Synaptic mechanisms in extinction of conditioned fear

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DESCRIPTION (provided by applicant): Long-term potentiation (LTP)-like synaptic enhancements in cortico-amygdala and thalamo-amygdala pathways contribute to the acquisition of fear memory to auditory stimulation. The conditioned fear response can be diminished or even eliminated when the conditioned stimulus (CS) is repeatedly non-reinforced, resulting in fear extinction. Extinction of conditioned fear, however, does not reflect 'unlearning' of the original CS-unconditioned stimulus (US) association formed in the amygdala but may involve the formation of new associations inhibiting retrieval of conditioned fear memory. This indicates that fear learning-induced synaptic enhancements in the CS pathways might be retained following extinction training. Nevertheless, the results of several recent experimental and modeling studies suggest that depotentation-like decreases of synaptic strength in auditory inputs to the LA, potentiated by fear conditioning, could contribute to extinction of conditioned fear under certain conditions, indicating that the role of extinction-associated synaptic modifications could not be ruled out. Here we propose a combined behavioral and electrophysiological study aiming to address specific questions concerning the nature of plastic modifications in the CS pathways associated with fear extinction. In Aim 1, we will characterize synaptic modifications in cortical and thalamic inputs to the LA associated with extinction of conditioned fear. We will examine synaptic transmission in both cortico-amygdala and thalamo-amygdala pathways in slices from rats trained and extinguished (at 30 min or 24 hr following conditioning) in fear conditioning training paradigm at the level of compound and unitary synaptic currents. In Aim 2 will explore synaptic mechanisms of depotentiation in cortical and thalamic inputs and compare them to synaptic changes induced by extinction of conditioned fear. By investigating these mechanisms and comparing them to the mechanisms of behavior-induced plasticity associated with fear extinction (as proposed in Aim 1), and to the effects of depotentiation-inducing stimulation in slices from fear- conditioned rats (at 30 min and 24 hr post-conditioning), we will address a question whether depotentiation of synaptic responses undergoing LTP in slices and synaptic plasticity which might be involved in extinction of conditioned fear are mechanistically similar. These experiments will illuminate the nature of synaptic modifications in the conditioned stimulus pathways, which may contribute to fear extinction. A better understanding of the basic mechanisms of synaptic plasticity in the neural circuit of fear conditioning will permit the rational development of novel therapeutic treatments for anxiety disorders. It could also help to optimize the treatments leading to suppression of unwanted memories in posttraumatic stress disorder (PTSD) patients. PUBLIC HEALTH RELEVANCE: These studies are important to our understanding the mechanisms of synaptic plasticity in the amygdala in relation to fear conditioning and fear extinction. A better knowledge of the cellular mechanisms of fear conditioning and extinction will permit the rational development of novel therapeutic treatments for anxiety disorders. It could also help to optimize the treatments of postraumatic stress disorder (PTSD) patients.