Gil Vantomme

All Publications

• Region-selective control of the thalamic reticular nucleus via cortical layer 5 pyramidal cells NATURE NEUROSCIENCE Hadinger, N., Bosz, E., Toth, B., Vantomme, G., Luethi, A., Acsady, L. 2023; 26 (1): 116-+

  Abstract

  Corticothalamic pathways, responsible for the top-down control of the thalamus, have a canonical organization such that every cortical region sends output from both layer 6 (L6) and layer 5 (L5) to the thalamus. Here we demonstrate a qualitative, region-specific difference in the organization of mouse corticothalamic pathways. Specifically, L5 pyramidal cells of the frontal cortex, but not other cortical regions, establish monosynaptic connections with the inhibitory thalamic reticular nucleus (TRN). The frontal L5-TRN pathway parallels the L6-TRN projection but has distinct morphological and physiological features. The exact spike output of the L5-contacted TRN cells correlated with the level of cortical synchrony. Optogenetic perturbation of the L5-TRN connection disrupted the tight link between cortical and TRN activity. L5-driven TRN cells innervated thalamic nuclei involved in the control of frontal cortex activity. Our data show that frontal cortex functions require a highly specialized cortical control over intrathalamic inhibitory processes.

  View details for DOI 10.1038/s41593-022-01217-z

  View details for Web of Science ID 001057340200002

  View details for PubMedID 36550291

  View details for PubMedCentralID PMC9829539

• Noradrenergic circuit control of non-REM sleep substates CURRENT BIOLOGY Osorio-Forero, A., Cardis, R., Vantomme, G., Guillaume-Gentil, A., Katsioudi, G., Devenoges, C., Fernandez, L. J., Luthi, A. 2021; 31 (22): 5009-+

  Abstract

  To understand what makes sleep vulnerable in disease, it is useful to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-rapid-eye-movement sleep (NREMS). However, sensory vigilance persists in NREMS in animals and humans, suggesting that wake promotion could remain functional. Here, we demonstrate that consolidated mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the ∼50-s timescale in the thalamus. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while noradrenaline (NA) levels declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart-rate variations, both of which are correlates of sensory arousability. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock, or entrain sleep-spindle clustering and heart-rate variations, suggesting that both fore- and hindbrain-projecting LC neurons show coordinated infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic, but not cortical, circuits was required for sleep-spindle clustering and involved NA release into primary sensory and reticular thalamic nuclei that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC constitutes a vigilance-promoting mechanism that renders mammalian NREMS vulnerable to disruption on the close-to-minute timescale through sustaining thalamocortical and autonomic sensory arousability. VIDEO ABSTRACT.

  View details for DOI 10.1016/j.cub.2021.09.041

  View details for Web of Science ID 000721720700001

  View details for PubMedID 34648731

• Genetic, cellular and structural characterization of the membrane potential-dependent cell-penetrating peptide translocation pore. eLife Trofimenko, E., Grasso, G., Heulot, M., Chevalier, N., Deriu, M. A., Dubuis, G., Arribat, Y., Serulla, M., Michel, S., Vantomme, G., Ory, F., Dam, L. C., Puyal, J., Amati, F., Lüthi, A., Danani, A., Widmann, C. 2021; 10

  Abstract

  Cell-penetrating peptides (CPPs) allow intracellular delivery of bioactive cargo molecules. The mechanisms allowing CPPs to enter cells are ill-defined. Using a CRISPR/Cas9-based screening, we discovered that KCNQ5, KCNN4, and KCNK5 potassium channels positively modulate cationic CPP direct translocation into cells by decreasing the transmembrane potential (Vm). These findings provide the first unbiased genetic validation of the role of Vm in CPP translocation in cells. In silico modeling and live cell experiments indicate that CPPs, by bringing positive charges on the outer surface of the plasma membrane, decrease the Vm to very low values (-150 mV or less), a situation we have coined megapolarization that then triggers formation of water pores used by CPPs to enter cells. Megapolarization lowers the free energy barrier associated with CPP membrane translocation. Using dyes of varying dimensions in CPP co-entry experiments, the diameter of the water pores in living cells was estimated to be 2(-5) nm, in accordance with the structural characteristics of the pores predicted by in silico modeling. Pharmacological manipulation to lower transmembrane potential boosted CPPs cellular internalization in zebrafish and mouse models. Besides identifying the first proteins that regulate CPP translocation, this work characterized key mechanistic steps used by CPPs to cross cellular membrane. This opens the ground for strategies aimed at improving the ability of cells to capture CPP-linked cargos in vitro and in vivo.

