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Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems
Open accessAbstract
Summary The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.
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TL;DR
The dorsal raphe (DR) serotonin system contains anatomically and functionally distinct sub-systems, with cortical- and subcortical-projecting neurons differing in location, Vglut3 co-expression, collateralization, inputs, physiological responses, and behavior. Amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal cortex-projecting neurons promote active coping.
Key findings
- DR serotonin neurons projecting to subcortical regions localized more dorsally, while olfactory bulb and cortical-projecting neurons localized more ventrally; the subcortical and anterior cortical clusters overlapped by 17.4% and 39.6% of their volumes, respectively. Vglut3&Tph2 neurons overlapped 66%±0.6% with the anterior cortical cluster but only 19%±1.1% with the subcortical cluster.
- OFC- and CeA-projecting DR serotonin neurons showed largely complementary whole-brain collateralization patterns; many known DR targets were innervated by neither subpopulation. cTRIO input mapping found starter cells were predominantly serotonin neurons (97%±2% for OFC-projecting, 94%±4% for CeA-projecting), with OFC-projecting neurons receiving proportionally more input from lateral hypothalamus, lateral habenula, and most medulla nuclei, while CeA-projecting neurons received more input from CeA, BNST, PVH, and nucleus of the solitary tract.
- Both OFC- and CeA-projecting DR serotonin neurons were activated by reward, but OFC-projecting neurons showed significant pre-lever-press ramping compared with CeA-projecting neurons. To foot-shock, all 7 OFC-projecting mice showed long-lasting Ca2+ reduction, whereas all 8 CeA-projecting mice showed transient elevation.
- Chemogenetic activation of either OFC- or CeA-projecting neurons decreased locomotion. CeA-projecting neuron activation promoted anxiety-like behavior and Tph2 depletion was anxiolytic; OFC-projecting neuron Tph2 depletion enhanced anxiety-like behavior. OFC-projecting neuron activation enhanced escape behavior in the forced-swim test, and Tph2 deletion increased immobility; CeA-projecting neuron activation did not affect immobility, while Tph2 depletion reduced it.
Methods
- Viral-genetic retrograde tracing combined with Tph2/Vglut3 staining and registration to the Allen reference brain was used to map cell-body distributions of DR serotonin neurons projecting to eight target regions (PVH, CeA, LHb, dLGN, OB, OFC, PIR, ENT; n=4 per region).
- iDISCO+ whole-brain clearing and light-sheet imaging mapped collateralization of OFC- and CeA-projecting DR serotonin neurons; cTRIO rabies tracing identified monosynaptic inputs to these subpopulations.
- Fiber photometry with GCaMP6m recorded reward and foot-shock responses; gain- and loss-of-function experiments used hM3Dq chemogenetic activation and conditional Tph2 knockout, followed by open field, elevated plus maze, auditory fear conditioning, and forced-swim tests.
Limitations
- Stated: dual-color retrograde tracing had low co-labeling efficiency, preventing strong conclusions about individual DR serotonin neurons targeting multiple areas; subdivisions are not absolute, and each characterized sub-system may still be heterogeneous, with DRSert→OB possibly better described by a two-cluster model.
- Stated: Tph2 depletion is irreversible and compensatory circuit changes may occur before behavioral testing, so it may not reveal the full function of serotonin release; a small fraction of OFC- and CeA-projecting Tph2+ neurons came from median raphe, which may contribute to loss-of-function phenotypes.
- Stated: CeA-projecting Tph2 depletion’s forced-swim effect cannot be ruled out as secondary to movement; cTRIO counts did not adjust for possible double counting across consecutive sections and may underestimate posterior thalamic subregions. Evident from the text: fiber photometry during the manipulated behaviors was technically difficult, and many DR targets were not innervated by either OFC- or CeA-projecting subpopulation, implying additional uncharacterized sub-systems.
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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
“Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell body distributions within the DR and differentially co-express a vesicular glutamate transporter.”
- Also stated in: § DR Serotonin Neurons that Co-express Vglut3 Preferentially Project to Cortical Regions · plain
“many OB- and cortical-projecting serotonin neurons were Vglut3+, whereas subcortical-projecting serotonin neurons were mostly Vglut3−”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § DR Serotonin Neurons that Co-express Vglut3 Preferentially Project to Cortical Regions · plain
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
“our data was nevertheless consistent with OFC-projecting DR serotonin neurons had more overlap with OB-projecting ones than with CeA-projecting ones”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
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
“Likewise, serotonin neurons projecting to the OB, PIR, and OFC also exhibited considerable overlap, which we combined to produce an anterior cortical cluster (DRTph2→AC).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
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
“exhibit opposite responses to aversive stimuli”
- Also stated in: § DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment · plain
“DRSert→OFC and DRSert→CeA neurons showed opposing responses to foot-shock”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Mild electrical foot-shock is an aversive or punishing stimulus.
