Conditional anterograde tracing reveals distinct targeting of individual serotonin cell groups (B5-B9) to the forebrain and brainstem
Open accessAbstract
Serotoninergic innervation of the central nervous system is provided by hindbrain raphe nuclei (B1-B9). The extent to which each raphe subdivision has distinct topographic organization of their projections is still unclear. We provide a comprehensive description of the main targets of the rostral serotonin (5-HT) raphe subgroups (B5-B9) in the mouse brain. Adeno-associated viruses that conditionally express GFP under the control of the 5-HT transporter promoter were used to label small groups of 5-HT neurons in the dorsal (B7d), ventral (B7v), lateral (B7l), and caudal (B6) subcomponents of the dorsal raphe (DR) nucleus as well as in the rostral and caudal parts of the median raphe (MR) nucleus (B8 and B5, respectively), and in the supralemniscal (B9) cell group. We illustrate the distinctive and largely non-overlapping projection areas of these cell groups: for instance, DR (B7) projects to basal parts of the forebrain, such as the amygdala, whereas MR (B8) is the main 5-HT source to the hippocampus, septum, and mesopontine tegmental nuclei. Distinct subsets of B7 have preferential brain targets: B7v is the main source of 5-HT for the cortex and amygdala while B7d innervates the hypothalamus. We reveal for the first time the target areas of the B9 cell group, demonstrating projections to the caudate, prefrontal cortex, substantia nigra, locus coeruleus and to the raphe cell groups. The broad topographic organization of the different raphe subnuclei is likely to underlie the different functional roles in which 5-HT has been implicated in the brain. The present mapping study could serve as the basis for genetically driven specific targeting of the different subcomponents of the mouse raphe system.
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Serotonergic projections from the dorsal and medial Raphe nuclei are among the first to emerge and arrive in the PFC around E16/E17 in rodents and postnatal weeks 10-13 in humans.
“The brain matures from the brainstem to the more frontal cortical regions, and it is therefore not surprising that serotonergic projections from both the dorsal as well as the medial Raphe nuclei (DRN, MRN respectively) are among the first to emerge and are set towards cortical regions where they arrive in the PFC around E16/E17 in rodent and week postnatal 10–13 in humans [113–116].”
From Development of prefrontal cortex (2022) · cites this paper as [115]
The Results sections on the ventral dorsal raphe (B7v) and median raphe (B8) report serotonergic innervation of the medial prefrontal cortex, supporting the projection-to-PFC part of the claim. The paper does not establish that these projections are among the first to emerge or that they arrive at E16/E17 in rodents or postnatal weeks 10–13 in humans; its mapping study concerns mice, not human developmental timing. The indexed copy provides section labels but no page numbers for these passages. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAxons seen in hippocampus likely originated from Vglut3+ cells in MR.
“[Note that axons seen in hippocampus likely originated from Vglut3+ cells in MR (Muzerelle et al., 2016), though the majority of labeled somata were located in the ventral portion of pDR; see Figure 7—figure supplement 3C].”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Muzerelle et al., 2016
The MR serotonin neurons project to structures near the midline, whereas the DR serotonin neurons target more lateral regions.
“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).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Muzerelle et al., 2016
DRN 5-HT neurons send highly divergent projections that target many functionally distinct brain regions.
“DRN 5-HT neurons send highly divergent projections that target many functionally distinct brain regions (Azmitia and Segal, 1978; Muzerelle et al., 2016; Vertes, 1991).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Muzerelle et al., 2016
The dorsolateral subregion innervates many subcortical sensory and hypothalamic nuclei, in addition to motor nuclei in the brainstem.
“The dorsolateral subregion innervates many subcortical sensory and hypothalamic nuclei, in addition to motor nuclei in the brainstem (Lee et al., 2008; Muzerelle et al., 2016).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Muzerelle et al., 2016
The localization of 5-HT-V to the dorsomedial posterior B6 tail of the DRN suggests that this subtype may innervate ventricular and subventricular regions and the choroid plexus and primarily target non-neuronal cells.
“The localization of this subtype to the dorsomedial posterior B6 tail of the DRN also suggests that this subtype may innervate ventricular and subventriclar regions and the choroid plexus and primarily target non-neuronal cells (Muzerelle et al., 2016).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Muzerelle et al., 2016
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Sargin, D., Jeoung, H.-S., Goodfellow, N. M., & Lambe, E. K. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00073 · Cited by 54 · see citing works
Serotonin neuron abnormalities in the BTBR mouse model of autism
Guo, Y., & Commons, K. G. (2017) · Autism Research · doi:10.1002/aur.1665 · Cited by 51 · see citing works
Two major network domains in the dorsal raphe nucleus
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Turcotte-Cardin, V., Vahid-Ansari, F., Luckhart, C., Daigle, M., Geddes, S. D., Tanaka, K. F., Hen, R., James, J., Merali, Z., Béïque, J.-C., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0352-18.2018 · Cited by 36 · see citing works
Long-Term Impact of Early-Life Stress on Serotonin Connectivity
Ramkumar, R., Edge-Partington, M., Terstege, D. J., Adigun, K., Ren, Y., Khan, N. S., Rouhi, N., Jamani, N. F., Tsutsui, M., Epp, J. R., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.01.024 · Cited by 30 · see citing works
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Kast, R. J., Wu, H.-H., Williams, P., Gaspar, P., & Levitt, P. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00020 · Cited by 20 · see citing works
Self-citation
- Authors
- Muzerelle, A., Scotto-Lomassese, S., Bernard, J. F., Soiza-Reilly, M., & Gaspar, P.
- Affiliations
- Inserm (FR)
- Venue
- Brain Structure and Function
- Published
- 2014-11-18
- Volume
- 221
- Issue
- 1
- Pages
- 535-561
- ISSN
- 1863-2653 (ISSN-L)
- 1863-2661
- PMC
- PMC4750555
- OpenAlex
- W2064063251
- Cited by
- 303
- References
- 82
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 34 · 2023: 25 · 2022: 24 · 2021: 34 · 2020: 48 · 2019: 27 · 2018: 24 · 2017: 27 · 2016: 15 · 2015: 8
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Brain Structure and Function (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- serotonin, raphe nuclei, dorsal raphe nucleus, median raphe, topographic organization, forebrain, brainstem, amygdala, hippocampus, hypothalamus, prefrontal cortex, substantia nigra, locus coeruleus, caudate nucleus, mice
- MeSH terms
- Animals, Brain Stem, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Serotonin, Prosencephalon, Integrases, 5' Untranslated Regions, Serotonin Plasma Membrane Transport Proteins, Neuroanatomical Tract-Tracing Techniques, Serotonergic Neurons, Midbrain Raphe Nuclei
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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