Posterior thalamic nucleus modulation of tactile stimuli processing in rat motor and primary somatosensory cortices

Rodents move rhythmically their facial whiskers and compute differences between signals predicted and those resulting from the movement to infer information about objects near their head. These computations are carried out by a large network of forebrain structures that includes the thalamus and the primary somatosensory (S1BF) and motor (M1wk) cortices. Spatially and temporally precise mechanorreceptive whisker information reaches the S1BF cortex via the ventroposterior medial thalamic nucleus (VPM). Other whisker-related information may reach both M1wk and S1BF via the axons from the posterior thalamic nucleus (Po). However, Po axons may convey, in addition to direct sensory signals, the dynamic output of computations between whisker signals and descending motor commands. It has been proposed that this input may be relevant for adjusting cortical responses to predicted vs. unpredicted whisker signals, but the effects of Po input on M1wk and S1BF function have not been directly tested or compared in vivo. Here, using electrophysiology, optogenetics and pharmacological tools, we compared in adult rats M1wk and S1BF in vivo responses in the whisker areas of the motor and primary somatosensory cortices to passive multiwhisker deflection, their dependence on Po activity, and their changes after a brief intense activation of Po axons. We report that the latencies of the first component of tactile-evoked local field potentials in M1wk and S1BF are similar. The evoked potentials decrease markedly in M1wk, but not in S1BF, by injection in Po of the GABA A agonist muscimol. A brief high-frequency electrical stimulation of Po decreases the responsivity of M1wk and S1BF cells to subsequent whisker stimulation. This effect is prevented by the local application of omega-agatoxin, suggesting that it may in part depend on GABA release by fast-spiking parvalbumin (PV)-expressing cortical interneurons. Local optogenetic activation of Po synapses in different cortical layers also diminishes M1wk and S1BF responses. This effect is most pronounced in the superficial layers of both areas, known to be the main source and target of their reciprocal cortico-cortical connectionsThis work was supported by a Grant from Spain’s Ministerio de Economia y Competitividad (BFU2012–36107) to ÁN, and the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 720270 (HBP SGA1) to FC

Posterior thalamic nucleus axon terminals have different structure and functional impact in the motor and somatosensory vibrissal cortices

Rodents extract information about nearby objects from the movement of their whiskers through dynamic computations that are carried out by a network of forebrain structures that includes the thalamus and the primary sensory (S1BF) and motor (M1wk) whisker cortices. The posterior nucleus (Po), a higher order thalamic nucleus, is a key hub of this network, receiving cortical and brainstem sensory inputs and innervating both motor and sensory whisker-related cortical areas. In a recent study in rats, we showed that Po inputs differently impact sensory processing in S1BF and M1wk. Here, in C57BL/6 mice, we measured Po synaptic bouton layer distribution and size, compared cortical unit response latencies to “in vivo” Po activation, and pharmacologically examined the glutamatergic receptor mechanisms involved. We found that, in S1BF, a large majority (56%) of Po axon varicosities are located in layer (L)5a and only 12% in L2–L4, whereas in M1wk this proportion is inverted to 18% and 55%, respectively. Light and electron microscopic measurements showed that Po synaptic boutons in M1wk layers 3–4 are significantly larger (~ 50%) than those in S1BF L5a. Electrical Po stimulation elicits different area-specific response patterns. In S1BF, responses show weak or no facilitation, and involve both ionotropic and metabotropic glutamate receptors, whereas in M1wk, unit responses exhibit facilitation to repetitive stimulation and involve ionotropic NMDA glutamate receptors. Because of the different laminar distribution of axon terminals, synaptic bouton size and receptor mechanisms, the impact of Po signals on M1wk and S1BF, although simultaneous, is likely to be markedly different.This study was supported by European Union’s Horizon 2020 (Grant Agreement no. 785907 HBP SGA2) and Ministerio de Economía y Competitividad/Fondo Europeo para el Desarrollo Regional (MINECO/FEDER) Grant BFU2017-88549 to F.C., and MINECO/FEDER Grant BFU2012-36107 to A.N

Subset of cortical layer 6b neurons selectively innervates higher order thalamic nuclei in mice

The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells (“layer 6b cells”) taking advantage of the transgenic mouse Tg(Drd1a-cre)FK164Gsat/Mmucd (Drd1a-Cre), that selectively expresses Cre-recombinase in a subpopulation of layer 6b neurons across the entire cortical mantle. At P8, 18% of layer 6b neurons are labeled with Drd1a-Cre::tdTomato in somatosensory cortex (SS), and some co-express known layer 6b markers. Using Cre-dependent viral tracing, we identified topographical projections to higher order thalamic nuclei. VGluT1+ synapses formed by labeled layer 6b projections were found in posterior thalamic nucleus (Po) but not in the (pre)thalamic reticular nucleus (TRN). The lack of TRN collaterals was confirmed with single-cell tracing from SS. Transmission electron microscopy comparison of terminal varicosities from layer 5 and layer 6b axons in Po showed that L6b varicosities are markedly smaller and simpler than the majority from L5. Our results suggest that L6b projections to the thalamus are distinct from both L5 and L6a projectionsZ.M.’s laboratory is supported by Medical Research Council (G00900901), Biotechnology and Biological Sciences Research Council (BB/1021833) and The Wellcome Trust (092071/Z/10/Z). E.G. held an MRC Doctoral Studentship; S.H. is supported from Daiichi Sankyo Foundation of Life Science, Japan, L.U. is supported by OXION Wellcome Trust Initiative, Oxford. Y.K. is supported from the Pennsylvania Department of Health using Tobacco CURE Funds SAP#4100062216; P.K. from National Institutes of Health (NIH) R01DC009607 and a visiting Fellowship at St. Catherine’s College, Oxford. F.C.’s laboratory is supported by Human Brain Project (European Flagship, Ref. GA 604102 and Ministerio de Economia y Competitividad MINECO (Spain; Grant BFU2017-88549-P)

Area-specific synapse structure in branched posterior nucleus axons reveals a new level of complexity in thalamocortical networks

Thalamocortical posterior nucleus (Po) axons innervating the vibrissal somatosensory (S1) and motor (MC) cortices are key links in the brain neuronal network that allows rodents to explore the environment whisking with their motile snout vibrissae. Here, using fine-scale high-end 3D electron microscopy, we demonstrate in adult male C57BL/6 wild-type mice marked differences between MC versus S1 Po synapses in (1) bouton and active zone size, (2) neurotransmitter vesicle pool size, (3) distribution of mitochondria around synapses, and (4) proportion of synapses established on dendritic spines and dendritic shafts. These differences are as large, or even more pronounced, than those between Po and ventro-posterior thalamic nucleus synapses in S1. Moreover, using single-axon transfection labeling, we demonstrate that the above differences actually occur on the MC versus the S1 branches of individual Po cell axons that innervate both areas. Along with recently-discovered divergences in efficacy and plasticity, the synaptic structure differences reported here thus reveal a new subcellular level of complexity. This is a finding that upends current models of thalamocortical circuitry, and that might as well illuminate the functional logic of other branched projection axon systems.This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme (Grant 785907 HBP SGA2), by Spain’s Ministerio de Ciencia, Innovación y Universidades (BFU 2107-88549-P) to F.C., and by Grants of the Helmholtz Society (JHRL)

Identification and neuromodulation of brain states to promote recovery of consciousness

Experimental and clinical studies of consciousness identify brain states (i.e., transient, relevant features of the brain associated with the state of consciousness) in a non-systematic manner and largely independent from the research into the induction of state changes. In this narrative review with a focus on patients with a disorder of consciousness (DoC), we synthesize advances on the identification of brain states associated with consciousness in animal models and physiological (sleep), pharmacological (anesthesia) and pathological (DoC) states of altered consciousness in human. We show that in reduced consciousness the frequencies in which the brain operates are slowed down and that the pattern of functional communication in the brain is sparser, less efficient, and less complex. The results also highlight damaged resting state networks, in particular the default mode network, decreased connectivity in long-range connections and in the thalamocortical loops. Next, we show that therapeutic approaches to treat DoC, through pharmacology (e.g., amantadine, zolpidem), and (non-)invasive brain stimulation (e.g., transcranial current stimulation, deep brain stimulation) have shown some effectiveness to promote consciousness recovery. It seems that these deteriorated features of conscious brain states may improve in response to these neuromodulation approaches, yet, targeting often remains non-specific and does not always lead to (behavioral) improvements. Furthermore, in silico model-based approaches allow the development of personalized assessment of the effect of treatment on brain-wide dynamics. Although still in infancy, the fields of brain state identification and neuromodulation of brain states in relation to consciousness are showing fascinating developments that, when united, might propel the development of new and better targeted techniques for DoC. For example, brain states could be identified in a predictive setting, and the theoretical and empirical testing (i.e., in animals, under anesthesia and patients with a DoC) of neuromodulation techniques to promote consciousness could be investigated. This review further helps to identify where challenges and opportunities lay for the maturation of brain state research in the context of states of consciousness. Finally, it aids in recognizing possibilities and obstacles for the clinical translation of these diagnostic techniques and neuromodulation treatment options across both the multi-modal and multi-species approaches outlined throughout the review. This paper presents interactive figures, supported by the Live Paper initiative of the Human Brain Project, enabling the interaction with data and figures illustrating the concepts in the paper through EBRAINS (go to https://wiki.ebrains.eu/bin/view/Collabs/live-paper-states-altered-consciousness and get started with an EBRAINS account).NA is research fellow, OG is Research Associate, and SL is research director at FRS-FNRS. JA is postdoctoral fellow at the FWO. The study was further supported by the University and University Hospital of Liège, the BIAL Foundation, the Belgian National Funds for Scientific Research (FRS-FNRS), the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3), the FNRS PDR project (T.0134.21), the ERA-Net FLAG-ERA JTC2021 project ModelDXConsciousness (Human Brain Project Partnering Project), the fund Generet, the King Baudouin Foundation, the Télévie Foundation, the European Space Agency (ESA) and the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Programme, the Public Utility Foundation 'Université Européenne du Travail', "Fondazione Europea di Ricerca Biomedica", the BIAL Foundation, the Mind Science Foundation, the European Commission, the Fondation Leon Fredericq, the Mind-Care foundation, the DOCMA project (EU-H2020-MSCA–RISE–778234), the National Natural Science Foundation of China (Joint Research Project 81471100) and the European Foundation of Biomedical Research FERB Onlus

Análisis anatómico-funcional del flujo de información en el núcleo posterior del tálamo de roedores

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Anatomía, Histología y Neurociencia. Fecha de lectura: 14-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 14-03-201

Thalamic Foxp2 regulates output connectivity and sensory‑motor impairments in a model of Huntington’s Disease

Here, we demonstrate in a HD mouse model a clear and early thalamo-striatal aberrant connectivity associated with a reduction of thalamic Foxp2 levels. Recovering thalamic Foxp2 levels in the mouse rescued motor coordination and sensory skills concomitant with an amelioration of neuropathological features and with a repair of the structural and functional connectivity through a restoration of neurotransmitter release. In addition, reduction of thalamic Foxp2 levels in wild type mice induced HD-like phenotypes