- Also stated in: § DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment · plain
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
“serotonin neurons projecting to subcortical regions localized more in the dorsal DR, whereas those that project to the OB and three cortical areas preferentially localized in the ventral DR”
- Also stated in: § DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations · plain
“DRTph2→SC and DRTph2→AC clusters preferentially occupied dorsal and ventral DR, respectively”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
- Also stated in: § DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations · plain
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
“We found that serotonin neurons projecting to the four subcortical sites appeared largely overlapping, which we combined to produce a subcortical cluster (DRTph2→SC)”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
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
“serotonin neurons projecting to subcortical regions localized more in the dorsal DR, whereas those that project to the OB and three cortical areas preferentially localized in the ventral DR”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
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
“receive biased inputs from presynaptic partners”
- Also stated in: § DRSert→OFC and DRSert→CeA Neurons receive biased input from specific nuclei · plain
“While presynaptic inputs to these two DR serotonin subpopulations originated from similar brain regions, there were striking quantitative differences.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § DRSert→OFC and DRSert→CeA Neurons receive biased input from specific nuclei · plain
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
“We found that Vglut3 also subdivided the DR serotonin neurons roughly into dorsal and ventral compartments”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Co-express Vglut3 Preferentially Project to Cortical Regions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell body distributions within the DR and differentially co-express a vesicular glutamate transporter.”
- Also stated in: § DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations · plain
“Co-staining of DR sections with tryptophan hydroxylase 2 (Tph2) revealed that serotonin neurons projecting to specific output sites have stereotyped cell body locations in the DR.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
- Also stated in: § DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations · plain
- It may state two separate claims as one. 36
- The quote only partly states this claim. 1
- Probably not a substantial claim. 31
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
“DRTph2→SC and DRTph2→AC clusters preferentially occupied dorsal and ventral DR, respectively, albeit with partial overlaps that accounted for 17.4% of the DRTph2→SC volume and 39.6% of the DRTph2→AC volume”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Project to Specific Targets Have Stereotyped Locations
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Tph2 staining reliably identifies serotonin-producing neurons.
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
“3D rendering suggested that DRSert→OFC and DRSert→CeA axons exhibited complementary whole-brain projection patterns, preferentially innervating superficial (cortical) and deep (subcortical) regions”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > OFC- and CeA-projecting DR Serotonin Neurons Have Largely Complementary Collateralization Patterns
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“the OFC and OB were intensively innervated by DRSert→OFC axons but lacked DRSert→CeA axons”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > OFC- and CeA-projecting DR Serotonin Neurons Have Largely Complementary Collateralization Patterns
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“we found that it had 66%±0.6% (mean±SEM) overlap with the DRTph2→AC but only 19%±1.1% overlap with the DRTph2→SC cluster”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Co-express Vglut3 Preferentially Project to Cortical Regions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“activation of DRSert→OFC neurons did not affect center entry or center time in the open field, or open-arm entry or time in open arms of the EPM”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→CeA but not DRSert→OFC Neurons Promote Anxiety-like Behavior
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Avoidance of the center in the open field and of the open arms in the elevated plus maze indicates anxiety-like behavior.
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
“Neither activation nor Tph2 depletion of DRSert➔OFC neurons affected fear learning and memory recall”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→CeA but not DRSert→OFC Neurons Promote Anxiety-like Behavior
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“all recordings from the DRSert group showed an activation after the onset of licking, and the evoked activity persisted during the reward consumption period”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment
What the sources say
- Not checked yetcites Li et al., 2016
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Sucrose water is a rewarding stimulus.
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
“Both our gain- and loss-of-function manipulations in the forced-swim test suggest that DRSert→OFC neurons, but not DRSert→CeA neurons, mediate this effect (Figure 7).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“The seven mice from the DRSert group showed more varied responses, including one that exhibited a biphasic response composed of a transient elevation followed by long-lasting depression”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Mild electrical foot-shock is an aversive or punishing stimulus.
