Differential activation of anatomically defined neuronal subpopulations in the amygdala during fear conditioning and extinction

The amygdala is a key structure of the neuronal circuitry mediating expression \nand extinction of conditioned fear. However, fear memories are thought to be \nencoded in a larger network comprising the medial prefrontal cortex (mPFC) \nand the hippocampus (HC). Thus, amygdala projections to the mPFC and to \nthe HC are likely to be involved in fear learning, yet the cellular substrates of \nthat learning remain unknown. To examine the role of identified amygdala \nprojection neurons in the expression and extinction of conditioned fear \nresponses, I used a combination of in vivo retrograde tracing techniques and \nanalysis of expression of the activity-dependent immediate early genes (IEGs) \ncFos and Zif268. I show that amygdala neurons projecting to the mPFC or to \nthe HC exhibit differential cFos and Zif268 expression in fear conditioned \nanimals compared with non-conditioned control animals and with animals \nsubjected to extinction. In particular, extinction resulted in a selective induction \nof cFos in mPFC projecting neurons. A more detailed analysis revealed that \nneurons projecting to the infralimbic subdivision of the mPFC (IL), but not those \nprojecting to the prelimbic subdivision (PL), account for the specific cFos \nexpression in mPFC-projecting neurons following extinction. To investigate the \nphysiological correlates of fear extinction in anatomically defined \nsubpopulations of amygdala projection neurons I used an electrophysiological \nex vivo approach. In these experiments, I recorded from identified BA neurons \nprojecting to PL or IL in slices obtained from mice subjected to extinction. \nExtinction differentially affects intrinsic properties of PL- and IL-projecting cells. \nWhile there was no change in PL-projecting neurons, IL-projecting BA cells \nshowed a learning-related increase in spike half-width and a concomitant \ndecrease in the fast after-hyperpolarization (AHPfast). In control animals, spike \nhalf-width and AHPfast were controlled by the activation of voltage-dependent \npotassium channels (VDPCs) and large-conductance Ca2+ dependent \npotassium channels (BK-channels). After extinction training only VDPCs \ncontribute to the AHPfast in IL-projecitng cells. This indicates a specific \nmodulation of BK-channels in IL-projecting neurons following extinction \nlearning. Our findings suggest that a change in the balance of activity between \nIL- and PL-projecting BA neurons may be involved in the extinction of \nconditioned fear. \n