GABAergic Thalamic Reticular Nucleus Research Articles

A single psychotomimetic dose of ketamine decreases thalamocortical spindles and delta oscillations in the sedated rat

BackgroundIn patients with psychotic disorders, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the spindle deficit observed in schizophrenia. MethodsAn electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine in the sensorimotor and associative/cognitive thalamocortical (TC) systems. ResultsUnder the control condition, spontaneously-occurring spindles (intra-frequency: 10–16 waves/s) and delta-frequency (1–4 Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200–700 Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30–80 Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma−/higher-frequency TC oscillations. ConclusionThe present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway.

GABAB receptor subtypes differentially regulate thalamic spindle oscillations

Following the discovery of GABAB receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABAB receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABAB1a, GABAB1b and GABAB2 form two heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K+ channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABAB(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABAB(1a,2) receptors function as heteroreceptors and inhibit glutamate release. Both GABAB(1a,2) and GABAB(1b,2) receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABAB receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABAB receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABAB(1a,2) and GABAB(1b,2) receptors on spindle oscillations. We found that selectively GABAB(1a,2) heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABAB(1b,2) receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABAB(1a,2) and GABAB(1b,2) receptors.This article is part of the “Special Issue Dedicated to Norman G. Bowery”.

The Global Spike: Conserved Dendritic Properties Enable Unique Ca2+ Spike Generation in Low-Threshold Spiking Neurons.

Low-threshold Ca2+ spikes (LTS) are an indispensible signaling mechanism for neurons in areas including the cortex, cerebellum, basal ganglia, and thalamus. They have critical physiological roles and have been strongly associated with disorders including epilepsy, Parkinson's disease, and schizophrenia. However, although dendritic T-type Ca2+ channels have been implicated in LTS generation, because the properties of low-threshold spiking neuron dendrites are unknown, the precise mechanism has remained elusive. Here, combining data from fluorescence-targeted dendritic recordings and Ca2+ imaging from low-threshold spiking cells in rat brain slices with computational modeling, the cellular mechanism responsible for LTS generation is established. Our data demonstrate that key somatodendritic electrical conduction properties are highly conserved between glutamatergic thalamocortical neurons and GABAergic thalamic reticular nucleus neurons and that these properties are critical for LTS generation. In particular, the efficiency of soma to dendrite voltage transfer is highly asymmetric in low-threshold spiking cells, and in the somatofugal direction, these neurons are particularly electrotonically compact. Our data demonstrate that LTS have remarkably similar amplitudes and occur synchronously throughout the dendritic tree. In fact, these Ca2+ spikes cannot occur locally in any part of the cell, and hence we reveal that LTS are generated by a unique whole-cell mechanism that means they always occur as spatially global spikes. This all-or-none, global electrical and biochemical signaling mechanism clearly distinguishes LTS from other signals, including backpropagating action potentials and dendritic Ca2+/NMDA spikes, and has important consequences for dendritic function in low-threshold spiking neurons.SIGNIFICANCE STATEMENT Low-threshold Ca2+ spikes (LTS) are critical for important physiological processes, including generation of sleep-related oscillations, and are implicated in disorders including epilepsy, Parkinson's disease, and schizophrenia. However, the mechanism underlying LTS generation in neurons, which is thought to involve dendritic T-type Ca2+ channels, has remained elusive due to a lack of knowledge of the dendritic properties of low-threshold spiking cells. Combining dendritic recordings, two-photon Ca2+ imaging, and computational modeling, this study reveals that dendritic properties are highly conserved between two prominent low-threshold spiking neurons and that these properties underpin a whole-cell somatodendritic spike generation mechanism that makes the LTS a unique global electrical and biochemical signal in neurons.

Patch Clamp Electrophysiology and Capillary Electrophoresis–Mass Spectrometry Metabolomics for Single Cell Characterization

