Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training

Abstract

Memories are thought to be sparsely encoded in neuronal networks, but little is known about why a given neuron is recruited or allocated to a particular memory trace. Previous research shows that in the lateral amygdala (LA), neurons with increased CREB are selectively recruited to a fear memory trace. CREB is a ubiquitous transcription factor implicated in many cellular processes. Which process mediates neuronal memory allocation? One hypothesis is that CREB increases neuronal excitability to bias neuronal recruitment, although this has not been shown experimentally. Here we use several methods to increase neuronal excitability and show this both biases recruitment into the memory trace and enhances memory formation. Moreover, artificial activation of these neurons alone is a sufficient retrieval cue for fear memory expression, showing that these neurons are critical components of the memory trace. These results indicate that neuronal memory allocation is based on relative neuronal excitability immediately before training.

Neuronal Allocation to a Hippocampal Engram

“…Research focusing on other brain regions show that a neuron's participation in a given engram may be biased experimentally by manipulating its intrinsic excitability (Han et al, 2009;Zhou et al, 2009;Sano et al, 2014;Yiu et al, 2014). However, it is unknown whether the same rules of allocation apply to the DG.…”

“…However, it is unknown whether the same rules of allocation apply to the DG. We (Han et al, 2007(Han et al, , 2009Yiu et al, 2014) and others (Zhou et al, 2009;Gouty-Colomer et al, 2016), previously examined how neurons in the lateral nucleus of the amygdala (LA) are allocated to an engram supporting a discrete cue fear memory (in which an initially motivationally neutral auditory cue is paired with an aversive foot shock) (Davis, 1992;LeDoux, 2000;Maren, 2003). Increasing the function of the transcription factor CREB (Ca 2+ /cAMP response element-binding protein) in individual principal LA neurons increased the likelihood that a particular neuron would become part of a fear/threat memory engram (Han et al, 2007(Han et al, , 2009Zhou et al, 2009).…”

“…Furthermore, genetic ablation or suppression of LA neurons overexpressing CREB (and not an equal number of random LA neurons) impaired memory expression (Han et al, 2009;Zhou et al, 2009). Subsequent experiments showed that neurons with high CREB function were preferentially allocated to the LA fear memory engram owing to increased excitability (Zhou et al, 2009;Yiu et al, 2014). Specifically, increasing the excitability of a small population of LA neurons in the minutes before training using chemogenetics or optogenetics also resulted in preferential allocation of these more excitable neurons to the resulting engram (Yiu et al, 2014).…”

“…Subsequent experiments showed that neurons with high CREB function were preferentially allocated to the LA fear memory engram owing to increased excitability (Zhou et al, 2009;Yiu et al, 2014). Specifically, increasing the excitability of a small population of LA neurons in the minutes before training using chemogenetics or optogenetics also resulted in preferential allocation of these more excitable neurons to the resulting engram (Yiu et al, 2014). Artificially increasing excitability in a subset of neurons immediately before training may exaggerate endogenous processes that mediate normal memory encoding.…”

“…Artificially increasing excitability in a subset of neurons immediately before training may exaggerate endogenous processes that mediate normal memory encoding. Thus, during natural engram formation, neurons that happen to be more excitable at the time of training are likely allocated to the resulting engram (Yiu et al, 2014;Gouty-Colomer et al, 2016). Using this principle, viral vectors have been designed to express constructs to first allocate neurons to an engram and subsequently manipulate the function of these same neurons Sano et al, 2014).…”