Embryonic sensory thalamus nuclei-specific genes revealed by genetic labelling and FACS isolation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68450 | GEO | 2016/09/21
SECONDARY ACCESSION(S): PRJNA282956
REPOSITORIES: GEO
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Project description:The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, is known to regulate thalamocortical interactions critical for sensory processing, attention and cognition. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders. Currently, little is known about the organizational principles underlying its divergent functions. We performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that TRN cellular heterogeneity is characterized by a transcriptomic gradient of two negatively correlated gene expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core/shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections to the functionally distinct first-order and higher order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. Taken together, our study provides a comprehensive atlas for TRN neurons at the single-cell resolution, and links molecularly defined subnetworks to the functional organization of the thalamo-cortical circuits.
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Project description:We collected single-cell RNAseq data from neurons of five thalamocortical projection systems (motor, somatosensory, visual, auditory, and prefrontal). Cells of each projection system were retrogradely labeled from their cortical target area, microdissected, and collected individually. By combining single-cell transcriptomics with in situ RNA hybridization, we found heterogeneity not only between thalamic nuclei but also within nuclei, with graded transitions between cell identities.
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Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.
2020-04-17 | GSE147183 | GEO
Project description:The thalamus is organized into nuclei that have distinct input and output connectivities with the cortex. While first-order (FO) nuclei – also called core nuclei – relay input from sensory organs on the body surface and project to primary sensory areas, higher-order (HO) nuclei – matrix nuclei – instead receive their driver input from the cortex and project to secondary and associative areas within cortico-thalamo-cortical loops. Input-dependent processes have been shown to play a critical role in the emergence of FO thalamic neuron identity from a ground state HO neuron identity, yet how this identity emerges during development remains unknown. Here, using single-nucleus RNA sequencing of the developing embryonic thalamus we show that FO thalamic identity emerges after HO identity, and that peripheral input is critical for the maturation of excitatory, but not inhibitory FO-type neurons. Our findings reveal that subsets of HO neurons are developmentally co-opted into FO-type neurons, providing a mechanistic framework for the diversification of thalamic neuron types during development and evolution.
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Project description:Nuclei of the mammalian thalamus are aggregations of neurons with unique architectures and input-output connections, yet the molecular determinants of their organizational specificity remain unknown. By comparing expression profiles of thalamus and cerebral cortex in adult rhesus monkeys we identified transcripts that are unique to dorsal thalamus or to individual nuclei within it. Real-time quantitative polymerase chain reaction and in situ hybridization analyses confirmed the findings. Expression profiling of individual nuclei microdissected from the dorsal thalamus revealed additional subsets of nucleus-specific genes. Functional annotation using Gene Ontology (GO) vocabulary and Ingenuity Pathway analysis revealed over-representation of GO categories related to development, morphogenesis, cell-cell interactions, and extracellular matrix within the thalamus- and nucleus-specific genes-many involved in the Wnt signaling pathway. Examples included the transcription factor TCF7L2, localized exclusively to excitatory neurons, a calmodulin-binding protein PCP4, the bone extracellular matrix molecules SPP1 and SPARC, and other genes involved in axon outgrowth and cell matrix interactions. Other nucleus-specific genes such as CBLN1 are involved in synaptogenesis. The genes identified likely underlie nuclear specification, cell phenotype and connectivity during development and their maintenance in the adult thalamus. Experiment Overall Design: To determine the molecular underpinnings of nuclear specificity in the dorsal thalamus we isolated micro-punches of tissue from nucleus-specific regions and processed them for microarray analysis. Replicate samples from 5 separate dorsal thalamic nuclei were processed and compared to identify genes unique to each region. Affymetrix U133A Gene Chips were used. All of the samples were isolated from untreated adult monkey brain.
2008-06-15 | E-GEOD-6708 | biostudies-arrayexpress
Project description:The thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The complex array of thalamic nuclei develops from a restricted pool of neural progenitors. We apply longitudinal single-cell RNA-sequencing and regional abrogation of Sonic hedgehog (Shh) to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei. These data reveal that the complex architecture of the thalamus is established early during embryonic brain development through the coordinated action of four cell differentiation lineages derived from Shh-dependent and independent progenitors. We systematically characterize the gene expression programs that define these thalamic lineages across time and demonstrate how their disruption upon Shh depletion causes pronounced locomotor impairment resembling infantile Parkinson’s disease. These results reveal key principles of thalamic development and provide mechanistic insights into neurodevelopmental disorders resulting from thalamic dysfunction.
2022-10-16 | GSE211701 | GEO
Project description:Dysfunction of the thalamocortical pathway has been implicated in multiple psychiatric disorders, but mechanisms by which these defects emerge remain poorly understood. We explored this question in the context of the 22q11.2 microdeletion, which represents a significant genetic risk for schizophrenia, leveraging emerging technologies of in vitro brain organogenesis using chimeric brain organoids derived from human induced pluripotent stem cells. Here we show that the 22q11.2 microdeletion leads to transcriptional dysregulation in thalamic organoids that is enriched for psychiatric disease risk genes, including elevated expression of FOXP2, which represents the most significantly dysregulated transcription factor in glutamatergic neurons and astroctyes. In a co-culture model fusing thalamic and cortical organoids, we demonstrate that the 22q11.2 deletion mediates an overgrowth of thalamic axons via overexpression of FOXP2, which then subsequently mediates the overgrowth of reciprocal corticothalamic axons. Dysregulation of FOXP2 leads to downregulation of ROBO2, an axon repulsive receptor important for thalamocortical axon pathfinding, and knockdown of ROBO2 in control organoids phenocopies excessive outgrowth of thalamic axons. Together, our study suggests that early steps in thalamocortical pathway development may be dysregulated in a model of genetic risk for schizophrenia, and contribute to neural phenotypes in 22q11.2 microdeletion syndrome.
2024-02-22 | GSE245719 | GEO
Project description:Purpose: We aimed to resolve if there is a matched expression of neuropeptide receptor(s) and their ligand(s) between the sensory trunk of the trigeminal nerve (Pr5) and the ventrobasal hypothalamus on postnatal day 7 (P7) in mice. We hypothesized that a coincidence of neuropeptide expression and release from the ventrobasal thalamus and the cognate receptor(s) for the specific neuropeptide(s) in trigeminal neurons could allow for novel hypotheses be built on intercellular communication between peripheral axons and their postsynaptic targets in the thalamus. Thereby, this work can be informative of the developmental integration of the whisker pathway, one of the major sensory modalities in laboratory rodents. To this end, we used single-cell RNA-seq on cells dissociated from the ventrobasal thalamus and Pr5 on P7. Results: We tested this hypothesis by single-nucleus RNA-seq performed in parallel on the ventrobasal thalamus and Pr5 at P7. At this developmental stage, the ventrobasal thalamus contained two subtypes of Slc17a6+(glutamatergic) neurons, one subtype of Gad1/Gad2+ (GABA) neurons, astroglia, oligodendrocytes, and vascular components (n = 923 nuclei isolated from n = 3 pups of mixed sex). Slc17a6+ neurons, which we recognize as cortically projecting glutamate neurons, co-expressed molecular components underpinning barrel map formation (e.g., Grin1, Adcy1, Prkaca,99 Ache, Slc6a4) and a significant amount of the thalamocortical neuronal marker Cck, while other neuropeptides/hormones were absent or barely present (e.g., Npy, Sst). At the same time, we harvested n = 731 nuclei from the Pr5 by micro-excision at P7, of which ∼98% expressed Slc17a6, thus qualifying, in total or in part, as centrally-projecting sensory neurons. This neuronal cohort harbored axon guidance molecules, and neuropeptide receptors. Conclusions: We suggest that neuropeptides, particularly galanin, could participate in guidance decisions of Pr5 axons given the complementarity of ligand-receptor expression patterns, and that Galr1 expression could be a time locked feature for those neurons that actively undergo neuritogenesis at a given time.
2024-04-01 | GSE230180 | GEO
Project description:Embryonic sensory thalamus nuclei-specific genes revealed by genetic labelling and FACS isolation
| PRJNA282956 | ENA