Fear-related disorders are thought to reflect strong and persistent fear memories. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) form strong reciprocal synaptic connections that play a key role in acquisition and extinction of fear memories. While synaptic contacts of BLA cells onto mPFC neurons are likely to play a crucial role in this process, the BLA connects with several additional nuclei within the fear circuit that could relay fear-associated information to the mPFC, and the contribution of direct monosynaptic BLA-mPFC inputs is not yet clear. Here we establish an optogenetic stimulation protocol that induces synaptic depression in BLA-mPFC synapses. In behaving mice, optogenetic high-frequency stimulation of BLA inputs to mPFC interfered with retention of cued associations, attenuated previously acquired cue-associated responses in mPFC neurons and facilitated extinction. Our findings demonstrate the contribution of BLA inputs to mPFC in forming and maintaining cued fear associations.

The ability to switch flexibly between aversive and neutral behaviors based on predictive cues relies on learning driven by surprise or errors in outcome prediction. Surprise can occur as absolute value of the error (unsigned error) or its direction (signed errors; positive when something unexpected is delivered and negative when something expected is omitted). Signed and unsigned errors coexist in the brain and were associated with different systems, but how they interact and form across large networks remains vague. We recorded simultaneously in the amygdala and dorsal anterior cingulate cortex (dACC) of monkeys performing a reversal aversive-conditioning paradigm and quantified changes in interregional correlations when contingencies shift. We report that errors exist in different magnitudes and that they differentially develop at millisecond resolution. Our results support a model where unsigned errors first develop in the amygdala during successful learning and then propagate into the dACC, where signed errors develop and are distributed back to the amygdala.

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The ability to distinguish danger from safety is crucial for survival. On the other hand, anxiety disorders can result from failures to dissociate safe cues from those that predict dangerous outcomes. The amygdala plays a major role in learning and signaling danger, and recently, evidence accumulates that it also acquires information to signal safety. Traditionally, safety is explored by paradigms that change the value of a previously dangerous cue, such as extinction or reversal; or by paradigms showing that a safe cue can inhibit responses to another danger-predicting cue, as in conditioned-inhibition. In real-life scenarios, many cues are never paired or tested with danger and remain neutral all along. A detailed study of neural responses to unpaired conditioned-stimulus (CSϪ) can therefore indicate whether information on safety-by-comparison is also acquired in the amygdala. We designed a multiple-CS study, with CSϪ from both visual and auditory modalities. Using discriminative aversiveconditioning, we find that responses in the primate amygdala develop for CSϪ of the same modality and of a different modality from that of the aversive CSϩ. Moreover, we find that responses are comparable in proportion, sign (increase/decrease), onset, and magnitude. These results indicate that the primate amygdala actively acquires signals about safety, and strengthen the hypothesis that failure in amygdala processing can result in failure to distinguish dangerous cues from safe ones and lead to maladaptive behaviors.

Functional abnormalities in the dorsal-anterior-cingulate-cortex (dACC) underlie anxiety disorders and specifically post-traumatic stress disorder (PTSD). Promising and common behavioral approaches have limited effectiveness and many subjects exhibit spontaneous recovery of fear, as also evident in animal models following extinction training. Here, we use low-frequency stimulation (LFS), a protocol shown to induce long-term depression, with the aim of affecting synaptic plasticity induced by fear acquisition and extinction. We use aversive conditioning of either tone or visual stimuli paired with an aversive air-puff to the eye in a trace-conditioning paradigm. We find that LFS in the nonhuman primate (Macaca fascicularis) dACC, when combined with extinction training, was successful in preventing spontaneous recovery of the memory 24 -72 h following extinction. We simultaneously record single-units and local-fieldpotentials across the dACC, and show that LFS gradually depressed evoked responses. Moreover, this decrease in neural excitability predicted the successful reduction of overnight spontaneous recovery on a day-by-day basis. Finally, we show that this effect occurs when using either visual or auditory modality as the conditioned stimulus, and that the reduction was specific to the conditioned modality. Our results suggest that the primate dACC is actively involved in maintaining the original aversive memory, and propose that a combination of LFS with behavioral therapy might significantly improve treatment in severe cases.