An Integrated Index: Engrams, Place Cells, and Hippocampal Memory

Abstract

The hippocampus and its extended network contribute to encoding and recall of episodic experiences. Drawing from recent anatomical, physiological, and behavioral studies, we propose that hippocampal engrams function as indices to mediate memory recall. We broaden this idea to discuss potential relationships between engrams and hippocampal place cells, as well as the molecular, cellular, physiological, and circuit determinants of engrams that permit flexible routing of information to intra- and extrahippocampal circuits for reinstatement, a feature critical to memory indexing. Incorporating indexing into frameworks of memory function opens new avenues of study and even therapies for hippocampal dysfunction.

Keywords: engram; hippocampus; index; learning and memory; place cell; reinstatement.

Figure 1.. Comparing and contrasting hippocampal place cells and engram-tagged (immediate early gene-expressing) neurons.

Place cell activity has precise temporal structure both during exploration and rest, whereas engram-tagged neurons are simultaneously and experimentally reactivated. Place cell density appears moderate, and this density of active place cells is relatively stable in any given context. Conversely, engram-tagged cells in the hippocampus are sparse, with familiar contexts exhibiting low levels of tagged expression. Engram cells exhibit considerably less stability in their context-dependent reinstatement over time as compared to place cells, although both are highly unstable with time. Remote timepoints for reactivation of experience-dependent engram cells remain unknown. While there are overlapping behavioral correlates of place and engram cell activity, place cell research has led the field in its correlation to behavior.

Figure 2.

Hippocampal Memory Indexing Theory.

Figure 3.. Hippocampal (DG-CA3-CA2-CA1) circuit architecture and anatomical loops permits flexible integration and routing of experiential information.

(A) Examples of hippocampal inputs (blue arrows). (B) Examples of hippocampal outputs (orange arrows). Note that the projections shown are not exhaustive. Brain regions: anterior cingulate cortex (ACC); bed nucleus of the stria terminalis (BNST); basolateral/basomedial amygdala (BLA/BMA); central amygdala (CEA); dentate gyrus (DG); dorsal raphe nucleus (DRN); entorhinal cortex (EC); cornu ammonis regions (CA1–3); infralimbic cortex (IL); locus coeruleus (LC); anterior/lateral hypothalamic area (A/LHA); lateral septum (LS); medial septum (MS); nucleus accumbens (NAC); orbital frontal cortex (OFC); prelimbic cortex (PL); nucleus reuniens (RE); retrosplenial cortex (RSC); subiculum (SUB); supramammillary nucleus (SUM); ventral tegmental area (VTA). Brain region images were generated using Brain Explorer 2.0 [Allen Mouse Brain Atlas; (Lein et al., 2007)].

Figure 4.. Hippocampal engrams may index experience to reinstate experiential memory.

(A) Distinct experiences are thought to be encoded within DG-CA3-CA2-CA1 connections, with engram-bearing cells being functionally linked to other neurons for the same episode. Recall can then be driven by partial input (cues) that reinstate activity (filled-in circles/squares) within hippocampal circuits to drive extrahippocampal reinstatement via its diverse outputs and connectivity to other engram-bearing cells. PCs: principal cells; INs: inhibitory neurons. (B) Hippocampal cells may register more than one experience in distinct patterns of connectivity prescribed by activity-dependent gene expression (shown here as combinations of 1 and 0’s).

Figure 5.

Outstanding challenges for hippocampal indexing and memory research.