Divergent Modulation of Dopaminergic Neurons by Hypocretin/Orexin Receptors 1 and 2 Shapes Dopaminergic Cell Activity and Socioemotional Behavior
8 affiliations
- 1Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
- 2University of Lausanne
- 3Laboratory of Behavioral Genetics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- 4Department of Biotechnology and Biosciences and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, Milano, Italy
- 5Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
- 6CHUV and UNIL, Lausanne, Switzerland
- 7The University of Manchester, UK
- 8Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. Electronic address: [email protected]
Abstract
BACKGROUND Many neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA afferents from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DA VTA neurons arises from lateral hypothalamic area hypocretin/orexin (OX) neurons. Despite being a major input, the differential actions of OX peptides A and B on their receptors (OX 1 R and OX 2 R) in DA neurons is poorly understood. METHODS Using genetically engineered mice whose DA cells selectively lack OX input via Hcrtr1 (DA Ox1R-KO ) or Hcrtr2 (DA Ox2R-KO ), we assessed DA VTA neuron intrinsic excitability ex vivo , and evaluated behavioral phenotypes across socio-emotional and cognitive domains. RESULTS We discovered previously unrecognized effects of OX peptides on DA VTA cell response. While OXA enhanced DA VTA neuron firing via OX 1 R, OXB diminished firing via OX 2 R. Behaviorally, DA OX 1 R loss generated anxiety-like responding and context-dependent hyperactivity, while DA OX 2 R loss decreased sociability and compromised aversion-driven learning. Loss of either OX 1 R or OX 2 R in DA cells elicited impulsivity and compulsivity-like behavioral patterns. CONCLUSIONS We evidence distinct functions of OX 1 R vs OX 2 R signaling in modulating the intrinsic excitability of DA VTA neurons, and influencing DA-related behaviors. Our data implicate OX→DA signaling pathways in neuropsychiatric endophenotypes relevant to obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders, and inform therapeutic strategies targeting orexin receptors.
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BibTeX
@article{tzanoulinou2026divergent,
title = {{Divergent Modulation of Dopaminergic Neurons by Hypocretin/Orexin Receptors 1 and 2 Shapes Dopaminergic Cell Activity and Socioemotional Behavior}},
author = {Stamatina Tzanoulinou and Simone Astori and Laura Clara Grandi and Francesca Gullo and Richie Kalusivikako and Simran Rai and Galina Limorenko and Mehdi Tafti and Andrea Becchetti and Anne Vassalli},
journal = {Biological Psychiatry},
year = {2026},
month = jun,
doi = {10.1016/j.biopsych.2026.05.022},
url = {https://doi.org/10.1016/j.biopsych.2026.05.022},
note = {CC BY},
}
RIS
TY - JOUR
TI - Divergent Modulation of Dopaminergic Neurons by Hypocretin/Orexin Receptors 1 and 2 Shapes Dopaminergic Cell Activity and Socioemotional Behavior
AU - Stamatina Tzanoulinou
AU - Simone Astori
AU - Laura Clara Grandi
AU - Francesca Gullo
AU - Richie Kalusivikako
AU - Simran Rai
AU - Galina Limorenko
AU - Mehdi Tafti
AU - Andrea Becchetti
AU - Anne Vassalli
PY - 2026
DA - 2026/06/19
JO - Biological Psychiatry
DO - 10.1016/j.biopsych.2026.05.022
UR - https://doi.org/10.1016/j.biopsych.2026.05.022
AB - BACKGROUND Many neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA afferents from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DA VTA neurons arises from lateral hypothalamic area hypocretin/orexin (OX) neurons. Despite being a major input, the differential actions of OX peptides A and B on their receptors (OX 1 R and OX 2 R) in DA neurons is poorly understood. METHODS Using genetically engineered mice whose DA cells selectively lack OX input via Hcrtr1 (DA Ox1R-KO ) or Hcrtr2 (DA Ox2R-KO ), we assessed DA VTA neuron intrinsic excitability ex vivo , and evaluated behavioral phenotypes across socio-emotional and cognitive domains. RESULTS We discovered previously unrecognized effects of OX peptides on DA VTA cell response. While OXA enhanced DA VTA neuron firing via OX 1 R, OXB diminished firing via OX 2 R. Behaviorally, DA OX 1 R loss generated anxiety-like responding and context-dependent hyperactivity, while DA OX 2 R loss decreased sociability and compromised aversion-driven learning. Loss of either OX 1 R or OX 2 R in DA cells elicited impulsivity and compulsivity-like behavioral patterns. CONCLUSIONS We evidence distinct functions of OX 1 R vs OX 2 R signaling in modulating the intrinsic excitability of DA VTA neurons, and influencing DA-related behaviors. Our data implicate OX→DA signaling pathways in neuropsychiatric endophenotypes relevant to obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders, and inform therapeutic strategies targeting orexin receptors.
SN - 0006-3223
SN - 1873-2402
ER -