Thalamic reticular nucleus in the thalamocortical loop

Journal Pre-proof Thalamic reticular nucleus in the thalamocortical loop Norio Takata

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S0168-0102(19)30638-8

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https://doi.org/10.1016/j.neures.2019.12.004

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Neuroscience Research

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3 December 2019

Please cite this article as: Takata N, Thalamic reticular nucleus in the thalamocortical loop, Neuroscience Research (2019), doi: https://doi.org/10.1016/j.neures.2019.12.004

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Review article

Thalamic reticular nucleus in the thalamocortical loop Norio Takata

Affiliations Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku,

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Tokyo 160-8582, Japan

Corresponding Author Norio Takata, Ph.D.

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Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan. Tel: +81-3-5363-3934

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E-mail address: [email protected]

HIghlights

The thalamic reticular nucleus (TRN) is a key modulator of a thalamocortical loop.

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TRN is composed of diverse and heterogeneous neurons.

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Dynamical regulation of functional connectivity in the cortex by TRN is proposed

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Abstract

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Dynamic binding of different brain areas is critical for various cognitive functions. The

thalamic reticular nucleus (TRN) is a GABAergic nucleus that constrains information flow through thalamocortical loop by providing inhibitory innervation to the thalamus. In this review, I summarize anatomical and single-cell-level physiological studies of the rodent TRN. Diversity and heterogeneity of TRN neurons in terms of axonal innervation, molecular expression, and 1

physiological characteristics are described. I also outline thalamocortical and cortico-cortical connections with emphasis on interaction with the TRN. In summary, it is proposed that functional connectivity among brain regions are modulated with gating of transthalamic information flow by the TRN.

1. Introduction Flexibly changing functional connectivity between brain regions is critical for various cognitive functions such as sensory filtering, change detection, and attention (Nakajima et al., 2019; Wimmer et al., 2015; Yu et al., 2009). Dr. Francis Crick once proposed that the thalamic reticular

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nucleus (TRN) represented an internal attentional searchlight in the brain (Crick, 1984) that should accompany interregional functional connectivity modulation. This review focuses on the anatomy and physiology of the TRN, based mainly on the rodent brain to better understand the modulation of

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functional connectivity by the TRN. In addition to a classical view of the TRN controlling

information flow from the thalamus to the cortex, I will describe a role of the TRN in modulating

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information flow between cortices (Krol et al., 2018; Sherman, 2007, 2006; Sherman and Guillery, 1998). There are many excellent reviews on the TRN. A literature search with PubMed as of 31

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August 2019 using the keywords "thalamic reticular nucleus"[TIAB] AND "review"[PT] retrieved 58 articles, although it did not retrieve several important ones, e.g. (Crabtree, 2018; Fuentealba and Steriade, 2005; Steriade, 2005; Steriade and Deschenes, 1984). Topics covered by these reviews

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demonstrate a diversity of functional roles performed by the TRN such as in sleep (Lüthi, 2014), epilepsy (Shin, 2006), tinnitus (Zhang, 2013), and schizophrenia (Pinault, 2017; Pratt and Morris,

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2015). Evidence summarized in this review would help understand basic physiological mechanism underlying these multifaceted functions of the TRN.

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2. Anatomical organization of the TRN While the TRN seems to be a monolithic structure composed of GABAergic neurons

(Houser et al., 1980), accumulating evidence has demonstrated a great diversity of the TRN in terms of its cellular morphology, molecular expression, axonal connectivity, and physiological activity (Vantomme et al., 2019). A basic perspective on the anatomical organization of the TRN is presented first, followed by detailed descriptions. 2

2.1 Location, shape, and overall connections The thalamus is subdivided into three parts: the epithalamus, dorsal thalamus, and ventral thalamus (Swanson et al., 2019). The dorsal thalamus is the main part of the diencephalon. Based on network organization of the thalamus, the dorsal thalamus is composed of 39 gray matter regions, and projects to the cerebral cortex topographically. The epithalamus and ventral thalamus is composed of 2 and 5 regions, respectively, and project subcortically (Note that there are various classification strategies for the thalamus based on its cytoarchitecture, input, and output that do not necessarily match each other. (For details, see Halassa and Sherman, 2019)). The TRN is a

