Mediodorsal thalamic nucleus mediates resistance to ethanol through Ca_v3.1 T-type Ca²⁺ regulation of neural activity

Drug-induced unconsciousness can be achieved using numerous types of anesthetics with varying modes of action (Alkire and Miller, 2005; Mashour, 2014). Ethanol, one of the most frequently abused drugs in human society, can induce sleep-like loss of consciousness at high doses (Morozova et al., 2014). While possible neuropharmacological and neural correlates of ethanol sedation have been proposed using in vitro and in vivo methods (Blomeley et al., 2011; Givens and Breese, 1990; Koob et al., 2013; White et al., 1990), recent studies have highlighted the slowing of thalamocortical-driven rhythms as a potent marker of unconsciousness (Baker et al., 2014; Schiff, 2008). However, the region and the mechanism linked to thalamic modulation during ethanol-induced unconsciousness remain poorly understood.

Physiological correlates of thalamocortical rhythmic activities and consciousness state of the brain have been studied extensively (Llinás et al., 1998; Alkire et al., 2008; Steriade et al., 1993; Kim et al., 2001). T-type calcium channels are known generators of thalamocortical rhythms, through the modulation of cell excitability and rebound burst firing (Simms and Zamponi, 2014; Crunelli et al., 2018). During sleep, the transition from wakefulness to unconsciousness is associated with membrane hyperpolarization of thalamic neurons (Steriade et al., 1993; Royer et al., 2012). Similarly, it has been shown that in ethanol sedation, as in natural sleep or absence seizure, the loss of consciousness is characterized by a switch from tonic to burst firing in thalamic neurons, which involves GABAergic inhibition-driven de-inactivation of Ca_v3.1 (Cacna1g) T-type channels resulting in slow oscillatory response of the thalamocortical network (White et al., 1990; Jia et al., 2008; Jia et al., 2007; Iyer et al., 2011). Acute intoxication at high doses of ethanol (Newton et al., 2008; Shin et al., 2005) induces both slow oscillations in the delta-theta frequency range and a loss of righting reflex (LORR), a classical proxy to assess the loss of consciousness. It has been shown that mice lacking global or thalamic Ca_v3.1 showed altered slow oscillations and sleep architecture (Anderson et al., 2005; Lee et al., 2004); delayed sleep induction under several anesthetics (i.e. isoflurane, halothane, sevoflurane, and pentobarbital) (Petrenko et al., 2007); and increased resistance to drug-induced absence seizures (Kim et al., 2001). Notably, the absence or blockade of Ca_v3.1 resulted in an increased preference for ethanol consumption and novelty-seeking behavior (Newton et al., 2008; Shin et al., 2005). In the current studies, we investigate the role of Ca3.1-mediated T-currents in brain state modulation during ethanol-induced sleep.

The thalamus is one of the major regions expressing Ca_v3.1 T-type calcium channels (Talley et al., 1999) and holds a central role in information transmission and integration (Schiff et al., 2014). In vitro and in vivo studies using genetically modified mice have revealed that Ca_v3.1 T-type channels play a key role in the genesis of thalamocortical rhythms, such as 3 Hz spike-and-wave discharges, a signature of absence seizures (Kim et al., 2001; Song et al., 2004) and delta waves (Royer et al., 2012; Lee et al., 2013; McCormick and Pape, 1990). Previous investigations on thalamic control of consciousness revealed that nuclei within the dorsal medial thalamus (dMT) hold an important modulatory function in the interaction of attention and arousal (Schiff, 2008; Saalmann, 2014). Particularly, the centromedian (CM) thalamic nucleus, and not the ventrobasal nucleus (VB), showed rapid shifts in local field potential (LFP) preceding brain state transitions such as non-rapid eye movement (NREM) and propofol-induced anesthesia (Baker et al., 2014). The paraventricular thalamic nucleus (PVN) showed critical involvement in wake/sleep cycle regulation (He et al., 2015). The centrolateral (CL) thalamic nucleus has been implicated in the modulation of arousal, behavior arrest (Giber et al., 2015), and improvement of level of consciousness during seizures (Gummadavelli et al., 2015). Notably, the direct electrical stimulation of the intralaminar nuclei (ILN) and, in particular, CL, promoted hallmarks of arousal and awakening in primates under propofol and ketamine propofol anesthesia. The MD, a subnucleus of dMT, on the other hand, has only recently been implicated in disorders of consciousness (He et al., 2015) and ketamine/ethanol-induced loss of consciousness (Choi et al., 2015) through the alteration of thalamocortical functional connectivity. In anesthetized primates, the stimulation of ILN and MD increased arousal and wakefulness score (Bastos et al., 2021). However, several key questions remain to be answered: (1) Is there a specific role for MD Ca_v3.1 T-type calcium channels in the control of ethanol-induced loss of consciousness? (2) Does Ca_v3.1 T-type calcium channel-driven neuronal firing pattern have any role in the control of consciousness?

