Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state
Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of...
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eLife Sciences Publications Ltd
2025-08-01
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| Online Access: | https://elifesciences.org/articles/105955 |
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| author | Christopher R Lee Gillian A Matthews Mackenzie E Lemieux Elizabeth M Wasserlein Matilde Borio Raymundo L Miranda Laurel R Keyes Gates P Schneider Caroline Jia Andrea Tran Faith Aloboudi May G Chan Enzo Peroni Grace Pereira Alba López-Moraga Anna Pallé Eyal Y Kimchi Nancy Padilla-Coreano Romy Wichmann Kay M Tye |
| author_facet | Christopher R Lee Gillian A Matthews Mackenzie E Lemieux Elizabeth M Wasserlein Matilde Borio Raymundo L Miranda Laurel R Keyes Gates P Schneider Caroline Jia Andrea Tran Faith Aloboudi May G Chan Enzo Peroni Grace Pereira Alba López-Moraga Anna Pallé Eyal Y Kimchi Nancy Padilla-Coreano Romy Wichmann Kay M Tye |
| author_sort | Christopher R Lee |
| collection | DOAJ |
| description | Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT) in mice, which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRNDAT projections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photostimulation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRNDAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRNDAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRNDAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli, suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual. |
| format | Article |
| id | doaj-art-db73e8f0e09e454eaebd1eeb39ae6913 |
| institution | Matheson Library |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-db73e8f0e09e454eaebd1eeb39ae69132025-08-01T10:33:38ZengeLife Sciences Publications LtdeLife2050-084X2025-08-011410.7554/eLife.105955Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like stateChristopher R Lee0https://orcid.org/0000-0002-5952-9924Gillian A Matthews1https://orcid.org/0000-0001-6754-0333Mackenzie E Lemieux2https://orcid.org/0000-0001-6015-8668Elizabeth M Wasserlein3Matilde Borio4Raymundo L Miranda5https://orcid.org/0009-0009-9694-1545Laurel R Keyes6https://orcid.org/0000-0001-5433-9948Gates P Schneider7Caroline Jia8Andrea Tran9Faith Aloboudi10May G Chan11https://orcid.org/0009-0005-6664-3521Enzo Peroni12Grace Pereira13https://orcid.org/0000-0003-4371-7020Alba López-Moraga14https://orcid.org/0000-0002-2084-4855Anna Pallé15Eyal Y Kimchi16https://orcid.org/0000-0003-4327-1102Nancy Padilla-Coreano17https://orcid.org/0000-0001-9293-2697Romy Wichmann18https://orcid.org/0000-0002-4506-8813Kay M Tye19https://orcid.org/0000-0002-2435-0182Salk Institute for Biological Studies, La Jolla, United States; Neurosciences Graduate Program, University of California San Diego, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United StatesSalk Institute for Biological Studies, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; Neurosciences Graduate Program, University of California San Diego, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United StatesSalk Institute for Biological Studies, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United StatesSalk Institute for Biological Studies, La Jolla, United States; Neurosciences Graduate Program, University of California San Diego, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United StatesSalk Institute for Biological Studies, La Jolla, United StatesSalk Institute for Biological Studies, La Jolla, United StatesSalk Institute for Biological Studies, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United StatesThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United StatesSalk Institute for Biological Studies, La Jolla, United States; Neurosciences Graduate Program, University of California San Diego, La Jolla, United States; Howard Hughes Medical Institute, La Jolla, United States; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United States; Kavli Institute for Brain and Mind, La Jolla, United StatesAffiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT) in mice, which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRNDAT projections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photostimulation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRNDAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRNDAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRNDAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli, suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.https://elifesciences.org/articles/105955valencesocialdorsal raphe nucleusdopamineamygdalaloneliness |
| spellingShingle | Christopher R Lee Gillian A Matthews Mackenzie E Lemieux Elizabeth M Wasserlein Matilde Borio Raymundo L Miranda Laurel R Keyes Gates P Schneider Caroline Jia Andrea Tran Faith Aloboudi May G Chan Enzo Peroni Grace Pereira Alba López-Moraga Anna Pallé Eyal Y Kimchi Nancy Padilla-Coreano Romy Wichmann Kay M Tye Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state eLife valence social dorsal raphe nucleus dopamine amygdala loneliness |
| title | Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state |
| title_full | Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state |
| title_fullStr | Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state |
| title_full_unstemmed | Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state |
| title_short | Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state |
| title_sort | separable dorsal raphe dopamine projections mimic the facets of a loneliness like state |
| topic | valence social dorsal raphe nucleus dopamine amygdala loneliness |
| url | https://elifesciences.org/articles/105955 |
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