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component of the ventral thalamus, and is a narrow band structure of GABAergic cells that lies

adjacent to the dorsal and lateral part of the thalamus (Fig. 1a). A major connectional diagram of TRN is shown in Fig. 1b (Guillery et al., 1998). Almost all sensory information to the cortex, except

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for olfactory input, passes through the thalamus. The TRN receives primary inputs from both the thalamus and the cortex as axon collaterals of excitatory glutamatergic projections. These fibers

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constitute fascicles penetrating the TRN that in turn sends inhibitory GABAergic fibers back to the thalamus. This simplified diagram implies a role of the TRN in controlling information reaching the

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cerebral cortex. Dr. Crick once described the thalamus as the gateway to the cortex, and the TRN as the guardian of the gateway (Crick, 1984). The thalamus, except for the TRN, has fewer internal connections and is organized as a collection of parallel inputs to the cortex. On the contrary, the TRN

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is highly interconnected to the thalamus (Fig. 1c) (Swanson et al., 2019). The fact that the TRN is the only hub in the thalamus further supports the idea that the TRN modulates information flow from the

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thalamus to the cortex.

2.2 Sectors and tiers

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Based on anatomical and physiological evidence, the TRN can be divided into several

sectors that correspond to distinct functional modalities such as a dorsocaudal visual sector (visTRN), a ventrocaudal auditory sector (audTRN), and a ventrocentral somatosensory sector (ssTRN) (Fig. 2a, 2b Connectivity) (Crabtree, 2018; Shosaku et al., 1989). Each of these sectors is connected to different thalamic nuclei and their associated cortical areas (Fig. 2b Connectivity) (Vantomme et al., 2019). Most sectors in the TRN are subdivided into three tiers along the axis 3

starting from the thalamoreticular border to the cortex: inner, middle, and outer tiers that are defined as subdivisions of TRN with distinct but relevant axonal connections with the cortex or the thalamus (Guillery et al., 1998; Kimura et al., 2005; Lam and Sherman, 2011; Pinault and Deschênes, 1998). As for the auditory cortex, the primary and non-primary auditory areas, which send collateral projections to outer and middle tiers in the TRN, respectively, send axons to the auditory thalamus in similar topography, but to the audTRN in different topography (Kimura et al., 2005).

2.3 Three morphologically distinct cell types Three morphologically distinct populations of neurons were reported in the TRN (Deleuze

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and Huguenard, 2006; Spreafico et al., 1991) (but see Lübke, 1993). These neurons are referred to as f, F, and R-types (Fig. 2c): (1) f-type neurons have two primary polar dendrites extending for a long distance from the cell body, located caudally in sensory sectors of the TRN; (2) F-type neurons are

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the dominant subtype with two to four primary dendrites emerging from the two poles of the soma, located throughout the TRN; and (3) R-type neurons are multipolar cells with dendrites radiating in

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all directions, located preferentially in the anterior limbic sector of the TRN (Fig. 2b Morphology).

2.4 Neurochemical diversity of TRN neurons

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While TRN cells are homogeneously stained for the neurotransmitter gamma aminobutyric acid (GABA) (Penny et al., 1984), glutamic acid decarboxylase (GAD), and vesicular GABA transporters such as vesicular GABA transporter-2 (VGAT2) (Halassa et al., 2011), TRN cells show

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heterogeneous expression patterns in terms of Ca2+ binding proteins such as calretinin (CR), parvalbumin (PV), and somatostatin (SOM) (Fig. 2b Molecular) (Vantomme et al., 2019). CR-

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positive neurons are located in the anterior and in the dorsal part of the TRN (Lizier et al., 1997). In addition, a majority of the commissural neurons in the TRN does not express CR (Lizier et al.,

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1997). PV- or SOM-positive neurons are located across the entire TRN, although the number of SOM-positive cells was significantly lower in the central tier of the middle sector of the TRN (Fig. 2b Molecular) (Clemente-Perez et al., 2017). Only a minority (10-20%) of neurons expressed both PV and SOM (Clemente-Perez et al., 2017). For expression patterns of other molecules such as the K+-Cl- cotransporter KCC2 and peptides, see (Barthó et al., 2004; Pinault, 2004).

