Memory Allocation: Mechanisms and Function

Abstract

Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry.

Keywords: allocation; engram; fear; memory; neuronal excitability; reward.

Figure 1

Using Pavlovian fear conditioning to study memory. (a) An initially motivationally neutral conditioned stimulus (CS), such as a tone, is paired with an aversive unconditioned stimulus (US), such as a foot shock. The US elicits an unconditioned response (UCR), an activity burst. Upon subsequent presentation of the tone CS in a novel context, rodents exhibit a conditioned response (CR), such as freezing. (b) Circuit diagram depicting converging sensory inputs to the lateral nucleus of the amygdala (LA) critical for auditory fear conditioning. Auditory information (CS pathway) travels from the auditory thalamus [medial geniculate nucleus, medial portion (MGm) and adjacent posterior intralaminar nucleus (PIN)], as well as from secondary auditory cortical regions (ACx), to the LA (see LeDoux et al. 1985, Linke et al. 2000). Information about the foot shock (US pathway) is relayed to the LA through the somatosensory thalamic nuclei (including the PIN) (see Lanuza et al. 2008, LeDoux et al. 1990, McDonald 1998, Shi & Davis 1999).

Figure 2

Schematic depicting allocation process in the lateral nucleus of the amygdala. (a) Although the majority of excitatory principal neurons (PNs) respond to both tone [conditioned stimulus (CS)] and shock [unconditioned stimulus (US)] inputs, only a small subset of these eligible neurons become allocated to a given auditory fear memory. Eligible PNs compete against one another for allocation, and neurons with increased excitability (filled green circles) at the time of training are more likely to win this competition and become allocated to that engram (circles outlined in red, also depicted in the graph on right). This has been shown using several different methods of increasing excitability, including overexpressing the transcription factor Ca²⁺/cAMP response element–binding protein (CREB), manipulating potassium channels, and using excitatory chemogenetic or optogenetic constructs. (b) In contrast, neurons with decreased excitability during training (filled teal circles) are less likely than their neighboring PNs with basal excitability to be allocated to an engram (circles outlined in red, also depicted in the graph on right). This has been shown by expressing a dominant-negative form of CREB and an inward-rectifying potassium channel (Kir2.1) (see Gouty-Colomer et al. 2015, Han et al. 2007, Kim et al. 2013, Rashid et al. 2016, Rogerson et al. 2016, Yiu et al. 2014, Zhou et al. 2009).

Figure 3

Allocation has been observed across several brain regions, including the CA1 region of the (a) dorsal hippocampus (CA1), dentate gyrus (DG), and piriform cortex, and (b) the insular cortex and lateral nucleus of the amygdala (LA). Representative publications are noted.

Figure 4

Schematic depiction of valence-agnostic allocation, summarizing experimental results from Choi et al. (2011). (a) A small, random population of principal neurons (PNs) in the piriform (odor) cortex are infected with the excitatory opsin ChR2. Photostimulation of this population (conditioned stimulus, CS) is paired with an aversive shock (unconditioned stimulus, US). Subsequent photostimulation of this population induces conditioned avoidance behavior (conditioned response, CR). Therefore, artificial activation of this random population of neurons alone is sufficient to elicit recall of an aversive memory by activating the engram supporting this memory. (b) Photostimulation of a similar small, random population of PNs in the piriform cortex is paired with water (appetitive US). Subsequent photostimulation induces conditioned licking (CR), showing that artificial activation of these neurons alone is sufficient to elicit recall of a rewarding memory. (c) The same random population of PNs can become first part of an appetitive memory and then part of an aversive memory. These data suggest that the PNs in the piriform cortex are valence agnostic rather than hardwired or genetically predetermined to be part of an aversive or appetitive memory.

Figure 5

Similarities between rodent and human imaging data on allocation and memory linking. (a, i) In the rodent lateral nucleus of the amygdala (LA), a population of excitatory principal neurons (PNs) is more excitable (light blue) than its neighbors (white) in the prestimulus period. During event 1, these more excitable neurons are allocated to the engram underlying event 1 (dark blue). Once allocated, neurons remain transiently excited for a limited period of time (roughly 6 h). If event 2 occurs within this window of increased excitability, then an overlapping population is allocated to the engram for event 2 (coallocation) (green). The memories are linked by virtue of coallocation. Following this period of increased excitation, previously allocated neurons show a decrease in excitability. If event 2 occurs beyond the time window of increased excitability (>6 h), then a new nonoverlapping population of neurons is relatively more excitable and this population is allocated to event 2 (disallocation) (green). The memories are separated. (a, ii) Coallocation may also occur following cue-induced recall of event 1. Allocated neurons are reactivated and remain transiently more excitable (dark blue) than their neighbors (white). If event 2 occurs within this window of excitability (<6 h), then an overlapping population is allocated to event 2 (coallocation) (green). If event 2 occurs beyond this time window (>6 h), then a nonoverlapping population is allocated to event 2 (disallocation) (green). (b) A similar process is thought to occur in human brains (Eichenbaum 2000, Schlichting & Frankland 2017). (b, i) Activation of a single functional MRI (fMRI) voxel (square) represents the average response across a population of neurons. Active voxels (light blue), relative to baseline voxels (white), are more likely to be allocated to the engram underlying event 1 (dark blue). If event 2 occurs after a short delay (top arrow), then overlapping populations may be engaged (green) and the memories may be linked. In contrast, if event 2 occurs after a long delay (bottom arrow), then dissimilar activation patterns (green) may be engaged (similar to disallocation) and memories may be separated. (b, ii) A similar mechanism supports memory integration across events related by shared content. The familiar elements in event 2 serve as a retrieval cue, leading to reactivation of event 1 representation. Event 2 may then be encoded in an overlapping (integrated) (top arrow) or nonoverlapping (separated) (bottom arrow) neural representation.

Figure 6

Coallocation and memory linking are mediated by neuronal excitability, as demonstrated by experimental results from Rashid et al. (2016) (see also Choi et al. 2011). A random small subset of principal neurons in the lateral nucleus of the amygdala (LA) is infected with the excitatory opsin ChR2 (light blue). Photostimulation of these neurons immediately before event 1 allocates these neurons to the engram underlying event 1 (dark blue). These neurons remain more excitable for roughly 6 h. If event 2 occurs less than 6 h later, then these same neurons are more excitable than their neighbors and coallocated, thus linking the memories. In contrast, if event 2 occurs 24 h later, then a different population of neurons is more excitable and allocated to event 2 (disallocation), thus separating the memories. Two distinct memories acquired 24 h apart may be artificially coallocated and linked if infected neurons are photostimulated prior to both event 1 and event 2.