Anterior Cingulate Cortex to Ventral Hippocampus Circuit Mediates Contextual Fear Generalization

Abstract

Contextual fear memory becomes less context-specific over time, a phenomenon referred to as contextual fear generalization. Overgeneralization of contextual fear memory is a core symptom of post-traumatic stress disorder (PTSD), but circuit mechanisms underlying the generalization remain unclear. We show here that neural projections from the anterior cingulate cortex (ACC) to ventral hippocampus (vHPC) mediate contextual fear generalization in male mice. Retrieval of contextual fear in a novel context at a remote time point activated cells in the ACC and vHPC, as indicated by significantly increased C-fos ϩ cells. Using chemogenetic or photogenetic manipulations, we observed that silencing the activity of ACC or vHPC neurons reduced contextual fear generalization at the remote time point, whereas stimulating the activity of ACC or vHPC neurons facilitated contextual fear generalization at a recent time point. We found that ACC neurons projected to the vHPC unidirectionally, and importantly, silencing the activity of projection fibers from the ACC to vHPC inhibited contextual fear generalization at the remote time point. Together, our findings reveal an ACC to vHPC circuit that controls expression of fear generalization and may offer new strategies to prevent or reverse contextual fear generalization in subjects with anxiety disorders, especially in PTSD. Significance StatementOvergeneralization of contextual fear memory is a cardinal feature of PTSD, but circuit mechanisms underlying it remain unclear. Our study indicates that neural projections from the anterior cingulate cortex to ventral hippocampus control the expression of contextual fear generalization. Thus, manipulating the circuit may prevent or reverse fear overgeneralization in subjects with PTSD.

Brain functional networks associated with social bonding in monogamous voles

“…Our data showed functional connectivity changes occurred in the hippocampus 24 hr after the onset of cohabitation (ACC–vHIP, LS–dHIP; Figure 5 ), which has demonstrated to be critical in encoding spatial and mnemonic information in rodents ( Lin et al, 2017 ). ACC–vHIP activity has been associated with the regulation of fear in novel environments and in contextual fear generalization in rodents ( Bian et al, 2019 ). However, the vHIP has also shown to contribute in social memory processing ( Chiang et al, 2018 ), and the ACC is proposed to integrate new information to modify future behavior ( Kolling et al, 2016 ).…”

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

“…The latter (ACC→NAc) connection is functionally reduced in first-episode schizophrenia ( Lin et al, 2018 ). The ACC also projects to further key structures of the extended vSub/VTA circuit, such as the amygdala and the vHC ( Figure 2 )—these connections are crucial for attribution of the appropriate levels of significance during associative learning ( Bian et al, 2019 ; Ortiz et al, 2019 ).…”

Brain functional connectivity modulates social bonding in monogamous voles

“…The dHIP-DG increase in connectivity may be related to partner-memory consolidation, since it has been shown that the DG plays an important role in social recognition (Kesner, 2018). Also, ACC-vHIP activity has been previously associated with the regulation of fear in novel environments and in contextual fear generalization in rodents (Bian et al, 2019). However, the ventral regions of CA1 and CA3 have also shown to contribute in social memory processing (Chiang et al, 2018; S. B.…”