scholarly journals A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe Pet1 neurons

2020 ◽  
Author(s):  
Benjamin W. Okaty ◽  
Nikita Sturrock ◽  
Yasmin Escobedo Lozoya ◽  
YoonJeung Chang ◽  
Rebecca A. Senft ◽  
...  
Keyword(s):  
Single Cell ◽  
Functional Organization ◽  
Dorsal Raphe ◽  
Molecular Heterogeneity ◽  
Electrophysiological Properties ◽  
Efferent Projections ◽  
Brainstem Raphe ◽  
And Behavior ◽  
Distinct Subtype ◽  
Dorsal Raphé

AbstractAmong the brainstem raphe nuclei, the dorsal raphe nucleus (DR) contains the greatest number of Pet1-lineage neurons, a predominantly serotonergic group distributed throughout DR subdomains. These neurons collectively regulate diverse physiology and behavior and are often therapeutically targeted to treat affective disorders. Characterizing Pet1 neuron molecular heterogeneity and relating it to anatomy is vital for understanding DR functional organization, with potential to inform therapeutic separability. Here we use high-throughput and DR subdomain-targeted single-cell transcriptomics and intersectional genetic tools to map molecular and anatomical diversity of DR-Pet1 neurons. We describe up to fourteen neuron subtypes, many showing biased cell body distributions across the DR. We further show that P2ry1-Pet1 DR neurons – the most molecularly distinct subtype – possess unique efferent projections and electrophysiological properties. These data complement and extend previous DR characterizations, combining intersectional genetics with multiple transcriptomic modalities to achieve fine-scale molecular and anatomic identification of Pet1 neuron subtypes.

scholarly journals A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe Pet1 neurons

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Benjamin W Okaty ◽  
Nikita Sturrock ◽  
Yasmin Escobedo Lozoya ◽  
YoonJeung Chang ◽  
Rebecca A Senft ◽  
...  
Keyword(s):  
Single Cell ◽  
Functional Organization ◽  
Dorsal Raphe ◽  
Molecular Heterogeneity ◽  
Electrophysiological Properties ◽  
Efferent Projections ◽  
Brainstem Raphe ◽  
And Behavior ◽  
Distinct Subtype ◽  
Dorsal Raphé

Among the brainstem raphe nuclei, the dorsal raphe nucleus (DR) contains the greatest number of Pet1-lineage neurons, a predominantly serotonergic group distributed throughout DR subdomains. These neurons collectively regulate diverse physiology and behavior and are often therapeutically targeted to treat affective disorders. Characterizing Pet1 neuron molecular heterogeneity and relating it to anatomy is vital for understanding DR functional organization, with potential to inform therapeutic separability. Here we use high-throughput and DR subdomain-targeted single-cell transcriptomics and intersectional genetic tools to map molecular and anatomical diversity of DR-Pet1 neurons. We describe up to fourteen neuron subtypes, many showing biased cell body distributions across the DR. We further show that P2ry1-Pet1 DR neurons – the most molecularly distinct subtype – possess unique efferent projections and electrophysiological properties. These data complement and extend previous DR characterizations, combining intersectional genetics with multiple transcriptomic modalities to achieve fine-scale molecular and anatomic identification of Pet1 neuron subtypes.

scholarly journals Neuron-type specificity of dorsal raphe projections to ventral tegmental area

2021 ◽  
Author(s):  
Anna J. Chang ◽  
Lihua Wang ◽  
Federica Lucantonio ◽  
Maya Adams ◽  
Andy Lemire ◽  
...  
Keyword(s):  
Single Cell ◽  
Ventral Tegmental Area ◽  
Cell Types ◽  
Dorsal Raphe ◽  
Physiological Data ◽  
Differential Distribution ◽  
Ventral Tegmental ◽  
And Behavior ◽  
Long Timescales ◽  
Dorsal Raphé

