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

doi:10.1016/j.isci.2023.108050

Pre- and postsynaptic N-methyl-D-aspartate receptors are required for sequential printing of fear memory engrams

iScience. 2023 Sep 25;26(11):108050. doi: 10.1016/j.isci.2023.108050. eCollection 2023 Nov 17.

Authors

Ilaria Bertocchi^{1

2}, Florbela Rocha-Almeida³, María Teresa Romero-Barragán³, Marco Cambiaghi⁴, Alejandro Carretero-Guillén⁵, Paolo Botta⁶, Godwin K Dogbevia^{1

7}, Mario Treviño^{1

8}, Paolo Mele², Alessandra Oberto², Matthew E Larkum⁹, Agnes Gruart³, Rolf Sprengel¹, José Maria Delgado-García³, Mazahir T Hasan^{1

5

10}

Affiliations

¹ Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.
² Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, 10043 Turin, Italy.
³ Division of Neurosciences, University Pablo de Olavide, Ctra. de Utrera, km. 1 41013 Seville, Spain.
⁴ Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, Verona, Italy.
⁵ 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.
⁶ CNS drug development, Copenhagen, Capital Region, Denmark.
⁷ Health Canada, 70 Colombine Driveway, Ottawa, ON K1A0K9, Canada.
⁸ Laboratorio de Plasticidad Cortical y Aprendizaje Perceptual, Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, Mexico.
⁹ NeuroCure, Charité-Universitatsmedizin, Virchowweg 6, 10117 Berlin, Germany.
¹⁰ Ikerbasque - Basque Foundation for Science, Bilbao, Spain.

Abstract

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.

Keywords: Behavioral neuroscience; Cellular neuroscience.