Emergence of functional sensory subtypes as defined by transient receptor potential channel expression

The existence of heterogeneous populations of dorsal root ganglion (DRG) neurons conveying different somatosensory information is the basis for the perception of touch, temperature, and pain. A differential expression of transient receptor potential (TRP) cation channels contributes to this functional heterogeneity. However, little is known about the development of functionally diverse neuronal subpopulations. Here, we use calcium imaging of acutely dissociated mouse sensory neurons and quantitative reverse transcription PCR to show that TRP cation channels emerge in waves, with the diversification of functional groups starting at embryonic day 12.5 (E12.5) and extending well into the postnatal life. Functional responses of voltage-gated calcium channels were present in DRG neurons at E11.5 and reached adult levels by E14.5. Responses to capsaicin, menthol, and cinnamaldehyde were first seen at E12.5, E16.5, and postnatal day 0 (P0), when the mRNA for TRP cation channel, subfamily V, member 1 (TRPV1), TRP cation channel, subfamily M, member 8 (TRPM8), and TRP cation channel, subfamily A, member 1 (TRPA1), respectively, was first detected. Cold-sensitive neurons were present before the expression or functional responses of TRPM8 or TRPA1. Our data support a lineage relationship in which TRPM8- and TRPA1-expressing sensory neurons derive from the population of TRPV1-expressing neurons. The TRPA1 subpopulation of neurons emerges independently in two distinct classes of nociceptors: around birth in the peptidergic population and after P14 in the nonpeptidergic class. This indicates that neurons with similar receptive properties can be generated in different sublineages at different developmental stages. This study describes for the first time the emergence of functional subtypes of sensory neurons, providing new insight into the development of nociception and thermoreception

The boundary cap: a source of neural crest stem cells that generate multiple sensory neuron subtypes

The boundary cap (BC) is a transient neural crest-derived group of cells located at the dorsal root entry zone (DREZ) that have been shown to differentiate into sensory neurons and glia in vivo. We find that when placed in culture, BC cells self-renew, show multipotency in clonal cultures and express neural crest stem cell (NCSCs) markers. Unlike sciatic nerve NCSCs, the BC-NCSC (bNCSCs) generates sensory neurons upon differentiation. The bNCSCs constitute a common source of cells for functionally diverse types of neurons, as a single bNCSC can give rise to several types of nociceptive and thermoreceptive sensory neurons. Our data suggests that BC cells comprise a source of multipotent sensory specified stem cells that persist throughout embryogenesis

Editorial overview: Rare CNV disorders and neuropsychiatric phenotypes: opportunities, challenges, solutions

In this issue, our outstanding colleagues review the recent exponential growth in our understanding of copy number variants (CNV) in neuropsychiatric disorders. The impact of DNA dosage changes on phenotypic traits was first understood, and leveraged for genetic mapping, by Drosophila geneticists nearly a century ago. Evidence for DNA dosage changes influencing human phenotypes came several decades later with the observation that Down Syndrome is caused by an extra copy of chromosome 21. This was followed by discoveries that dosage changes far smaller than the scale of a whole chromosome, limited to smaller sets of genes, could also cause clinical syndromes. These hallmark syndromes have set the stage for our current understanding of CNV disorders, and in this issue, we review several classic syndromes, including Williams syndrome or 7q11.23 deletion, reviewed by Osbourne and Mervis; 22q11 deletion syndrome reviewed by Gur et al; and 16p11.2 deletion/duplication, reviewed by Chung and colleagues. DNA dosage changes can also affect single genes; the impact of NRXN1 dosage changes is reviewed by Fuccillo and Pak

Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration

Although cardinal cortical interneuron identity is established upon cell-cycle exit, it remains unclear whether specific interneuron subtypes are pre-established, and if so, how their identity is maintained prior to circuit integration. We conditionally removed Sox6 (Sox6-cKO) in migrating somatostatin (Sst+) interneurons and assessed the effects on their mature identity. In adolescent mice, five of eight molecular Sst+ subtypes were nearly absent in the Sox6-cKO cortex without a reduction in cell number. Sox6-cKO cells displayed electrophysiological maturity and expressed genes enriched within the broad class of Sst+ interneurons. Furthermore, we could infer subtype identity prior to cortical integration (embryonic day 18.5), suggesting that the loss in subtype was due to disrupted subtype maintenance. Conversely, Sox6 removal at postnatal day 7 did not disrupt marker expression in the mature cortex. Therefore, Sox6 is necessary during migration for maintenance of Sst+ subtype identity, indicating that subtype maintenance requires active transcriptional programs

Ghrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels

Peer reviewe

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

Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems

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

Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium—schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genome-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP