Low-Frequency Stimulation Depresses the Primate Anterior-Cingulate-Cortex and Prevents Spontaneous Recovery of Aversive Memories

Abstract

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.

Activity in prelimbic cortex subserves fear memory reconsolidation over time

“…Based on this neuronal circuitry, one speculation would be that inactivating the PL cortex during reconsolidation attenuates the input to the basolateral nucleus of the amygdala and/or hippocampus, brain hubs that modulate the maintenance of emotional memories charged with negative valence (Nader et al 2000;Debiec et al 2002;Lee et al 2004Lee et al , 2006Parsons et al 2006;Tronson et al 2006;de Oliveira Alvares et al 2008;Rehberg et al 2010;Giachero et al 2013). Of note, the rat PL cortex has a similar anatomy and connectivity to that of the primate dorsal anterior cingulate cortex (McDonald 1998;Stefanacci and Amaral 2002), which has a similar functional role in maintaining the original aversive memory (Klavir et al 2012). In humans, this area is suggested to be dysfunctional (commonly hyperactive) in anxiety disorders, such as post-traumatic stress (Fani et al 2012;Pitman et al 2012;Admon et al 2013).…”

Encoding of fear learning and memory in distributed neuronal circuits

“…For instance, studies performed in rodents and non-human primates used artificial stimulation protocols to induce LTP or LTD in prefrontal regions during fear extinction 99,100 . These studies showed that LTP-inducing stimulation in the rodent ILc or LTD-inducing stimulation in the monkey dorsal anterior cingulate cortex (dACC, an analog of the rodent PLc) both facilitate fear inhibition during extinction 99,100 . Together with studies presented above, these data suggest the existence of parallel pathways regulating fear expression.…”

Amygdala–prefrontal interactions in (mal)adaptive learning

“…A working framework that has been established over the past decade suggests that fear expression and fear suppression are supported by different subdivisions of the mPFC. The more dorsal mPFC (called the prelimbic (PL) cortex in rodents and dorsal anterior cingulate (dACC) in primates) increases activity during fear conditioning and expression, whereas the ventral mPFC (called the infralimbc (IL) cortex in rodents and ventral mPFC (vmPFC) in primates) is active during expression of non-aversive associations or safety [56,57,58,59]. Accordingly, interactions of the more dorsal PFC with the BLA is suggested to support threat-related behavior [50,52,60,61], whereas the vmPFC is proposed to interact with the amygdala during fear suppression [61,62].…”

“…Importantly, in addition to processing aversive stimuli, the dACC/PL is a prominent region for response adjustment in a broad range of circumstances when cues change their meaning [57,65,66]. Cue discrimination in the mPFC is likely shaped by convergent inputs from multiple cortical as well as subcortical structures [67,68].…”