Cited by 304Single-cell and spatial transcriptomicsNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

The DOI matches its Crossref record; 95 of the 97 references it cites were found in a registry or an index; none of the 66 sources its claims cite is checked for support yet.

Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei

Open access

Ren, Jing, Isakova, Alina, Friedmann, Drew, Zeng, Jiawei, Grutzner, Sophie M, Pun, Albert, Zhao, Grace Q, Kolluru, Sai Saroja, Wang, Ruiyu, Lin, Rui, Li, Pengcheng, Li, Anan, Raymond, Jennifer L, Luo, Qingming, Luo, Minmin, Quake, Stephen R, Luo, Liqun·2019·eLife

DOI 10.7554/elife.49424PMC PMC6812963

Published version of a preprint

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Abstract

Serotonin neurons of the dorsal and median raphe nuclei (DR, MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behavior. To gain a fundamental understanding of their molecular heterogeneity, we used plate-based single-cell RNA-sequencing to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. Systematic in situ hybridization mapped specific clusters to the principal DR, caudal DR, or MR. These transcriptomic clusters differentially express a rich repertoire of neuropeptides, receptors, ion channels, and transcription factors. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that DR serotonin neurons co-expressing vesicular glutamate transporter-3 preferentially innervate the cortex, whereas those co-expressing thyrotropin-releasing hormone innervate subcortical regions in particular the hypothalamus. Reconstruction of 50 individual DR serotonin neurons revealed diverse and segregated axonal projection patterns at the single-cell level. Together, these results provide a molecular foundation of the heterogenous serotonin neuronal phenotypes.

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TL;DR

Plate-based single-cell RNA-sequencing of 999 mouse dorsal and median raphe serotonin neurons identified 11 transcriptomic clusters with distinct spatial, molecular, and projection features. Intersectional viral tracing and single-neuron reconstruction showed that Vglut3+ and Trh+ DR serotonin neurons preferentially innervate cortical versus subcortical targets, while individual DR serotonin neurons have highly diverse whole-brain arborization patterns.

Key findings

scRNA-seq of 999 Tph2+ serotonin neurons from 14 adult mouse brains resolved 11 transcriptomic clusters: six principal DR clusters (DR-1–6), one caudal DR cluster (cDR), and four median raphe clusters (MR-1–4); HCR-smFISH with 16 markers mapped these clusters to pDR, cDR, or MR locations.
Co-transmitter and neuropeptide expression was heterogeneous: 65% of serotonin neurons expressed Vglut3, 35% expressed Gad1, Gad2, or both, 13% expressed Vglut3 plus Gad1/Gad2, and 14% expressed none of these glutamate/GABA markers; Trh was expressed in 14% and Crh in 7% of serotonin neurons.
Intersectional Sert-Flp with Vglut3-Cre or Trh-Cre showed that Vglut3+ pDR serotonin neurons preferentially innervate cortical regions, whereas Trh+ pDR serotonin neurons innervate subcortical regions including anterior/medial hypothalamus and thalamic nuclei; whole-brain mapping used n = 3 mice per genotype.
Reconstruction of 50 individual DR serotonin neurons revealed total axon lengths from 1.9 cm to 26.3 cm, with cortex-projecting neurons having the longest axons; 37/50 projections were unilateral, and 34/46 forebrain-projecting neurons had >80% of forebrain axon length in either cortical or subcortical regions.

Methods

Serotonin neurons were labeled using Sert-Cre;Ai14 mice, acutely dissociated from brain slices of postnatal day 40–45 mice (six females, eight males), FACS-sorted, and processed with Smart-seq2; 709 cells came from eight MR/pDR/cDR samples and 290 cells from six pDR-only samples, yielding 999 cells after QC.
Clustering used Seurat v3.0 with PCA and Louvain clustering; HCR-based smFISH against 16 cluster markers plus Tph2 was used to map transcriptomic clusters anatomically.
For projection mapping, Sert-Flp mice were crossed with Vglut3-Cre or Trh-Cre and injected with AAV-CreON/FlpON-mGFP; brains were cleared with AdipoClear, imaged by light-sheet microscopy, segmented with a 3D U-Net, and aligned to the Allen Common Coordinate Framework. Single-neuron reconstructions used dual-AAV sparse labeling and fMOST in 14 Sert-Cre mice.

Limitations

Stated: single-neuron reconstruction was limited in scope to 50 reconstructed cells out of approximately 9000 DR serotonin neurons, and larger-scale reconstruction integrated with molecular identity and function is needed.
Stated: whole-brain tracing showed inter-individual variability in total labeled axons and detailed projection patterns, and heterogeneity within Vglut3+ or Trh+ populations may contribute; larger experiments or single-cluster Cre lines are required.
Stated/evident: the Sert-Flp line can drive reporter expression outside raphe serotonin neurons due to transient developmental Sert expression; the paper also notes that whether Gad1/Gad2+ serotonin neurons actually release GABA remains to be determined, and MR cluster anatomical organization was less obvious with clusters more intermingled.

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Crossref · 10.7554/elife.49424

