NEUROSCIENCE

Intense threat switches dorsal rapheserotonin neurons to a paradoxicaloperational modeChangwoo Seo1,2*, Akash Guru1,2*, Michelle Jin1†, Brendan Ito1, Brianna J. Sleezer1,Yi-Yun Ho1,2, Elias Wang1‡, Christina Boada1§, Nicholas A. Krupa1,Durgaprasad S. Kullakanda1, Cynthia X. Shen1, Melissa R. Warden1,2¶

Survival depends on the selection of behaviors adaptive for the currentenvironment. For example, a mouse should run from a rapidly looming hawk butshould freeze if the hawk is coasting across the sky. Although serotonin has beenimplicated in adaptive behavior, environmental regulation of its functional roleremains poorly understood. In mice, we found that stimulation of dorsal rapheserotonin neurons suppressed movement in low- and moderate-threat environmentsbut induced escape behavior in high-threat environments, and that movement-relateddorsal raphe serotonin neural dynamics inverted in high-threat environments.Stimulation of dorsal raphe g-aminobutyric acid (GABA) neurons promotedmovement in negative but not positive environments, and movement-related GABAneural dynamics inverted between positive and negative environments. Thus,dorsal raphe circuits switch between distinct operational modes to promoteenvironment-specific adaptive behaviors.

The decision to move or to refrain frommovement depends on the structure of theenvironment and the internal state of theanimal. Imminent threats may provoke a“fight-or-flight” response, whereas distant

or uncertain threats may induce either vigilantfreezing or a delayed, strategic avoidance re-sponse (1, 2). Hunger may encourage travel to adistant food source, but a sated animal may notfind this goal worth the energy expenditure orrisk (3).Neuromodulatory systems receive input from

brain regions that represent environmental struc-ture and internal state (4) and are essential forthe coordinated regulation of the neural circuitsthat controlmovement.Whereas dopamine (DA)promotes behavioral activation in vertebrates (5, 6),forebrain serotonin (5-hydroxytryptamine; 5-HT)is more strongly associated with behavioral in-hibition (7, 8); elevated 5-HT promotes pausingand waiting (9–11), whereas reduced 5-HT pro-motes impulsivity and perseverative responding(12, 13). Paradoxically, selective serotonin re-uptake inhibitors (SSRIs) reduce immobility inthe forced swim test (FST) and tail suspension test(TST) (14), as does stimulation of the prefrontal-dorsal raphe nucleus (DRN) projection (15). We

sought to investigatewhether differences in envi-ronmental threat level underlie this discrepancy.We used fiber photometry (16) to monitor the

population dynamics of DRN 5-HT neurons infreely behavingmice (fig. S1A).We injected AAV5-CAG-FLEX-GCaMP6s (17) into the DRN of SERT-Cremice (18) and implanted an optical fiber overtheDRN (Fig. 1A and fig. S1B).Movement onset inthe open field test (OFT; Fig. 1B) was associatedwith a robust reduction in DRN 5-HT fluores-cence (Fig. 1, C toE; GFP control data, Fig. 1E andfig. S1, C to E). We then recorded DRN 5-HT ac-tivity during performance of a cued reward ap-proach task (Fig. 1F and fig. S2, A andB), inwhichmice crossed an operant chamber to receive areward, and found that activity decreased uponmovement in this environment (Fig. 1, G to I;movement offset, fig. S3, A and B).We also foundthat DRN 5-HT activity decreased upon move-ment to avoid a shock in a cued avoidance task(Fig. 1, J to M, and fig. S2, C and D; movementoffset, fig. S3, C and D).Next, we examined DRN 5-HT neural activity

during the TST (Fig. 2A), a high-threat environ-ment (19), and observed an increase in DRN 5-HTfluorescence upon movement onset (Fig. 2, B toD; GFP data, Fig. 2D and fig. S1, F to H; move-ment offset, fig. S3, E and F).We also observed anincrease in DRN 5-HT fluorescence upon move-ment onset in escape (failed) trials in the avoid-ance task (Fig. 2, E and F), during which micewere also in direct contact with the stressor.Finally,wemicroendoscopically recordedDRN5-HTactivity (20) and observed similar environment-dependent switching of movement dynamics insingle DRN 5-HT neurons (figs. S4 and S5). Thus,DRN 5-HT neural activity decreases upon move-ment initiation in low- or moderate-threat en-

vironments, but high-threat, escape-provokingenvironments invert this response.To probe the causal role of DRN 5-HT neurons

in regulating movement in different environ-ments, we optogenetically (21) activated 5-HTneurons (Fig. 3A and fig. S6A) during these be-haviors. Optical stimulation of DRN 5-HT neu-rons reduced speed in the OFT [Fig. 3, B and C;ChR2, 3.67 ± 0.31 cm/s; enhanced yellow fluo-rescent protein (eYFP), 5.16 ± 0.44 cm/s], as ex-pected (10). Speed decreased upon stimulationin both approach and avoidance tasks (approach:Fig. 3, D and E, and fig. S6, B and C; ChR2, 3.0 ±0.3 cm/s; eYFP, 7.1 ± 1.0 cm/s; avoidance: Fig. 3,GandH, and fig. S6,DandE;ChR2, 2.2±0.4 cm/s;eYFP, 3.8 ± 0.4 cm/s), and latency to chambercrossing was greater in stimulated animals inboth tasks (Fig. 3, F and I). TST stimulation inthe same mice produced an increase in move-ment (Fig. 3, J to L). These data provide causalevidence for a switch in DRN 5-HT neuron func-tion from suppression to facilitation of move-ment in high-threat escape conditions.We then investigated the movement-related

dynamics of DRN GABA neurons using fiberphotometry in Vgat-ires-Cre mice (22) (fig. S7,A and B, and fig. S8). Activity decreased uponmovement to cross the chamber in the approachtask (Fig. 4, A to C; movement offset, fig. S3, GandH) but increased uponmovement to cross thechamber in the avoidance task (Fig. 4, F to H;movement offset, fig. S3, I and J), switching ata lower threat level than DRN 5-HT neurons.Recordings during avoidance training revealedrapid switching after the first few shocks (figs. S9and S10).Approach and avoidance differ in environ-

mental valence, and we found that movement-related dynamics also switched in other valencedenvironments. Wheel running (Fig. 4K) induceda reduction in DRN GABA activity (Fig. 4, L to N;GFP data, Fig. 4N and fig. S7, C to E), but DRNGABA neural activity increased upon movementduring the TST (Fig. 4, P to S; GFP data, Fig. 4Sand fig. S7, F to H; movement offset, fig. S3, Kand L) and upon movement in escape (failed)trials in the avoidance task (fig. S7, I to L).Finally, we investigated whether DRN GABA

neurons have a causal role in movement regu-lation. Optogenetic stimulation of GABA DRNneurons (fig. S11, A and B) had no impact onspeed (Fig. 4, D and E, and fig. S11, C and D;ChR2, 7.3 ± 0.7 m/s; eYFP, 6.7 ± 1.0 m/s), noron latency to chamber crossing (fig. S11E) inthe approach task or on wheel mobility (Fig. 4O),but stimulation in these same mice inducedhigher speed in the OFT (fig. S12, A to D). Stim-ulation increased speed (Fig. 4, I and J, and fig.S11, F and G; ChR2, 7.7 ± 0.7 m/s; eYFP, 4.0 ±0.2 m/s) and reduced latency (fig. S11H) in theavoidance task, and increased movement in theTST (Fig. 4T), thereby revealing a causal role forDRN GABA neurons in promoting movement inenvironments with negative valence.These findings show that changes in environ-

mental threat intensity and valence switch thefunctional roles of DRN5-HT andGABAneurons

RESEARCH

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1Department of Neurobiology and Behavior, CornellUniversity, Ithaca, NY 14853, USA. 2Cornell Neurotech,Cornell University, Ithaca, NY 14853, USA.*These authors contributed equally to this work. †Presentaddress: Neurobiology of Relapse Section, National Institute onDrug Abuse (NIDA) Intramural Research Program, Baltimore,MD 21224, USA. ‡Present address: Department of ElectricalEngineering, Stanford University, Stanford, CA 94305, USA.§Present address: School of Medicine, New York University,New York, NY 10016, USA.¶Corresponding author. Email: mrwarden@cornell.edu

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Fig. 1. DRN 5-HTneural activity decreases upon movement in low- ormoderate-threat environments. (A) GCaMP6s expression in DRN5-HT neurons in a SERT-Cre mouse. (B) OFT schematic. (C) Example OFTphotometry from a SERT::GCaMP6s mouse. Black, GCaMP DF/F; red,speed. (D) Mean DF/F aligned to OFTmovement onset. (E) Mean DF/Fbefore and after OFTmovement onset in GCaMP (n = 9) and GFP (n = 3)mice. (F) Approach task schematic. (G) Example approach photometry

from the same mouse. (H) Mean DF/F aligned to approach movementonset. (I) Mean DF/F before and after approach movement onset in GCaMP(n = 7) mice. (J) Avoidance task schematic. (K) Example avoidancephotometry data from the same mouse. (L) Mean DF/F aligned to avoidancemovement onset. (M) Mean DF/F before and after avoidance movementonset inGCaMP (n=7)mice. *P<0.05, **P<0.01 (Wilcoxon signed-rank test);ns, not significant. Shaded areas in (D), (H), and (L) indicate SEM.

