the external control unit is provided by 10-µm-thick, highly flexible polyimide cables making the probes suitable for both acute and chronic in vivo experiments. Optical and electrical properties of the probes are reported, as well as their in vivo validation in acute optogenetic studies in transgenic mice. The depth-dependent optical stimulation of both excitatory and inhibitory neurons is demonstrated by altering the brain activity in the cortex and the thalamus. Local network responses elicited by 20-ms-long light pulses of different optical power (20 µW and 1 mW), as well as local modulation of single unit neuronal activity to 1-s-long light pulses with low optical intensity (17 µW) are presented. The ability to modulate neural activity makes these devices suitable for a broad variety of optogenetic experiments.
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Encéfalo/metabolismo , Fibras Ópticas , Optogenética/instrumentación , Semiconductores , Animales , Encéfalo/fisiología , Fenómenos Electrofisiológicos , Ratones , Fenómenos Ópticos , SilicioRESUMEN
Cannabis is the most consumed illicit substance in France, and its use can lead to dependency. Lille university hospital, le Pari association, offers patients wanting to stop using cannabis a support therapy based on positive feedback led by nurses, as well as symptomatic treatment of anxiety and sleep disorders.
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Atención Ambulatoria , Abuso de Marihuana/enfermería , Abuso de Marihuana/rehabilitación , Síndrome de Abstinencia a Sustancias/enfermería , Síndrome de Abstinencia a Sustancias/rehabilitación , Adulto , Trastornos de Ansiedad/enfermería , Trastornos de Ansiedad/psicología , Humanos , Masculino , Abuso de Marihuana/psicología , Motivación , Relaciones Enfermero-Paciente , Refuerzo en Psicología , Trastornos del Inicio y del Mantenimiento del Sueño/enfermería , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Apoyo Social , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Slow waves represent one of the prominent EEG signatures of non-rapid eye movement (non-REM) sleep and are thought to play an important role in the cellular and network plasticity that occurs during this behavioral state. These slow waves of natural sleep are currently considered to be exclusively generated by intrinsic and synaptic mechanisms within neocortical territories, although a role for the thalamus in this key physiological rhythm has been suggested but never demonstrated. Combining neuronal ensemble recordings, microdialysis, and optogenetics, here we show that the block of the thalamic output to the neocortex markedly (up to 50%) decreases the frequency of slow waves recorded during non-REM sleep in freely moving, naturally sleeping-waking rats. A smaller volume of thalamic inactivation than during sleep is required for observing similar effects on EEG slow waves recorded during anesthesia, a condition in which both bursts and single action potentials of thalamocortical neurons are almost exclusively dependent on T-type calcium channels. Thalamic inactivation more strongly reduces spindles than slow waves during both anesthesia and natural sleep. Moreover, selective excitation of thalamocortical neurons strongly entrains EEG slow waves in a narrow frequency band (0.75-1.5 Hz) only when thalamic T-type calcium channels are functionally active. These results demonstrate that the thalamus finely tunes the frequency of slow waves during non-REM sleep and anesthesia, and thus provide the first conclusive evidence that a dynamic interplay of the neocortical and thalamic oscillators of slow waves is required for the full expression of this key physiological EEG rhythm.
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Potenciales de Acción/fisiología , Neuronas/fisiología , Sueño/fisiología , Tálamo/fisiología , Animales , Canales de Calcio Tipo T/metabolismo , Corteza Cerebral/fisiología , Electroencefalografía , Masculino , Ratas , Ratas WistarRESUMEN
Since their discovery more than 30 years ago, low-threshold T-type Ca(2+) channels (T channels) have been suggested to play a key role in many EEG waves of non-REM sleep, which has remained exclusively linked to the ability of these channels to generate low-threshold Ca(2+) potentials and associated high-frequency bursts of action potentials. Our present understanding of the biophysics and physiology of T channels, however, highlights a much more diverse and complex picture of the pivotal contributions that they make to different sleep rhythms. In particular, recent experimental evidence has conclusively demonstrated the essential contribution of thalamic T channels to the expression of slow waves of natural sleep and the key role played by Ca(2+) entry through these channels in the activation or modulation of other voltage-dependent channels that are important for the generation of both slow waves and sleep spindles. However, the precise contribution to sleep rhythms of T channels in cortical neurons and other sleep-controlling neuronal networks remains unknown, and a full understanding of the cellular and network mechanisms of sleep delta waves is still lacking.
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Potenciales de Acción/fisiología , Encéfalo/fisiología , Canales de Calcio Tipo T/fisiología , Fases del Sueño/fisiología , Animales , Electroencefalografía/métodos , Humanos , Red Nerviosa/fisiologíaRESUMEN
The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.
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Potenciales de Acción/fisiología , Canales de Calcio Tipo T/fisiología , Neocórtex/fisiología , Neuronas/fisiología , Tálamo/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Neurológicos , Neocórtex/citología , Tálamo/citología , Vigilia/fisiologíaRESUMEN
Advanced nursing practices are procedures enabling nurses to carry out, in a structured and predefined manner, tasks usually entrusted to doctors. Introduced in France by the Berland reports of 2003 and 2006, advanced nursing practices remain under-developed in the fields of psychiatry and addictology. In this context, Lille regional and university hospital has set up an outpatient programme for alcohol withdrawal, a scheme coordinated by a nurse, authorised to modifythe treatment dosage according to the patient's clinical state and who is supported by a network of caregivers during the period of medicalised withdrawal.
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Enfermería de Práctica Avanzada , Alcoholismo/enfermería , Alcoholismo/rehabilitación , Servicio Ambulatorio en Hospital , Conducta Cooperativa , Francia , Hospitales de Distrito , Hospitales Universitarios , Humanos , Comunicación InterdisciplinariaRESUMEN
Background: Computed tomography (CT) is increasingly used for assessing skeletal muscle characteristics. In cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), reduced limb muscle mass predicts poor clinical outcomes. However, the degree to which quantity or quality of respiratory and nonrespiratory muscles is affected by these diseases remains controversial. Methods: Thoracic CT images of 29 CF, 21 COPD and 20 normal spirometry control subjects were analysed to measure indices of muscle quantity (volume or cross-sectional area) and quality (radiodensity) in respiratory (diaphragm, abdominal) and nonrespiratory (pectoralis, lumbar paraspinal) muscles. Multivariable linear regression assessed relationships of CT measurements with body mass index (BMI), forced expiratory volume in 1â s (FEV1) % pred, inflammation and infection biomarkers, nutritional status and CF genotype. Results: Diaphragm volume in CF was significantly higher than in COPD (by 154%) or controls (by 140%). Abdominal muscle area in CF was also greater than in COPD (by 130%). Nonrespiratory muscles in COPD had more low radiodensity muscle (marker of lipid content) compared to CF and controls. In CF but not COPD, higher BMI and FEV1 % pred were independently associated with higher diaphragm and/or abdominal muscle quantity indices. Serum creatinine also predicted respiratory and nonrespiratory muscle quantity in CF, whereas other biomarkers including genotype correlated poorly with muscle CT parameters. Conclusions: Our data suggest that the CF diaphragm undergoes hypertrophic remodelling, whereas in COPD the nonrespiratory muscles show altered muscle quality consistent with greater lipid content. Thoracic CT can thus identify distinctive respiratory and nonrespiratory muscle remodelling signatures associated with different chronic lung diseases.
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Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40-60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.
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Estado de Conciencia , Epilepsia Tipo Ausencia , Femenino , Ratas , Humanos , Animales , Estado de Conciencia/fisiología , Roedores , Convulsiones , Tálamo , Electroencefalografía/métodos , Neuronas/fisiología , Corteza CerebralRESUMEN
In this Letter I stress the role of causal reversibility (time symmetry), together with causality and locality, in the justification of the quantum formalism. First, in the algebraic quantum formalism, I show that the assumption of reversibility implies that the observables of a quantum theory form an abstract real C^{â} algebra, and can be represented as an algebra of operators on a real Hilbert space. Second, in the quantum logic formalism, I emphasize which axioms for the lattice of propositions (the existence of an orthocomplementation and the covering property) derive from reversibility. A new argument based on locality and Soler's theorem is used to derive the representation as projectors on a regular Hilbert space from the general quantum logic formalism. In both cases it is recalled that the restriction to complex algebras and Hilbert spaces comes from the constraints of locality and separability.
