title: Activating positive memory engrams suppresses depression-like behaviour.
abstract: Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders. Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia. The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments, although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus-amygdala-nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Ramirez
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: MacDonald
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Moffa
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Redondo
authors.affiliation: 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tonegawa
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D003863:Depression / Q000523:psychology* / Q000628:therapy*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D062308:Optogenetics; D057181:Pleasure / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013315:Stress, Psychological / Q000523:psychology; D013997:Time Factors
chemical_list: D016760:Proto-Oncogene Proteins c-fos