In this study, we identified that knockout (KO) and MD-specific silencing of Ca_v3.1 T-type calcium channels results in increased ethanol resistance in mice. Using single-unit recordings, we compared MD activity of wild-type (WT) and KO mice while the mice transitioned from conscious to unconscious state and found that the KO mice showed more sustained MD activity, whereas the WT mice showed clearly reduced MD activity. Furthermore, and consistently with their resistant phenotype, KO mice showed sustained MD firing, well within the wakefulness level, under ethanol consumption. Finally, we demonstrate that both the optogenetic and electrical stimulations in MD, mimicking the sustained firing pattern of KO mice, were sufficient to induce the increased ethanol resistance in WT mice. These results reveal a causal control of brain state by MD during ethanol-induced unconsciousness and with an underlying neural mechanism governed by Ca_v3.1 T-type calcium channels.

To understand the role of T-type Ca²⁺ channels in modulating the consciousness level, we compared the ethanol resistance between WT and Ca_v3.1 KO (Cacna1g−/−) littermates. We used the forced walking task (FWT; Figure 1A), an analog to the LORR assay, which enables a continuous and high-temporal resolution assessment of the loss of movement (Hwang et al., 2010) (LOM). Moreover, the FWT objectively measures the latency to and duration of the first LOM, but also the total time spent in LOM using automatized analysis of video confirmed by electromyograms (EMGs) or accelerometer recordings (Figure 1B and Figure 1—figure supplement 1; see Methods). The continuously running treadmill (6 cm/s) ensures a normalized behavior within and between animals before injection (i.e. baseline forced walking) and allows for reduced intervention from experimenters for the monitoring of both electrophysiological (Figure 1—figure supplement 1, upper panel) and analyzed behavioral (Figure 1—figure supplement 1, lower panel).

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Figure 1—source data 1

Two-way analysis of variance (ANOVA) for latency to and duration of first loss of movement (fLOM), and total time spent in LOM; main factor gene, two levels (Ca_v3.1 wild-type [WT] and Ca_v3.1 knockout [KO]); main factor dose, three levels (2.0 g/kg, 3.0 g/kg, and 4.0 g/kg).

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Ca_v3.1 silencing in the MD, but not VB, increased ethanol resistance in mice

A great majority of Ca_v3.1 expression is found in the thalamic region (Talley et al., 1999) and was shown to specifically correlate with the modulation of thalamocortical-related rhythms and stability of sleep level (Anderson et al., 2005; Lee et al., 2004). To identify a possible role of the thalamic region in ethanol resistance, we knocked down the expression of Ca_v3.1 in the MD and a VB region, two regions possibly involved in a thalamic control of consciousness (He et al., 2015; Choi et al., 2015; Cheong et al., 2009), using a lentivirus (LV)-mediated short hairpin (shRNA) delivery.

We found that compared to shControl-injected mice, Ca_v3.1 knockdown (KD) of MD resulted in an increased latency to (Figure 2A1; t(27) = –3.0045, p=0.0057; Student’s t-test) and duration of (Figure 2A2; t(27) = 2.1448, p=0.0411; Student’s t-test) fLOM, and total time spent in LOM (Figure 2A3; t(27) = 2.6641, p=0.0128, two-tailed test) for 3.0 g/kg i.p. injection of ethanol. However, we found that compared to shControl-injected mice, Ca_v3.1 KD of VB did not change the latency to (t(8) = –1.0093, p=0.3423, two-tailed test), duration of (t(8) = –0.0983, p=0.9241, two-tailed test) fLOM and total time spent in LOM (t(8) = –0.6317, p=0.5452, two-tailed test) for the same 3.0 g/kg i.p. injection of ethanol (Figure 2—figure supplement 1). Representative traces of mice activity showed that mice with Ca_v3.1 KD in MD (Figure 2—figure supplement 2A) had a more delayed and fragmented early period of LOM compared to MD LV-shControl- and VB-injected mice, as in mutant mice.