The visual selection of specific cells within an ex vivo brain slice, combined with whole-cell patch clamp recording and capillary electrophoresis (CE)–mass spectrometry (MS)-based metabolomics, yields high chemical information on the selected cells. By providing access to a cell’s intracellular environment, the whole-cell patch clamp technique allows one to record the cell’s physiological activity. A patch clamp pipet is used to withdraw ∼3 pL of cytoplasm for metabolomic analysis using CE–MS. Sampling the cytoplasm, rather than an intact isolated neuron, ensures that the sample arises from the cell of interest and that structures such as presynaptic terminals from surrounding, nontargeted neurons are not sampled. We sampled the rat thalamus, a well-defined system containing gamma-aminobutyric acid (GABA)-ergic and glutamatergic neurons. The approach was validated by recording and sampling from glutamatergic thalamocortical neurons, which receive major synaptic input from GABAergic thalamic reticular nucleus neurons, as well as neurons and astrocytes from the ventral basal nucleus and the dorsal lateral geniculate nucleus. From the analysis of the cytoplasm of glutamatergic cells, approximately 60 metabolites were detected, none of which corresponded to the compound GABA. However, GABA was successfully detected when sampling the cytoplasm of GABAergic neurons, demonstrating the exclusive nature of our cytoplasmic sampling approach. The combination of whole-cell patch clamp with single cell cytoplasm metabolomics provides the ability to link the physiological activity of neurons and astrocytes with their neurochemical state. The observed differences in the metabolome of these neurons underscore the striking cell to cell heterogeneity in the brain.

Acute effect of carbamazepine on corticothalamic 5-9-Hz and thalamocortical spindle (10-16-Hz) oscillations in the rat

A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)-thalamocortical (TC) network, more specifically on CT 5-9-Hz and TC spindle (10-16-Hz) oscillations. Two to three successive 5-9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5-9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5-9-Hz depolarizing wave-hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately -70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5-9-Hz waves can trigger TC spindles.

Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

A single psychotomimetic dose of ketamine disrupts corticothalamic dynamics

Event Abstract Back to Event A single psychotomimetic dose of ketamine disrupts corticothalamic dynamics Paul Anderson1, 2, 3*, Terence O'Brien1, Nigel C. Jones1 and Didier Pinault2, 3 1 University of Melbourne, Department of Medicine (Royal Melbourne Hospital), Australia 2 Université de Strasbourg, Faculté de Médecine, France 3 INSERM U666, physiopathologie et psychopathologie cognitive de la schizophrénie, France Sensory and cognitive deficits are common in schizophrenia. The underlying anatomo-functional mechanisms remain elusive. There is a growing body of literature indicating the involvement of dysfunctional thalamic networks in the pathophysiology of schizophrenia, including disturbances in function-related gamma frequency (30-80 Hz) oscillations. A postulated mechanism of these impairments is the reduced N-Methyl d-Aspartate receptor (NMDAr) activation at glutamatergic synapses on GABAergic interneurons. Ketamine is a non-competitive NMDAr antagonist that when administered at sub-anaesthetic doses in humans and rodents produces symptoms reminiscent of psychosis and also induces aberrant gamma oscillations in cortical and sub-cortical structures, including the thalamus. Corticothalamic and thalamocortical pathways are glutamatergic and work together during brain operations, including during cognition and sensory information processing. Corticothalamic pathways originate from layer VI and innervate simultaneously GABAergic thalamic reticular nucleus neurons and thalamocortical neurons of the dorsal thalamus. The goal of the present study was to explore the spatiotemporal dynamics of the corticothalamic and thalamocortical pathways in the rat somatosensory system under physiological (vehicle) and pathological (ketamine) conditions. We conducted under light anesthesia (4) multisite cell-to-network recordings in the rat somatosensory thalamus. Its background activity was challenged by stimulation of the vibrissae. Sensory stimulation evoked a short-latency (3.3 ± 0.1 ms, n=30 from 3 animals) prethalamic response and a longer latency (9.6 ± 0.1 ms, n = 30 from 3 animals) corticothalamic response. A single injection of ketamine (2.5 mg/kg, sc) significantly increased the power of gamma oscillations (~240 % of vehicle, p < 0.001) and decreased the amplitude of the sensory-evoked corticothalamic response (vehicle condition: -0.35 ± 0.02 mV; ketamine condition: -0.26 ± 0.05 mV, p < 0.001, n = 20). In conclusion, the present results support the hypothesis that the psychotomimetic effects of ketamine are characterized by a reduction of the sensory signal-to-gamma noise ratio in corticothalamic systems. Acknowledgements Paul Anderson is supported by an Australian Rotary Health PhD scholarship Keywords: gamma oscillations, Ketamine, Schizophrenia, sensory processing, Thalamus Conference: Bernstein Conference 2012, Munich, Germany, 12 Sep - 14 Sep, 2012. Presentation Type: Poster Topic: Sensory processing and perception Citation: Anderson P, O'Brien T, Jones NC and Pinault D (2012). A single psychotomimetic dose of ketamine disrupts corticothalamic dynamics. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference 2012. doi: 10.3389/conf.fncom.2012.55.00141 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 May 2012; Published Online: 12 Sep 2012. * Correspondence: Mr. Paul Anderson, University of Melbourne, Department of Medicine (Royal Melbourne Hospital), Melbourne, Australia, p.anderson2@student.unimelb.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Paul Anderson Terence O'Brien Nigel C Jones Didier Pinault Google Paul Anderson Terence O'Brien Nigel C Jones Didier Pinault Google Scholar Paul Anderson Terence O'Brien Nigel C Jones Didier Pinault PubMed Paul Anderson Terence O'Brien Nigel C Jones Didier Pinault Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Evolution of the thalamus: a morphological and functional review