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
“The DRSert→OFC and DRSert→CeA groups showed similar activation pattern”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Rests on an assumption: Sucrose water is a rewarding stimulus.
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
“While presynaptic inputs to these two DR serotonin subpopulations originated from similar brain regions, there were striking quantitative differences.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons receive biased input from specific nuclei
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“chemogenetic activation of both DRSert→OFC and DRSert→CeA neurons significantly decreased locomotion compared with controls”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > Both DRSert→OFC and DRSert→CeA Neurons Suppress Locomotion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“in all eight mice from the DRSert→CeA group, foot-shock induced a transient elevation of Ca2+ signals, followed by a small depression in a subset”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Mild electrical foot-shock is an aversive or punishing stimulus.
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
“Tph2 depletion from DRSert→OFC neurons caused a significant decrease in center time and center entry compared with controls (Figure 6B), as well as a significant decrease in open-arm time in the EPM”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→CeA but not DRSert→OFC Neurons Promote Anxiety-like Behavior
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Avoidance of the center in the open field and of the open arms in the elevated plus maze indicates anxiety-like behavior.
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
“activation of DRSert→CeA neurons promoted anxiety-like behavior, causing significantly decreased center entry and center time in the open field (Figure 6C) and activation significantly decreased open arm entry and open arm time (Figure 6G) compared to all controls except one case.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→CeA but not DRSert→OFC Neurons Promote Anxiety-like Behavior
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Avoidance of the center in the open field and of the open arms in the elevated plus maze indicates anxiety-like behavior.
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
“Tph2 depletion from DRSert→CeA neurons appeared anxiolytic, causing a significant increase in center entry in the open field (Figure 6D) and open arm time in EPM”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→CeA but not DRSert→OFC Neurons Promote Anxiety-like Behavior
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Avoidance of the center in the open field and of the open arms in the elevated plus maze indicates anxiety-like behavior.
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
“We found that, for nine out of ten datasets, one cluster had the same expressive power as multiple clusters and the only sub-system that might be better described as two clusters is DRSert→OB.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Previous studies showed that DR serotonin neurons, when treated as a whole, were activated during reward consumption in freely moving mice (Li et al., 2016).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment
What the sources say
- Not checked yetcites Li et al., 2016
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Sucrose water is a rewarding stimulus.
In the paper
“The dorsal raphe nucleus (DR) contains ~35% of ~26,000 serotonin-producing neurons in the mouse brain and is the predominant source of serotonergic innervation of the forebrain (Ishimura et al., 1988).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Introduction
What the sources say
- Not checked yetcites Ishimura et al., 1988 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“DR serotonin neurons as a whole receive monosynaptic inputs from diverse brain regions (Ogawa et al., 2014; Pollak Dorocic et al., 2014; Weissbourd et al., 2014).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons receive biased input from specific nuclei
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“recent studies on the effects of acute activation of DR serotonin neurons have reported divergent findings, including reinforcement (Liu et al., 2014), promotion of waiting for delayed reward rather than reinforcement (Fonseca et al., 2015; Miyazaki et al., 2012), promotion of anxiety-like behaviors and suppression of locomotion (Teissier et al., 2015; Urban et al., 2016), and suppression of locom”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It is the most widely used pharmacological target for treating depression and anxiety (Belmaker and Agam, 2008; Ravindran and Stein, 2010)”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Introduction
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.”
- Also stated in: § Discussion · plain
“Here we provide evidence for the existence of parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · plain
None of the sources cited for this claim have been checked yet.
