Molecular and anatomical organization of the dorsal raphe nucleus
Abstract
The dorsal raphe nucleus (DRN) is an important source of neuromodulators and has been implicated in a wide variety of behavioral and neurological disorders. The DRN is subdivided into distinct anatomical subregions comprised of multiple cell types, and its complex cellular organization has impeded efforts to investigate the distinct circuit and behavioral functions of its subdomains. Here we used single-cell RNA sequencing, in situ hybridization, anatomical tracing, and spatial correlation analysis to map the transcriptional and spatial profiles of cells from the mouse DRN. Our analysis of 39,411 single-cell transcriptomes revealed at least 18 distinct neuron subtypes and 5 serotonergic neuron subtypes with distinct molecular and anatomical properties, including a serotonergic neuron subtype that preferentially innervates the basal ganglia. Our study lays out the molecular organization of distinct serotonergic and non-serotonergic subsystems, and will facilitate the design of strategies for further dissection the DRN and its diverse functions.
Data availability
The sequencing datasets generated in this study are available on the NCBI Gene Expression Omnibus (accession number: GSE134163). R data files containing the processed and annotated scRNA-seq data in the form of Seurat objects are also available on the Harvard Dataverse (https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/QB5CC8).
-
Molecular and anatomical organization of the dorsal raphe nucleusNCBI Gene Expression Omnibus, GSE134163.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS103226)
- Bernardo L Sabatini
Howard Hughes Medical Institute
- Bernardo L Sabatini
National Institute of Mental Health (MH100568)
- Bernardo L Sabatini
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were performed in accordance with protocols approved by the Harvard Standing Committee on Animal Care following guidelines described in the U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals (HMS IACUC protocol #IS00000571). All surgery was performed under isoflurane anesthesia.
Copyright
© 2019, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 14,646
- views
-
- 1,896
- downloads
-
- 154
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
When subjects navigate through spatial environments, grid cells exhibit firing fields that are arranged in a triangular grid pattern. Direct recordings of grid cells from the human brain are rare. Hence, functional magnetic resonance imaging (fMRI) studies proposed an indirect measure of entorhinal grid-cell activity, quantified as hexadirectional modulation of fMRI activity as a function of the subject’s movement direction. However, it remains unclear how the activity of a population of grid cells may exhibit hexadirectional modulation. Here, we use numerical simulations and analytical calculations to suggest that this hexadirectional modulation is best explained by head-direction tuning aligned to the grid axes, whereas it is not clearly supported by a bias of grid cells toward a particular phase offset. Firing-rate adaptation can result in hexadirectional modulation, but the available cellular data is insufficient to clearly support or refute this option. The magnitude of hexadirectional modulation furthermore depends considerably on the subject’s navigation pattern, indicating that future fMRI studies could be designed to test which hypothesis most likely accounts for the fMRI measure of grid cells. Our findings also underline the importance of quantifying the properties of human grid cells to further elucidate how hexadirectional modulations of fMRI activity may emerge.
-
- Developmental Biology
- Neuroscience
Environmental insults, including mild head trauma, significantly increase the risk of neurodegeneration. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative deficits, nor do we know how sex and age compound the outcome. Using a Drosophila model, we demonstrate that exposure to mild head trauma causes neurodegenerative conditions that emerge late in life and disproportionately affect females. Increasing age-at-injury further exacerbates this effect in a sexually dimorphic manner. We further identify sex peptide signaling as a key factor in female susceptibility to post-injury brain deficits. RNA sequencing highlights a reduction in innate immune defense transcripts specifically in mated females during late life. Our findings establish a causal relationship between early head trauma and late-life neurodegeneration, emphasizing sex differences in injury response and the impact of age-at-injury. Finally, our findings reveal that reproductive signaling adversely impacts female response to mild head insults and elevates vulnerability to late-life neurodegeneration.