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Local field potential (LFP) oscillations are often accompanied by synchronization of activity within a widespread cerebral area. Thus, the LFP and neuronal coherence appear to be the result of a common mechanism that underlies neuronal assembly formation. We used the olfactory bulb as a model to investigate: (1) the extent to which unitary dynamics and LFP oscillations can be correlated and (2) the precision with which a model of the hypothesized underlying mechanisms can accurately explain the experimental data. For this purpose, we analyzed simultaneous recordings of mitral cell (MC) activity and LFPs in anesthetized and freely breathing rats in response to odorant stimulation. Spike trains were found to be phase-locked to the gamma oscillation at specific firing rates and to form odor-specific temporal patterns. The use of a conductance-based MC model driven by an approximately balanced excitatory-inhibitory input conductance and a relatively small inhibitory conductance that oscillated at the gamma frequency allowed us to provide one explanation of the experimental data via a mode-locking mechanism. This work sheds light on the way network and intrinsic MC properties participate in the locking of MCs to the gamma oscillation in a realistic physiological context and may result in a particular time-locked assembly. Finally, we discuss how a self-synchronization process with such entrainment properties can explain, under experimental conditions: (1) why the gamma bursts emerge transiently with a maximal amplitude position relative to the stimulus time course; (2) why the oscillations are prominent at a specific gamma frequency; and (3) why the oscillation amplitude depends on specific stimulus properties. We also discuss information processing and functional consequences derived from this mechanism.
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Potenciales de Acción/fisiología , Modelos Neurológicos , Neuronas/fisiología , Bulbo Olfatorio , Biología de Sistemas/métodos , Animales , Masculino , Odorantes , Bulbo Olfatorio/citología , Bulbo Olfatorio/fisiología , Reconocimiento de Normas Patrones Automatizadas , Ratas , Ratas Wistar , Respiración , Procesamiento de Señales Asistido por ComputadorRESUMEN
This paper reports on the development, characterization and in vivo validation of compact optical neural probes. These novel intracerebral devices comprise micro light-emitting diodes ( µLEDs) integrated along their slender probe shanks with up to 20 µLEDs per device. Blue light with a peak wavelength of 455 nm is emitted from circular apertures 100 µm in diameter. The µLEDs are structured on GaN-on-sapphire wafers and subsequently transferred onto silicon (Si) carrier wafers. The wafer-scale transfer process provides the opportunity to process the functional GaN layer stack from both sides and hence enables maximizing the efficiency of the µLEDs. Combined with standard MEMS fabrication processes for Si, linear µLED arrays with small inter- µLED distances are achieved on thin probe shanks with cross-sections measuring [Formula: see text]. Devices are interconnected using highly flexible polyimide cables in order to mechanically decouple them from the peripheral electronics during in vivo experiments. Assembled probes emit a peak optical radiant flux of 440 µW (emittance 56 mW mm -2) at 5 mA driving current. Thermal characterization of test probes reveals a temperature increase of 1.5 K measured using an integrated thermistor. Electrical functionality stress tests have been carried out to evaluate the device passivation against the physiological environment. It is estimated to endure at least 48 h during continuously pulsed µLED operation. A compact driving circuitry enables low-noise µLED operation in in vivo optogenetic experiments. The radiant flux necessary to elicit an acceptable neuronal response is determined between 1.36 µW and 17.5 µW. Probe validation successfully demonstrates the layer-specific stimulation in the cortex in multiple in vivo trials.
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Optogenética , Silicio , Electricidad , Luz , NeuronasRESUMEN
Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders. Haploinsufficiency of EHMT1, encoding a histone methyltransferase, is associated with several neurodevelopmental disorders, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1 D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to neurodevelopmental disorders. Specifically, we show that Ehmt1 D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory, and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity. The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1 D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1 D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the neurodevelopmental disorders associated with EHMT1 haploinsufficiency.
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A growing body of data suggests that information coding can be achieved not only by varying neuronal firing rate, but also by varying spike timing relative to network oscillations. In the olfactory bulb (OB) of a freely breathing anaesthetized mammal, odorant stimulation induces prominent oscillatory local field potential (LFP) activity in the beta (10-35 Hz) and gamma (40-80 Hz) ranges, which alternate during a respiratory cycle. At the same time, mitral/tufted (M/T) cells display respiration-modulated spiking patterns. Using simultaneous recordings of M/T unitary activities and LFP activity, we conducted an analysis of the temporal relationships between M/T cell spiking activity and both OB beta and gamma oscillations. We observed that M/T cells display a respiratory pattern that pre-tunes instantaneous frequencies to a gamma or beta regime. Consequently, M/T cell spikes become phase-locked to either gamma or beta LFP oscillations according to their frequency range and respiratory pattern. Our results suggest that slow respiratory dynamics pre-tune M/T cells to a preferential fast rhythm (beta or gamma) such that a spike-LFP coupling might occur when units and oscillation frequencies are in a compatible range. This double-coupling process might define two complementary beta- and gamma-neuronal assemblies along the course of a respiratory cycle.