The neural circuitry of fear conditioning : a theoretical account

In the last decades, fear conditioning has been established as one of the most successful paradigms for studying the neural substrates of emotional learning. Experimental research has revealed a complex circuitry of brain regions—most prominently the amygdala—underlying the acquisition, extinction and generalization of conditioned fear. As the wealth of experimental data grows, theoretical models that help interpret results and generate new hypotheses play an increasingly important role. In this thesis, two computational models of the neural substrates of fear conditioning are presented. The first model is a biologically realistic spiking neural network model of the central amygdala, the main output structure of the amygdala. Based on a recent experimental study that demonstrated the importance of tonic extrasynaptic inhibition for fear generalization, the effects of changes in neuronal membrane conductance on input processing are analyzed in the model. Consistent with experimental results, it is shown that subpopulation-specific changes in tonic inhibitory conductance increase the responsiveness of the network to phasic inputs, presumably causing the increase in fear generalization. On the basis of this result, the model is analyzed from a functional perspective. It is argued that tonic inhibition in the central amygdala acts as a controller by which network sensitivity is flexibly adjusted to relevant features of the environment, such as predictability of threat, and concrete predictions that follow from this proposition as well as possible adjustment mechanisms are discussed. In addition, a systems level model is presented that is based on a recent high-level approach to conditioning and proposes a specific physiological implementation in the basolateral amygdala, prefrontal cortex and the intercalated cell clusters of the amygdala. It is a central hypothesis of the model that the interaction between fear and extinction neurons in the basal amygdala, which has been described experimentally, is a neural substrate of the switching between socalled latent states, which allow the animal to organize its experience and infer structure in the environment. Important behavioral phenomena are reproduced in the model and the effect of de-activation of model structures is shown to be in good agreement with results from lesion studies. Finally, predictions and questions that follow from the main hypothesis are considered. Taken together, the two models provide a coherent theoretical account of the neural basis of acquisition and extinction of conditioned fear, as well as the control of fear generalization. Importantly, this account combines different levels of analysis. By virtue of this combination, the scope of predictions that can be derived is expanded and the models become more amenable to experimental testing