Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders1-4. In mammals, repeated presentations of a conditioned stimulus (CS) that was previously paired to a noxious stimulus leads to the gradual disappearance of conditioned fear responses. Although much evidence suggests that this extinction process depends on plastic events in the amygdala1-7, the underlying mechanisms remain unclear. Intercalated (ITC) amygdala neurons constitute likely mediators of extinction because they receive CS information from the basolateral amygdala (BLA)8, 9, and contribute inhibitory projections to the central nucleus (CEA)10, 11, the main output station of the amygdala for conditioned fear responses12. Thus, following extinction training, ITC cells could reduce the impact of CS-related BLA inputs to CEA via feed-forward inhibition. Here, we tested the hypothesis that ITC neurons mediate extinction by lesioning them with a toxin that selectively targets cells expressing μ-opioid receptors (μORs). Electron microscopic observations revealed that the incidence of μOR-immunoreactive synapses is much higher in ITC cell clusters than in BLA or CEA and that μORs typically have a post-synaptic location in ITC cells. In keeping with this, bilateral infusions of the μOR agonist dermorphin conjugated to the toxin saporin in the vicinity of ITC neurons caused a 34% reduction in the number of ITC cells but no significant cell loss in surrounding nuclei. Moreover, ITC lesions caused a marked deficit in the expression of extinction that correlated negatively with the number of surviving ITC neurons but not CEA cells. Because ITC cells exhibit an unusual pattern of receptor expression, these findings open new avenues for the treatment of anxiety disorders.

Brain activity in sleep plays a crucial role in memory consolidation, an offline process that determines the long-term strength of memory traces. Consolidation efficacy differs across individuals, but the brain activity dynamics underlying these differences remain unknown. Here, we studied how interindividual variability in fear memory consolidation relates to neural activity in brain structures that participate in Pavlovian fear learning. From the end of training to testing 24 h later, some rats showed increased and others decreased conditioned fear responses. We found that overnight bidirectional changes in fear memory were selectively correlated with modifications in theta coherence between the amygdala, medial prefrontal cortex, and hippocampus during paradoxical sleep. Thus, our results suggest that theta coordination in the limbic system may influence interindividual differences in memory consolidation of aversive experiences.amygdala | fear conditioning | prefrontal cortex | hippocampus | Granger causality R ecently formed memories undergo a period of consolidation (1, 2), and neuronal activity taking place during sleep is thought to play a critical role in this process (3-7). Consolidation of emotional memories determines their long-term retention, and interindividual variations in memory performance have been related to various factors affecting consolidation, including neuromodulatory transmission (8), levels of circulating stress hormones (9), or genetic factors (10). Several strongly interconnected brain structures are involved in the formation and maintenance of emotional memories, including the hippocampus (Hi), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) (11-13). The latter structure in particular was shown to mediate the facilitating effects of emotions on memory consolidation (14). Indeed, we form more vivid and enduring memories for emotionally arousing experiences (15). Via the release of peripheral stress hormones (16), emotional arousal causes long-lasting increases in the firing rate of BLA neurons (17), and pharmacologic manipulations that prevent this increased activity interfere with memory for events that took place shortly before, in many learning tasks (18). Importantly, in most learning paradigms, the same interventions performed shortly before testing long-term memory recall have no effect, indicating that the BLA can facilitate the consolidation of memories in other brain structures (14,18).Potentially related to the facilitation of emotional memories by BLA activity, various lines of evidence implicate posttraining paradoxical sleep (PS) in memory consolidation (6,19). These include PS reactivation of brain areas implicated in prior learning (20) and spontaneous replay of waking activity patterns during PS (21). In fact, it was suggested that the distinct pattern of neuronal activity occurring during PS favors memory consolidation (4,22) and that emotional memories are particularly susceptible to this effect (5, 23). Indeed, after fear conditioning, the respons...

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