Parietal-Frontal Pathway Controls Relapse of Fear Memory in a Novel Context.

ABSTRACT

Background: Fear responses significantly affect daily life and shape our approach to uncertainty. However, the potential resurgence of fear in unfamiliar situations poses a significant challenge to exposure-based therapies for maladaptive fear responses. Nonetheless, how novel contextual stimuli are associated with the relapse of extinguished fear remains unknown. Methods: Using a context-dependent fear renewal model, the functional circuits and underlying mechanisms of the posterior parietal cortex (PPC) and anterior cingulate cortex (ACC) were investigated using optogenetic, histological, in vivo, and ex vivo electrophysiological and pharmacological techniques. Results: We demonstrated that the PPC-to-ACC pathway governs fear relapse in a novel context. We observed enhanced populational calcium activity in the ACC neurons that received projections from the PPC and increased synaptic activity in the basolateral amygdala-projecting PPC-to-ACC neurons upon renewal in a novel context, where excitatory postsynaptic currents amplitudes increased but inhibitory postsynaptic current amplitudes decreased. In addition, we found that parvalbumin-expressing interneurons controlled novel context-dependent fear renewal, which was blocked by the chronic administration of fluoxetine. Conclusions: Our findings highlight the PPC-to-ACC pathway in mediating the relapse of extinguished fear in novel contexts, thereby contributing significant insights into the intricate neural mechanisms that govern fear renewal.

To improve outcomes for exposure-based therapy, it is vital to understand the renewal of fear after extinction in new environments. Using optogenetics and other techniques, Joo et al. found that a brain circuit connecting the posterior parietal cortex (PPC) to the anterior cingulate cortex (ACC) is crucial for the return of fear memories in mice exposed to a novel context. Certain PPC→ACC neuron types and their connections to the amygdala became more active during fear renewal in a novel context, and inhibiting parvalbumin-expressing interneurons reduced this fear response. This study provides insights into the brain mechanisms underlying the reappearance of fear in unfamiliar situations.