Thalamic Reticular Nucleus Neurons Research Articles

MGluR1 and mGluR5 Synergistically Control Cholinergic Synaptic Transmission in the Thalamic Reticular Nucleus.

Acetylcholine (ACh) signaling is involved in a wide range of processes, including arousal, attention, and learning. An increasing number of studies indicate that cholinergic control of these functions is highly deterministic, mediated by synaptic afferents that generate reliable and precise responses in postsynaptic neurons. However, mechanisms that govern plastic changes of cholinergic synaptic strength are poorly understood, even though they are likely critical in shaping the impact of cholinergic inputs on neuronal networks. We have recently shown that in the thalamic reticular nucleus (TRN), synaptic release of ACh generates excitatory-inhibitory biphasic postsynaptic responses, mediated by the activation of α4β2 nicotinic (nAChRs) and M2 muscarinic receptors (mAChRs), respectively. Here, using voltage-clamp recordings from TRN neurons in thalamocortical slices of mice, we demonstrate that the activation of Group I metabotropic glutamate receptors (mGluRs) by ambient or synaptically released glutamate evokes transient increases of nicotinic EPSCs. Additionally, we find that the selective Group I mGluR agonist DHPG [(S)-3,5-dihydroxyphenylglycine] evokes long-term potentiation of nicotinic EPSCs (mGluR-nLTP), dependent on increases in postsynaptic Ca(2+) concentration and the activation of phospholipase C. Both the induction and the maintenance of mGluR-nLTP require synergistic activation of mGluR1 and mGluR5. Together, our results show that postsynaptic Group I mGluRs are critically involved in the regulation of cholinergic synaptic strength on different time scales, suggesting that cholinergic control of local thalamic circuits is highly context-dependent and regulated by the overall levels of glutamatergic afferent activity. Cholinergic signaling controls information processing and plasticity in neuronal circuits, but the mechanisms underlying the regulation of cholinergic synaptic strength on different time scales are unknown. Here we identify mGluR1 and mGluR5 as key elements in the dynamic regulation of cholinergic synaptic inputs onto neurons of the TRN. Our findings highlight potential mechanisms that regulate cholinergic signaling in the mammalian brain.

Lack of Intrinsic GABAergic Connections in the Thalamic Reticular Nucleus of the Mouse.

It is generally thought that neurons in the thalamic reticular nucleus (TRN) form GABAergic synapses with other TRN neurons and that these interconnections are important for the function of the TRN. However, the existence of such intrinsic connections is controversial. We combine two complementary approaches to examine intrinsic GABAergic connections in the TRN of the mouse. We find that optogenetic stimulation of TRN neurons and their axons evokes GABAergic IPSCs in TRN neurons in mice younger than 2 weeks of age but fails to do so after that age. Blocking synaptic release from TRN neurons through conditional deletion of vesicular GABA transporter has no effect on spontaneous IPSCs recorded in TRN neurons aged 2 weeks or older while dramatically reducing GABAergic transmission in thalamic relay neurons. These results demonstrate that except for a short period after birth, the TRN of the mouse lacks intrinsic GABAergic connections. The thalamic reticular nucleus has a critical role in modulating information transfer from the thalamus to the cortex. It has been proposed that neurons in the thalamic reticular nucleus are interconnected through GABAergic synapses and that these connections serve important functions. Our results show that except for the first 2 weeks after birth, the thalamic reticular nucleus of the mouse lacks intrinsic GABAergic connections.

Neuronal Expression and Cell-Type-Specific Gene-Silencing of Best1 in Thalamic Reticular Nucleus Neurons Using pSico-Red System.