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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These 999 MR and DR serotonin neurons comprised 11 clusters (Figure 1B; Figure 1—figure supplement 2).”
- Also stated in: § Abstract · plain
  “we used plate-based single-cell RNA-sequencing to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Single-cell RNA-sequencing defines 11 transcriptomic clusters of serotonin neurons in the dorsal and median raphe
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Instead, Trh+ serotonin axons project to the anterior and medial hypothalamus, posterior amygdala, and the lateral geniculate nucleus in the thalamus, none of which were targeted by Vglut3+ axons (Figure 6D).”
- Also stated in: § Abstract · plain
  “Whole-brain axonal projection mapping revealed that DR serotonin neurons co-expressing vesicular glutamate transporter-3 preferentially innervate the cortex, whereas those co-expressing thyrotropin-releasing hormone innervate subcortical regions in particular the hypothalamus.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Viral-genetic tools to access different serotonin neuron subtypes
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In the paper
“Comparing marker genes enriched in R1–R3-derived serotonin neurons from Okaty et al. and MR-1–MR-4 transcriptomic clusters from our current study (Figure 3—figure supplement 4) indeed suggests an approximate correspondence: R1-derived serotonin neurons correspond to our MR-1 cluster, R2 to MR-4 cluster, and R3 to both MR-2 and MR-3 clusters.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Okaty et al., 2015 source
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In the paper
“Our transcriptome data suggest that each DR/MR serotonin neuron type can be distinguished from others by the expression of two marker genes (Figure 1D; Figure 3—figure supplement 1–3), supporting the view that neuronal subtypes are generally specified by unique combination of genes rather than single genes (Li et al., 2017).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and projection-defined serotonin sub-systems
What the sources say
- Not checked yetcites Li et al., 2017
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In the paper
“By contrast, we could not discern obvious difference in spatial distributions among the four MR types, despite the fact that MR serotonin neurons have heterogenous developmental origin (Jensen et al., 2008).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Jensen et al., 2008 source
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None of the sources cited for this claim have been checked yet.
In the paper
“The rest of the DR serotonin neurons were divided into thalamus-projecting and brainstem/cerebellum-projecting groups based on the highest density of axons (Figure 8—figure supplement 3B,C), one of which likely projecting to the spinal cord (brain 36) as previously reported (Bowker et al., 1981; Bowker et al., 1982).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Whole-brain axonal arborization patterns of individual serotonin neurons
What the sources say
- Not checked yetcites Bowker et al., 1981 source
- Not checked yetcites Bowker et al., 1982 source
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It may state two separate claims as one.
In the paper
“Gene expression patterns of specific serotonin neuron clusters can in principle allow genetic access to these specific subpopulations for anatomical tracing, physiological recording, and functional perturbation (Luo et al., 2018).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Viral-genetic tools to access different serotonin neuron subtypes
What the sources say
- Not checked yetcites Luo et al., 2018 source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, our HCR-smFISH experiments support the notion that Clusters 1–6 correspond to pDR serotonin neurons, Cluster 7 corresponds to cDR serotonin neurons, and Clusters 8–11 correspond to MR serotonin neurons.”
- Also stated in: § Abstract · plain
  “Systematic in situ hybridization mapped specific clusters to the principal DR, caudal DR, or MR.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Anatomical organization of transcriptomically defined serotonin clusters
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In the paper
“It has been reported that vesicular monoamine transporters (Slc8a1 for Vmat1; Slc8a2 for Vmat2) can transport GABA into synaptic vesicles (Stensrud et al., 2014), and virtually all serotonin neurons expressed Vmat2 (Figure 1—figure supplement 1D; Figure 4A left).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Molecular properties of MR and DR serotonin neurons
What the sources say
- Not checked yetcites Stensrud et al., 2014 source
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Probably not a substantial claim.
In the paper
“However, DR and MR contain not only serotonin neurons but also GABAergic and glutamatergic neurons that do not express Tph2 (and hence do not release serotonin), some of which may project to the same target regions (McDevitt et al., 2014).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Viral-genetic tools to access different serotonin neuron subtypes
What the sources say
- Not checked yetcites McDevitt et al., 2014 source
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In the paper
“Transcription factors (TFs) have been shown to be the best molecular feature for cell type definition (Schaum et al., 2018).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Molecular properties of MR and DR serotonin neurons
What the sources say
- Not checked yetcites Schaum et al., 2018 source
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“DR serotonin neurons derive entirely from rhombomere 1 of the developing mouse brain, whereas MR serotonin neurons derive predominantly from rhombomeres 1, 2, and 3 (Alonso et al., 2013; Bang et al., 2012; Jensen et al., 2008).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Alonso et al., 2013 source
- Not checked yetcites Bang et al., 2012
- Not checked yetcites Jensen et al., 2008 source
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Evidence has suggested that the DR and MR serotonin systems differ in developmental origin, connectivity, physiology, and behavioral function (Alonso et al., 2013; Calizo et al., 2011; Okaty et al., 2019).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Alonso et al., 2013 source
- Not checked yetcites Calizo et al., 2011 source
- Not checked yetcites Okaty et al., 2019 source
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None of the sources cited for this claim have been checked yet.
In the paper
“The MR serotonin neurons project to structures near the midline, whereas the DR serotonin neurons target more lateral regions (Jacobs and Azmitia, 1992; Muzerelle et al., 2016; Vertes, 1991; Vertes et al., 1999).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Jacobs and Azmitia, 1992
- Not checked yetcites Muzerelle et al., 2016 source
- Not checked yetcites Vertes, 1991 source
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In the paper
“Groups B1–B3 are located in the medulla and provide descending serotonergic innervation to the spinal cord and other parts of the medulla. Groups B4–B9 are located in the pons and midbrain, including the dorsal raphe (DR; groups B6 and B7) and median raphe (MR; groups B5 and B8) nucleus, and provide ascending innervation to the forebrain and midbrain.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Dahlström and Fuxe, 1964
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“As a specific example, we recently found that DR serotonin neurons that project to frontal cortex and amygdala constitute two sub-systems with distinct cell body locations, axonal collateralization patterns, biased inputs, physiological response properties, and behavioral functions (Ren et al., 2018).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Ren et al., 2018 source
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None of the sources cited for this claim have been checked yet.
In the paper
“In neural circuits where cell types have been well studied by anatomical and physiological methods, there is an excellent correspondence between cell types defined by transcriptomes and the classical methods (Li et al., 2017; Shekhar et al., 2016).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Li et al., 2017
- Not checked yetcites Shekhar et al., 2016 source
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Serotonin neurons in the central nervous system are spatially clustered in the brainstem, originally designated as groups B1–B9 (Dahlström and Fuxe, 1964).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Introduction
What the sources say
- Not checked yetcites Dahlström and Fuxe, 1964
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Collectively,~12,000 serotonin neurons from the DR and MR in mice (~0.015% of all CNS neurons) innervate the entire forebrain (Ishimura et al., 1988) and modulate diverse physiological and behavioral functions.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion
What the sources say
- Not checked yetcites Ishimura et al., 1988 source
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The MR serotonin neurons derive from three separate rhombomeres (R1–R3), and Okaty et al. sampled these three populations separately, allowing us to ask the question of whether developmental origins correspond to transcriptomic clusters in adult.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Okaty et al., 2015 source
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In the paper
“By searching Allen Brain Institute development brain database and using multiplex fluorescent in situ hybridization (ML-FISH), Kast et al. (2017) found that the cDR expressed distinct gene markers comparing to pDR, and tracing from these neurons showed cDR was different from the MR and DR in efferent innervation.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Kast et al., 2017 source
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It may state two separate claims as one.
In the paper
“The cDR has been suggested to be more similar to the MR than to the pDR in afferent innervation (Commons, 2015).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Commons, 2015 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In our previous study, we characterized two projection-defined parallel DR serotonin sub-systems.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and projection-defined serotonin sub-systems
What the sources say
- Not checked yetcites Ren et al., 2018 source
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Probably not a substantial claim.
In the paper
“We found that serotonin neurons that project to the orbitofrontal cortex (OFC) and central amygdala (CeA) differ in input and output patterns, physiological response properties, and behavioral functions (Ren et al., 2018).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and projection-defined serotonin sub-systems
What the sources say
- Not checked yetcites Ren et al., 2018 source
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It may state two separate claims as one.
In the paper
“These data support and extend our previous finding (Ren et al., 2018) for the preferential ventral pDR location of Vglut3+ serotonin neurons, which is highly expressed in DR-4 and DR-5 clusters.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Ren et al., 2018 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“Because DR serotonin neurons derive exclusively from rhombomere 1 (R1), and the single-cell RNA-seq data was obtained from just 8 cells, the Okaty et al. dataset is limited in providing information about heterogeneity within DR serotonin neurons.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and cell body distribution
What the sources say
- Not checked yetcites Okaty et al., 2015 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“Forebrain-projecting serotonin neurons have been estimated to have very long axons based on the total serotonin fiber density and number of serotonin neurons (Wu et al., 2014).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Results > Whole-brain axonal arborization patterns of individual serotonin neurons
What the sources say
- Not checked yetcites Wu et al., 2014
Strength:hedged· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Given that CeA-projecting DR serotonin neurons do not innervate most of the hypothalamus (Ren et al., 2018), and Trh+ serotonin neurons only partially innervate CeA, these two populations are at most partially overlapping.”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Relationship between molecular identity and projection-defined serotonin sub-systems
What the sources say
- Not checked yetcites Ren et al., 2018 source
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, several studies have reported that subgroups of serotonin neurons in the MR and DR express Vglut3 and indeed, subsequent slice recording confirmed that serotonin terminals can co-release glutamate and serotonin (Domonkos et al., 2016; Liu et al., 2014; Ren et al., 2018; Sengupta et al., 2017; Varga et al., 2009; Wang et al., 2019).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Integrating multiple features within individual serotonin sub-systems
What the sources say
- Not checked yetcites Domonkos et al., 2016 source
- Not checked yetcites Liu et al., 2014 source
- Not checked yetcites Ren et al., 2018 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“While the reported projection and arborization complexity of individual DR neurons appear qualitatively similar to our findings, these studies cannot be directly compared because the Gagnon and Parent study did not validate the serotonin identity of individually traced DR neurons, which could include Tph2-negative long-distance projecting GABAergic and glutamatergic neurons (Bang and Commons, 2012”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Insights from single-cell reconstruction
What the sources say
- Not checked yetcites Gagnon and Parent, 2014
- Not checked yetcites Bang and Commons, 2012
Load-bearingStrength:hedged· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Our previous study suggests that DR serotonin sub-systems have biased input but segregated output (Ren et al., 2018).”
§ Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei > Discussion > Integrating multiple features within individual serotonin sub-systems
What the sources say
- Not checked yetcites Ren et al., 2018 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.

79 of 79

The paper relies on this without support.
The heterogeneity of DR and MR serotonin neurons must be reflected at the molecular level.
“Ultimately, the heterogeneity of DR and MR serotonin neurons must be reflected at the molecular level.”
The paper relies on this without support.
The DR contains approximately 9000 serotonin neurons.
“our study is still limited by the scope (50 reconstructed cells out of 9000 DR serotonin neurons).”

2 of 2

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Vglut3 is assigned two different gene symbols
Minor
The results identify Vglut3 as Slc17a8, but the Animals section calls the Vglut3-Cre line Slc18a8-Cre.

1 of 1

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Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A. R., Kamitaki, N., Martersteck, E. M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.05.002 · Cited by 7,110
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907 · cited 3×
“The Ai14 tdTomato Cre reporter mice (JAX Strain 7914) Ren et al. eLife 2019;8:e49424.”
BackgroundInfluential
Full-length RNA-seq from single cells using Smart-seq2
Picelli, S., Faridani, O. R., Björklund, Å. K., Winberg, G., Sagasser, S., & Sandberg, R. (2014) · Nature Protocols · doi:10.1038/nprot.2014.006 · Cited by 4,137 · cited 1×
“cDNA synthesis and library preparation were performed using the Smart-seq2 protocol (Picelli et al., 2014).”
Method
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Zeisel, A., Muñoz-Manchado, A. B., Codeluppi, S., Lönnerberg, P., La Manno, G., Juréus, A., Marques, S., Munguba, H., He, L., Betsholtz, C., et al. (2015) · Science · doi:10.1126/science.aaa1934 · Cited by 3,124 · cited 1×
“…powerful tool for unbiased identification of transcriptomic cell types in the brain (Darmanis et al., 2015; Li et al., 2017; Mickelsen et al., 2019; Rosenberg et al., 2018; Saunders et al., 2018; Tasic et al., 2016; Tasic et al., 2018; Welch et al., 2019; Zeisel et al., 2018; Zeisel et al., 2015).”
Method
Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris
The Tabula Muris Consortium, coordination, O., coordination, L., processing, O. C. A., sequencing, L. P. A., analysis, C. D., annotation, C. T., Writing group, Supplemental text writing group, & Principal investigators (2018) · Nature · doi:10.1038/s41586-018-0590-4 · Cited by 2,842 · cited 3×
“Transcription factors Transcription factors (TFs) have been shown to be the best molecular feature for cell type definition (Schaum et al., 2018).”
BackgroundMethodInfluential