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Fig. 2. DRN 5-HTneural activity increases upon movementin high-threat environments. (A) TSTschematic. (B) ExampleTST photometry from the mouse in Fig. 1. Black, GCaMPDF/F; red, movement. (C) Mean DF/F aligned to TSTmovementonset. (D) Mean DF/F before and after TSTmovement onsetin GCaMP (n = 8) and GFP (n = 2) mice. (E) Mean DF/F alignedto escape movement onset during failed avoidance trials.(F) Mean DF/F before and after escape movement onset inGCaMP (n = 7) mice. *P < 0.05, **P < 0.01 (Wilcoxon signed-rank test). Shaded areas in (C) and (E) indicate SEM.

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Fig. 3. DRN 5-HT stimulation suppresses or promotes movement atdifferent threat levels. (A) ChR2-eYFP expression in DRN 5-HTneurons ina SERT-Cre mouse. (B) Speed aligned to light onset, OFT (SERT::ChR2-eYFP, n = 7; SERT::eYFP, n = 7). (C) Mean speed during stimulation, OFT.(D) Speed aligned to light/cue onset, approach task (SERT::ChR2-eYFP,n = 7; SERT::eYFP, n = 6). (E) Mean speed during stimulation, approachtask. (F) Latency to cross, approach task. P < 0.0001 (log-rank test).(G) Speed aligned to light/cue onset, avoidance task (SERT::ChR2-eYFP,

n = 7; SERT::eYFP, n = 6). (H) Mean speed during stimulation, avoidancetask. (I) Latency to cross distribution, avoidance task. P < 0.0001(log-rank test). (J) Movement aligned to light onset, TST (SERT::ChR2-eYFP, n = 7; SERT::eYFP, n = 6). (K) Mean difference between pre- andpost-light onset movement, TST. (L) SERT::ChR2-eYFP movement beforeand after light onset, TST. *P < 0.05, **P < 0.01 (Wilcoxon rank sumtest). Shaded areas in (B), (D), (G), and (J) and vertical lines in (C), (E),(H), and (K) indicate SEM.

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in movement regulation. The notion that move-ment in states of extreme threatmay be differentlyregulated is not without precedent. Paradoxicalkinesia hasbeenobserved inakinetic Parkinsonianpatients (23), andDA-depletedakinetic rats attemptescape in deep water (24), suggesting alternativemotor regulation in fight-or-flight situations. DRNfunction during stress is regulated by a numberof systems that may play a role in environment-dependent functional switching; SSRI-inducedTST immobility reduction requires DRN nor-epinephrine (25); DRN corticotropin-releasingfactor inhibits 5-HT release and promotes ac-tive coping or the reverse, depending on stress

history (26, 27); and DRN activation is dam-pened by prefrontal activity during controlla-ble stress (28).Our experiments probed the neural dynamics

and functional roles of two distinct DRN cell typesin movement regulation. Our findings showthat urgent escape conditions switch DRN 5-HT neurons from suppression of movement tofacilitation, and that DRN GABA neurons se-lectively facilitate movement in environmentswith negative valence, consistent with the neuraldynamics that we observed in both cell types.These results reveal a role for DRN circuits inrapid, environment-specific behavioral regulation.

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Fig. 4. DRN GABA stimulation promotes movement in environmentswith negative valence. (A) Approach photometry example from aVgat::GCaMP6s mouse. Black, GCaMP DF/F; red, speed. (B) Mean DF/Faligned to approach movement onset. (C) Mean DF/F before and afterapproach movement onset (n = 11). (D) Speed aligned to stimulation/cueonset, approach (Vgat::ChR2-eYFP, n = 8; Vgat::eYFP, n = 7). (E) Meanspeed during stimulation, approach. (F) Example avoidance photometry.(G) Mean DF/F aligned to avoidance movement onset. (H) Mean DF/Fbefore and after avoidance movement onset (n = 10). (I) Speed alignedto stimulation/cue onset, avoidance (Vgat::ChR2-eYFP, n = 8; Vgat::eYFP,n = 7). (J) Mean speed during stimulation, avoidance. (K) Wheelschematic. (L) Example wheel photometry. (M) Mean DF/F aligned to