In the paper
“However, a physiological and circuitry-based theory of how the serotonin system is organized to carry out its diverse functions remains elusive (Dayan and Huys, 2015; Muller and Jacobs, 2010).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Introduction
What the sources say
- Not checked yetcites Dayan and Huys, 2015
- Not checked yetcites Muller and Jacobs, 2010
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Whole-brain input mapping suggested heterogeneity of DR serotonin neurons has also been implicated with respect to presynaptic inputs (Weissbourd et al., 2014).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Introduction
What the sources say
- Not checked yetcites Weissbourd et al., 2014 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Based on retrograde tracing DR subregions may preferentially project to different targets (reviewed in Waselus et al., 2011).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Introduction
What the sources say
- Not checked yetcites Waselus et al., 2011 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“~60% of DR serotonin neurons co-express the vesicular glutamate transporter Vglut3 in the rat (Gras et al., 2002) and co-release glutamate in the mouse (Liu et al., 2014; Sengupta et al., 2017).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Co-express Vglut3 Preferentially Project to Cortical Regions
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“Thus, the DR serotonin system has a coordinated spatial and neurochemical organization with respect to its projection targets, although these subdivisions are not absolute.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DR Serotonin Neurons that Co-express Vglut3 Preferentially Project to Cortical Regions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Thus, DRSert→OFC neurons and frontal cortex→DRSert neurons may constitute a reciprocal loop to promote active coping in the face of challenge.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Immobility in the forced-swim test represents a passive coping strategy in the face of challenge and is often used to indicate a depression-like state in rodent models (Petit-Demouliere et al., 2005).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
What the sources say
- Not checked yetcites Petit-Demouliere et al., 2005 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
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
“These data indicate that DRSert→OFC and DRSert→CeA neurons respond similarly to reward, differently while anticipating an action that leads to reward, and oppositely to punishment.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC and DRSert→CeA Neurons Are Both Activated by Reward But Show Opposite Responses to Punishment
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Mild electrical foot-shock is an aversive or punishing stimulus.
- Rests on an assumption: Sucrose water is a rewarding stimulus.
In the paper
“A recent large-scale meta-analysis provided strong evidence for the efficacy of selective serotonin reuptake inhibitors in treating depression (Cipriani et al., 2018).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
What the sources say
- Not checked yetcites Cipriani et al., 2018 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Our retrograde tracing combined with image registration provides a more comprehensive view of the spatial organization of DR serotonergic projections in the mouse (Figure 1).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Anatomical Organization of the DR Serotonin System
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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
“These analyses further indicate that the collateralization of individual DR serotonin neurons can be extremely broad (e.g., DRSert→OFC neurons also innervate OB anteriorally and ENT posteriorally) yet highly specific (e.g., DRSert→OFC neurons innervate cortical amygdala but avoid the nearby basolateral amygdala).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Anatomical Organization of the DR Serotonin System
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“Taken together, these data suggest that activation of DRSert→OFC (but not DRSert→CeA) neurons promotes active coping in the face of challenge”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC but not DRSert→CeA Neurons Enhance Active Coping
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Immobility and struggle in the forced-swim test indicate passive and active coping, respectively.
None of the sources cited for this claim have been checked yet.
In the paper
“Thus, the input-output architecture of the DR serotonin system differs from that of the locus coeruleus norepinephrine system with more homogeneous input and output (Schwarz et al., 2015), and resembles more closely those of the midbrain dopamine systems (Beier et al., 2015; Lerner et al., 2015), with biased input and segregated output.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Anatomical Organization of the DR Serotonin System
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“We want to emphasize that each sub-system we characterized may still be heterogeneous in their composition.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Anatomical Organization of the DR Serotonin System
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Thus, the DR serotonin system contains at least two, and likely more, parallel sub-systems with distinct innervation patterns.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > OFC- and CeA-projecting DR Serotonin Neurons Have Largely Complementary Collateralization Patterns
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“Glutamate released from DRSert→OFC neurons may also contribute to this effect.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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
“this suggests that DRSert→CeA neurons inhibit escape behavior, although we cannot rule out this being a secondary effect on movement”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Results > DRSert→OFC but not DRSert→CeA Neurons Enhance Active Coping
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Immobility and struggle in the forced-swim test indicate passive and active coping, respectively.