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We then characterized the change in Ca_v3.1 expression following the shControl and shCa_v3.1 KD injections in three test regions: MD (left and right), CM, and CL (left and right side), and a negative control region SMT (submedial thalamic nuclei, left and right side). The average intensity was obtained from two coronal brain slices for each mouse used in the experiment (see Methods sections, Ca_v3.1 Intensity quantification). Our results show that the targeting of the KD was very specific to the bilateral MD (p<0.001; Figure 2D). We noted that the CM (p<0.05) and a marginal unilateral KD of the CL were also observed (p<0.01). Notably, we tested the correlation between the level of KD in MD and the total time in LOM and observed a significant association (Figure 2D inset; R=0.599, p=0.018). This result highlights that the Ca_v3.1 KD was specific to MD and with an intensity associated with ethanol-induced LOM.

During the open-field test, Ca_v3.1 null mutant mice showed significantly increased locomotor activity compared to WT mice as shown by total distance moved (Figure 2—figure supplement 2C; ANOVA: GROUP F(3) = 8.45, p=0.0004; Ca_v3.1 WT vs Ca_v3.1 KO: p=0.0001). The mice with MD-specific Ca_v3.1 KD, however, did not show any significant difference in total distance moved compared to shControl-injected control mice (MD LV-shControl vs MD LV-shCacna1g [Ca_v3.1 KD]: p=0.868; Holm-Sidak correction), indicating that the ethanol resistance in MD Ca_v3.1 KD mice was not attributed to hyperlocomotion observed in Ca_v3.1 KO mice.

Lack of Ca3.1 in MD neurons removes thalamic burst in NREM sleep

Thalamic neurons are known to follow a state-dependent activity (Poulet et al., 2012); however, the nature of this state-dependent activity has not been studied for the MD. In order to understand the relationship between MD neuron firing and level of consciousness, we investigated the association between the neural activity in MD and brain states at different levels of consciousness (Figure 3, Figure 3—figure supplement 1).

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We observed two major populations of neuronal spike waveform present in MD single-unit recordings of Ca_v3.1 WT mice, also described in previous works (Schiff and Reyes, 2012; Destexhe, 2009): (1) a majority of regular spiking (RS) cells characterized by wide spike waveform (36/39 neurons, 92.3%), i.e., spike-to-valley width >250 μs (Figure 3B) and high bursting propensity; (2) a minority of narrow spiking (NS; also known as fast spiking) cells showing short spike-to-valley width, i.e., <250 μs, lower bursting characteristics (Figure 3, Figure 3—figure supplement 2A3 and A4) and fast-paced tonic firing (10–50 Hz; data not shown). The RS and NS neurons were found in MD of WT and mutant mice; however, MD RS mutant neurons showed an absence of short inter-spike intervals (ISI, i.e. indicative of the absence of burst) in auto-cross-correlogram (Figure 3—figure supplement 2) and a clear reduction in total bursting represented as bursting index (Figure 3B; ratio of spikes count <10 ms and >50 ms based on autocross-correlogram). Since RS cells have the profile of the major population of MD, i.e., excitatory neurons, we focused on the analysis of RS neurons mainly in the remainder of this study.

During the deep sleep state NREM, thalamic neural firing is known to switch from tonic to burst firing (Llinás and Steriade, 2006). We found that a lack of Ca_v3.1 T-type calcium channels resulted in a near absence of burst (see Methods for definition) in mutant mice (Figure 3C1 and C2; 4/44 bursting neurons; Z(77) = 7.20, p<0.0001, rank-sum test) compared to WT mice (34/34 bursting neurons; 5.76±5.51 burst events/min).

Under ethanol, MD neurons lacking Ca_v3.1 show no burst and a wake state-like neural activity

In order to identify the mechanism linked to Ca_v3.1 mutant mice’s ethanol-resistant phenotype, we recorded neural firing of neurons during the FWT and following a hypnotic dose of ethanol (3.0 g/kg, i.p. injection). We focused on the fLOM as it is most analogous to the classical LORR and showed the most consistency between animals (Hwang et al., 2010). fLOM also illustrates best the acute effect induced by ethanol before secondary metabolization enters into play.

Under ethanol, we observed that in WT mice, a majority of neurons showed burst firing mode (Figure 4A1; 20/33 bursting neurons). We found a significantly higher burst event rate (Figure 4B1; p<0.0001, rank-sum test with Holm-Bonferroni correction) and in the ratio of burst-to-total spike (Figure 4B2; p<0.0001, rank-sum test with Holm-Bonferroni correction) comparing walk (awake active) to fLOM (unconscious, unresponsive). Mutant neurons, consistent with NREM data, did not show burst firing during fLOM (0/36 bursting neurons).

