title: Active Dentate Granule Cells Encode Experience to Promote the Addition of Adult-Born Hippocampal Neurons.
abstract: The continuous addition of new dentate granule cells (DGCs), which is regulated exquisitely by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to affect the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+imaging to track the real-time activity of individual DGCs in freely behaving mice. For the first time, we found that active DGCs responded to a novel experience by increasing their Ca2+event frequency preferentially. This elevated activity, which we found to be associated with object exploration, returned to baseline by 1 h in the same environment, but could be dishabituated via introduction to a novel environment. To transition seamlessly between environments, we next established a freely controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences increased the number of newborn neurons accumulatively compared with a single experience. Finally, optogenetic silencing of existing DGCs during novel environmental exploration perturbed experience-induced neuronal addition. Our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active DGCs.SIGNIFICANCE STATEMENTAdult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By couplingin vivoCa2+imaging of dentate granule neurons with a novel, unrestrained virtual reality system for rodents, we discovered that a new experience increased firing of active dentate granule neurons rapidly and robustly. Exploration in multiple novel virtual environments, compared with a single environment, promoted dentate activation and enhanced the addition of new hippocampal neurons accumulatively. Finally, silencing this activation optogenetically during novel experiences perturbed experience-induced neuronal addition.
authors.affiliation: Medical Scientist Training Program.|Molecular and Cellular Pharmacology Program.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kirschen
authors.affiliation: Genetics Program.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Applied Mathematics and Statistics Program.
authors.forename: Mu
authors.identifier: 0000-0002-1116-4735
authors.initials: M
authors.lastname: Tian
authors.affiliation: Medical Scientist Training Program.|Department of Biomedical Engineering.
authors.forename: Bryce
authors.identifier: 0000-0001-7828-3053
authors.initials: B
authors.lastname: Schroeder
authors.affiliation: Department of Neurobiology and Behavior, and.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurobiology and Behavior, and.
authors.forename: Guoming
authors.initials: G
authors.lastname: Man
authors.affiliation: Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, New York 11794.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Neurobiology and Behavior, and shaoyu.ge@stonybrook.edu.
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Ge
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D018794:Problem-Based Learning
keywords: dentate granule cell; enriched environment; hippocampal neurogenesis; novel experience; virtual reality