Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in the mouse dorsal and median raphe nuclei

The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons that regulate diverse behavioral functions. However, their whole-brain input-output circuits remain incompletely elucidated. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We found that these neurons received inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus had divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons projected to the lateral habenula through multiple pathways. Correlation and cluster analysis revealed that glutamatergic and GABAergic neurons in the same raphe nucleus received heterogeneous inputs and sent different collateral projections. This connectivity atlas further elucidates the anatomical architecture of the raphe nuclei, which could facilitate better understanding of their behavioral functions.

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Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in mouse dorsal and median raphe nucleus

10.1101/2020.12.15.422858 ◽

2020 ◽

Author(s):

Zhengchao Xu ◽

Zhao Feng ◽

Meng-Ting Zhao ◽

Qingtao Sun ◽

Lei Deng ◽

...

Keyword(s):

Brain Connectivity ◽

Brain Regions ◽

Gabaergic Neurons ◽

Raphe Nucleus ◽

Brain Atlas ◽

Median Raphe ◽

Median Raphe Nucleus ◽

Whole Brain ◽

Lateral Habenula ◽

Median Raphé

The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons regulating diverse behavioral functions. Their whole-brain input-output circuits remain incompletely understood. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We discovered that these neurons receive inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus have divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons project to the lateral habenula via multiple pathways. Correlation and cluster analysis indicated that glutamatergic and GABAergic neurons in the same raphe nucleus receive inputs from heterogeneous neurons in upstream brain regions and send different collateral projections. This connectivity atlas provides insights into the cell heterogeneity, anatomical connectivity and behavioral functions of the raphe nucleus.

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A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei

Neuron ◽

10.1016/j.neuron.2014.07.002 ◽

2014 ◽

Vol 83 (3) ◽

pp. 663-678 ◽

Cited By ~ 217

Author(s):

Iskra Pollak Dorocic ◽

Daniel Fürth ◽

Yang Xuan ◽

Yvonne Johansson ◽

Laura Pozzi ◽

...

Keyword(s):

Raphe Nuclei ◽

Brain Atlas ◽

Median Raphe ◽

Serotonergic Neurons ◽

Whole Brain ◽

Raphé Nuclei ◽

Median Raphé

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

10.7554/elife.49424.043 ◽

2019 ◽

Cited By ~ 5

Author(s):

Jing Ren ◽

Alina Isakova ◽

Drew Friedmann ◽

Jiawei Zeng ◽

Sophie M Grutzner ◽

...

Keyword(s):

Single Cell ◽

Raphe Nuclei ◽

Author Response ◽

Median Raphe ◽

Whole Brain ◽

Serotonin Neurons ◽

Raphé Nuclei ◽

Median Raphé

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

eLife ◽

10.7554/elife.49424 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 24

Author(s):

Jing Ren ◽

Alina Isakova ◽

Drew Friedmann ◽

Jiawei Zeng ◽

Sophie M Grutzner ◽

...

Keyword(s):

Single Cell ◽

Glutamate Transporter ◽

Raphe Nuclei ◽

Molecular Heterogeneity ◽

Median Raphe ◽

Axonal Projection ◽

Whole Brain ◽

Serotonin Neurons ◽

Raphé Nuclei ◽

Median Raphé

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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Further evidence of an opposite effect of dorsal and median raphe nuclei on the proestrous surge of LH

Acta Endocrinologica ◽

10.1530/acta.0.1220696 ◽

1990 ◽

Vol 122 (6) ◽

pp. 696-702 ◽

Cited By ~ 5

Author(s):

H. Morello ◽

L. Caligaris ◽

B. Haymal ◽

S. Taleisnik

Keyword(s):

Dorsal Raphe Nucleus ◽

Raphe Nucleus ◽

Raphe Nuclei ◽

Constant Light ◽

Median Raphe ◽

Median Raphe Nucleus ◽

Lh Release ◽

Raphé Nuclei ◽

Dorsal Raphé ◽

Median Raphé

Abstract. The effect of stimulation or lesions of either the dorsal or the median raphe nucleus on the proestrous surge of LH and on ovulation was studied in rats kept under constant illumination. Electrochemical stimulation (anodic DC of 100 μA during 30 sec) was applied at noon on the day of proestrus through chronically implanted electrodes. Lesions of the raphe nuclei were made by passing a cathodic current of 1 mA for 20 sec through nichrome electrodes stereotaxically implanted. Blood samples from freely behaving rats were obtained hourly through cannulae inserted into the jugular vein. Rats under constant light from diestrous day 1 or diestrous day 2 showed a delay in the onset of the LH surge of the next proestrus. Stimulation applied into the median raphe nucleus inhibited proestrous LH release and blocked ovulation, whereas stimulation of the dorsal raphe nucleus resulted in enhanced LH release in rats under constant light from diestrous day 2 but not from diestrous day 1. In turn, in rats bearing lesions in the dorsal raphe nucleus LH surges were decreased and ovulation was blocked, but rats with lesions in the median raphe nucleus exhibited enhanced LH release. It is concluded that the dorsal and the median raphe nuclei exert opposite effects on the proestrous surge of LH and on ovulation.

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