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
“one interpretation is that activation of DRSert→OFC neurons results in release of both glutamate and serotonin that have opposing effects on anxiety-like behavior.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
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 conclusion, our behavioral analyses demonstrate that anatomically-segregated DR subsystems have distinct, and sometimes even opposing, functions (Figure 7E).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“DRSert→CeA neurons collateralize to other amygdala nuclei, BNST, and PVH (Figure 2), all of which have been implicated as anxiety-related regions (Calhoon and Tye, 2015).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
What the sources say
- Not checked yetcites Calhoon and Tye, 2015
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Bartlett’s test shows no significant difference among variance of groups.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Reported values of axonal labeling density for individual brain regions were normalized both to the volume of the region itself and the total labeling density for that sample to eliminate variability due to injection volume.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At the start of each recording session, fluorescence values in the 490-nm and 405-nm channels were approximately matched to ensure accurate fitting and subtraction during analysis.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Multiple comparisons were corrected when appropriate by adjusting pvalues using the Holm-Sidak method.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“According to the most recent report regarding the CNO and clozapine’s influence on locomotion/anxiety related behavior test, there is no side effect when the dose of CNO is 1 mg/kg, but significant side-effect when the dose of CNO is 10 mg/kg.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“According to histogram of dependent variable, the distributions of data meet normality assumption.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Animals were randomly assigned to experimental groups.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A current source density (CSD) analysis was performed by calculating the second spatial derivative of the LFP (Nicholson and Freeman, 1975). This was used to estimate the magnitude, direction, and location of synaptic current recorded in the LFPs.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
What the sources say
- Not checked yetcites Nicholson and Freeman, 1975
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“One mouse died before all the assays were completed.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All male mice used in gain- and loss-of-function behavioral experiments were test naïve for individual behavioral paradigms, and were individually housed with one female partner.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All the mice that survived the surgery were included in the data analysis.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“These decisions were made prior to analysis and were agreed upon by four separate anatomical experts.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not adjust for the possibility of double counting cells from consecutive sections, which would result in overestimates/tion, the extent of which would depend on the size of the cells in the regions quantified.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All procedures followed animal care and biosafety guidelines approved by Stanford University’s Administrative Panel on Laboratory Animal Care and Administrative Panel of Biosafety in accordance with NIH guidelines.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Optogenetic activation of prefrontal cortical neuron terminals in the DR has previously been shown to promote active coping (Warden et al., 2012).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
What the sources say
- Not checked yetcites Warden et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sessions were videotaped and independently analyzed by two researchers blind to genotype.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > METHOD DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample sizes were chosen based on those used in previous papers.”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Chemogenetic activation of DR serotonin neurons has recently been reported to reduce immobility in the forced-swim test (Teissier et al., 2015).”
§ Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems > Discussion > Distinct Functions of the DRSert→OFC and DRSert→CeA Sub-systems
What the sources say
- Not checked yetcites Teissier et al., 2015 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
Tph2 staining reliably identifies serotonin-producing neurons.
“Co-staining of DR sections with tryptophan hydroxylase 2 (Tph2) revealed that serotonin neurons projecting to specific output sites have stereotyped cell body locations in the DR.”
The paper relies on this without support.
Avoidance of the center in the open field and of the open arms in the elevated plus maze indicates anxiety-like behavior.
“Excessive avoidance of the center in the open field or the open arms of the elevated plus maze (EPM) are widely used as indications of anxiety-like behavior.”
The paper relies on this without support.
Immobility and struggle in the forced-swim test indicate passive and active coping, respectively.
“Immobility and struggle (escape behavior) in the forced-swim test are often used as indications of passive and active coping in the face of challenge, respectively.”
The paper relies on this without support.
Mild electrical foot-shock is an aversive or punishing stimulus.
“we recorded responses to punishment by subjecting the same set of mice to mild electrical shocks.”
The paper relies on this without support.
Sucrose water is a rewarding stimulus.
“we trained mice to lever press for a sucrose water reward in a fixed-ratio paradigm.”
The paper relies on this without support.
The behavioral paradigms used engage the DR serotonin system.
“We subjected the same sets of mice to a series of behavioral paradigms known to engage the DR serotonin system in a fixed sequence (STAR Methods).”
The paper relies on this without support.
Median raphe serotonin neurons make only a small contribution to the loss-of-function phenotypes.
“Although the vast majority of Tph2+ neurons that project to OFC and CeA were from DR, a small fraction were from median raphe (Figure S5E); thus median raphe serotonin neurons may have a small contribution to the loss-of-function phenotypes described below.”
The authors state this as an assumption.
The sectioning angle is parallel for each brain.
“we assumed a parallel sectioning angle for each brain.”
The paper relies on this without support.
A large fraction of DR serotonin neurons likely co-release glutamate.
“since a large fraction of DR serotonin neurons likely co-releases glutamate, Tph2 depletion specifically addresses the function of serotonin in these neurons.”
The paper relies on this without support.
Chemogenetic silencing requires a higher CNO concentration than chemogenetic activation.
“First, chemogenetic silencing requires a higher CNO concentration than does chemogenetic activation; as the active component of CNO may be clozapine (Gomez et al., 2017), which engages several serotonin receptors at high concentrations (Meltzer, 1994), this strategy may ectopically affect serotonin-related behavior.”
The paper relies on this without support.
1 mg/kg clozapine increases locomotor activity in the open field test.
