Pre- and postsynaptic N-methyl-D-aspartate receptors are required for sequential printing of fear memory engrams
Ilaria Bertocchi,
Florbela Rocha-Almeida,
María Teresa Romero-Barragán,
Marco Cambiaghi,
Alejandro Carretero-Guillén,
Paolo Botta,
Godwin K. Dogbevia,
Mario Treviño,
Paolo Mele,
Alessandra Oberto,
Matthew E. Larkum,
Agnes Gruart,
Rolf Sprengel,
José Maria Delgado-García,
Mazahir T. Hasan
Affiliations
Ilaria Bertocchi
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany; Department of Neuroscience ''Rita Levi Montalcini'', Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy; Corresponding author
Florbela Rocha-Almeida
Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain
María Teresa Romero-Barragán
Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain
Marco Cambiaghi
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, Verona, Italy
Alejandro Carretero-Guillén
Laboratory of Brain Circuits Therapeutics, Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Sede Building, Barrio Sarriena, s/n, 48940 Leioa, Spain
Paolo Botta
CNS drug development, Copenhagen, Capital Region, Denmark
Godwin K. Dogbevia
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany; Health Canada, 70 Colombine Driveway, Ottawa, ON K1A0K9, Canada
Mario Treviño
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany; Laboratorio de Plasticidad Cortical y Aprendizaje Perceptual, Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, Mexico
Paolo Mele
Department of Neuroscience ''Rita Levi Montalcini'', Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy
Alessandra Oberto
Department of Neuroscience ''Rita Levi Montalcini'', Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy
Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain
Rolf Sprengel
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
José Maria Delgado-García
Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain; Corresponding author
Mazahir T. Hasan
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany; Laboratory of Brain Circuits Therapeutics, Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Sede Building, Barrio Sarriena, s/n, 48940 Leioa, Spain; Ikerbasque – Basque Foundation for Science, Bilbao, Spain; Corresponding author
Summary: The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for “printing” memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning. Further, we tagged fear-activated neurons during associative learning for optogenetic memory recall. We found that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, but not expression. Our results provide strong evidence that NMDAR-dependent synaptic plasticity drives multi-trace systems consolidation for the sequential printing of fear memory engrams from BLA to mPFC and, subsequently, to the other regions, for flexible memory retrieval.