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Items 101–200 of 302

Exploring the diversity of biological processes regulated by glial cell line-derived neurotrophic factor, a pleiotropic molecule with therapeutic potential
Porcari, C., Cattaneo, S., Crippa, L., Simonato, M., & Bettegazzi, B. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1618330 · Cited by 16
U-FISH: a fluorescent spot detector for imaging-based spatial-omics analysis and AI-assisted FISH diagnosis
Xu, W., Cai, H., Zhang, Q., Wang, Z., Yang, J., Wu, X., Li, C., Cui, C., Liu, C., Jin, H., et al. (2025) · Genome biology · doi:10.1186/s13059-025-03736-x · Cited by 16
“3d) revealed consistency in the distribution of several genes, including Trh, Gad1, Npas1, Ret, Syt2, C1ql2, Met, and Tacr3, which are also studied in Jing Ren et al.’s (2019) research [27].”
Optogenetic stimulation of dynorphinergic neurons within the dorsal raphe activate kappa opioid receptors in the ventral tegmental area and ablation of dorsal raphe prodynorphin or kappa receptors in dopamine neurons blocks stress potentiation of cocaine reward
Abraham, A. D., Casello, S. M., Land, B. B., & Chavkin, C. (2022) · Addiction Neuroscience · doi:10.1016/j.addicn.2022.100005 · Cited by 15
The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics
Weber, L. M., Divecha, H. R., Tran, M. N., Kwon, S., Spangler, A., Montgomery, K. D., Tippani, M., Bharadwaj, R. A., Kleinman, J. E., Page, S. C., et al. (2023) · eLife · doi:10.7554/elife.84628 · Cited by 33
Molecular Organization of Autonomic, Respiratory, and Spinally-Projecting Neurons in the Mouse Ventrolateral Medulla
Schwalbe, D. C., Stornetta, D. S., Abraham‐Fan, R., Souza, G. M. P. R., Jalil, M., Crook, M. E., Campbell, J. N., & Abbott, S. B. G. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.2211-23.2024 · Cited by 17
Dorsal raphe serotonin neurotransmission is required for the expression of nursing behavior and for pup survival
Muzerelle, A., Soiza‐Reilly, M., Hainer, C., Ruet, P.-L., Lesch, K., Bäder, M., Alenina, N. V., Scotto‐Lomassese, S., & Gaspar, P. (2021) · Scientific Reports · doi:10.1038/s41598-021-84368-6 · Cited by 16
Sex-Specific Role for Dopamine Receptor D2 in Dorsal Raphe Serotonergic Neuron Modulation of Defensive Acoustic Startle and Dominance Behavior
Lyon, K. A., Rood, B. D., Wu, L., Senft, R. A., Goodrich, L. V., & Dymecki, S. M. (2020) · eNeuro · doi:10.1523/eneuro.0202-20.2020 · Cited by 16
“Transcriptome data coupled with structure-function maps in mice show that the serotonergic and dopaminergic neuronal systems are themselves heterogeneous, comprised of functionally specialized neuronal subtypes, manifesting distinct mRNA profiles, efferent projections, electrophysiological properties, and functions (J…”
Background
Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction
Pomrenze, M. B., Walker, L. C., & Giardino, W. J. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108769 · Cited by 16
Altered Serotonin 2A (5-HT2A) Receptor Signaling Underlies Mild TBI-Elicited Deficits in Social Dominance
Collins, S. M., O’Connell, C. J., Reeder, E. L., Norman, S. V., Lungani, K., Gopalan, P., Gudelsky, G. A., & Robson, M. J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.930346 · Cited by 16
“5-HT neurons reside in the midbrain raphe nucleus and project to various brain regions including the cortex, hippocampus, and amygdala (Ren et al., 2018; Ren et al., 2019).”
Background
Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors
Yoshida, K., Tsutsui‐Kimura, I., Kono, A., Yamanaka, A., Kobayashi, K., Watanabe, M., Mimura, M., & Tanaka, K. F. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107829 · Cited by 15
Highly efficient and super-bright neurocircuit tracing using vector mixing-based virus cocktailPreprint
Sun, P., Jin, S., Tao, S., Wang, J., Li, A., Li, N., Wu, Y., Kuang, J., Liu, Y., Wang, L., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/705772 · Cited by 15
Self-citation
Median Raphe Nonserotonergic Neurons Modulate Hippocampal Theta Oscillations
Huang, W., Ikemoto, S., & Wang, D. V. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1536-21.2022 · Cited by 19
Predicting the distribution of serotonergic axons: a supercomputing simulation of reflected fractional Brownian motion in a 3D-mouse brain model
Janušonis, S., Haiman, J. H., Metzler, R., & Vojta, T. (2023) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2023.1189853 · Cited by 16
ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling
Miquel-Rio, L., Sarriés-Serrano, U., Sancho‐Alonso, M., Florensa-Zanuy, E., Paz, V., Ruiz‐Bronchal, E., Manashirov, S., Campa, L., Pilar-Cuéllar, F., & Bortolozzi, A. A. (2024) · iScience · doi:10.1016/j.isci.2024.109787 · Cited by 14
“84 Therefore,an exhaustively comparative analysis between male and female mice will provide evidence of sex differences linked to ERS activation in 5-HT neurons and depressive phenotype.”
Reorganization of postmitotic neuronal chromatin accessibility for maturation of serotonergic identity
Zhang, X. L., Spencer, W. C., Tabuchi, N., Kitt, M. M., & Deneris, E. S. (2022) · eLife · doi:10.7554/elife.75970 · Cited by 14
Anatomical and molecular features of the amygdalohippocampal transition area and its role in social and emotional behavior processes
Sedwick, V. M., & Autry, A. E. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104893 · Cited by 15
Parallel streams of raphe VGLUT3‐positive inputs target the dorsal and ventral hippocampus in each hemisphere
Fortin‐Houde, J., Henderson, F. J., Dumas, S., Ducharme, G., & Amilhon, B. (2023) · The Journal of Comparative Neurology · doi:10.1002/cne.25452 · Cited by 19
“In the ventral part of the DR (DRV or B7v), VGLUT3-positive neurons colocalize extensively with 5-HT (Okaty et al., 2020; Ren et al., 2019) while in the dorsal part of the DR (DRD or B7d) a population of purely VGLUT3-positive neurons has been described (Hioki et al., 2010).”
BackgroundResultInfluential
Inhibition of hyperactivity of the dorsal raphe 5‐HTergic neurons ameliorates hippocampal seizure
Cheng, H., Qi, Y., Lai, N., Yang, L. C., Xu, C., Wang, S., Guo, Y. C., Chen, Z., & Wang, Y. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13648 · Cited by 14
The role of brain serotonin signaling in excessive alcohol consumption and withdrawal: A call for more research in females
Castle, M., & Flanigan, M. E. (2024) · Neurobiology of Stress · doi:10.1016/j.ynstr.2024.100618 · Cited by 13
“5HT release upon alcohol intoxication in the vHipp of P rats likely requires MRN 5HT neurons, as this is the predominant 5HT input to this region (Ren et al., 2019).”
Striatal Serotonin Release Signals Reward Value
Spring, M. G., & Nautiyal, K. M. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.0602-24.2024 · Cited by 13
From B1 to B9: a guide through hindbrain serotonin neurons with additional views from multidimensional characterization
Soiza‐Reilly, M., & Gaspar, P. (2020) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-444-64125-0.00002-5 · Cited by 13
Fluorochromized tyramide-glucose oxidase as a multiplex fluorescent tyramide signal amplification system for histochemical analysis
Yamauchi, K., Okamoto, S., Ishida, Y., Konno, K., Hoshino, K., Furuta, T., Takahashi, M., Koike, M., Isa, K., Watanabe, M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-19085-9 · Cited by 13
A Molecular Landscape of Mouse Hippocampal Neuromodulation
Smith, S. J., & von Zastrow, M. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2022.836930 · Cited by 13
Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle
Natsubori, A., Hirai, S., Kwon, S., Ono, D., Deng, F., Wan, J., Miyazawa, M., Kojima, T., Okado, H., Karashima, A., et al. (2023) · iScience · doi:10.1016/j.isci.2022.105830 · Cited by 13
“This is supported by the anatomical and functional features of raphe serotonergic neurons, namely the widespread projection from the raphe nuclei to almost all brain regions and state-dependent firing activities.(4,5) In addition to cortical neurons, astrocytes, a type of glial cell that functions to adjust local brai…”
Background
