GABAergic Thalamic Reticular Nucleus Neurons Research Articles

Activating PV-positive neurons in ventral thalamic reticular nucleus reduces pain sensitivity in mice

Previous studies have demonstrated that thalamic reticular nucleus (TRN) and the sub-nuclei play important roles in pain sensation. Our previous findings showed that activating parvalbumin-positive (PV+) neurons in dorsal sector of TRN (dTRN) could reduce the pain threshold and consequently increase the pain sensitivity of mice. Recent studies have shown that activation of GABAergic projection of TRN to ventrobasal thalamus (VB) alleviated pathological pain. GABAergic neurons in TRN are mainly PV+ neurons. However, the exact roles of ventral TRN (vTRN) PV+ neurons in pain sensation remain unclear. In this study, the designer receptors exclusively activated by designer drugs (DREADD) method was used to activate the PV+ neurons in vTRN of PV-Cre transgenic mice, and the mechanical threshold and thermal latency were measured to investigate the regulatory effects of vTRN on pain sensitivity in mice. Thereafter, PV-Cre transgenic mice, conditional anterograde axonal tract tracing, and immunohistochemistry were used to investigate the distribution of PV+ neurons fibers in vTRN. The results showed that the activation of PV+ neurons in vTRN increased the mechanical threshold and thermal latency, which indicated reduction of pain sensitivity. The fibers of these neurons mainly projected to ventral posterolateral thalamic nucleus (VPL), ventral posteromedial thalamic nucleus (VPM), ventrolateral thalamic nucleus (VL), centrolateral thalamic nucleus (CL) and various other brain regions. These findings indicated that activation of PV+ neurons in the vTRN decreased pain sensitivity in mice, which provided additional evidence on the mechanisms of PV+ neurons of TRN in regulating neuralgia.

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.

Optogenetic Stimulation of the Corticothalamic Pathway Affects Relay Cells and GABAergic Neurons Differently in the Mouse Visual Thalamus

The dorsal lateral geniculate nucleus (dLGN) serves as the primary conduit of retinal information to visual cortex. In addition to retinal input, dLGN receives a large feedback projection from layer VI of visual cortex. Such input modulates thalamic signal transmission in different ways that range from gain control to synchronizing network activity in a stimulus-specific manner. However, the mechanisms underlying such modulation have been difficult to study, in part because of the complex circuitry and diverse cell types this pathway innervates. To address this and overcome some of the technical limitations inherent in studying the corticothalamic (CT) pathway, we adopted a slice preparation in which we were able to stimulate CT terminal arbors in the visual thalamus of the mouse with blue light by using an adeno-associated virus to express the light-gated ion channel, ChIEF, in layer VI neurons. To examine the postsynaptic responses evoked by repetitive CT stimulation, we recorded from identified relay cells in dLGN, as well as GFP expressing GABAergic neurons in the thalamic reticular nucleus (TRN) and intrinsic interneurons of dLGN. Relay neurons exhibited large glutamatergic responses that continued to increase in amplitude with each successive stimulus pulse. While excitatory responses were apparent at postnatal day 10, the strong facilitation noted in adult was not observed until postnatal day 21. GABAergic neurons in TRN exhibited large initial excitatory responses that quickly plateaued during repetitive stimulation, indicating that the degree of facilitation was much larger for relay cells than for TRN neurons. The responses of intrinsic interneurons were smaller and took the form of a slow depolarization. These differences in the pattern of excitation for different thalamic cell types should help provide a framework for understanding how CT feedback alters the activity of visual thalamic circuitry during sensory processing as well as different behavioral or pathophysiological states.

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.

Excitatory and anti‐oscillatory actions of nitric oxide in thalamus

The dorsal lateral geniculate nucleus (dLGN) not only serves as the obligatory pathway for visual information transfer from the retina to neocortex but can also generate intrathalamic rhythmic activities associated with different arousal states and certain pathological conditions. The gating activity of thalamocortical circuits is under neuromodulatory control by various brainstem nuclei as well as intrinsic thalamic neurons (e.g. thalamic reticular nucleus (TRN) neurons and dLGN interneurons). In this study, we examined the effect of the putative neuromodulator nitric oxide (NO) on thalamic neuron excitability. There are multiple potential sources of NO in thalamus: cholinergic terminals originating from brainstem nuclei, GABAergic TRN neurons, and local GABAergic interneurons. Using whole cell recording techniques in in vitro thalamic slices, we found that the NO donor SNAP produced a robust, long-lasting depolarization in TRN neurons, a weaker depolarization in thalamocortical relay neurons, and no effect in local interneurons. SNAP preferentially depolarized stereotypical TRN neurons that could produced strong burst discharge. In contrast, SNAP had little effect on atypical burst and non-burst TRN cells. The NO donor SIN-1 and the endogenous NO precursor, L-arginine, mimicked the SNAP-mediated actions. The NO-mediated depolarizations were blocked by the guanylyl cyclase inhibitor ODQ indicating involvement of the cGMP pathway. In addition, the phosphodiesterase (PDE) inhibitor zaprinast depolarized and occluded the NO-mediated depolarization in TRN neurons. At the circuit level, NO activation significantly attenuated intrathalamic rhythmic activities likely resulting from the shifting of the firing mode of thalamic neurons, perhaps both TRN and thalamocortical neurons, from burst- to tonic-discharge mode. These alterations in thalamic neuron excitability not only change rhythmic circuit activity, but could also influence sensory information processing through thalamocortical circuits.