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Notably, in WT, we observed that ethanol induced a significant decrease in total firing from walking to fLOM states (Figure 4A1 and C; p<0.0001, rank-sum test with Holm-Bonferroni correction) and well below wakefulness level (home cage awake state). As in sleep, we found that a majority of RS neurons showed decreased tonic firing (total number of spikes) together with an increase in burst firing, indicating a switch in firing mode under ethanol sleep. Interestingly, the mutant mice did not show a significant decrease in total firing (Figure 4C; p=0.130, rank-sum test with Holm-Bonferroni correction) and showed no bursts as in sleep.

We quantified the change in activity of individual neurons using Z-score normalized to the home cage wakeful state. Here, we also observed that WT RS neurons showed a significantly reduced Z-score under ethanol fLOM, whereas in mutant mice, cells did not (Figure 4D1; normalized from home cage wake state; t(62) = –5.1400, p<0.0001, Student’s t-test). Remarkably, we found that a majority of WT MD neurons (29/31) showed individual significantly decreased Z-scores (Figure 4D2; Z-threshold defined from a p-value of 0.05). During fLOM, mutant RS neurons subdivided into three populations (Figure 4D2) with decreasing (12/33, 36.4%), maintaining (11/33, 30%), and increasing (10/33, 30.3%) activity as measured by the Z-score with respect to wakefulness (i.e. home cage wake state). These results were consistent in individual mice (Figure 4—figure supplement 1A) and the distribution of neural population spiking (Figure 4—figure supplement 1B), validating that a significant drop in neural activity is associated with LOM.

Finally, we asked whether the firing modes and properties (tonic firing rate, burst firing rate; see supplementary methods) of single MD neurons would form distinct qualitative representations of ‘brain stages’ using a lowered dimensional uniform manifold approximation and projection (UMAP) representation (McInnes et al., 2018). We observed that for awake and active (i.e. walk), the brain state representation formed two adjacent clusters that confounded both wild and mutant neurons (Figure 4E, left panel). The REM and NREM states, the WT neurons formed two additional interconnected clusters, whereas the mutant neurons tended to overlap with the clusters attributed to the ‘awake’ brain state (Figure 4E, second to left panel). Ethanol-induced fLOM, similarly to REM and NREM clusters, was distinct from awake clusters in WT mice and overlapped with the NREM clusters (Figure 4E, third to left panel). Here also, mutant MD neurons showed overlap with the awake clusters rather than the ‘low consciousness’ brain states. These results indicate that the firing mode and properties could define a brain state representation that shows distinctions in levels of consciousness. Moreover, the mutant showed a representation of ‘low consciousness’ states overlapping with WT ‘awake’ states consistent with the hypothesis of resistance to loss of consciousness.

Altogether, these results indicate that, in WT, ethanol induced a strong reduction in neural activity and a switch to bursting firing mode correlated with loss of consciousness. However, under ethanol, MD mutant neurons maintained their activity to a level within home cage wake state without switching to bursting. This indicates that the drop in neural activity under ethanol is modulated by Ca_v3.1 T-type calcium channels. In its absence, MD mutant neurons display an overall reduced activity in all brain states; however, under ethanol, they remain within state wakeful levels.

Under ethanol, 20 Hz neurostimulation of MD induces mutant-like resistance to loss of consciousness in WT mice

We observed that the maintenance of neural activity in MD excitatory neurons might be at the origin of the ethanol resistance in mutant mice. We hypothesized that artificially maintaining MD neural activity within the wakeful level would sustain consciousness under ethanol. In addition, we hypothesized that the triggering of burst firing under ethanol would potentiate loss of consciousness under ethanol. To test this possibility, we used electric and optogenetic stimulations during the FWT in WT mice under a hypnotic dose of ethanol.

MD neurons in WT mice showed a spike firing range of 0–50 Hz with an average neural firing around ~20 Hz during home cage wakefulness (Figure 4—figure supplement 1B). Using the 20 Hz stimulation (Figure 5A, inter-pulse interval = 50 ms, pulse width = 6.25 ms) in MD neurons transduced with excitatory channelrhodopsin (Gangadharan et al., 2016; Lee et al., 2019) (aav-SYN-ChR2-sfGFP; Figure 5B and Figure 5—figure supplements 1 and 2; see Methods), we observed an increase in ethanol resistance, which was demonstrated by a significant increase in latency to fLOM (Figure 5D1; Z(13) = –2.372, p=0.013; rank-sum test). The duration of fLOM (Figure 5D2; Z(13) = 2.256, p=0.020; rank-sum test) and total time spent in LOM (Figure 5D3; Z(13) = 2.488, p=0.009; rank-sum test) were also significantly reduced. We verified that optogenetic stimulation of MD neurons at 20 Hz (Figure 5—figure supplement 1) induced action potentials at the same frequency with a latency response of about ~5 ms (Figure 5—figure supplement 1B2; pulse width = 6.25 ms). We also observed that, although marginally higher, optogenetic stimulation did not induce any significant increase in locomotor activity (Figure 5—figure supplement 1C; F(1,12) = 3.6232, p=0.0812) in the control and stimulated group, which indicates that the stimulation-induced increase in ethanol resistance was not due to an increase in locomotor activity.