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2.5 Axonal innervation 2.5.1 Synaptic inputs to thalamic relay cells In this section, synaptic inputs to thalamic relay cells are described, because some of them have collaterals to innervate TRN. Relay cells are excitatory neurons, constitute the dorsal thalamus, and innervate the cortex to relay information from the periphery, subcortex, or cortex to the neocortex. There are three major types of synapses that account for 95% of inputs to thalamic relay cells (Çavdar et al., 2011; Sherman and Guillery, 2013, 1998): 1) RL (round vesicles and large terminals) type is a driver-input and comes from sensory, gustatory, and vestibular ascending

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pathways, deep cerebellar nuclei, mammillary bodies, and cortical layer 5 (L5). These are

glutamatergic and form multiple asymmetric synapses per terminal (Çavdar et al., 2011); 2) RS

(round vesicles and small terminals) type represents a modulatory input and comes from cortical

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layer 6 (L6) or brainstem cholinergic nuclei. Most RS terminals form a single synapse per terminal. The majority of synapses formed in the thalamus is this RS type; 3) F (flattened vesicles) type forms

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symmetric GABAergic synapses from interneuronal axons and the TRN. F terminals commonly form single synaptic junctions per terminal. Physiological influence of the L6 corticothalamic innervation

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is dynamic (Crandall et al., 2015). Specifically, during low frequency activity of L6 neurons, corticothalamic effects are mainly suppressive, whereas high frequency activity converts the influence to enhancement. This switching depends on short-term synaptic plasticity across multiple

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corticothalamic circuits including the TRN. Note that local GABAergic interneurons are virtually absent in most rodent thalamic nuclei excluding the visual thalamus.

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Depending on their principal “driver” inputs, thalamic nuclei are divided into two groups: “first-order (FO)” and “higher-order (HO)” (Guillery, 1995). FO nuclei receive RL type driver inputs

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from ascending pathways; HO nuclei receive most or all of their driver inputs from cortical L5. Modulatory RS synapses constitute 70-80% of total synapses in the thalamus irrespective of FO or HO nuclei. Driver RL synapses occupy ~15% and ~10% in FO and HO thalamic nuclei, respectively. GABAergic F synapses occupy ~10% and ~20% in FO and HO thalamic nuclei, respectively. These results were obtained in the rat thalamus (Çavdar et al., 2011). These data indicate that driver inputs (RL) represent the minority while the modulatory inputs (RS) represent the majority of terminals in 5

all thalamic nuclei including FO and HO. In addition, the above results imply that TRN innervation of the thalamus is more on HO than FO thalamic nuclei (Çavdar et al., 2011). 2.5.2 Cortico-cortical connections In this section, cortico-cortical connections are explained to contrast this direct corticocortical connection with indirect, transthalamic corticocortical connection that might be modulated by the TRN. Cortico-cortical connectivity is indicated in a schematic diagram (Fig. 3) following an influential model by (Felleman and Van Essen, 1991). Feedforward projections come from the supragranular layer (and infragranular layer) and target layer 4 (L4), while feedback

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projections come from the infragranular layer (and supragranular layer) and target supragranular and infragranular layers. While the above connectivity diagram was proposed for monkey visual cortical areas, there is a striking difference in the laminar pattern of corticocortical connections based on

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anatomical connections of monkeys and that based on physiological properties of the mouse brain (Çavdar et al., 2011; De Pasquale and Sherman, 2011). For further discussion on direct anatomical

