Brain-wide mapping of contextual fear memory engram ensembles supports the dispersed engram complex hypothesis

Abstract

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, and cortex. It has been hypothesized that engrams for a specific memory are distributed among multiple brain regions that are functionally connected. Here, we report the hitherto most extensive engram map for contextual fear memory by characterizing activity-tagged neurons in 409 regions using SHIELD-based tissue phenotyping. The mapping was aided by a novel engram index, which identified cFos + brain regions holding engrams with a high probability. Optogenetic manipulations confirmed previously known engrams and revealed new engrams. Many of these engram holding-regions were functionally connected to the CA1 or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engrams, which mimics natural memory recall, conferred a greater level of memory recall than reactivation of a single engram ensemble. Overall, our study supports the hypothesis that a memory is stored in functionally connected engrams distributed across multiple brain regions.

MouseCircuits.org: An online repository to guide the circuit era of disordered affect

“…Chemogenetic activation of vHPC→mPFC during the forced swim test leads to differences in immobility, swimming, and climbing while optogenetic photostimulation results in differences in climbing and swimming only (30). Less subtle differences have been identified in experiments not covered, including differences in specific behavioral outcomes when a circuit is targeted with optogenetics versus chemogenetics (87).…”

“…A highly distributed pattern of activity and connectivity was observed, suggesting network redundancy within the brain (87). Single region activation of engram ensembles conferred fear memory recall (albeit not at the same level as multiple engram ensemble activation) demonstrating the ability of neurons within unitary regions to drive behavior despite not acting on their own endogenously (87). Figure 3 is that several pathways promote negative affect with some manipulations and positive affect with others, highlighting the complexity of the brain's architecture.…”

“…In a study utilizing activity-dependent tagging to label neurons activated during fear conditioning across 409 brain regions gives weight to this concept. A highly distributed pattern of activity and connectivity was observed, suggesting network redundancy within the brain (87). Single region activation of engram ensembles conferred fear memory recall (albeit not at the same level as multiple engram ensemble activation) demonstrating the ability of neurons within unitary regions to drive behavior despite not acting on their own endogenously (87).…”

“…Behaviors arise from coordinated activity in distributed networks across the entire brain (117). In fear learning for example, it was recently demonstrated that the memory is stored in connected engrams dispersed across the brain (87). While individual circuit findings cannot easily be interpreted in a brain-wide context, as data from individual cell types and pathways is added to a shared resource such as MouseCircuits.org, the interplay is likely to emerge over time.…”

Odor Modulates the Temporal Dynamics of Fear Memory Consolidation

“…Here, remote memories retain rich contextual detail (Suzuki and Naya, 2011) as long as the trace in the HPC is dominant at the time of retrieval. However, there is evidence to suggest that engrams are in fact, encoded in parallel across both brain regions (Kirchhoff et al, 2000;Blumenfeld and Ranganath, 2007;Qin et al, 2007;Goshen et al, 2011;Lesburgueres et al, 2011;Tayler et al, 2013) and that the architecture of memory traces formed during encoding are sparse but distributed (Rao-Ruiz et al, 2019;Roy et al, 2019) supporting a third, more flexible model, competitive trace theory (CTT). CTT suggests that multiple traces exist (e.g., HPC and PFC) and that memories do become more schematized or decontextualized over time and more reliant on neocortical storage but that the HPC can function to recontextualize memories, at any time, even at remote time points (Yassa and Reagh, 2013).…”