Enlargement of the forebrain, including elaboration of the thalamus, has occurred independently within different groups of vertebrates. Dorsal and ventral thalamic territories can be identified in most vertebrates, with variations in the presence of GABAergic neuronal components. An inhibitory thalamic reticular nucleus-like input to the dorsal thalamus might be a common feature, as might the organizational plan of two divisions of the dorsal thalamus, the lemnothalamus and collothalamus. Differential, independent elaboration of these divisions occurred in mammals and sauropsids (reptiles and birds), making their evolutionary relationships challenging to discern. Not all of the crucial features identified for mammalian thalamocortical circuitry are present in other vertebrates, but birds share the most features identified to date. These include specific and nonspecific thalamic relay neurons, reciprocal pallial projections, and a GABAergic thalamic reticular nucleus with some but not all hodological features. Because birds share many higher-level cognitive abilities and, thus, possibly higher-level consciousness, with mammals, comparison of the thalamocortical (thalamopallial) circuitry might prove a fruitful resource for testing functional hypotheses. Comparisons with selected other vertebrates that likewise have relatively large brain:body ratios and also exhibit some cognitively sophisticated behaviors, such as cichlid fish, might also prove valuable.

Increased glutamate, GABA and glutamine in lateral geniculate nucleus but not in medial geniculate nucleus caused by visual attention to novelty

This study is concerned with cortico-thalamic neural mechanisms underlying attentional phenomena. Previous results from this laboratory demonstrated that the visual sector of the GABAergic thalamic reticular nucleus is selectively c- fos activated in rats that are naturally paying attention to features of a novel-complex environment, and that this activation is dependent on top-down glutamatergic inputs from the primary visual cortex. By contrast, the acoustic sector of the thalamic reticular nucleus is not activated despite noise generated by exploration and c- fos activation of brainstem acoustic centers (e.g. dorsal cochlear nucleus, inferior colliculus). A prediction of these results is that the levels of the neurotransmitters glutamate and GABA, and the glutamate-related amino acid glutamine, will be increased in the lateral geniculate nucleus (LGN), but not in the medial geniculate nucleus (MGN) of rats that explore a novel-complex environment in comparison to levels of these amino acids in control rats. By means of neurochemical analysis of these amino acids (HPLC) the results of this study confirmed this prediction. The results are consistent with the previously proposed ‘focal attention’ hypothesis postulating that a focus of attention in the primary visual cortex generates top-down center-surround facilitatory-inhibitory effects on geniculocortical transmission via corticoreticulogeniculate pathways. The results also supports the notion that a main function of corticothalamic pathways to relay thalamic nuclei is attention-dependent modulation of thalamocortical transmission.

Attentional activation of the visual thalamic reticular nucleus depends on ‘top-down’ inputs from the primary visual cortex via corticogeniculate pathways

This study is concerned with corticothalamic neural mechanisms underlying attentional phenomena. Previous results from this laboratory demonstrated that the visual sector of the GABAergic thalamic reticular nucleus is activated by attention in rats. Here it is demonstrated that Fos-detected activation of the visual reticular sector in rats, induced by attentive exploration of a novel-complex environment, is dependent on ‘top-down’ cortical inputs from the primary visual cortex, on the basis (a) that activation of the visual reticular sector is drastically diminished after ibotenate lesions mostly restricted to layer 6 of the primary visual cortex, which gives origin to the corticogeniculate pathway that innervates both the visual reticular sector and the dorsal lateral geniculate nucleus; and (b) the lesions did not induce retrograde degeneration nor diminution of Fos label in the geniculate. The results are consistent with the previously proposed hypothesis that a focus of attention in V1 generates a column of increased thalamocortical transmission in LGN by means of monosynaptic glutamatergic corticogeniculate inputs, and decreased transmission of surrounding regions by disynaptic cortico-reticulo-geniculate (ultimately GABAergic) inputs. The results also suggest that attentional modulation of thalamocortical transmission is a main function of corticothalamic pathways to sensory relay nuclei.