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connection between cortical areas, see chapters 4 and 5 of (Sherman and Guillery, 2013). Note that there is parallel direct and transthalamic corticocortical pathways. It’s suggested that cortical areas

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connected directly also have a transthalamic connection through a HO thalamic relay (Theyel et al., 2010). It might be possible that the selection of which cortical areas are functionally connected is dynamically regulated by TRN activity, because conjoint activation of these two parallel pathways

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might be necessary to achieve strong enough activation in the target cortical areas that results in functional linking among activated areas (chapter 5 of Sherman and Guillery, 2013). Further

mechanism.

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physiological investigation is necessary to prove the existence of such coincidence detection

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2.5.3 Thalamocortical and corticothalamic connections

Thalamocortical (TC) and corticothalamic (CT) glutamatergic inputs can be divided into

“Class 1” and “Class 2” that refer to structural and functional parameters, whereas “driver” and “modulator” refer to the role of an input (Sherman and Guillery, 2013) (Fig. 4a). Currently, all known driver inputs are Class 1, thus Class 1 and driver inputs are equivalent (at least for now). Class 1 inputs activate only ionotropic receptors and lack metabotropic glutamate receptor responses, 6

show paired pulse depression, and exhibit large excitatory postsynaptic potentials (EPSPs) (Fig. 4a left). Class 2 inputs activate metabotropic receptors, show paired-pulse facilitation, and exhibit small EPSPs (Fig. 4a right). While Class 1 driver inputs constitute only 10-15% of all synaptic inputs in the thalamus, Class 1 inputs represent main information relays carrying messages to the cortex. While it is commonly reported that thalamocortical projections terminate exclusively in L4 of the cortex (Fig. 3), all cortical layers (from 1 to 6) of the rodent brain receive thalamic inputs (Meyer et al., 2010; Sherman and Guillery, 2013). For inputs from FO thalamus to the primary cortex (e.g., from the ventral posterior medial nucleus to the primary somatosensory cortex) and inputs from

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HO thalamus to the secondary cortex (e.g. from the posterior medial nucleus to the secondary

somatosensory cortex), cortical L4-6 receives exclusively Class 1 inputs from the thalamus (Sherman and Guillery, 2013). Cortical layer 2/3 (L2/3) receives a mixture of Class 1 and Class 2 inputs from

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the thalamus; Three fourths of the cells in L2/3 receives Class 2 inputs, and the rest receives Class 1. These TC Class 1 and 2 inputs send axon collaterals to the TRN. Cortical L6 is the source of the

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Class 2 corticothalamic (CT) feedback, which also innervate the TRN and cortical L4, the recipient of thalamocortical innervation (Reichova and Sherman, 2004). These TC collaterals and CT

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projections from L6 are main inputs to the TRN (Fig. 3). The HO thalamus receives driver input from cortical L5. Importantly, this Class 1 input from L5 innervating the HO nucleus of the thalamus has no direct input to the TRN (Bourassa et al., 1995).

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2.5.4 Innervation to, from, and within the TRN As described above, the principal innervation to the TRN comes from collaterals of thalamic

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relay nuclei and cortical L6 (Pinault, 2004) (Note that SOM-expressing neurons in the TRN lack cortical inputs (Clemente-Perez et al., 2017)). These are glutamatergic and recognized as excitatory.

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Thalamic FO and HO inputs can overlap in the TRN, enabling integration of information. There is another glutamatergic projection from the basolateral amygdala to the TRN that amplifies tone response in the auditory thalamus (medial geniculate body) and auditory cortex (Aizenberg et al., 2019). In addition to these glutamatergic inputs from the cortex and thalamus, the TRN receives GABAergic, cholinergic, and monoaminergic innervations (Brown and McKenna, 2015; Pratt and Morris, 2015). GABAergic projections come from the globus pallidus (GP) (Kayahara and Nakano, 7