Selective serotonin reuptake inhibitors suppress sharp wave ripples in the ventral hippocampus
Shiozaki, H., Kuga, N., Kayama, T., Ikegaya, Y., & Sasaki, T. (2023) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2023.04.003 · Cited by 13
Mapping the 5-HTergic neural pathways in perimenopausal mice and elucidating the role of oestrogen receptors in 5-HT neurotransmission
Wang, H., Sun, Y., Wang, W., Wang, X., Zhang, J., Bai, Y., Wang, K., Luan, L., Yan, J., & Qin, L. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e27976 · Cited by 13
“The axons of these cells innervate most brain regions and primarily express 5-HT1AR and 5-HT2AR [21].”
Background
Dorsal raphe neurons integrate the values of reward amount, delay, and uncertainty in multi-attribute decision-making
Feng, Y.-Y., Bromberg-Martin, E. S., & Monosov, I. E. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114341 · Cited by 18
New insights into the effects of serotonin on Parkinson's disease and depression through its role in the gastrointestinal tract
Sancho‐Alonso, M., Sarriés-Serrano, U., Miquel-Rio, L., Yanes-Castilla, C., Paz, V., Meana, J. J., Perelló, M., & Bortolozzi, A. A. (2024) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.sjpmh.2024.07.002 · Cited by 12
Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal
Álvarez-Bagnarol, Y., García, R., Vendruscolo, L. F., & Morales, M. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01620-5 · Cited by 12
Upper brainstem cholinergic neurons project to ascending and descending circuits
Zhao, P., Jiang, T., Wang, H., Jia, X., Li, A., Gong, H., & Li, X. (2023) · BMC Biology · doi:10.1186/s12915-023-01625-y · Cited by 12
“However, a few of them have synchronous collaterals in the ascending and descending circuits [7].”
BackgroundSelf-citation
Neighbouring-slice Guided Multi-View Framework for brain image segmentation
Hu, X., Li, Z., Wu, Y., Liu, J., Luo, X., & Ren, J. (2024) · Neurocomputing · doi:10.1016/j.neucom.2024.127315 · Cited by 12
Self-citation
Differential expression of serotonin2B receptors in GABAergic and serotoninergic neurons of the rat and mouse dorsal raphe nucleus
Cathala, A., Lucas, G., López-Terrones, E., Revest, J., Artigas, F., & Spampinato, U. (2022) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2022.103750 · Cited by 12
Perinatal exposure to bisphenol A or S: Effects on anxiety-related behaviors and serotonergic system
Bonaldo, B., Casile, A., Ostuni, M. T., Bettarelli, M., Nasini, S., Marraudino, M., Panzica, G., & Gotti, S. (2023) · Chemosphere · doi:10.1016/j.chemosphere.2023.140827 · Cited by 11
Neuropeptide and serotonin co-transmission sets the activity pattern in the C. elegans egg-laying circuit
Butt, A., Damme, S. V., Santiago, E. R., Olson, A., Beets, I., & Koelle, M. R. (2024) · Current Biology · doi:10.1016/j.cub.2024.07.064 · Cited by 11
C. elegans interprets dietary quality through context-dependent serotonergic modulationPreprint
Feng, L., Marquina-Solis, J., Yue, L., Harnagel, A., Greenfeld, Y., & Bargmann, C. I. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.05.631367 · Cited by 11
Strain in the Midbrain: Impact of Traumatic Brain Injury on the Central Serotonin System
O’Connell, C. J., Brown, R. S., Peach, T. M., Traubert, O. D., Schwierling, H. C., Notorgiacomo, G. A., & Robson, M. J. (2024) · Brain Sciences · doi:10.3390/brainsci14010051 · Cited by 10
A review of cell-type specific circuit mechanisms underlying epilepsy
Zhao, P., Ding, X., Li, L., & Jiang, G. (2024) · Acta Epileptologica · doi:10.1186/s42494-024-00159-2 · Cited by 13
“5-HT 5-HT neurons in the brainstem have abundant axons in the whole brain [92] and play a crucial role in controlling breathing, cardiac function, and arousal—all of which are impaired during seizures [93].”
Background
Neuronal Transplantation for Alzheimer’s Disease and Prospects for Generating Exogenic Neurons as a Source of Cells for Implantation
Strell, P., Johnson, S. T., Carchi, C., & Low, W. C. (2023) · Cell Transplantation · doi:10.1177/09636897231164712 · Cited by 10
Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus
Wang, J., Li, W., Li, Z., Xue, Z., Zhang, Y., Yuan, Y., Shi, Y., Shan, S., Han, W., Li, F. R., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113078 · Cited by 9
Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus
Mitsui, K., & Takahashi, A. (2024) · BioEssays · doi:10.1002/bies.202300213 · Cited by 9
“[45] Specifically,Vglut3-positive5-HTneuronalaxonspredominantlyinner-vate the anterolateral cortical regions, including the olfactory bulb, piriform, and primary motor cortices, whereas thyrotropin-releasing hormone (Trh)-positive 5-HT neuronal axons show a preference for subcortical areas such as…”
Background
A subcortical switchboard for exploratory, exploitatory, and disengaged statesPreprint
Ahmadlou, M., Shirazi, M. Y., Zhang, P., Rogers, I. L. M., Dziubek, J., & Hofer, S. B. (2023) · bioRxiv · doi:10.1101/2023.12.20.572654 · Cited by 6
Acanthoscurria gomesiana spider‐derived Mygalin in the prelimbic prefrontal cortex modulates neuropathic pain and depression comorbid
Medeiros, A. C., de Medeiros, P. S., Ruggiero, R. N., Gregorio, D. D., Gobbi, G., Júnior, P. I. S., dos Santos, W. F., Coimbra, N. C., & de Freitas, R. L. (2023) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23353 · Cited by 8
A Light-Responsive Neural Circuit Suppresses Feeding
Liu, H., Qu, N., Gonzalez, N. I. V., Palma, M. A., Chen, H., Xiong, J., Choubey, A., Li, Y., Li, X., Yu, M., et al. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.2192-23.2024 · Cited by 9
Early environmental influences on the orbito-frontal cortex function and its effects on behavior
Ruge, O., Hoppe, J. P. M., Molle, R. D., & Silveira, P. P. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106013 · Cited by 12
Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
Miquel-Rio, L., Jericó-Escolar, J., Sarriés-Serrano, U., Yanes-Castilla, C., Torres‐López, M., Argibay, U., Paz, V., Casal, C., Muñoz‐Moreno, E., López-Gil, X., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01073-1 · Cited by 9
“In addition, we also found reduced Egr-1 expression in the DR of D-PD mice locally injected with AAV-h-α -Syn.”
Fluorescent transgenic mouse models for whole-brain imaging in health and disease
Arias, A., Manubens-Gil, L., & Dierssen, M. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.958222 · Cited by 9
Immortal orexin cell transplants restore motor-arousal synchrony during cataplexy
Pintwala, S. K., Fraigne, J. J., Belsham, D. D., & Peever, J. H. (2023) · Current Biology · doi:10.1016/j.cub.2023.03.077 · Cited by 9
Uncovering the role of FOXA2 in the Development of Human Serotonin Neurons
Xu, T., Cao, L., Duan, J., Li, Y., Li, Y., Hu, Z., Li, S., Zhang, M., Wang, G., Guo, F., et al. (2023) · Advanced Science · doi:10.1002/advs.202303884 · Cited by 7
Preferential in vivo inhibitory action of serotonin in rat infralimbic versus prelimbic cortex: relevance for antidepressant treatments
López-Terrones, E., Celada, P., Riga, M. S., & Artigas, F. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab396 · Cited by 8
Dual-color GRAB sensors for monitoring spatiotemporal serotonin release in vivoPreprint
Deng, F., Wan, J., Li, G., Dong, H., Xia, X., Wang, Y., Li, X., Zhuang, C., Zheng, Y., Liu, L. D., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.27.542566 · Cited by 8
Serotonergic reinforcement of a complete swallowing circuit
Schoofs, A., Miroschnikow, A., Schlegel, P., Zinke, I., Schneider-Mizell, C. M., Cardona, A., & Pankratz, M. J. (2023) · doi:10.1101/2023.05.26.542464 · Cited by 7
“Anatomical and functional studies have identified specific vagal ganglia that project to specific regions of the brainstem and segregate in a modality-specific manner (Bai et al., 2019; Borgmann et al., 2021; Gong et al., 2020; Grove et al., 2022; Prescott and Liberles, 2022; Ran et al., 2022; Ren et al., 2019; Willia…”
Background
Functional Diversity of Serotonin Neurons in the Dorsal and Median Raphe Nuclei in Emotional Responses
Ohmura, Y., & Nagayasu, K. (2025) · Neuropsychopharmacology Reports · doi:10.1002/npr2.70015 · Cited by 8