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In order to validate this observation, we then bilaterally implanted mice with twisted wires for bipolar, local electric stimulation of MD (Figure 5—figure supplement 3). As in the optogenetics experiment, we used a continuous pulse train of 20 Hz electric stimulation (Figure 5—figure supplement 4A; upper panel; inter-pulse interval = 50 ms, pulse width = 1 ms) in addition to a burst-like stimulation (Figure 5—figure supplement 1A; lower panel; 4 pulses at 4 ms interval and interburst interval of 1 s) that showed, respectively, tonic-like and burst-like entrainment in thalamic neurons (Lee et al., 2012). We observed that our 20 Hz tonic-like stimulation significantly increased the latency to fLOM (Figure 5—figure supplement 1B1; tonic-like vs no stim.: p=0.008; tonic-like vs burst-like: p=0.007; rank-sum test with Holm-Bonferroni correction) and significantly decreased the total time spent in LOM (Figure 5B3; tonic-like vs no stim.: p=0.008; tonic-like vs burst-like: p=0.007, rank-sum test with Holm-Bonferroni correction). No significant changes in the duration of the fLOM were observed (duration of fLOM) (Figure 5B2; tonic-like vs no stim.: p=0.917; tonic-like vs burst-like: p=0.606; rank-sum test with Holm-Bonferroni correction).

Interestingly, we observed that burst-like electrical stimulation (Figure 5—figure supplement 4A; lower panel; ISI = 4 ms, inter-burst interval = 1 s, pulse width = 1 ms) did not induce any significant change in ethanol sensitivity compared to the no stimulation group (latency to fLOM: p=0.365; duration of fLOM: p=0.835; total time spent in LOM: p=1; rank-sum test with Holm-Bonferroni correction). This result suggests that burst firing alone might not have a role in ethanol resistance.

Altogether, these results suggest that the maintenance of MD firing at wakefulness level (20 Hz) causally drives resistance to loss of consciousness after a hypnotic dose of ethanol. Burst-like stimulation alone did not promote or reduce loss of consciousness. This result supports the idea that neural activity maintenance in MD promotes the maintenance of consciousness even under heavy sedatives.

In this work, we identified that the neural activity in MD plays a causal role in the maintenance of consciousness. Whole body Ca_v3.1 KO and MD-specific Ca_v3.1 KD mice showed resistance to loss of consciousness induced by hypnotic dose of ethanol. In WT mice, MD neurons demonstrated a reduced firing rate in natural (sleep) and ethanol-induced unconscious states compared to awake states. This neural activity reduction was impaired in KO mice. In particular, transition to an unconscious state was accompanied by a switch of firing mode from tonic firing to burst firing in WT mice, whereas this mode shift disappeared in KO mice. Finally, optogenetic or electric stimulations of the MD after ethanol injection were sufficient to induce a resistance to loss of motion, supporting that the level of neural firing in the MD is critical to maintain conscious state and delay unconscious state. We showed that the expression of Ca_v3.1 T-type calcium channels in MD is a cellular modulator associated with this effect.

Source behavioral data and representative figure and images are available on the open mendeley repository: https://doi.org/10.17632/7fr427426m.1. Additional data (heavy recording and images) can be provided upon request.

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   Mediodorsal thalamic nucleus mediates resistance to ethanol through Cav3.1 T-type Ca2+ regulation of neural activity.

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Author details

1. Charles-francois V Latchoumane

   Institute for Basic Science, Center for Cognition and Sociality, Daejeon, Republic of Korea

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7018-0439

2. Joon-Hyuk Lee

   Institute for Basic Science, Center for Cognition and Sociality, Daejeon, Republic of Korea

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1984-7020

3. Seong-Wook Kim

   Institute for Basic Science, Center for Cognition and Sociality, Daejeon, Republic of Korea

   Contribution

   Conceptualization, Formal analysis, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Jinhyun Kim

   Korea Institute of Science and Technology, Center for Functional Connectomics, Seoul, Republic of Korea

   Contribution

   Resources, Software, Methodology

   Competing interests

   No competing interests declared

5. Hee-Sup Shin

   Institute for Basic Science, Center for Cognition and Sociality, Daejeon, Republic of Korea

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   shin@ibs.re.kr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4260-3718

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