1998), substantia nigra pars reticulata (SNr) (Gulcebi et al., 2012), and basal forebrain neurons (Jourdain et al., 1989). Cholinergic innervation is from the basal forebrain and the pedunculopontine and laterodorsal nuclei of the brain stem (Beierlein, 2014). Acetylcholine (ACh) exerts its action through postsynaptic nAChR and pre- and postsynaptic mAChRs. Dopamine projections from substantia nigra pars compacta (SNc) inhibit GABA transmission from the GP to the TRN through D4 receptors at the presynapse (Govindaiah et al., 2010). Serotonergic (5-HT) innervation from the dorsal raphe modulates TRN activity through 5-HT1A and 2A receptors (Pratt and Morris, 2015). Projections from the TRN to the thalamus are topographically well-organized (Lam and

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Sherman, 2007). Basically, most individual TRN neurons innervate a restricted territory inside a single thalamic nucleus in a parallel manner, and only a minority (<5%) of TRN cells project into two distinct but functionally related nuclei in the rat (Pinault and Deschênes, 1998) (However, note

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that in the cat the dual projections were observed in 50-70% of TRN neurons (Crabtree, 1996)).

Several patterns of axonal projections of TRN neurons onto the thalamus were observed depending

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on the degree of overlap of dendritic arbors of individual TRN neurons (Pinault, 2004); a1) Two adjacent TRN neurons without overlap of their dendritic trees innervate two adjacent districts within

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a given thalamic nucleus, a2) Two TRN neurons with an overlap of their dendritic arbors have overlapping axonal terminals , b1) a TRN neuron can have axonal projections to two distinct but functionally related thalamic nuclei, b2) Two TRN neurons with overlapping dendritic fields can

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innervate two distinct thalamic nuclei. Based on these characteristic innervation patterns of the TRN, Dr. Pinault proposed that the TRN may be involved in two types of control over information: 1) one

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type for “parallel processing” with ordered parallel TRN axonal projections toward thalamic nuclei (a1 and a2 above), and 2) another type for “combining processing” that involves divergent axonal

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projections toward at least two separate thalamic nuclei (b1 and b2) (Pinault, 2004). A single axonal arbor of a TRN neuron in the thalamus contains a total of ~4,000 ± 1,000 boutons (Pinault and Deschênes, 1998).

TRN cells are electrically coupled through gap junctions (GJs) (Haas and Landisman, 2012; Pinault, 2017). In the ssTRN of rodents, about one-third to one-half of TRN neurons form electrical synapses through GJs (Crabtree, 2018). On average, nine cells are coupled through GJs. Activity8

dependent long-term depression of GJs is reported (Haas et al., 2011). The presence of recurrent GABAergic synapses within the TRN is still elusive (Crabtree, 2018; Makinson et al., 2017). Some studies report that interconnections within the TRN through GABAergic synapses present only for the first 2 weeks after birth (Hou et al., 2016).

3. Physiological activity of the TRN One characteristic of TRN and thalamic relay neurons is that they express sufficiently dense low-threshold T-type (“T” for transient) Ca2+ channels (Crunelli et al., 2006; Huguenard and Prince, 1992). Thus, opening of this channel generates an inward, depolarizing current, IT, leading to all-or-

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none, low-threshold spikes (LTSs) (Fig. 4b bottom). The presence or absence of IT determines the firing mode (tonic or burst) of the TRN and relay neurons (Fig. 4b). When the membrane potentials of TRN cells are relatively depolarized, depolarizing currents result in tonic firing due to a lack of IT

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currents because the channel is inactivated at this membrane potential (Fig. 4b top). When the

membrane potentials of TRN cells are hyperpolarized for more than 100 ms, which is a refractory

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period for IT, the Ca2+ channel becomes de-inactivated leading to burst firing upon depolarization current (Fig. 4b bottom).

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There are slight differences in Ca2+ channel expression in the TRN and thalamic relay neurons. The primary Ca2+ channels expressed by the TRN are CaV3.3, and that by relay neurons are CaV3.1 (Crunelli et al., 2006). Inactivation of IT is much slower in the TRN than in relay cells,

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resulting in prolonged burst firing in the TRN (Pinault, 2004). Subcellular distributions are also different. TRN neurons express CaV3.3 at dendrites, while thalamic relay cells express CaV3.1 in

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soma (Crunelli et al., 2006).

While it is established that hyperpolarization is necessary for de-inactivation of IT currents,

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it has also been shown that a small fraction of CaV3 channels are constantly open even at resting membrane potential, constituting a window component of the T-type Ca2+ current, ITwindow (Dreyfus et al., 2010). In addition, LTS-driven spike bursts can be evoked at depolarized potentials when most of CaV3 channels are inactivated (Dreyfus et al., 2010). It has been reported that PV-expressing neurons in the TRN display robust burst firing, while SOM-expressing neurons showed less burst activity (Clemente-Perez et al., 2017), suggesting heterogeneity in expression levels of CaV3 in the 9

TRN. Reciprocal connection between excitatory relay cells and the inhibitory TRN can sustain various network oscillations (Huguenard and McCormick, 2007; Pinault, 2004). For example, this circuit can generate sleep spindles in a frequency range of 8-14 Hz with a duration of sub-second during non-rapid eye movement (NREM) sleep (Steriade et al., 1993). PV- but not SOM-positive neurons in TRN are considered to be a main generator of this rhythm, because PV-neurons show large T-currents and strong post-inhibitory rebound burst firing (Clemente-Perez et al., 2017). Too much synchronization of the circuit results in pathophysiological condition and causes 3-Hz spike

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and wave pattern of generalized absence epilepsy (Bal et al., 1995). This circuit can also generate gamma oscillations (40 Hz), which are modulated by monoaminergic and cholinergic inputs (Pinault and Deschênes, 1992).

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Note that there is physiological diversity among TRN neurons depending on their position and/or neurochemical expression. Specifically, it was reported that more than half of dorsal TRN

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neurons were non-burst type, while majority of ventral TRN neurons displayed a stereotypical burst discharge (Lee et al., 2007). Moreover, sensory-projecting neurons in caudal TRN that innervate the

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visual thalamus, and limbic-projecting neurons in rostral TRN that innervate the anterior-limbic thalamus showed arousal correlated and spindle correlated activation, respectively (Halassa et al., 2014). Even within the same position in the TRN, neurons expressing PV or SOM showed distinct

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physiology and axonal input/output patterns (Clemente-Perez et al., 2017). PV-, but not SOMexpressing neurons exhibited strong post-inhibitory rebound burst firing. Furthermore, while each

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sector in the TRN is considered dedicated to unimodal sensory processing, cross-modal sensory interaction is reported in the TRN (Kimura, 2017, 2014). For further discussion on subnetworks in

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TRN, see (Crabtree, 2018).

Conflicts of interest The author declares no competing financial interests.

Acknowledgements This work was supported by KAKENHI (16H01620, 18H04952, 19K06944). 10

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Figure legends Fig. 1. Anatomical organization of the TRN (a) Transparent mouse brain with its internal structures, the thalamus in green and TRN in red. (prepared with Brain Explorer® 2 using Common Coordinate Framework version 3 from the Allen Institute for Brain Science) (Lau et al., 2008) (b) Simplified connection diagram of the thalamus, cortex, and TRN, overlaid on a picture of in situ hybridization data against a GABA synthesizing enzyme, GAD67. (in situ image is adapted from © 2004 Allen Institute for Brain Science. Allen Mouse Brain Atlas. Available from: mouse.brain-

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map.org. Experiment ID: 79556706) (Lein et al., 2007)

(c) Intrathalamic macroconnectome represented as directed and weighted monosynaptic connection matrix. M1-3 refers to module 1-3, which was defined by clustering analysis on synaptic

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connectivity in the thalamus. M1 and M3 consist of gray matter regions in dorsal and ventral

thalamus. Black and red bars at the left and top of the matrix indicate left and right side of the brain,

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respectively. Log-weighted connection strength is represented in a copper colormap from dark- to white-color, representing weak- and strong-axonal connection, respectively. Rows corresponding to

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TRN in the left and right hemisphere are indicated by a green arrow and arrowhead, respectively. TRN is the only hub in the thalamus with heavy intrathalamic connections (adapted from Swanson et

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al., 2019).