wheel movement onset. (N) Mean DF/F before and after wheel movementonset in GCaMP (n = 9) and GFP (n = 3) mice. (O) Mean mobile timein 3-min stimulation or nonstimulation blocks, wheel (Vgat::ChR2-eYFP,n = 7; Vgat::eYFP, n = 7; P = 0.9015, Wilcoxon rank sum test). (P) TSTschematic. (Q) TST photometry example. (R) Mean DF/F aligned toTSTmovement onset. (S) Mean DF/F before and after TSTmovementonset in GCaMP (n = 9) and GFP (n = 3) mice. (T) Mean mobile timein 3-min stimulation or nonstimulation blocks, TST (Vgat::ChR2-eYFP,n = 7; Vgat::eYFP, n = 7; P = 0.007, Wilcoxon rank sum test). **P < 0.01,***P < 0.001 [Wilcoxon signed-rank test (photometry) or Wilcoxonrank sum test (optogenetics)]. Shaded areas in (B), (G), (M),and (R) and vertical lines in (E), (J), (O), and (T) indicate SEM.

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ACKNOWLEDGMENTS

We thank T. J. Davidson and C. B. Schaffer for photometryadvice; P. Dayan, I. T. Ellwood, R. M. Harris-Warrick, R. R. Hoy,J. H. Goldberg, J. R. Fetcho, E. Troconis, and D. A. Bulkin for helpfuldiscussions and/or comments on the manuscript; T. Bollu fortechnical advice; G. Paquelet for microendoscopy advice; U. Lee forcontributions to figure design; A. K. Recknagel for expert technicalassistance; and the Warden laboratory and Cornell Neurobiologyand Behavior for training and support. Funding: Supported by theMong Family Foundation (C.S., Y.-Y.H., A.G.), the Taiwan Ministryof Education (Y.-Y.H.), NIH DP2MH109982 (M.R.W.), the AlfredP. Sloan Foundation (M.R.W.), the Whitehall Foundation(M.R.W.), and the Brain and Behavior Research Foundation(M.R.W.). M.R.W. is a Robertson Neuroscience Investigator–NewYork Stem Cell Foundation. Author contributions: C.S. andM.R.W. conceived the project and designed the experiments;C.S., M.J., B.I., B.J.S., C.B., and N.A.K. performed stereotaxicsurgery and histology; C.S., M.J., C.B., N.A.K., and D.S.K.

conducted photometry and optogenetic experiments; A.G.,B.I., B.J.S., and C.S. conducted single cell physiologyexperiments; C.S. and Y.-Y.H. developed the behavioral dataacquisition methods; C.S., A.G., B.J.S., M.J., E.W., C.X.S., andM.R.W. analyzed the data; C.S. and M.R.W. prepared themanuscript; and M.R.W. supervised all aspects of the work.Competing interests: The authors declare no competingfinancial interests. Data and materials availability: All dataare available in the manuscript or the supplementary materials.We thank the University of North Carolina vector core forthe ChR2, eYFP, and GFP vectors; the University of Pennsylvaniavector core for the GCaMP6s vector; and the Stanford vectorcore for the GCaMP6m vector. These were made availableunder a material transfer agreement.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/363/6426/538/suppl/DC1Materials and MethodsFigs. S1 to S12Table S1References (29, 30)

9 August 2018; accepted 4 January 201910.1126/science.aau8722

Seo et al., Science 363, 538–542 (2019) 1 February 2019 5 of 5

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Intense threat switches dorsal raphe serotonin neurons to a paradoxical operational mode

A. Krupa, Durgaprasad S. Kullakanda, Cynthia X. Shen and Melissa R. WardenChangwoo Seo, Akash Guru, Michelle Jin, Brendan Ito, Brianna J. Sleezer, Yi-Yun Ho, Elias Wang, Christina Boada, Nicholas

DOI: 10.1126/science.aau8722 (6426), 538-542.363Science 

, this issue p. 538Scienceactivity decreased when movement was initiated in low-threat environments but increased in high-threat environments.Recordings from these neurons indicated that movement-related neural tuning flipped between environments. Neuralenvironments, but when this same neural population was stimulated in high-threat environments, mice tried to escape.

found that mice paused when serotonin neurons were transiently stimulated in low- or medium-threatet al.way? Seo Could it be that the brain in a state of emergency or under intense threat operates in a fundamentally different

Flipping behavior under threat

ARTICLE TOOLS http://science.sciencemag.org/content/363/6426/538

MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2019/01/30/363.6426.538.DC1

REFERENCES

http://science.sciencemag.org/content/363/6426/538#BIBLThis article cites 30 articles, 1 of which you can access for free

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