“far below 1 mg/kg clozapine that has been reported to elevate locomotor activity in the open field test.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Those in the dorsal raphe project widely throughout the cortex and increase or decrease their activity to reward and punish, respectively.76,78”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [78]
In the citing paper
“In addition, deletion of either serotonin synthetic enzyme tryptophan hydroxylase 1 (Tph1) or vGluT3 (Slc18a8) from 5-HT/vGluT3+ neurons results in increased anxiety-like behaviors, suggesting that disrupting signaling from either transmitter has similar consequences.78,80”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [78]
In the citing paper
“Glutamate co-release from Vglut3+ serotonin terminals has indeed been reported at the hippocampus (Varga et al., 2009), orbital prefrontal cortex (Ren et al., 2018), nucleus accumbens (Liu et al., 2014), ventral tegmental area (Wang et al., 2019), and basolateral amygdala (Sengupta et al., 2017).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“Accumulating evidence indicates that there are subgroup-specific projection patterns within the DR serotonin system (Niederkofler et al., 2016; Ren et al., 2018).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“We found that serotonin axons from Vglut3+ population preferentially targeted cortical regions (Figure 6D), consistent with our previous results (Ren et al., 2018).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing 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).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“the cell body locations of these traced neurons (Figure 8—figure supplement 1B) were consistent with our previous results (Ren et al., 2018) as well as single-cell transcriptome, HCR-smFISH, and whole-brain bulk tracing data.”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing 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).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“The last finding is consistent with our previous study indicating that ~23% of CeA-projecting DR serotonin neurons are Vglut3+ (Ren et al., 2018).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing 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.”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“In our previous study, we characterized two projection-defined parallel DR serotonin sub-systems.”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing 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.”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“Comparisons of the projection patterns of Vglut3+ (this study) with OFC-projecting DR serotonin neurons (Ren et al., 2018) suggest that the latter is a large subset of the former.”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing 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).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“Our previous study suggests that DR serotonin sub-systems have biased input but segregated output (Ren et al., 2018).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“Together with our study on the projection-defined serotonin sub-systems (Ren et al., 2018), we believe it is unlikely that the major function of the forebrain-projecting serotonin system is to broadcast information non-discriminately.”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Ren et al., 2018
In the citing paper
“Functional differences exist between projection-defined subpopulations of DRN 5-HT neurons (Ren et al., 2018), but it is unknown if these subpopulations map onto molecularly defined subtypes.”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Ren et al., 2018
In the citing paper
“Consistent with previous reports (Ren et al., 2018; Waterhouse et al., 1986), we found that most subcortical-projecting neurons were located in the dorsal DRN, whereas most cortical-projecting neurons were located in the ventral DRN.”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Ren et al., 2018
In the citing paper
“It has been reported that cortical-projecting subpopulations of DRN 5-HT neurons express Slc17a8, in agreement with the extensive overlap between the spatial distribution of cortical-projecting neurons and Slc17a8 expression (Ren et al., 2018).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Ren et al., 2018
In the citing paper
“contains mostly Slc17a8-enriched 5-HT-IV subtype neurons that innervate cortex (Ren et al., 2018).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Ren et al., 2018
Citations
Cites
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
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Metadata
- Authors
- Ren, J., Friedmann, D., Xiong, J., Liu, C. D., Ferguson, B. R., Weerakkody, T., DeLoach, K. E., Ran, C., Pun, A., Sun, Y., Weissbourd, B., Neve, R. L., Huguenard, J., Horowitz, M. A., & Luo, L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Stanford University (US)
- Stanford Medicine (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Luo, Liqun
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 175
- Issue
- 2
- Pages
- 472-487.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6173627
- OpenAlex
- W2888526386
- Semantic Scholar
- 364f5903d96b83ef72cbb2223bffebb6a6c26848
- Cited by
- 498
- References
- 72
- Citations by year
- 2026: 61 · 2025: 71 · 2024: 73 · 2023: 74 · 2022: 45 · 2021: 59 · 2020: 66 · 2019: 43 · 2018: 5
- FWCI
- 19.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- BRAIN initiative
- National Institutes of Health (R01 NS104698)
- National Science Foundation (NeuroNex)
- HHMI
- 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
- dorsal raphe nucleus, serotonergic neurons, vesicular glutamate transporter, amygdala projections, presynaptic input, anxiety-like behavior, active coping, aversive stimuli
- MeSH terms
- Adaptation, Psychological, Amygdala, Animals, Anxiety, Brain, Female, Frontal Lobe, Male, Mice, Inbred C57BL, Neurons, Serotonin, Mice, Dorsal Raphe Nucleus
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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
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