The midbrain dorsal raphe (DR) and ventral tegmental area (VTA) contain two of the brain’s main ascending neuromodulatory transmitters: serotonin and dopamine. We studied the pathway from DR to VTA using single-cell RNA sequencing, anatomical tracing, and electrophysiology and behavior in mice. Single-cell sequencing confirmed a differential distribution of dopamine cell types between medial and lateral aspects of the VTA. This molecular diversity included differential expression of a subset of glutamatergic and serotonergic receptors. Anatomical data showed that distinct serotonergic and glutamatergic populations of DR neurons project to distinct medial-lateral locations in VTA. Physiological data showed that serotonergic neurons are positioned to excite putative dopaminergic neurons in lateral VTA on short timescales (within trial), and inhibit them on long timescales (on the next trial). Our results reveal precise anatomical specificity of DR projections to VTA, and suggest a functional role for serotonergic modulation of dopaminergic function across multiple timescales.

scholarly journals Author response: A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe Pet1 neurons

2020 ◽  
Author(s):  
Benjamin W Okaty ◽  
Nikita Sturrock ◽  
Yasmin Escobedo Lozoya ◽  
YoonJeung Chang ◽  
Rebecca A Senft ◽  
...  
Keyword(s):  
Single Cell ◽  
Dorsal Raphe ◽  
Author Response ◽  
Dorsal Raphé

scholarly journals Single-cell analysis of antiviral neuroinflammatory responses in the mouse dorsal raphe nucleus

2019 ◽  
Author(s):  
Kee Wui Huang ◽  
Bernardo L. Sabatini
Keyword(s):  
Gene Delivery ◽  
Single Cell ◽  
Dorsal Raphe Nucleus ◽  
Single Cell Analysis ◽  
Critical Evaluation ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Viral Gene ◽  
Transcriptional Responses ◽  
Dorsal Raphé

ABSTRACTNeuroinflammatory processes have been implicated in neurodegenerative and psychiatric diseases, and limit the utility of viruses for gene delivery. Here we analyzed 60,212 single-cell RNA profiles to assess both global and cell type-specific transcriptional responses in the mouse dorsal raphe nucleus following axonal infection of neurons by rabies viruses. We identified several leukocyte populations, which infiltrate the brain, that are distinct from resident immune cells. Additionally, we uncovered transcriptionally distinct states of microglia along an activation trajectory that may serve different functions, ranging from surveillance to antigen presentation and cytokine secretion. Our study also provides a critical evaluation of the compatibility between rabies-mediated connectivity mapping and single-cell transcriptional profiling. These findings provide additional insights into the distinct contributions of various cell types in the antiviral response, and will serve as a resource for the design of strategies to circumvent immune responses to improve the efficacy of viral gene delivery.

Functional organization of the dorsal raphe efferent system with special consideration of nitrergic cell groups

2011 ◽  
Vol 41 (4) ◽  
pp. 281-293 ◽  
Author(s):  
Rani K. Vasudeva ◽  
Rick C.S. Lin ◽  
Kimberly L. Simpson ◽  
Barry D. Waterhouse
Keyword(s):  
Functional Organization ◽  
Dorsal Raphe ◽  
Special Consideration ◽  
Efferent System ◽  
Cell Groups ◽  
Dorsal Raphé

scholarly journals Molecular and anatomical organization of the dorsal raphe nucleus

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kee Wui Huang ◽  
Nicole E Ochandarena ◽  
Adrienne C Philson ◽  
Minsuk Hyun ◽  
Jaclyn E Birnbaum ◽  
...  
Keyword(s):  
Single Cell ◽  
Dorsal Raphe Nucleus ◽  
Cell Types ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Molecular Organization ◽  
Serotonergic Neuron ◽  
Multiple Cell ◽  
Dorsal Raphé

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 of the DRN and its diverse functions.

scholarly journals Estrogen withdrawal alters oxytocin signaling in the paraventricular hypothalamus and dorsal raphe nucleus to increase postpartum anxiety

2020 ◽  
Author(s):  
Valerie L. Hedges ◽  
Elizabeth C. Heaton ◽  
Claudia Amaral ◽  
Lauren E. Benedetto ◽  
Clio L. Bodie ◽  
...  
Keyword(s):  
Postpartum Period ◽  
Dorsal Raphe Nucleus ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Postpartum Anxiety ◽  
Syrian Hamsters ◽  
Estrogen Withdrawal ◽  
And Behavior ◽  
The Brain ◽  
Dorsal Raphé

