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

Abstract

Competitive synaptic interactions between principal neurons (PNs) with differing intrinsic excitability were recently shown to determine which dorsal lateral amygdala (LAd) neurons are recruited into a fear memory trace. Here, we explored the contribution of these competitive interactions in determining the stimulus specificity of conditioned fear associations. To this end, we used a realistic biophysical computational model of LAd that included multi-compartment conductance-based models of 800 PNs and 200 interneurons. To reproduce the continuum of spike frequency adaptation displayed by PNs, the model included three subtypes of PNs with high, intermediate, and low spike frequency adaptation. In addition, the model network integrated spatially differentiated patterns of excitatory and inhibitory connections within LA, dopaminergic and noradrenergic inputs, extrinsic thalamic and cortical tone afferents to simulate conditioned stimuli as well as shock inputs for the unconditioned stimulus. Last, glutamatergic synapses in the model could undergo activity-dependent plasticity. Our results suggest that plasticity at both excitatory (PN–PN) and di-synaptic inhibitory (PN–ITN and, particularly, ITN–PN) connections are major determinants of the synaptic competition governing the assignment of PNs to the memory trace. The model also revealed that training-induced potentiation of PN–PN synapses promotes, whereas that of ITN–PN synapses opposes, stimulus generalization. Indeed, suppressing plasticity of PN–PN synapses increased, whereas preventing plasticity of interneuronal synapses decreased the CS specificity of PN recruitment. Overall, our results indicate that the plasticity configuration imprinted in the network by synaptic competition ensures memory specificity. Given that anxiety disorders are characterized by tendency to generalize learned fear to safe stimuli or situations, understanding how plasticity of intrinsic LAd synapses regulates the specificity of learned fear is an important challenge for future experimental studies.

Computational Models of the Amygdala in Acquisition and Extinction of Conditioned Fear

“…Hence, assignment of LA neurons to a memory trace depends on a competitive process, consistent with experimental data [89]. The nature, specificity, and details of synaptic competition in fear memory trace formation are further examined in two subsequent biophysical modeling studies [31,90].…”

Low-threshold spiking interneurons perform feedback inhibition in the lateral amygdala

“…Feedback inhibition is a circuit mechanism thought to be critical for the formation of specific engrams within the amygdala (Kim et al 2013;. Furthermore, the dendritic location of feedback interneuron inputs on principal neurons elsewhere endows these neurons with the capability of regulating excitatory inputs to the level of single dendritic branches and even spines (Golding et al 2002;Kampa et al 2006;Humeau and Luthi 2007;Lovett-Barron et al 2012;Bar Ilan et al 2013;Kim et al 2013Kim et al , 2016Cichon and Gan 2015) determining the exact locus of synaptic plasticity and formation of specific memories (Cichon and Gan 2015. In essence, the abovementioned mechanisms might be instrumental in parsing the LA into distinct sensory/functional compartments as is the case in other cortical regions (e.g. Fino and Yuste 2011;Adesnik et al 2012;Zhang et al 2014).…”

Might the olfactory bulb be an origin of olfactory auras in focal epilepsy?

“…The amygdala, associated with emotions, fear, anxiety, and other psychological phenomena is another region of great synaptic plasticity throughout life and may be influenced by hormones, DNA methylation by alcohol, hypoxia, neurotoxins, and other exogenous factors (Arruda‐Carvalho and Clem, ; Alisch et al ., ; Kuhn et al ., ; Li and Rainnie, ; Marin, ; Boitard et al ., ; Dall’Oglio et al ., ; Galvin et al ., ; Kim et al ., ; Stolyarova and Izquierdo, ).…”

“…The hippocampus must be plastic to enable the formation of new memory engrams and to facilitate deletion of others of no permanent importance (Moser et al, 1994;Engert and Bornhoeffer, 1999;Sanders et al, 2012;Yang et al, 2014;Attardo et al, 2015;Ryan et al, 2015), whereas stability of hippocampal dendritic spines is associated with the conservation of long-term memories (Yang et al, 2009). The amygdala, associated with emotions, fear, anxiety, and other psychological phenomena is another region of great synaptic plasticity throughout life and may be influenced by hormones, DNA methylation by alcohol, hypoxia, neurotoxins, and other exogenous factors (Arruda-Carvalho and Clem, 2014;Alisch et al, 2014;Kuhn et al, 2014;Li and Rainnie, 2014;Marin, 2014;Boitard et al, 2015;Dall'Oglio et al, 2015;Galvin et al, 2015;Kim et al, 2015;Stolyarova and Izquierdo, 2015). The olfactory bulb is another of the most synaptically plastic structures of the brain (Pomeroy et al, 1990;Mouly and Sullivan, 2010), yet its epileptogenic potential is unknown because this aspect has been little investigated or even considered in animals or humans.…”