“In fact, some researchers have suggested the existence of subgroups of MRN serotonin neurons [25, 33].”
Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control
Deng, Y., Deng, G., Grobe, J. L., & Cui, H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.691226 · Cited by 7
Serotonergic regulation of appetite and sodium appetite
Shin, Y., Kim, S., & Sohn, J. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13328 · Cited by 7
“…neurotensin receptor, corticotropin-releasing hormone (CRH) receptor, neuropeptide Y (NPY) receptor, oxytocin receptor, orexin receptor, calcitonin receptor, somatostatin receptor, μ / κ -opioid receptor, galanin receptor and gastric inhibitory polypeptide (GIP) receptor 33,40,41 (Figure 1).”
Cannabinoids and monoaminergic system: implications for learning and memory
Zhao, S., Gu, Z.-L., Yue, Y.-N., Zhang, X., & Dong, Y. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1425532 · Cited by 7
“This group of neurons also release glutamate, indicating a possible regulation of 5-HT release by the ECS at their terminals (Ren et al., 2019; Wang et al., 2019; Okaty et al., 2020) (Figure 2A).”
Background
Serotonergic neurons in the treatment of mood disorders: The dialogue with astrocytes
Charvériat, M., & Guiard, B. P. (2021) · Progress in brain research · doi:10.1016/bs.pbr.2021.01.006 · Cited by 7
Sexually dimorphic effects of estrogen receptor 2 deletion in the dorsal raphe nucleus on emotional behaviors
He, J., Yan, J., Zha, X., Ding, X., Zhang, Y., Lu, Z., & Xu, X. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13195 · Cited by 7
Expression of SATB1 and SATB2 in the brain of bony fishes: what fish reveal about evolution
Lozano, D. D., López, J. M., Jiménez, S., Morona, R., Ruiz, V., Martínez, A., & Moreno, N. (2023) · Brain Structure and Function · doi:10.1007/s00429-023-02632-z · Cited by 8
Differential modulation of active expiration during hypercapnia by the medullary raphe in unanesthetized rats
Leirão, I. P., Zoccal, D. B., Gargaglioni, L. H., & da Silva, G. S. F. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02455-5 · Cited by 7
“However, most forebrain 5-HT arises from the dorsal raphe and median raphe nuclei (and not frommedullary raphe, based on current knowledge), and these nuclei receive reciprocal inputs from brain regions that regulate vigilance states [57, 71].”
Background
Correlation of Expression Changes between Genes Controlling 5-HT Synthesis and Genes Crh and Trh in the Midbrain Raphe Nuclei of Chronically Aggressive and Defeated Male Mice
Redina, O. E., Babenko, V. N., Смагин, Д. А., Kovalenko, I. L., Galyamina, A. G., & Kudryavtseva, N. N. (2021) · Genes · doi:10.3390/genes12111811 · Cited by 7
“Microinjection of CRH into the DRN has revealed that the interaction of CRH with these receptors can modulate behavioral consequences of uncontrolled stress in a dose-dependent manner.”
BackgroundResultInfluential
Estrous Cycle-Dependent Modulation of Sexual Receptivity in Female Mice by Estrogen Receptor Beta-Expressing Cells in the Dorsal Raphe Nucleus
Murakawa, T., Kogure, L., Hata, K., Hasunuma, K., Takenawa, S., Sano, K., & Ogawa, S. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.1137-24.2024 · Cited by 6
Neuropeptides as transmitters and regulators of the locus coeruleus noradrenergic system
Becker, L. J., Martin, M. M., Hughes, A. C., Mulvey, B., Kuo, C., Piantadosi, S. C., Bruchas, M. R., Martinowich, K., Meye, F. J., Schwarz, L. A., et al. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100081 · Cited by 5
Integrated single-cell atlases unveil the operation principles of whole-brain 5-HT neuronal subsystems
Song, Z., Huang, C.-X., Zhang, H., Ye, C., Guan, N. N., & Song, J. (2025) · Science Advances · doi:10.1126/sciadv.adv8128 · Cited by 9
“To compare the seven 5-HT neuron subpopulations identified from our manually collected scRNA-seq data with sub-type classifications in mice, we used the reported marker genes from three scRNA-seq studies on mouse 5-HT neuron subtypes as a reference ( 8 , 9 , 12 ).”
Synchrony of neuromodulatory systems during NREM sleep
Teng, S., Rodriguez, A. N. M., Wang, R., Chen, X., & Peng, Y. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2514202122 · Cited by 8
“On the other hand, Ren et al. reported that ACh and monoamine receptors including Adra2a are expressed in raphe 5 - HT neurons ( 48 ), suggesting that our Adra2a pharmacological manipulation could directly inhibit the 5 - HT system.”
Self-citation
α-1 Adrenoceptor Activation in the Dorsal Raphe Nucleus Decreases Food Intake in Fasted Rats
Flores, R., Dos‐Santos, R. C., Steinbach, R., Rodrigues‐Santos, I., de Jesus, A. A., Antunes‐Rodrigues, J., & Paschoalini, M. A. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.775070 · Cited by 6
Regulation of stress-induced sleep perturbations by dorsal raphe VGLUT3 neurons in male mice
Henderson, F. J., Dumas, S., Gangarossa, G., Bernard, V., Pujol, M., Poirel, O., Pietrancosta, N., Mestikawy, S. E., Daumas, S., & Fabre, V. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114411 · Cited by 8
Cocaine reward and memory after chemogenetic inhibition of distinct serotonin neuron subtypes in mice
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“…with previous research (Kim, 2009; Okaty, 2015; Brust, 2014; Niederkofler et al., 2016; Tessier et al., 2017; Hennessy et al., 2017; Ren et al., 2018; Ren et al., 2019), genetic and developmental differences may underlie functional differences across the broader serotonergic neuron population.”
Method
Neuron-type specificity of dorsal raphe projections to ventral tegmental areaPreprint
Chang, A. J., Wang, L., Lucantonio, F., Adams, M., Lemire, A. L., Dudman, J. T., & Cohen, J. Y. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.06.425641 · Cited by 8
“However, projection patterns from individual serotonin neurons are heterogeneous (Van Bockstaele et al., 1993; Gagnon and Parent, 2014; Ren et al., 2019).”
BackgroundMethodResult
Optogenetic activation of dorsal raphe serotonin neurons induces brain-wide activationPreprint
Hamada, H. T., Abe, Y., Takata, N., Taira, M., Tanaka, K. F., & Doya, K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.07.503074 · Cited by 7
Dorsal raphe neurons signal integrated value during multi-attribute decision-makingPreprint
Feng, Y.-Y., Bromberg-Martin, E. S., & Monosov, I. E. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.17.553745 · Cited by 6
Neurochemistry of the Central Nervous System
Ascenzi, B. M., Myers, M. W., & Buccilli, B. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-822404-5.00016-4 · Cited by 5
Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes
Sural, S., Walker, Z., & Hobert, O. (2025) · Science Advances · doi:10.1126/sciadv.adw1270 · Cited by 13
The mouse dorsal raphe nucleus as understood by temporal Fgf8 lineage analysis
Guajardo, H. M., Hatini, P. G., & Commons, K. G. (2020) · The Journal of Comparative Neurology · doi:10.1002/cne.25071 · Cited by 5
“…caudal third that with the MnR is associated with septohippocampal serotonin, a middle third correlating with the source of cortical serotonin and a rostral and lateral third where projections are known to be more subcortical than cortical (Commons, 2016; Muzerelle et al., 2016; Ren et al., 2019).”
BackgroundInfluential
Excessive folic acid intake combined with undernutrition during gestation alters offspring behavior and brain monoamine profiles
Ono, T., Hino, K., Kimura, T., Uchimura, Y., Ashihara, T., Higa, T., Kojima, H., Murakami, T., & Udagawa, J. (2022) · Congenital Anomalies · doi:10.1111/cga.12472 · Cited by 5
Perinatal Western-style diet alters serotonergic neurons in the macaque raphe nuclei
Dunn, G. A., Thompson, J. R., Mitchell, A. J., Papadakis, S., Selby, M., Fair, D. A., Gustafsson, H., & Sullivan, E. L. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1067479 · Cited by 6
“Recently, one research group found that cortical regions are primarily targeted by VGLUT3+ serotonergic neurons, regardless of DR subnuclei (Ren et al., 2019).”
Background
An experimental platform for stochastic analyses of single serotonergic fibers in the mouse brain
