Neuronal Ensembles Organize Activity to Generate Contextual Memory

Abstract

Contextual learning is a critical component of episodic memory and important for living in any environment. Context can be described as the attributes of a location that are not the location itself. This includes a variety of non-spatial information that can be derived from sensory systems (sounds, smells, lighting, etc.) and internal state. In this review, we first address the behavioral underpinnings of contextual memory and the development of context memory theory, with a particular focus on the contextual fear conditioning paradigm as a means of assessing contextual learning and the underlying processes contributing to it. We then present the various neural centers that play roles in contextual learning. We continue with a discussion of the current knowledge of the neural circuitry and physiological processes that underlie contextual representations in the Entorhinal cortex-Hippocampal (EC-HPC) circuit, as the most well studied contributor to contextual memory, focusing on the role of ensemble activity as a representation of context with a description of remapping, and pattern separation and completion in the processing of contextual information. We then discuss other critical regions involved in contextual memory formation and retrieval. We finally consider the engram assembly as an indicator of stored contextual memories and discuss its potential contribution to contextual memory.

Keywords: contextual fear conditioning; entorhinal cortex; hippocampus; memory engram; neural circuits.

FIGURE 1

Depictions of contextual learning. (A) The exposure of an animal to a context results in learning of that context. However, in the absence of any frightening stimulus, no fear response will occur to the neutral context. (B) Pairing of a shock with a contextual stimulus will cause fear responses upon return to that conditioned context, indicating a pairing of shock memory with memory of the contextual cues. Subsequent placement in a second neutral context will not provoke a fear response. (C) Depiction of an immediate shock protocol. A mouse which is shocked immediately upon being placed in a context and removed after will not pair shock learning with context as insufficient encoding of the context itself has occurred. (D) Pre-exposure to a context will alleviate the failure to learn after immediate shock. Animals pre-exposed to the same or similar context 24 h prior to immediate shock protocol will associate the shock with the context. (E) Auditory fear conditioning can be added to create a more complex contextual pairing in which the fear response is tied both to the visual context and the auditory context (the tone). The tone can cause a fear response in a neutral context and generalization of fear to that context.

FIGURE 2

A schematic diagram of the brain regions and related connections involved in contextual fear learning. While several regions feature more prominently than others in this process, a number of regions are involved in generating and refining contextual representations and associations. ADT, Anterodorsal Thalamus; EC, Entorhinal Cortex; HPC, Hippocampus; LC, Locus Coeruleus; LS, Lateral Septum; MGN, Medial Geniculate Nucleus; NR, Nucleus Reuniens; PAG, Periaqueductal gray; PBN, Parabrachial Nucleus; PFC, Prefrontal Cortex; RSC, Retrosplenial Cortex.

FIGURE 3

Schematic diagram of the major connections of the EC-HPC network. Axons from the EC layer III and CalB⁺ pyramidal cell clusters in EC layer II project along the temporoammonic pathway (ECIII/ECII CalB⁺ → CA1), which largely governs temporal features, The indirect pathway, which is involved in spatial and contextual learning, originates from Reelin⁺ stellate cells within EC layer II and projects to the classical tripartite synapse (ECII Reelin⁺ → DG → CA3 → CA1). Additional connections from DG to CA2, and CA2 to CA1 exist alongside the more heavily studied hippocampal pathways.

FIGURE 4

Context engram reactivation in the hippocampus can trigger fear memories. (A) An animal receives a shock in Context A (orange box) and generates a context specific ensemble (orange circles) into which the shock memory is tied (contextual fear conditioning). (B) Upon re-exposure to context A, the previously generated neural ensemble is activated (indicated by lightning bolts), and a fear response to the context is triggered. Using active cell tagging, the previous contextual ensemble is marked with an opsin for later reactivation. (C) The animal explores a novel context (Context B; green box), with no association to the shock training, learns the context and generates a new contextual ensemble (green circles) and exhibits no fear response. (D) Optogenetic reactivation of the Context A ensemble causes reactivation of the fear memory associated with Context A in the setting of Context B.