Hippocampal NPY Y2 receptors modulate memory depending on emotional valence and time. (December 2018)

• Record Type: Journal Article
• Authors: Hörmer, Birgit A.; Verma, Dilip; Gasser, Elisabeth; Wieselthaler-Hölzl, Anna; Herzog, Herbert; Tasan, Ramon O.
• Is Part Of: Neuropharmacology. Volume 143(2018)
• Page Start: 20
• Page End: 28
• Publication Date: 2018-12
• Subjects: Neuropeptide Y -- NPY -- Y receptors -- Fear -- Fear extinction -- Learning and memory; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.09.018
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Posttraumatic stress disorder is characterized by contextually inappropriate, dys-regulated and generalized fear expression and often resistant to therapy. The hippocampus integrates contextual information into spatial and emotional memories, but how diverse modulatory neurotransmitters are shaping this process is not known. Neuropeptide Y is a peptide-neurotransmitter, which modulates hippocampal excitability by activating several G-protein-coupled receptors. Postsynaptic Y1 receptors create strong anxiolytic and fear-suppressing behavior, while pre-synaptic Y2 receptors (Y2R) are mainly anxiogenic. The role of Y2Rs in spatial compared to emotional learning is, however, still controversial. Here we show that deletion of Y2Rs increased recall, but delayed extinction of contextual fear. Interestingly, spatial memory in the Barnes maze was enhanced during early and late testing, suggesting that Y2Rs suppress learning by hippocampal and extra-hippocampal mechanisms. To demonstrate sufficiency of hippocampal Y2Rs we performed viral vector-mediated, locally restricted re-expression of Y2Rs in the hippocampus of Y2KO mice. This treatment reduced spatial memory to the level of wildtype mice only during early, but not late recall. Furthermore, contextual fear was reduced, while induction of fear extinction appeared earlier. Our results suggest that hippocampal Y2R signaling inhibits learning in a time- and content-specific way, resulting in an early reduction of spatial memory and in a specific suppression of fear, by reducing fear recall and promoting fear extinction. We thus propose that reduction of hippocampal excitability through pre-synaptic Y2Rs may control the integration of contextual information into developing memories. Highlights: NPY and Y2 receptors are expressed by complementary neuronal populations of the dorsal hippocampus. Deletion of Y2 receptors increases contextual fear memory, while improving working memory and spatial memory. Re-expression of Y2 receptors in the dorsal hippocampus of Y2KO mice reduces contextual fear but decreases spatial memory. NPY may suppress contextual fear via Y2 receptors by inhibiting hippocampal memory processing.