Selective Erasure of a Fear Memory

Abstract

Memories are thought to be encoded by sparsely distributed groups of neurons. However, identifying the precise neurons supporting a given memory (the memory trace) has been a long-standing challenge. We have shown previously that lateral amygdala (LA) neurons with increased cyclic adenosine monophosphate response element-binding protein (CREB) are preferentially activated by fear memory expression, which suggests that they are selectively recruited into the memory trace. We used an inducible diphtheria-toxin strategy to specifically ablate these neurons. Selectively deleting neurons overexpressing CREB (but not a similar portion of random LA neurons) after learning blocked expression of that fear memory. The resulting memory loss was robust and persistent, which suggests that the memory was permanently erased. These results establish a causal link between a specific neuronal subpopulation and memory expression, thereby identifying critical neurons within the memory trace.

Neuronal Allocation to a Hippocampal Engram

“…Neuronal allocation to an engram based on relative CREB function or excitability at the time of training was initially described in the LA for auditory fear memory (Han et al, 2007(Han et al, , 2009Zhou et al, 2009). Since that time, a similar allocation process was shown in several other brain regions supporting many types of memory, including in the LA for encoding of cocaine-conditioned place preference memories , in the LA for aversive memories (Zhou et al, 2009), in the insular cortex for encoding conditioned taste aversion (Sano et al, 2014), and in the piriform cortex during a shock avoidance paradigm (Choi et al, 2011).…”

“…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.…”

“…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).…”

“…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).…”

Selective Manipulation of Neural Circuits

“…Conditional expression of the receptor allows only the genetically modified cells to take up the toxin. In this approach, when diphtheria toxin was administrated, it was transferred only into the targeted cells and induced cell death [78,182,183]. Cholera toxin B fragment and wheat germ agglutinin are highly sensitive retrograde tracers [184][185][186].…”