Mays, K. C., Haiman, J. H., & Janušonis, S. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1241919 · Cited by 5
Projection-defined median raphe Pet+ subpopulations are diversely implicated in seizure
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“The raphe nuclei, the primary resource of forebrain 5-HT, play an important role in regulating forebrain excitabilities by sending extensive innervations throughout almost the entire brain (Ren et al., 2019).”
Transcriptomic dynamics governing serotonergic dysregulation in the dorsal raphe nucleus following mild traumatic brain injury
O’Connell, C. J., Reeder, E. L., Hymore, J. A., Brown, R. S., Notorgiacomo, G. A., Collins, S. M., Gudelsky, G. A., & Robson, M. J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114695 · Cited by 5
“Although the identities of distinct 5-HT neuron subpopulations and their associated axonal projections have been mapped (Ren et al., 2018; Ren et al., 2019), precise functional control over complex behaviors/psychiatric states has yet to be attributed to each of the respective sub-populations of…”
Background
Complementary roles of serotonin and dopamine in model-based learning
Taira, M., & Sharpe, M. J. (2024) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2024.101464 · Cited by 7
Injections of the α-2 adrenoceptor agonist clonidine into the dorsal raphe nucleus increases food intake in satiated rats
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Illuminating complexity in serotonin neurons of the dorsal raphe nucleus
Baruni, J., & Luo, L. (2022) · Neuron · doi:10.1016/j.neuron.2022.07.013 · Cited by 5
Self-citation
Differential transcriptome profile underlying risky choice in a rat gambling task
Kwak, M. J., Kim, W. Y., Jung, S., Chung, Y., & Kim, J. (2022) · Journal of Behavioral Addictions · doi:10.1556/2006.2022.00068 · Cited by 5
Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter
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Modeling the cell-type-specific mesoscale murine connectome with anterograde tracing experiments
Koelle, S., Mastrovito, D., Whitesell, J. D., Hirokawa, K. E., Zeng, H., Meilă, M., Harris, J. A., & Mihalaş, Ş. (2023) · Network Neuroscience · doi:10.1162/netn_a_00337 · Cited by 5
“This small nucleus appears to contain a complex mix of molecularly distinct serotonergic neuron subtypes with some hints of subtype-specific projection patterns (Huang et al., 2019; Ren et al., 2018, 2019).”
BackgroundMethodInfluential
Adolescent social isolation disrupts developmental tuning of neuropeptide circuits in the hypothalamus to amygdala regulating social and defensive behavior
Arakawa, H., Tokashiki, M., Higuchi, Y., & Konno, T. (2024) · Peptides · doi:10.1016/j.peptides.2024.171178 · Cited by 4
The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomicsPreprint
Weber, L. M., Divecha, H. R., Tran, M. N., Kwon, S. H., Spangler, A., Montgomery, K. D., Tippani, M., Bharadwaj, R. A., Kleinman, J. E., Page, S. C., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.28.514241 · Cited by 5
“These genes included the 5-HT neuron marker genes TPH2 and SLC6A4 (Figure 3F, Supplementary Figure 14B, and Supplementary Table 7).”
BackgroundResultInfluential
A Novel Single Vector Intersectional AAV Strategy for Interrogating Cellular Diversity and Brain FunctionPreprint
Hughes, A. C., Pollard, B. G., Xu, B., Gammons, J. W., Chapman, P., Bikoff, J. B., & Schwarz, L. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.07.527312 · Cited by 5
Topographically organized dorsal raphe activity modulates forebrain sensory-motor computations and adaptive behaviorsPreprint
Mutlu, A. K., Serneels, B., Wiest, C., Trinh, A.-T., Bardenhewer, R., Palumbo, F., Frisvold, O. B., Aukrust, I. K. F., Ostenrath, A. M., & Yaksi, E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.06.641626 · Cited by 5
Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiologyPreprint
Drexler, R., Yalçın, B., Mancusi, R. A., Rogers, A. E., Shamardani, K., Woo, P. J., Ravel, A., Wu, S., Yabo, Y. A., Steger, L., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.10.693579 · Cited by 11
Synchronous activation of striatal cholinergic interneurons induces local serotonin release
Matityahu, L., Hobel, Z. B., Berkowitz, N., Malgady, J. M., Gilin, N., Plotkin, J. L., & Goldberg, J. A. (2026) · Nature Communications · doi:10.1038/s41467-026-70359-6 · Cited by 5
“Alter-natively, the 5-HT ﬁ bers that innervate the dorsal and ventral striatum may have different nAChR expression pro ﬁ les, leading to differential sensitivity to ACh 24,44 .”
An intersectional genetic approach for simultaneous cell type-specific labelling and gene knockout in the mouse
Huang, D.-F., Lin, C., Yang, T.-Y., Lien, C., Yang, C., & Huang, H. (2023) · Development · doi:10.1242/dev.201198 · Cited by 4
Calcitonin gene-related peptide (CGRP) exerts membrane, cellular and synaptic actions on serotonergic dorsal raphe neurons ex vivo: Functional implications for a role in dorsal raphe-controlled functions
Yang, Y. T., Leguizamón, C. R. R., Sheykhzade, M., Zhu, Y., & Kohlmeier, K. A. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110457 · Cited by 4
“3D reconstruction of the projections from different clusters of serotonergic neurons in the mouse DR reveals their connectivity to various nuclei, including neural regions of the limbic system (Ren et al., 2019).”
Past, present, and future of serotonin-targeting therapeutics for Alzheimer’s disease: Perspectives from DNA methylation
Liu, Y., Aquili, L., Wong, K.-H., Lu, Z.-L., & Lim, L. W. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102755 · Cited by 4
Differentiated Presynaptic Input to OLMɑ2 Cells Along the Hippocampal Dorsoventral Axis: Implications for Hippocampal Microcircuit Function
Thulin, A., Henriksson, K., Nogueira, I., & Kullander, K. (2025) · Hippocampus · doi:10.1002/hipo.70026 · Cited by 3
“…cells were identified in the dorsal and medial raphe nuclei, regions known for their serotonergic modulation of hippocampal activity, potentially contributing to the regulation of theta rhythms and behavioral states (Böhm et al. 2015; Chittajallu et al. 2013; Crooks et al. 2012; Ren et al. 2019).”
GABAergic miR-34a regulates Dorsal Raphè inhibitory transmission in response to aversive, but not rewarding, stimuli
Ielpo, D., Guzzo, S. M., Porcheddu, G. F., Viscomi, M. T., Catale, C., Reverte, I., Cabib, S., Cifani, C., Antonucci, G., Ventura, R., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2301730120 · Cited by 3
Rare CRHR2 and GRM8 variants identified as candidate factors associated with eating disorders in Japanese patients by whole exome sequencing
Oka, A., Hadano, S., Ueda, M. T., Nakagawa, S., Komaki, G., & Ando, T. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28643 · Cited by 4
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Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elementsPreprint
Nguyen, H. P., Chan, C. S. Y., Cintrón, D. L., Sheng, R. R., Harshman, L., Nobuhara, M., Ushiki, A., Biellak, C., An, K., Gordon, G., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.06.515311 · Cited by 5
The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomicsPreprint
Weber, L. M., Divecha, H. R., Tran, M. N., Kwon, S. H., Spangler, A., Montgomery, K. D., Tippani, M., Bharadwaj, R. A., Kleinman, J. E., Page, S. C., et al. (2023) · eLife · doi:10.7554/elife.84628.1 · Cited by 3
Serotonin drives choice-independent reconfiguration of distributed neural activityPreprint
Meijer, G. T., Catarino, J. A., Freitas-Silva, L., Laranjeira, I. C., & Mainen, Z. F. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.01.668048 · Cited by 6
“5-HT is released from the brainstem dorsal raphe nucleus (DRN) which projects throughout the entire brain 5,6 .”
Serotonergic regulation of cortical neurovascular coupling and hemodynamics upon awakening from sleep in mice
Natsubori, A., Kwon, S., Honda, Y., Kojima, T., Karashima, A., Masamoto, K., & Honda, M. (2024) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241238843 · Cited by 3
“18 –15,19–21 Therefore, the serotonergic system is predicted to have a unique function in the modulation of NVC and resulting CBF regulation.”