Assessing the cell-type expression pattern of a certain gene can be achieved by using cell-type-specific gene manipulation. Recently, cre-recombinase-dependent gene-silencing tool, pSico has become popular in neuroscientific research. However, pSico has a critical limitation that gene-silenced cell cannot be identified by fluorescence, due to an excision of the reporter gene for green fluorescence protein (GFP). To overcome this limitation, we newly developed pSico-Red, with mCherry gene as a reporter outside two loxP sites, so that red mCherry signal is detected in all transfected cells. When a cell expresses cre, GFP is excised and shRNA is enabled, resulting in disappearance of GFP. This feature of pSico-Red provides not only cell-type-specific gene-silencing but also identification of cre expressing cells. Using this system, we demonstrated for the first time the neuronal expression of the Bestrophin-1 (Best1) in thalamic reticular nucleus (TRN) and TRN-neuron-specific gene-silencing of Best1. We combined adeno-associated virus (AAV) carrying Best1-shRNA in pSico-Red vector and transgenic mouse expressing cre under the promoter of distal-less homeobox 5/6 (DLX5/6), a marker for inhibitory neurons. Firstly, we found that almost all of inhibitory neurons in TRN express Best1 by immunohistochemistry. Using pSico-Red virus, we found that 80% of infected TRN neurons were DLX5/6-cre positive but parvalbumin negative. Finally, we found that Best1 in DLX5/6-cre positive neurons were significantly reduced by Best1-shRNA. Our study demonstrates that TRN neurons strongly express Best1 and that pSico-Red is a valuable tool for cell-type-specific gene manipulation and identification of specific cell population.

Short-term depression of gap junctional coupling in reticular thalamic neurons of absence epileptic rats.

Gap junctional electrical coupling between neurons of the reticular thalamic nucleus (RTN) is critical for hypersynchrony in the thalamo-cortical network. This study investigates the role of electrical coupling in pathological rhythmogenesis in RTN neurons in a rat model of absence epilepsy. Rhythmic activation resulted in a Ca(2+) -dependent short-term depression (STD) of electrical coupling between pairs of RTN neurons in epileptic rats, but not in RTN of a non-epileptic control strain. Pharmacological blockade of gap junctions in RTN in vivo induced a depression of seizure activity. The STD of electrical coupling represents a mechanism of Ca(2+) homeostasis in RTN aimed to counteract excessive synchronization. Neurons in the reticular thalamic nucleus (RTN) are coupled by electrical synapses, which play a major role in regulating synchronous activity. This study investigates electrical coupling in RTN neurons from a rat model of childhood absence epilepsy, genetic absence epilepsy rats from Strasbourg (GAERS), compared with a non-epileptic control (NEC) strain, to assess the impact on pathophysiological rhythmogenesis. Whole-cell recordings were obtained from pairs of RTN neurons of GAERS and NEC in vitro. Coupling was determined by injection of hyperpolarizing current steps in one cell and monitoring evoked voltage responses in both activated and coupled cell. The coupling coefficient (cc) was compared under resting condition, during pharmacological interventions and repeated activation using a series of current injections. The effect of gap junctional coupling on seizure expression was investigated by application of gap junctional blockers into RTN of GAERS in vivo. At resting conditions, cc did not differ between GAERS and NEC. During repeated activation, cc declined in GAERS but not in NEC. This depression in cc was restored within 25s and was prevented by intracellular presence of BAPTA in the activated but not in the coupled cell. Local application of gap junctional blockers into RTN of GAERS in vivo resulted in a decrease of spike wave discharge (SWD) activity. Repeated activation results in a short-term depression (STD) of gap junctional coupling in RTN neurons of GAERS, depending on intracellular Ca(2+) mechanisms in the activated cell. As blockage of gap junctions in vivo results in a decrease of SWD activity, the STD observed in GAERS is considered a compensatory mechanism, aimed to dampen SWD activity.

Striatum and globus pallidus control the electrical activity of reticular thalamic nuclei

Through GABAergic fibers, globus pallidus (GP) coordinates basal ganglia global function. Electrical activity of GP neurons depends on their membrane properties and afferent fibers, including GABAergic fibers from striatum. In pathological conditions, abnormal electrical activity of GP neurons is associated with motor deficits. There is a GABAergic pathway from the GP to the reticular thalamic nucleus (RTn) whose contribution to RTn neurons electrical activity has received little attention. This fact called our attention because the RTn controls the overall information flow of thalamic nuclei to cerebral cortex. Here, we study the spontaneous electrical activity of RTn neurons recorded in vivo in anesthetized rats and under pharmacological activation or inhibition of the GP. We found that activation of GP predominantly diminishes the spontaneous RTn neurons firing rate and its inhibition increases their firing rate; however, both activation and inhibition of GP did not modified the burst index (BI) or the coefficient of variation (CV) of RTn neurons. Moreover, stimulation of striatum predominantly diminishes the spiking rate of GP cells and increases the spiking rate in RTn neurons without modifying the BI or CV in reticular neurons. Our data suggest a GP tight control over RTn spiking activity.

MGluR-mediated calcium signalling in the thalamic reticular nucleus

The thalamic reticular nucleus (TRN) plays a major role in modulating the transfer of information from the thalamus to the cortex. GABAergic inhibition via the TRN is differentially regulated by metabotropic glutamate receptors (mGluRs) and the effect of mGluRs on the membrane potential, on ion channels, and on the plasticity of electrical coupling of TRN neurons has been studied previously. Although mGluRs are generally known to trigger Ca2+ transients, mGluR-mediated Ca2+-transients in TRN neurons have not yet been investigated. In this study, we show that mGluRs can trigger Ca2+-transients in TRN neurons, that these transients depend on intracellular Ca2+-stores, and are mediated by IP3 receptors. Ca2+ transients caused by the group I mGluR agonist DHPG elicit a current that is sensitive to flufenamic acid and has a reversal potential around −40mV. Our results add mGluR-mediated Ca2+-signalling in the TRN to the state-dependent modulators of the thalamocortical system.

Electrical synapses and the development of inhibitory circuits in the thalamus.

The thalamus is a structure critical for information processing and transfer to the cortex. Thalamic reticular neurons are inhibitory cells interconnected by electrical synapses, most of which require the gap junction protein connexin36 (Cx36). We investigated whether electrical synapses play a role in the maturation of thalamic networks by studying neurons in mice with and without Cx36. When Cx36 was deleted, inhibitory synapses were more numerous, although both divergent inhibitory connectivity and dendritic complexity were reduced. Surprisingly, we observed non-Cx36-dependent electrical synapses with unusual biophysical properties interconnecting some reticular neurons in mice lacking Cx36. The results of the present study suggest an important role for Cx36-dependent electrical synapses in the development of thalamic circuits. Neurons within the mature thalamic reticular nucleus (TRN) powerfully inhibit ventrobasal (VB) thalamic relay neurons via GABAergic synapses. TRN neurons are also coupled to one another by electrical synapses that depend strongly on the gap junction protein connexin36 (Cx36). Electrical synapses in the TRN precede the postnatal development of TRN-to-VB inhibition. We investigated how the deletion of Cx36 affects the maturation of TRN and VB neurons, electrical coupling and GABAergic synapses by studying wild-type (WT) and Cx36 knockout (KO) mice. The incidence and strength of electrical coupling in TRN was sharply reduced, but not abolished, in KO mice. Surprisingly, electrical synapses between Cx36-KO neurons had faster voltage-dependent decay kinetics and conductance asymmetry (rectification) than did electrical synapses between WT neurons. The properties of TRN-mediated inhibition in VB also depended on the Cx36 genotype. Deletion of Cx36 increased the frequency and shifted the amplitude distributions of miniature IPSCs, whereas the paired-pulse ratio of evoked IPSCs was unaffected, suggesting that the absence of Cx36 led to an increase in GABAergic synaptic contacts. VB neurons from Cx36-KO mice also tended to have simpler dendritic trees and fewer divergent inputs from the TRN compared to WT cells. The findings obtained in the present study suggest that proper development of thalamic inhibitory circuitry, neuronal morphology, TRN cell function and electrical coupling requires Cx36. In the absence of Cx36, some TRN neurons express asymmetric electrical coupling mediated by other unidentified connexin subtypes.

Characterizing rare mis-sense variations of CACNA1I identified in a Swedish schizophrenia cohort

CACNA1I (hCaV3.3) encodes the α1 pore-forming subunit of human voltage-gated T-type calcium channels. CaV3.3 is expressed in a limited subset of neurons including GABAergic neurons of the thalamic reticular nucleus (TRN) where they support oscillatory activity essential for sleep spindle generation. CACNA1I is implicated in schizophrenia risk by emerging genetics including genome-wide association studies (PGC, 2014), and exome sequencing of trio samples (Gulsuner et al., 2013). In order to understand the impact of disease-associated sequence variation on the function of CaV3.3, we set out to analyze a complete set of rare mis-sense coding variations in CACNA1I in a Swedish cohort, including 15 variations identified in patients, 20 identified in control subjects, and 23 in both. We established a heterologous expression system of isogenic cell lines, each carrying single-copy inducible cDNA variants of hCaV3.3, and evaluated their functional impact on channel function by electrophysiology, calcium imaging, and biochemistry. We found at least five coding variations impaired overall channel protein abundance, as well as whole cell current density. In addition, we identified hCaV3.3 variants with altered voltage-dependence of channel activation and inactivation. Overall, we found that reduced calcium influx through hCaV3.3 is associated with the group of variants identified in patients, compared to those in both patients and controls. Our findings suggest that patient-specific rare variations of CACNA1I may influence channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Thalamic Circuit Mechanisms Link Sensory Processing in Sleep and Attention.