  View details for DOI 10.7554/eLife.69832

  View details for PubMedID 34713805

• A Thalamic Reticular Circuit for Head Direction Cell Tuning and Spatial Navigation CELL REPORTS Vantomme, G., Rovo, Z., Cardis, R., Beard, E., Katsioudi, G., Guadagno, A., Perrenoud, V., Fernandez, L. J., Luethi, A. 2020; 31 (10): 107747

  Abstract

  As we navigate in space, external landmarks and internal information guide our movement. Circuit and synaptic mechanisms that integrate these cues with head-direction (HD) signals remain, however, unclear. We identify an excitatory synaptic projection from the presubiculum (PreS) and the multisensory-associative retrosplenial cortex (RSC) to the anterodorsal thalamic reticular nucleus (TRN), so far classically implied in gating sensory information flow. In vitro, projections to TRN involve AMPA/NMDA-type glutamate receptors that initiate TRN cell burst discharge and feedforward inhibition of anterior thalamic nuclei. In vivo, chemogenetic anterodorsal TRN inhibition modulates PreS/RSC-induced anterior thalamic firing dynamics, broadens the tuning of thalamic HD cells, and leads to preferential use of allo- over egocentric search strategies in the Morris water maze. TRN-dependent thalamic inhibition is thus an integral part of limbic navigational circuits wherein it coordinates external sensory and internal HD signals to regulate the choice of search strategies during spatial navigation.

  View details for DOI 10.1016/j.celrep.2020.107747

  View details for Web of Science ID 000540571300021

  View details for PubMedID 32521272

• Regulation of Local Sleep by the Thalamic Reticular Nucleus FRONTIERS IN NEUROSCIENCE Vantomme, G., Osorio-Forero, A., Luethi, A., Fernandez, L. J. 2019; 13: 576

  Abstract

  In spite of the uniform appearance of sleep as a behavior, the sleeping brain does not produce electrical activities in unison. Different types of brain rhythms arise during sleep and vary between layers, areas, or from one functional system to another. Local heterogeneity of such activities, here referred to as local sleep, overturns fundamental tenets of sleep as a globally regulated state. However, little is still known about the neuronal circuits involved and how they can generate their own specifically-tuned sleep patterns. NREM sleep patterns emerge in the brain from interplay of activity between thalamic and cortical networks. Within this fundamental circuitry, it now turns out that the thalamic reticular nucleus (TRN) acts as a key player in local sleep control. This is based on a marked heterogeneity of the TRN in terms of its cellular and synaptic architecture, which leads to a regional diversity of NREM sleep hallmarks, such as sleep spindles, delta waves and slow oscillations. This provides first evidence for a subcortical circuit as a determinant of cortical local sleep features. Here, we review novel cellular and functional insights supporting TRN heterogeneity and how these elements come together to account for local NREM sleep. We also discuss open questions arising from these studies, focusing on mechanisms of sleep regulation and the role of local sleep in brain plasticity and cognitive functions.

  View details for DOI 10.3389/fnins.2019.00576

  View details for Web of Science ID 000470220100003

  View details for PubMedID 31231186

  View details for PubMedCentralID PMC6560175

• Thalamic reticular control of local sleep in mouse sensory cortex ELIFE Fernandez, L. J., Vantomme, G., Osorio-Forero, A., Cardis, R., Beard, E., Luthi, A. 2018; 7

  Abstract

  Sleep affects brain activity globally, but many cortical sleep waves are spatially confined. Local rhythms serve cortical area-specific sleep needs and functions; however, mechanisms controlling locality are unclear. We identify the thalamic reticular nucleus (TRN) as a source for local, sensory-cortex-specific non-rapid-eye-movement sleep (NREMS) in mouse. Neurons in optogenetically identified sensory TRN sectors showed stronger repetitive burst discharge compared to non-sensory TRN cells due to higher activity of the low-threshold Ca2+ channel CaV3.3. Major NREMS rhythms in sensory but not non-sensory cortical areas were regulated in a CaV3.3-dependent manner. In particular, NREMS in somatosensory cortex was enriched in fast spindles, but switched to delta wave-dominated sleep when CaV3.3 channels were genetically eliminated or somatosensory TRN cells chemogenetically hyperpolarized. Our data indicate a previously unrecognized heterogeneity in a powerful forebrain oscillator that contributes to sensory-cortex-specific and dually regulated NREMS, enabling local sleep regulation according to use- and experience-dependence.

  View details for DOI 10.7554/eLife.39111

  View details for Web of Science ID 000456236100001

  View details for PubMedID 30583750

  View details for PubMedCentralID PMC6342525

• Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs SCIENTIFIC REPORTS Fernandez, L. J., Pellegrini, C., Vantomme, G., Beard, E., Luthi, A., Astori, S. 2017; 7: 12271

  Abstract

  Thalamus and cortex represent a highly integrated processing unit that elaborates sensory representations. Interposed between cortex and thalamus, the nucleus Reticularis thalami (nRt) receives strong cortical glutamatergic input and mediates top-down inhibitory feedback to thalamus. Despite growing appreciation that the nRt is integral for thalamocortical functions from sleep to attentional wakefulness, we still face considerable gaps in the synaptic bases for cortico-nRt communication and plastic regulation. Here, we examined modulation of nRt excitability by cortical synaptic drive in Ntsr1-Cre x ChR2tg/+ mice expressing Channelrhodopsin2 in layer 6 corticothalamic cells. We found that cortico-nRt synapses express a major portion of NMDA receptors containing the GluN2C subunit (GluN2C-NMDARs). Upon repetitive photoactivation (10 Hz trains), GluN2C-NMDARs induced a long-term increase in nRt excitability involving a potentiated recruitment of T-type Ca2+ channels. In anaesthetized mice, analogous stimulation of cortical afferents onto nRt produced long-lasting changes in cortical local field potentials (LFPs), with delta oscillations being augmented at the expense of slow oscillations. This shift in LFP spectral composition was sensitive to NMDAR blockade in the nRt. Our data reveal a novel mechanism involving plastic modification of synaptically recruited T-type Ca2+ channels and nRt bursting and indicate a critical role for GluN2C-NMDARs in thalamocortical rhythmogenesis.

  View details for DOI 10.1038/s41598-017-12552-8

  View details for Web of Science ID 000411648500045

  View details for PubMedID 28947779

  View details for PubMedCentralID PMC5612942

• Quantifying Infra-slow Dynamics of Spectral Power and Heart Rate in Sleeping Mice JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Fernandez, L. J., Lecci, S., Cardis, R., Vantomme, G., Beard, E., Luthi, A. 2017

  Abstract

  Three vigilance states dominate mammalian life: wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. As more neural correlates of behavior are identified in freely moving animals, this three-fold subdivision becomes too simplistic. During wakefulness, ensembles of global and local cortical activities, together with peripheral parameters such as pupillary diameter and sympathovagal balance, define various degrees of arousal. It remains unclear the extent to which sleep also forms a continuum of brain states-within which the degree of resilience to sensory stimuli and arousability, and perhaps other sleep functions, vary gradually-and how peripheral physiological states co-vary. Research advancing the methods to monitor multiple parameters during sleep, as well as attributing to constellations of these functional attributes, is central to refining our understanding of sleep as a multifunctional process during which many beneficial effects must be executed. Identifying novel parameters characterizing sleep states will open opportunities for novel diagnostic avenues in sleep disorders. We present a procedure to describe dynamic variations of mouse non-REM sleep states via the combined monitoring and analysis of electroencephalogram (EEG)/electrocorticogram (ECoG), electromyogram (EMG), and electrocardiogram (ECG) signals using standard polysomnographic recording techniques. Using this approach, we found that mouse non-REM sleep is organized into cycles of coordinated neural and cardiac oscillations that generate successive 25-s intervals of high and low fragility to external stimuli. Therefore, central and autonomic nervous systems are coordinated to form behaviorally distinct sleep states during consolidated non-REM sleep. We present surgical manipulations for polysomnographic (i.e., EEG/EMG combined with ECG) monitoring to track these cycles in the freely sleeping mouse, the analysis to quantify their dynamics, and the acoustic stimulation protocols to assess their role in the likelihood of waking up. Our approach has already been extended to human sleep and promises to unravel common organizing principles of non-REM sleep states in mammals.

  View details for DOI 10.3791/55863

  View details for Web of Science ID 000415369500040

  View details for PubMedID 28809834

  View details for PubMedCentralID PMC5613791