Molecular Engrams

The main goal of my research team is to identify the bio-molecular framework on which aversive associative memories are built and maintained throughout their lifetime.

Research focus

Memory consolidation is a time-, gene- and protein-dependent process that transforms recently acquired information into long-term memory with a great degree of specificity. When this process is maladaptive, it can result in profound memory impairments that lie at the root of multiple neuropsychiatric disorders and dementias.
The biochemical alterations driving neuronal activity/plasticity of memory formation and its long-term storage occur in sparsely distributed networks of neuronal ensembles spanning multiple brain regions that form a physical trace of memory in the brain. These substrates of memory are collectively known as engrams. Research by myself, and others, has shown that bio-molecular adaptations in memory encoding engram cells of the hippocampus and cortex are necessary for the formation, adaptability and persistence of aversive memories.
Building on these findings, we now focus on systematic identification of proteomic adaptations at somatic and input-specific synaptic sites of engram neurons. In doing so, we aim to elucidate the bio-molecular architecture of intrinsic- and synaptic- neuronal plasticity signatures that drive memory stability and flexibility over time. Identifying how these molecular engrams of memory are regulated to enable information storage in neural circuits remains one of the most challenging questions of neuroscience that my team aims to answer.

Technical Toolbox

We make use of transgenic mouse lines, viral-vectors and associative-learning paradigms to specifically label sparse populations of memory-encoding engram neurons and the connections between them. The neurobiological profile of these neurons is generated by (i) combining cell/synapse-sorting with downstream transcriptomics/proteomics analysis, (ii) patch-clamp electrophysiology and (iii) spatiotemporally restricted manipulation of identified targets in combination with behavioral readouts.


To reach my goal I collaborate closely with the following research teams:
Guus Smit
Michel van den Oever
Sabine Spijker
Jan van Weering
Amsterdam Neuroscience
The O2Flow Facility MCBI
Steven Kushner at the Erasmus MC, Rotterdam
Hagen Tilgner at the Center for Neurogenetics, Brain and Mind Research Institute Weill Cornell Medical College, New York

Selected Publications

Interfering With Contextual Fear Memories by Post-reactivation Administration of Propranolol in Mice: A Series of Null Findings
Cox WR, Faliagkas L, Besseling A, van der Loo RJ, Spijker S, Kindt M, Rao-Ruiz P. Front Behav Neurosci. 2022 Jun 27;16:893572.

A Synaptic Framework for the Persistence of Memory Engrams
Rao-Ruiz, P., Visser, E., Mitrić M., Smit, A.B. & van den Oever, M.C.
Frontiers in Synaptic Neuroscience (2021) 13, ISSN:1663-3563

Engram-specific transcriptome profiling of contextual memory consolidation
Rao-Ruiz, P., Couey, J.J., Marcelo, I.M., Bouwkamp, C.G., Slump, D.E., Matos, M.R., van der Loo, R.J., Martins, G.J., van den Hout, M., van IJcken, W.F., Costa, R.M., van den Oever, M.C. & Kushner, S.A. (2019).
Nature communications (2019) 10:2232

Memory strength gates the involvement of a CREB-dependent cortical fear engram in remote memory
Matos, R.M., Visser, E., Kramvis, I., van der Loo, R.J., Gebuis, T., Zalm, R., Rao-Ruiz, P., Mansvelder, H.D., Smit, A.B. & van den Oever, M.C.
Nature communications (2019) 10:2315

Neuronal competition: microcircuit mechanisms define the sparsity of the engram
Rao-Ruiz P, Yu J, Kushner SA, Josselyn SA.
Curr Opin Neurobiol (2018) 54, 163-170

Emotional memory expression is misleading: delineating transitions between memory processes
Faliagkas L, Rao-Ruiz P & Kindt, M.
Current Opinion in Behavioral Sciences (2018), 19, 116-11.

Time-dependent changes in the mouse hippocampal synaptic membrane proteome after contextual fear conditioning
Rao-Ruiz P, Carney KE, Pandya N, van der Loo RJ, Verheijen MH, van Nierop P, Smit AB, Spijker S
Hippocampus (2015), 25(11):1250-61

Retrieval- specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear
Rao-Ruiz P, Rotaru DC, van der Loo RJ, Mansvelder HD, Stiedl O, Smit AB, Spijker S
Nature Neuroscience (2011), 14(10):1302-8.