The relative contributions of plasticity in the amygdala vs. its afferent pathways to conditioned fear remain controversial. Some believe that thalamic and cortical neurons transmitting information about the conditioned stimulus (CS) to the lateral amygdala (LA) serve a relay function. Others maintain that thalamic and/or cortical plasticity is critically involved in fear conditioning. To address this question, we developed a large-scale biophysical model of the LA that could reproduce earlier findings regarding the cellular correlates of fear conditioning in LA. We then conducted model experiments that examined 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, our model experiments suggest that plasticity at synapses between LA neurons plays a minor role in maintaining the fear memory.

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...

The lateral nucleus of amygdala (LA) is known to be a critical storage site for conditioned fear memory. Synaptic plasticity at auditory inputs to the dorsal LA (LAd) is critical for the formation and storage of auditory fear memories. Recent evidence suggests that two different cell populations (transient- and long-term plastic cells) are present in LAd and are responsible for fear learning. However, the mechanisms involved in the formation and storage of fear are not well understood. As an extension of previous work, a biologically realistic computational model of the LAd circuitry is developed to investigate these mechanisms. The network model consists of 52 LA pyramidal neurons and 13 interneurons. Auditory and somatosensory information reaches LA from both thalamic and cortical inputs. The model replicated the tone responses observed in the two LAd cell populations during conditioning and extinction. The model provides insights into the role of thalamic and cortical inputs in fear memory formation and storage.

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One of the main contributions of the dissertation is an explanation of how and why certain neurons are recruited into a memory trace. For this, we developed a biophysical model of the rodent lateral amygdala (LA) and then examined how particular LA neurons are assigned to the fear memory trace, i.e., how fear memory is formed in a rodent brain, after Pavlovian fear conditioning. The model 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. We also examined the relative contributions of plasticity in auditory afferent (thalamic, cortical) neurons vs. within LA. This revealed that plasticity in afferent pathways to LA is required for fear memory formation, but that once formed, the plasticity in afferent pathways was not needed. The model then provided insights into how 'competition' was implemented at the single cell level, including the role of excitatory connections among neurons, of disynaptic inhibition, and of neuromodulation. These principles should also apply to other forms of memory in brains. We then investigated another related concept of specificity of memory, i.e., how can memory of one music prevented from interfering with that of another. Analysis showed that formation of memory involves plasticity in the connections within LAd and this plasticity also ensures specificity for that memory. Neuronal network models presently use simplified single cells models with either one or two compartments. This is largely due to the fact that computational overhead become prohibitive with more detailed models. We report a procedure to develop a reduced order model matching passive properties, current injection traces, and preserving some synaptic integration features. Comparisons are made at both single cell and with a 100-cell network model. Analysis showed that a model with three compartments provides a good compromise between biological realism and ease of computation.