AbstractBackgroundEstrogen increases dramatically during pregnancy, but quickly drops below pre-pregnancy levels at birth and remains suppressed during the postpartum period. Clinical and rodent work suggests that this postpartum drop in estrogen results in an “estrogen withdrawal” state that is related to changes in affect, mood, and behavior. Most studies examining the effect of estrogen withdrawal on the brain have focused solely on the hippocampus.MethodsWe used a hormone-simulated pseudopregnancy model in Syrian hamsters, a first for this species. Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal. Subjects were tested for behavioral assays of anxiety and anhedonia during estrogen withdrawal. Following sacrifice, neuroplasticity in oxytocin-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) and its efferent targets was measured.ResultsEstrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus and open field, but did not differ from controls in sucrose preference. Furthermore, estrogen-withdrawn females had more oxytocin-immunoreactive cells and oxytocin mRNA in the PVH, as well as an increase in oxytocin receptor density in the dorsal raphe nucleus (DRN). Finally, blocking oxytocin receptors in the DRN during estrogen withdrawal prevented the high-anxiety behavioral phenotype in estrogen-withdrawn females.ConclusionsEstrogen withdrawal alters oxytocin signaling in the PVH and DRN to increase anxiety-like behavior during the postpartum period. More broadly, these experiments suggest Syrian hamsters as a novel organism in which to model the effects of postpartum estrogen withdrawal on the brain and anxiety-like behavior.

scholarly journals Circadian photoperiod alters TREK-1 channel function and expression in dorsal raphe serotonergic neurons

2020 ◽  
Author(s):  
Manuel A. Giannoni-Guzmán ◽  
Anna Kamitakahara ◽  
Valerie Magalong ◽  
Pat Levitt ◽  
Douglas G. McMahon
Keyword(s):  
Ex Vivo ◽  
Dorsal Raphe ◽  
Resting Membrane Potential ◽  
Mrna Levels ◽  
Serotonergic Neurons ◽  
Electrophysiological Properties ◽  
Pharmacological Inhibition ◽  
Serotonin Neurons ◽  
Long Photoperiod ◽  
Dorsal Raphé

AbstractSeasonal daylength has been linked to the development and prevalence of mood disorders, however, the neural mechanisms underlying this relationship remain unknown. Previous work in our laboratory has shown that developmental exposure to seasonal photoperiods has enduring effects on the activity of mouse dorsal raphe serotonergic neurons, their intrinsic electrical properties, as well as on depression and anxiety-related behaviors. Here we focus on the possible ionic mechanisms that underlie the observed photoperiodic programming of the electrophysiological properties of serotonin neurons, focusing on the twin-pore K+ channels TREK-1 and TASK-1 that set resting membrane potential and regulate excitability. Using multielectrode array recordings in ex vivo dorsal raphe slices, we examined the effects of pharmacological inhibition of these channels on the spike rates of serotonin neurons of mice from different photoperiods. Pharmacological inhibition of TREK-1 significantly increased spike frequency in Short and Equinox photoperiod cohorts, but did not further elevate the firing rate in slices from Long photoperiod mice, suggesting that TREK-1 function is reduced in Long photoperiods. In contrast, inhibition of TASK-1 resulted in increases in firing rates across all photoperiods, suggesting that it contributes to setting excitability, but is not regulated by photoperiod. To examine if photoperiod impacts transcriptional regulation of TREK-1, we quantified Kcnk2 mRNA levels specifically in dorsal raphe 5-HT neurons using triple-label RNAscope. We found that Long photoperiod significantly reduced levels of Kcnk2 in serotonin neurons co-expressing Tph2, and Pet-1, Photoperiodic effects on the function and expression of TREK-1 were blocked in melatonin 1 receptor knockout (MT-1KO) mice, consistent with previous findings that MT-1 signaling is necessary for photoperiodic programming of dorsal raphe 5-HT neurons. Taken together these results indicate that photoperiodic regulation of TREK-1 expression and function plays a key role in photoperiodic programming the excitability of dorsal raphe 5-HT neurons.

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