title: Self-directed exploration provides a Ncs1-dependent learning bonus.
abstract: Understanding the mechanisms of memory formation is fundamental to establishing optimal educational practices and restoring cognitive function in brain disease. Here, we show for the first time in a non-primate species, that spatial learning receives a special bonus from self-directed exploration. In contrast, when exploration is escape-oriented, or when the full repertoire of exploratory behaviors is reduced, no learning bonus occurs. These findings permitted the first molecular and cellular examinations into the coupling of exploration to learning. We found elevated expression of neuronal calcium sensor 1 (Ncs1) and dopamine type-2 receptors upon self-directed exploration, in concert with increased neuronal activity in the hippocampal dentate gyrus and area CA3, as well as the nucleus accumbens. We probed further into the learning bonus by developing a point mutant mouse (Ncs1(P144S/P144S)) harboring a destabilized NCS-1 protein, and found this line lacked the equivalent self-directed exploration learning bonus. Acute knock-down of Ncs1 in the hippocampus also decoupled exploration from efficient learning. These results are potentially relevant for augmenting learning and memory in health and disease, and provide the basis for further molecular and circuit analyses in this direction.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Ho-Suk
authors.initials: HS
authors.lastname: Mun
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.|Preclinical Laboratory for Translational Research into Affective Disorders, University of Zurich Hospital for Psychiatry, August-Forel-Str 7, CH-8008, Zurich, Switzerland.|Neuroscience Center Zurich, Zurich, CH-8057, Switzerland.
authors.forename: Bechara J
authors.initials: BJ
authors.lastname: Saab
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Enoch
authors.initials: E
authors.lastname: Ng
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Psychiatry, University of British Columbia, Vancouver, BC, V6T 2A1, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: McGirr
authors.affiliation: Federal State Budgetary Scientific Institution, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, 630117, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Lipina
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Georgiou
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.|Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D004777:Environment; D005106:Exploratory Behavior; D055785:Gene Knockdown Techniques; D007858:Learning; D008297:Male; D008810:Mice, Inbred C57BL; D051580:Neuronal Calcium-Sensor Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D065852:Spatial Memory
chemical_list: C000600618:DRD2 protein, mouse; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; C101464:frequenin calcium sensor proteins