The correlation between sleep integrity and attentional performance is normally interpreted as poor sleep causing impaired attention. Here, we provide an alternative explanation for this correlation: common thalamic circuits regulate sensory processing across sleep and attention, and their disruption may lead to correlated dysfunction. Using multi-electrode recordings in mice, we find that rate and rhythmicity of thalamic reticular nucleus (TRN) neurons are predictive of their functional organization in sleep and suggestive of their participation in sensory processing across states. Surprisingly, TRN neurons associated with spindles in sleep are also associated with alpha oscillations during attention. As such, we propose that common thalamic circuit principles regulate sensory processing in a state-invariant manner and that in certain disorders, targeting these circuits may be a more viable therapeutic strategy than considering individual states in isolation.

The Contribution of Thalamocortical Core and Matrix Pathways to Sleep Spindles.

Sleep spindles arise from the interaction of thalamic and cortical neurons. Neurons in the thalamic reticular nucleus (TRN) inhibit thalamocortical neurons, which in turn excite the TRN and cortical neurons. A fundamental principle of anatomical organization of the thalamocortical projections is the presence of two pathways: the diffuse matrix pathway and the spatially selective core pathway. Cortical layers are differentially targeted by these two pathways with matrix projections synapsing in superficial layers and core projections impinging on middle layers. Based on this anatomical observation, we propose that spindles can be classified into two classes, those arising from the core pathway and those arising from the matrix pathway, although this does not exclude the fact that some spindles might combine both pathways at the same time. We find evidence for this hypothesis in EEG/MEG studies, intracranial recordings, and computational models that incorporate this difference. This distinction will prove useful in accounting for the multiple functions attributed to spindles, in that spindles of different types might act on local and widespread spatial scales. Because spindle mechanisms are often hijacked in epilepsy and schizophrenia, the classification proposed in this review might provide valuable information in defining which pathways have gone awry in these neurological disorders.

Hypothalamic feedforward inhibition of thalamocortical network controls arousal and consciousness

During non-rapid eye movement (NREM) sleep, synchronous synaptic activity within the thalamocortical network generates predominantly low frequency oscillations (< 4 Hz) that are modulated by inhibitory inputs from the thalamic reticular nucleus (TRN). Whether TRN cells integrate sleep-wake signals from sub-cortical circuits remains unclear. Here, we identified a monosynaptic LHGABA-TRNGABA transmission that exerts a strong inhibitory control over TRN neurons. We showed that optogenetic activation of this circuit recapitulated state-dependent changes of TRN neuron activity in behaving mice and induced rapid arousal during NREM, but not REM sleep. During deep anesthesia, activation of this circuit induced sustained cortical arousal. In contrast, optogenetic silencing of LHGABA-TRNGABA increased the duration of NREM sleep and amplitude of delta (1–4 Hz) oscillations. Collectively, these results demonstrate that TRN cells integrate subcortical arousal inputs selectively during NREM sleep and may participate in sleep intensity.

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.

Thalamic control of sensory selection in divided attention.

How the brain selects appropriate sensory inputs and suppresses distractors is a central unsolved mystery in neuroscience. Given the well-established role of prefrontal cortex (PFC) in executive function1, its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection2–5. To test this idea and more generally dissect the circuits underlying sensory selection, we developed a cross-modal divided attention task in mice enabling genetic access to this cognitive process. By optogenetically perturbing PFC function in a temporally-precise window, the ability of mice to appropriately select between conflicting visual and auditory stimuli was diminished. Surprisingly, equivalent sensory thalamo-cortical manipulations showed that behavior was causally dependent on PFC interactions with sensory thalamus, not cortex. Consistent with this notion, we found neurons of the visual thalamic reticular nucleus (visTRN) to exhibit PFC-dependent changes in firing rate predictive of the modality selected. visTRN activity was causal to performance as confirmed via subnetwork-specific bi-directional optogenetic manipulations. Through a combination of electrophysiology and intracellular chloride photometry, we demonstrated that visTRN dynamically controls visual thalamic gain through feedforward inhibition. Combined, our experiments introduce a new subcortical model of sensory selection, where prefrontal cortex biases thalamic reticular subnetworks to control thalamic sensory gain, selecting appropriate inputs for further processing.

