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

Long-range projection neurons of the mouse ventral tegmental area: A single-cell axon tracing analysis

Pathways arising from the ventral tegmental area (VTA) release dopamine and other neurotransmitters during the expectation and achievement of reward, and are regarded as central links of the brain networks that create drive, pleasure, and addiction. While the global pattern of VTA projections is well-known, the actual axonal wiring of individual VTA neurons had never been investigated. Here, we labeled and analyzed the axons of 30 VTA single neurons by means of single-cell transfection with the Sindbis-pal-eGFP vector in mice. These observations were complemented with those obtained by labeling the axons of small populations of VTA cells with iontophoretic microdeposits of biotinylated dextran amine. In the single-cell labeling experiments, each entire axonal tree was reconstructed from serial sections, the length of terminal axonal arbors was estimated by stereology, and the dopaminergic phenotype was tested by double-labeling for tyrosine hydroxylase immunofluorescence. We observed two main, markedly different VTA cell morphologies: neurons with a single main axon targeting only forebrain structures (FPN cells), and neurons with multibranched axons targeting both the forebrain and the brainstem (F + BSPN cells). Dopaminergic phenotype was observed in FPN cells. Moreover, four “subtypes” could be distinguished among the FPN cells based on their projection targets: (1) “Mesocorticolimbic” FPN projecting to both neocortex and basal forebrain; (2) “Mesocortical” FPN innervating the neocortex almost exclusively; (3) “Mesolimbic” FPN projecting to the basal forebrain, accumbens and caudateputamen; and (4) “Mesostriatal” FPN targeting only the caudateputamen. While the F + BSPN cells were scattered within VTA, the mesolimbic neurons were abundant in the paranigral nucleus. The observed diversity in wiring architectures is consistent with the notion that different VTA cell subpopulations modulate the activity of specific sets of prosencephalic and brainstem structuresThe project was supported by Grants from the Fundación Eugenio Rodríguez Pascual, the Spanish MINECO (BFU2010-19695) and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 604102 (Human Brain Project

Analyzing thalamocortical tract-tracing experiments in a common reference space

Current mesoscale connectivity atlases provide limited information about the organization of thalamocortical projections in the mouse brain. Labeling the projections of spatially restricted neuron populations in thalamus can provide a functionally relevant level of connectomic analysis, but these need to be integrated within the same common reference space. Here, we present a pipeline for the segmentation, registration, integration and analysis of multiple tract-tracing experiments. The key difference with other workflows is that the data is transformed to fit the reference template. As a test-case, we investigated the axonal projections and intranuclear arrangement of seven neuronal populations of the ventral posteromedial nucleus of the thalamus (VPM), which we labeled with an anterograde tracer. Their soma positions corresponded, from dorsal to ventral, to cortical representations of the whiskers, nose and mouth. They strongly targeted layer 4, with the majority exclusively targeting one cortical area and the ones in ventrolateral VPM branching to multiple somatosensory areas. We found that our experiments were more topographically precise than similar experiments from the Allen Institute and projections to the primary somatosensory area were in agreement with single-neuron morphological reconstructions from publicly available databases. This pilot study sets the basis for a shared virtual connectivity atlas that could be enriched with additional data for studying the topographical organization of different thalamic nuclei. The pipeline is accessible with only minimal programming skills via a Jupyter Notebook, and offers multiple visualization tools such as cortical flatmaps, subcortical plots and 3D renderings and can be used with custom anatomical delineation

Anatomical dissection of the mimic facial musculature: iconographic review as a support to the complementary treatments in facial rejuvenation

A la hora de valorar las múltiples técnicas empleadas en el rejuvenecimiento facial y centrándonos de manera particular en aquellos procedimientos mínimamente invasivos complementarios a las intervenciones habituales en Cirugía Plástica-Estética, cobra especial relevancia el conocimiento exhaustivo de las estructuras musculares implicadas en la mímica facial. A tal efecto, se ha realizado un estudio anatómico en cadáveres frescos, en los que se han disecado las principales estructuras referidas. Se presenta un resumen iconográfico de los músculos faciales implicados, haciendo hincapié en su anatomía descriptiva y funcional, así como un recuerdo de las principales áreas problemáticas por alguna circunstancia especial (presencia de un nervio sensitivo o motor).To value the multiple technologies involved in facial rejuvenation and focusing in those minimally invasive complementary procedures to the usual Plastic and Aesthetic Surgeries, it´s very important the exhaustive knowledge of the muscular structures involved in the facial movements. To such an effect, an anatomical study has been realized in fresh corpses, dissecting the principal above-mentioned structures. We present an iconographic summary of the facial implied muscles, emphasizing in his descriptive and functional anatomy, as well as a recollection of the principal problematic areas for some special circumstance (presence of a sensory or motor nerv

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

Arquitectura y conexiones subcorticales de la corteza insular: estudio anatómico en el gato

Tesis doctoral inédita leída el 13-7-1990 en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Morfologí

Quantitative mapping of the local and extrinsic sources of GABA and Reelin to the layer Ia neuropil in the adult rat neocortex

Inputs to apical dendritic tufts have been considered to be crucial for associative learning, attention and similar ''feedback'' interactions and are located in neocortical layer Ia. Excitatory thalamic projections to apical tufts in layer Ia have been well characterized and their role in the cortical circuit has been emphasized. In addition, the neuropil and the extracellular matrix surrounding apical tufts are highly reactive to GABA and to the glycoprotein Reelin, respectively. Recently it has been shown that the GABA inhibition on apical dendrites can reduce the output of pyramidal cells in layer V, however, the origin of 89 % of the symmetric synapses in layer I still remains unknown. In the present study we have systematically analyzed the origin of the GABAergic neuropil in neocortical layer Ia in a qualitative and quantitative manner, and investigated the possible extrinsic origin of the rich extracellular Reelin content of the same layer. We show that the inhibitory inputs in a given spot in layer I come from cortical projections and arise mainly from Martinotti cells located directly under that same spot. Double bouquet and bipolar cells may also project to layer Ia although to a lesser extent and the external globus pallidus and zona incerta provide the remaining inhibitory inputs. Finally, our results suggest that Martinotti cells are also the main source of Reelin in layer Ia. The present data will help in the understanding of the cortical circuit and why it changes in pathological conditions