Assignment of Model Amygdala Neurons to the Fear Memory Trace Depends on Competitive Synaptic Interactions

Abstract

We used biophysical modeling to examine a fundamental, yet unresolved, question regarding how particular lateral amygdala (LA) neurons are assigned to fear memory traces. This revealed that neurons with high intrinsic excitability are more likely to be integrated into the memory trace, but that competitive synaptic interactions also play a critical role. Indeed, when the ratio of intrinsically excitable cells was increased or decreased, the number of plastic cells remained relatively constant. Analysis of the connectivity of plastic and nonplastic cells revealed that subsets of principal LA neurons effectively band together by virtue of their excitatory interconnections to suppress plasticity in other principal cells via the recruitment of inhibitory interneurons. IntroductionClassical fear conditioning is an experimental paradigm used to investigate how animals learn to fear new stimuli by experience. In this model, a neutral sensory stimulus [conditioned stimulus (CS)] acquires the ability to elicit fear responses after a few pairings with a noxious stimulus [unconditioned stimulus (US)]. While there is evidence that fear conditioning induces widespread synaptic plasticity in the brain, including at thalamic and cortical levels (Letzkus et al., 2011; Weinberger, 2011), there are also data indicating that the dorsal portion of the lateral amygdala (LAd) is a critical site of plasticity for the storage of pavlovian fear memories (LeDoux, 2000; Pape and Paré, 2010). What is less clear is how particular LAd neurons are assigned to the fear memory trace. Indeed, relatively few LAd neurons (25%) acquire an increased responsiveness to stimuli predicting adverse outcomes (Quirk et al., 1995;Repa et al., 2001; Rumpel et al., 2005), even though most receive the necessary inputs (Han et al., 2007).In a previous study, we developed a biophysical LAd model that reproduced experimental findings regarding the cellular correlates of fear conditioning in LA ( Fig. 1A-D; Kim et al., 2013). We used it to examine whether fear memories depend on (1) training-induced increases in the responsiveness of thalamic and cortical neurons projecting to LA, (2) plasticity at the synapses they form in LA, and/or (3) plasticity at synapses between LA neurons. These tests revealed that training-induced increases in the responsiveness of afferent neurons are required for fear memory formation. However, once the memory has been formed, this factor is no longer required because the efficacy of the synapses that thalamic and cortical neurons form with LA cells has augmented enough to maintain the memory. In contrast, plasticity at synapses between LA neurons was found to play a minor role in maintaining the fear memory.In the present study, we use the model to examine how particular LA neurons are assigned to fear memory traces. Previously, it was reported that LA cells expressing high levels of activated cAMP response element-binding protein (CREB; hereafter "activated CREB" is denoted as "CREB") are preferentially recruited into the memory trace...

Memory Allocation

“…Conversely, blocking CREB-induced increases in neuronal excitability (by co-expressing Kir2.1, an inwardly rectifying K þ channel, which reduces neuronal excitability) prevented their preferential allocation (Yiu et al, 2014). Our finding that neurons are recruited to an engram based on neuronal excitability was predicted by a recent biophysical modeling study (Kim et al, 2013). Why allocate?…”

Finding the engram

“…Experimentally increasing excitability in a subset of neurons at the time of training may mimic and amplify endogenous processes that occur during normal mem ory encoding. Thus, during natural engram formation, neurons that happen to be more excitable at the time of training are preferentially allocated to the resulting engram 109,112 , an effect predicted by in silico modelling data 113 .…”

Synaptic competition in the lateral amygdala and the stimulus specificity of conditioned fear: a biophysical modeling study

“…The biophysical model was then used to investigate how particular LAd neurons are assigned to the fear memory trace (Kim et al 2013b). Indeed, after fear conditioning, relatively few LAd neurons develop an increased CS responsiveness (Quirk et al 1995; Repa et al 2001) even though most receive the necessary inputs (Han et al 2007).…”