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Fig. 2. Cellular diversity of the TRN

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(a) Schematic representation of TRN sectors for somatosensory (ss), visual (vis), and auditory (aud) modalities. Rows of whiskers are indicated by A-E. Adapted from (Shosaku et al., 1989) with

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permission.

(b) Coronal schemes of the TRN at anterior, intermediate, and posterior location along a rostrocaudal axis showing heterogeneity of the TRN in its connectivity (left), cellular morphology (middle), and molecular expression (right). In a connectivity panel, colors indicate target nuclei in the thalamus. Copyright 2018 Frontiers (Crabtree, 2018) (c) Three morphological types in the TRN. Dendrites of f- and F-type neurons oriented mainly along 17

the major axis of the TRN. Copyright 2006 Society for Neuroscience (Deleuze and Huguenard,

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2006)

Fig. 3. The TRN in the thalamocortical circuit Schematic diagram of the thalamocortical and corticothalamic circuits with TRN innervation.

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Individual TRN neurons project to FO and/or HO thalamic nuclei (Pinault, 2004). In the thalamus, symbol size roughly represents relative counts of each kind of synapses, e.g. modulatory synapses constitute 70-80% of total synapses in the thalamus (Çavdar et al., 2011). Corticocortical feedforward or feedback connections are not determined to be a driver or modulator because of lack of physiological analyses of these pathways (Chap. 4 of Sherman and Guillery, 2013). Note that patterns of corticocortical connections presented here are originally proposed for monkeys, and significant difference is known for rodents (Chap. 5 of Sherman and Guillery, 2013). Local corticocortical connections such as driver inputs from L4 to L2/3 (Pasquale and Sherman, 2012) and

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modulator projections from L6 to L4 (Lee and Sherman, 2009) are omitted for clarity. While small in

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number, driver inputs carry “messages”.

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Fig. 4. Physiological activity of the TRN and relay cells (a) Class 1 (driver) and Class 2 (modulator) synaptic properties. (left) Thalamocortical synapse in cortical L4. Class 1 synapse is a depressing synapse whose EPSP amplitude shows paired-pulse depression to a stimulation train at 10 Hz, indicating high probability of transmitter release. (right) Thalamocortical synapse in cortical L2/3. Class 2 synapse is a facilitating synapse whose EPSP amplitude shows paired-pulse facilitation to a stimulation train, suggesting low probability of

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transmitter release. (b) Two modes of relay cell activity. Note that TRN cells also show these two modes of activity

because both TRN- and relay-cells express sufficient T-type Ca2+ channels although there are slight differences in the channel physiology (see text section 3). The same depolarizing current was

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injected into a cell with distinct initial holding potentials. (top) When holding potentials are slightly depolarized, T channels for Ca2+ conductance (T current or IT) are inactivated. Thus, the current

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injection does not induce a low threshold spike (LTS), resulting in a tonic activity response. (bottom) When holding potentials are relatively hyperpolarized, T channels are de-inactivated. In this case, the

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current injection results in LTS, leading to a burst response.

(c) Input response curve of a cell in tonic (■) or burst (●) mode. In tonic mode, larger current

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injection resulted in larger responses, resulting in linear input/output relationship that would be suited for faithful information transfer. In burst mode, response amplitude was almost constant

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regardless of a size of current injection, resulting in nonlinear input/output relationship. This would significantly increase the signal-to-noise (spontaneous activity) ratio, and powerfully activate the

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cortex. Adapted from (Sherman and Guillery, 2013)

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