Abstract:

Great strides have been made in understanding the neural mechanisms of the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are likely critical to this form of learning, but there is very little data regarding how this brain area becomes active during extinction of conditional fear. The current study examined the effect of treatments which impair the formation of extinction memories on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in the medial prefrontal cortex and other brain regions that underlie the extinction of conditional fear. Inhibitors of N-methyl-D-aspartic acid (NMDA) and opioid receptors were delivered to the basolateral amygdala (BLA) and ventrolateral periaqueductal gray matter (vIPAG) shortly before extinction training. Results from these experiments argue for a double dissociation between the BLA and vIPAG. In the amygdala NMDA, but not opioid, receptors in the BLA are necessary for the formation of long-term memory for fear extinction. Conversely, opioid receptor antagonism in the vIPAG disrupted the retention of extinction, but NMDA receptor blockade had no effect. Follow up experiments tested the effects of these extinction-impairing manipulations on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Data from these studies indicate that opioid receptor blockade in the vIPAG shortly before extinction training disrupted ERK phosphorylation in the amygdala and medial prefrontal cortex. However, blockade of NMDA receptors in the amygdala had no effect on ERK activity in mPFC following extinction training despite the fact that this treatment disrupts extinction learning. These data argue that opiodergic signaling derived from the vIPAG is capable of regulating plasticity in several brain regions during the extinction of conditional fear.