While synaptic plasticity in the lateral amygdala (LA) has been extensively studied as a mechanism for aversive learning, little is known about generalized changes in neuronal spiking activity. Moreover, we do not understand the mechanisms of "metaplasticity", or neuronal changes that modulate synaptic plasticity. Generalized plasticity and metaplasticity are important, however, because they could play a crucial role in aversive learning as well as contributing to the development of anxiety disorders and other mood disturbances. We have discovered a novel form of spike firing plasticity in principal neurons of the LA that is induced by high- frequency stimulation protocols. This form of plasticity could be induced during learning events, and could also have an important impact on subsequent synaptic plasticity. This project is directly relevant to the mission of the NIMH, because we have identified a novel and potentially critical form of neuronal plasticity underlying emotional learning. A long-lasting change in excitability in the amygdala could explain persistent aspects of anxiety disorders like PTSD that are notoriously refractory to treatment. Identifying the functional role of this change could lead directly to improved pharmacological and psychotherapeutic interventions for anxiety disorders. Using behavioral, viral and electrophysiological methods, we propose to test directly whether LA cells activated during fear conditioning exhibit this form of spike firing plasticity. We will then be able to confirm whether the spike firing plasticity, as predicted, alters the induction of synaptic plasticity. We propose he following Specific Aims to carry out this work: 1. Test the hypothesis that fear conditioning induces changes in spiking characteristics of LA principal cells. We will use a viral vector to express green fluorescent protein (GFP) under a component of the promoter for Arc, an immediate-early gene expressed during neuronal plasticity. We will then use GFP as a marker for cells activated by fear conditioning to visually target and record from activated neurons in acute brain slices. We will test whether the activated cells have altered firing properties compared to their non- activated neighbors. 2. Test the hypothesis that fear conditioning induces metaplastic changes at thalamo-LA synapses. Using similar techniques, we will determine whether fear conditioning and spike firing plasticity biases thalamo- LA synapses toward synaptic depression rather than potentiation.
This project is important because we have discovered a novel form of brain plasticity that might be a key to anxiety disorders like PTSD. We will study how these neuronal changes are involved in a rodent model of fear learning. The results of our experiments could provide biological insights into new therapies for these widespread psychological disorders.