Open-loop organization of thalamic reticular nucleus and dorsal thalamus: a computational model.

The thalamic reticular nucleus (TRN) is a shell of GABAergic neurons that surrounds the dorsal thalamus. Previous work has shown that TRN neurons send GABAergic projections to thalamocortical (TC) cells to form reciprocal, closed-loop circuits. This has led to the hypothesis that the TRN is responsible for oscillatory phenomena, such as sleep spindles and absence seizures. However, there is emerging evidence that open-loop circuits are also found between TRN and TC cells. The implications of open-loop configurations are not yet known, particularly when they include time-dependent nonlinearities in TC cells such as low-threshold bursting. We hypothesized that low-threshold bursting in an open-loop circuit could be a mechanism by which the TRN could paradoxically enhance TC activation, and that enhancement would depend on the relative timing of TRN vs. TC cell stimulation. To test this, we modeled small circuits containing TC neurons, TRN neurons, and layer 4 thalamorecipient cells in both open- and closed-loop configurations. We found that open-loop TRN stimulation, rather than universally depressing TC activation, increased cortical output across a broad parameter space, modified the filter properties of TC neurons, and altered the mutual information between input and output in a frequency-dependent and T-type calcium channel-dependent manner. Therefore, an open-loop model of TRN-TC interactions, rather than suppressing transmission through the thalamus, creates a tunable filter whose properties may be modified by outside influences onto the TRN. These simulations make experimentally testable predictions about the potential role for the TRN for flexible enhancement of cortical activation.

Inhibition of Cav3.2 T-type Calcium Channels by Its Intracellular I-II Loop

Voltage-dependent calcium channels (Cav) of the T-type family (Cav3.1, Cav3.2, and Cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. Enhanced T-type channel activity, especially Cav3.2, contributes to disease states, including absence epilepsy. Interestingly, the intracellular loop connecting domains I and II (I-II loop) of Cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating that this I-II loop plays an important regulatory role in T-type current. Here we describe that co-expression of this I-II loop or its proximal region (Δ1-Cav3.2; Ser(423)-Pro(542)) together with recombinant full-length Cav3.2 channel inhibited T-type current without affecting channel expression and membrane incorporation. Similar T-type current inhibition was obtained in NG 108-15 neuroblastoma cells that constitutively express Cav3.2 channels. Of interest, Δ1-Cav3.2 inhibited both Cav3.2 and Cav3.1 but not Cav3.3 currents. Efficacy of Δ1-Cav3.2 to inhibit native T-type channels was assessed in thalamic neurons using viral transduction. We describe that T-type current was significantly inhibited in the ventrobasal neurons that express Cav3.1, whereas in nucleus reticularis thalami neurons that express Cav3.2 and Cav3.3 channels, only the fast inactivating T-type current (Cav3.2 component) was significantly inhibited. Altogether, these data describe a new strategy to differentially inhibit Cav3 isoforms of the T-type calcium channels.

Activation of Group I and Group II Metabotropic Glutamate Receptors Causes LTD and LTP of Electrical Synapses in the Rat Thalamic Reticular Nucleus.

Compared with the extensive characterization of chemical synaptic plasticity, electrical synaptic plasticity remains poorly understood. Electrical synapses are strong and prevalent among the GABAergic neurons of the rodent thalamic reticular nucleus. Using paired whole-cell recordings, we show that activation of Group I metabotropic glutamate receptors (mGluRs) induces long-term depression of electrical synapses. Conversely, activation of the Group II mGluR, mGluR3, induces long-term potentiation of electrical synapses. By testing downstream targets, we show that modifications induced by both mGluR groups converge on the same signaling cascade--adenylyl cyclase to cAMP to protein kinase A--but with opposing effects. Furthermore, the magnitude of modification is inversely correlated to baseline coupling strength. Thus, electrical synapses, like their chemical counterparts, undergo both strengthening and weakening forms of plasticity, which should play a significant role in thalamocortical function.

