62 research outputs found
Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area
Publisher Copyright: © Nagaeva et al.The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.Peer reviewe
Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease.
Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease
Characterization of Nkx6-2-Derived Neocortical Interneuron Lineages
Ventral telencephalic progenitors expressing the homeodomain transcription factor Nkx6-2 have been shown to give rise to a multitude of cortical interneuron subtypes usually associated with origin in either the medial ganglionic eminence or the caudal ganglionic eminence. The function of Nkx6-2 in directing the fate of those progenitors has, however, not been thoroughly analyzed. We used a combination of genetic inducible fate mapping and in vivo loss-of-function to analyze the requirement of Nkx6-2 in determining the fate of cortical interneurons. We have found that interneuron subtypes are born with a characteristic temporal pattern. Furthermore, we extend the characterization of interneurons from the Nkx6-2 lineage through the application of electrophysiological methods. Analysis of these populations in Nkx6-2 null mice suggests that there is a small and partially penetrant loss of delayed non-fast spiking somatostatin/calretinin double positive cortical interneurons in the absence of Nkx6-2 gene function
Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss
Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss
Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence
Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe
Genetic identification of brain cell types underlying schizophrenia
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common variant genomic results consistently mapped to pyramidal cells, medium spiny neurons, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to sets of genes specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (synaptic genes, FMRP interactors, antipsychotic targets, etc.) generally implicate the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with medium spiny neurons did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia
Sensory neurons : Stem cells and development
The sensory nervous system is the only means we have of communicating
with the surrounding world. The neurons responsible for the sensation of
pain, touch, the ability to know the position of our limbs and part of
maintenance of body posture are located in the dorsal root ganglia (DRG).
Stem cell biology has, during the recent years greatly enhanced our
understanding of developmental processes. The aim of this thesis was to
isolate and characterize stem cells from the sensory nervous system and
to study the development of functional neuronal subtypes.
In the work presented 1 show the identification of a neural crest stem
cell (NCSC) that is located in the boundary cap (BC). The BC is a
transient structure present during embryogenesis lining the boundary
between the peripheral and central nervous system at the exit/entry zone
of sensory and motor efferents. This multipotent stem cell is unique as
compared to previously described NCSCs, in its ability to form sensory
neurons in vitro. The sensory neurons are functionally active as assayed
by calcium imaging using temperature stimuli and sensory specific
transient receptor potential (TRP)-channel ligands. 1 further show that
the boundary cap neural crest stem cell (bNCSC) can give rise to Schwann
cells that myclinate regenerating axons in vivo, suggesting a possibility
for the use of these stem cells for regenerative therapy. The bNCSC
express the well described stem cell marker, stage specific antigen 1
(SSEA-1) as well as proteins involved in the production of gamma amino
butyric acid (GABA). Furthermore, GABA drastically reduces the
proliferation of bNCSC, in a pathway independent of intracellular
signalling. Antagonizing endogenous production using GABAA receptor
antagonist bicuculline increases the same. This suggests GABA as a signal
to regulate proliferation in the BC stem cell niche and thus providing
the basis for a possible increase of production in response to an injury.
In the last part of the thesis 1 describe and define the developmental
emergence of different subtypes of developing sensory neurons based on
functional responses to capsaicin, menthol, and cinnamon aldehyde,
agonists to TRPV1, TRPM8 and TRPA 1 respectively
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