Cellular basis of extinction of conditioned fear and its renewal
The memory of fear extinction is context-dependent: fear, suppressed in the extinction context, can renew in other contexts, invalidating the exposure therapy. Understanding the neuronal circuits underlying fear extinction is, therefore, of clinical relevance. Recent research suggests mediation of fear extinction by highly specific neuronal circuits in the amygdala, prefrontal cortex and hippocampus. However, at the cellular level, the interrelations between these brain structures remain unclear. Using c-Fos immunohistochemistry, we found strong suggestions that the context specificity of extinction is mediated by prefrontal modulation of amygdala activity and that the hippocampus has a crucial role in contextual memory retrieval. We then aimed at characterization of amygdala neurons involved in retrieval of extinguished fear memories. The use of recently generated transgenic rats carrying gene encoding fusion of PSD-95/Venus protein enabled us to study the connections of the activated neurons. The rats were injected with two anterograde axonal transport tracers either into the infralimbic (IL) and prelimbic (PRL) cortices or into the prefrontal cortex and ventral hippocampus (vHIPP). We showed that most of the cells activated in the lateral nucleus of the amygdala (La) by the extinction training receive inputs from the IL, whereas the neurons activated by the renewal of fear mainly receive signals from the PRL and vHIPP. Such differences were absent in the central nucleus of the amygdala. This suggests that extinction and renewal activate different subpopulations of neurons in the La, and that they can be distinguished by their connections to the IL, PRL and vHIPP. We also observed different involvement of the inhibitory neurons within the La following fear extinction and fear renewal. Taken together, these data suggest an appealing possibility of increasing fear extinction and preventing fear renewal by very specific manipulations of the neurons in the La.
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