Authors: Ren, J., Isakova, A., Friedmann, D., Zeng, J., Grutzner, S. M., Pun, A., Zhao, G. Q., Kolluru, S. S., Wang, R., Lin, R., Li, P., Li, A., Raymond, J. L., Luo, Q., Luo, M., Quake, S. R., & Luo, L.
Affiliations: Howard Hughes Medical Institute (US)
Stanford University (US)
National Institute of Biological Sciences, Beijing (CN)
Stanford Medicine (US)
Wuhan National Laboratory for Optoelectronics (CN)
Chan Zuckerberg Biohub San Francisco (US)
Corresponding author: Ren, Jing
Quake, Stephen R
Luo, Liqun
ORCID: Ren, Jing
Isakova, Alina
Friedmann, Drew
Zhao, Grace Q
Kolluru, Sai Saroja
Wang, Ruiyu
Lin, Rui
Li, Pengcheng
Li, Anan
Raymond, Jennifer L
Luo, Qingming
Luo, Minmin
Quake, Stephen R
Luo, Liqun
Venue: eLife
Publisher: eLife Sciences Publications, Ltd
Published: 2019-10-24
Volume: 8
ISSN: 2050-084X (ISSN-L)
DOI: 10.7554/elife.49424
PMC: PMC6812963
OpenAlex: W2982239238
Semantic Scholar: 73c6ef27934225685f1623abe2f5530230da5ad5
Cited by: 304
References: 97
Citations by year: 2026: 32 · 2025: 52 · 2024: 50 · 2023: 59 · 2022: 42 · 2021: 41 · 2020: 25 · 2019: 2
FWCI: 9.10
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
creativecommons.org/licenses/by/4.0/ (am)
creativecommons.org/licenses/by/4.0/ (tdm)
Locations: eLife (publishedVersion, cc-by)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (R01 NS104698, NS057488)
National Science Foundation (NeuroNex)
Ministry of Science and Technology of the People's Republic of China (2015BAI08B02)
National Natural Science Foundation of China (91432114, 91632302)
Beijing Municipal Government
NSFC (61721092, 81827901)
Swiss National Science Foundation (PostDoc Mobility Fellowship)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: serotonergic neurons, dorsal raphe nucleus, median raphe nucleus, single-cell transcriptomics, neuronal heterogeneity, VGLUT3, thyrotropin-releasing hormone, hypothalamus, neuropeptides, single-neuron reconstruction, mice
MeSH terms: Animals, Brain Mapping, Neural Pathways, Raphe Nuclei, Sequence Analysis, RNA, Mice, Single-Cell Analysis, Serotonergic Neurons, Transcriptome

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Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei

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