Sleep slow wave-related homo and heterosynaptic LTD of intrathalamic GABAAergic synapses: involvement of T-type Ca2+ channels and metabotropic glutamate receptors.

Slow waves of non-REM sleep are suggested to play a role in shaping synaptic connectivity to consolidate recently acquired memories and/or restore synaptic homeostasis. During sleep slow waves, both GABAergic neurons of the nucleus reticularis thalami (NRT) and thalamocortical (TC) neurons discharge high-frequency bursts of action potentials mediated by low-threshold calcium spikes due to T-type Ca(2+) channel activation. Although such activity of the intrathalamic network characterized by high-frequency firing and calcium influx is highly suited to modify synaptic efficacy, very little is still known about its consequences on intrathalamic synapse strength. Combining in vitro electrophysiological recordings and calcium imaging, here we show that the inhibitory GABAergic synapses between NRT and TC neurons of the rat somatosensory nucleus develop a long-term depression (I-LTD) when challenged by a stimulation paradigm that mimics the thalamic network activity occurring during sleep slow waves. The mechanism underlying this plasticity presents unique features as it is both heterosynaptic and homosynaptic in nature and requires Ca(2+) entry selectively through T-type Ca(2+) channels and activation of the Ca(2+)-activated phosphatase, calcineurin. We propose that during slow-wave sleep the tight functional coupling between GABAA receptors, calcineurin, and T-type Ca(2+) channels will elicit LTD of the activated GABAergic synapses when coupled with concomitant activation of metabotropic glutamate receptors postsynaptic to cortical afferences. This I-LTD may be a key element involved in the reshaping of the somatosensory information pathway during sleep.

ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection.

Selective processing of behaviorally relevant sensory inputs against irrelevant ones is a fundamental cognitive function, impairments of which have been implicated in major psychiatric disorders. It is known that the thalamic reticular nucleus (TRN) gates sensory information en route to the cortex, however the underlying mechanisms remain unclear. Here we show in mice that deficiency of Erbb4 gene in somatostatin-expressing TRN neurons markedly altered behaviors dependent on sensory selection. Whereas performance in identifying targets from distractors was improved, the ability to switch attention between conflicting sensory cues was impaired. These behavioral changes were mediated by enhanced cortical drive onto TRN that promotes the TRN-mediated cortical feedback inhibition of thalamic neurons. Our results uncover a previously unknown role of ErbB4 in regulating cortico-TRN-thalamic circuit function. We propose that ErbB4 sets the sensitivity of TRN to cortical inputs at levels that can support sensory selection while allowing behavioral flexibility.

Mechanisms underlying desynchronization of cholinergic-evoked thalamic network activity.

Synchronous neuronal activity in the thalamocortical system is critical for a number of behaviorally relevant computations, but hypersynchrony can limit information coding and lead to epileptiform responses. In the somatosensory thalamus, afferent inputs are transformed by networks of reciprocally connected thalamocortical neurons in the ventrobasal nucleus (VB) and GABAergic neurons in the thalamic reticular nucleus (TRN). These networks can generate oscillatory activity, and studies in vivo and in vitro have suggested that thalamic oscillations are often accompanied by synchronous neuronal activity, in part mediated by widespread divergence and convergence of both reticulothalamic and thalamoreticular pathways, as well as by electrical synapses interconnecting TRN neurons. However, the functional organization of thalamic circuits and its role in shaping input-evoked activity patterns remain poorly understood. Here we show that optogenetic activation of cholinergic synaptic afferents evokes near-synchronous firing in mouse TRN neurons that is rapidly desynchronized in thalamic networks. We identify several mechanisms responsible for desynchronization: (1) shared inhibitory inputs in local VB neurons leading to asynchronous and imprecise rebound bursting; (2) TRN-mediated lateral inhibition that further desynchronizes firing in the VB; and (3) powerful yet sparse thalamoreticular connectivity that mediates re-excitation of the TRN but preserves asynchronous firing. Our findings reveal how distinct local circuit features interact to desynchronize thalamic network activity.

State-Dependent Architecture of Thalamic Reticular Subnetworks

Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function. PAPERFLICK: