Hypocretin/Orexin Neurons Contribute to Hippocampus-Dependent Social Memory and Synaptic Plasticity in Mice
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Hypocretin/orexin (Hcrt)-producing neurons in the lateral hypothalamus project throughout the brain, including to the hippocampus, where Hcrt receptors are widely expressed. Hcrt neurons activate these targets to orchestrate global arousal state, wake-sleep architecture, energy homeostasis, stress adaptation, and reward behaviors. Recently, Hcrt has been implicated in cognitive functions and social interaction. In the present study, we tested the hypothesis that Hcrt neurons are critical to social interaction, particularly social memory, using neurobehavioral assessment and electrophysiological approaches. The validated “two-enclosure homecage test” devices and procedure were used to test sociability, preference for social novelty (social novelty), and recognition memory. A conventional direct contact social test was conducted to corroborate the findings. We found that adult orexin/ataxin-3-transgenic (AT) mice, in which Hcrt neurons degenerate by 3 months of age, displayed normal sociability and social novelty with respect to their wild-type littermates. However, AT mice displayed deficits in long-term social memory. Nasal administration of exogenous Hcrt-1 restored social memory to an extent in AT mice. Hippocampal slices taken from AT mice exhibited decreases in degree of paired-pulse facilitation and magnitude of long-term potentiation, despite displaying normal basal synaptic neurotransmission in the CA1 area compared to wild-type hippocampal slices. AT hippocampi had lower levels of phosphorylated cAMP response element-binding protein (pCREB), an activity-dependent transcription factor important for synaptic plasticity and long-term memory storage. Our studies demonstrate that Hcrt neurons play an important role in the consolidation of social recognition memory, at least in part through enhancements of hippocampal synaptic plasticity and cAMP response element-binding protein phosphorylation.
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Orexin is associated with memory processing, motivation, reward, and addiction, which have been described as behaviors that are affected by TBI.
“Orexin is also associated with memory processing,113–116 motivation, reward,117 and addiction,118 which have been described as behaviors that are affected by TBI.9,119–123”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [116]
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- Authors
- Yang, L., Zou, B., Xiong, X., Pascual, C., Xie, J., Malik, A., Xie, J., Sakurai, T., & Xie, X. (.
- Affiliations
- AfaSci (United States) (US)
- Stanford Medicine (US)
- Kanazawa University (JP)
- Corresponding author
- Xie, Xinmin (Simon)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-03-20
- Volume
- 33
- Issue
- 12
- Pages
- 5275-5284
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3640412
- OpenAlex
- W2005346993
- Cited by
- 153
- References
- 64
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 14 · 2023: 6 · 2022: 16 · 2021: 14 · 2020: 13 · 2019: 14 · 2018: 9 · 2017: 6 · 2016: 12 · 2015: 10 · 2014: 10 · 2013: 2
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R41HL084990, R41HL84990)
- National Institute of Mental Health (R43MH076309, R01MH078194)
- National Institute on Drug Abuse (R44DA026363)
- National Institute of Neurological Disorders and Stroke (R43NS065555, R43NS073311)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- hypocretin/orexin, orexin neurons, social memory, social recognition memory, hippocampus, synaptic plasticity, long-term potentiation, paired-pulse facilitation, CREB, sociability, social novelty, CA1
- MeSH terms
- Ataxin-3, Orexins, Animals, Female, Habituation, Psychophysiologic, Hypothalamic Area, Lateral, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Neuronal Plasticity, Neurons, Neuropeptides, Nuclear Proteins, Organ Culture Techniques, Smell, Social Behavior, Transcription Factors, Cyclic AMP Response Element-Binding Protein, Long-Term Potentiation, Intracellular Signaling Peptides and Proteins, Mice, Sensory Gating, CA1 Region, Hippocampal, Memory, Long-Term
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