title: Hypocretin/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice.
abstract: 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.
authors.affiliation: AfaSci Research Laboratories, Redwood City, CA 94063, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Yang
authors.forename: Bende
authors.initials: B
authors.lastname: Zou
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Xiong
authors.forename: Conrado
authors.initials: C
authors.lastname: Pascual
authors.forename: James
authors.initials: J
authors.lastname: Xie
authors.forename: Adam
authors.initials: A
authors.lastname: Malik
authors.forename: Julian
authors.initials: J
authors.lastname: Xie
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Xinmin Simon
authors.initials: XS
authors.lastname: Xie
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D056547:CA1 Region, Hippocampal / Q000166:cytology* / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D006185:Habituation, Psychophysiologic / Q000502:physiology; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000166:cytology / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D000068797:Orexins; D009924:Organ Culture Techniques; D055139:Sensory Gating / Q000502:physiology; D012903:Smell / Q000502:physiology; D012919:Social Behavior; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D014157:Transcription Factors; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse