Distinct Contribution of Granular and Agranular Subdivisions of the Retrosplenial Cortex to Remote Contextual Fear Memory Retrieval

Abstract

The retrieval of recent and remote memories are thought to rely on distinct brain circuits and mechanisms. The retrosplenial cortex (RSC) is robustly activated during the retrieval of remotely acquired contextual fear memories (CFMs), but the contribution of particular subdivisions [granular (RSG) vs agranular retrosplenial area (RSA)] and the circuit mechanisms through which they interact to retrieve remote memories remain unexplored. In this study, using both anterograde and retrograde viral tracing approaches, we identified excitatory projections from layer 5 pyramidal neurons of the RSG to the CA1 stratum radiatum/lacunosum-moleculare of the dorsal hippocampus and the superficial layers of the RSA in male mice. We found that chemogenetic or optogenetic inhibition of the RSG-to-CA1, but not the RSG-to-RSA, pathway selectively impairs the retrieval of remote CFMs. Collectively, our results uncover a specific role for the RSG in remote CFM recall and provide circuit evidence that RSG-mediated remote CFM retrieval relies on direct RSG-to-CA1 connectivity. The present study provides a better understanding of brain circuit mechanisms underlying the retrieval of remote CFMs and may help guide the development of therapeutic strategies to attenuate remote traumatic memories that lead to mental health issues such as post-traumatic stress disorder.

Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation

“…We found that although the RSPag → PL projection was specifically active at recent recall (Figure 3I), its inhibition during this time did not affect memory retrieval (Figure 4J). Interestingly, it was recently reported that although the whole RSP is necessary for recent and remote recall, it is rather the granular subregion of the RSP and not the RSPag that is responsible for this effect, suggesting a dissociated role of the two RSP subregions which could explain our observations (Tsai et al, 2022). In contrast, INS → PL projection inhibition during recent recall resulted in decreased freezing (Figure 4K).…”

Disrupting direct inputs from the dorsal subiculum to the granular retrosplenial cortex impairs flexible spatial memory in the rat

“…Together, these findings emphasise the reliance of the three regions on each other, suggesting that together the subiculum and anterior thalamic nuclei facilitate information processing in the retrosplenial cortex, which is gated by its inputs from CA1 (Aggleton & O'Mara, 2022; Yamawaki, Corcoran, et al, 2019). In addition, a recent study found that some granular retrosplenial neurons in layer V project directly to CA1 of the dorsal hippocampus in mice (Tsai et al, 2022). These projections may help retrieve remotely acquired contextual fear memory, demonstrating a bidirectional interdependence between regions (Tsai et al, 2022).…”

“…In addition, a recent study found that some granular retrosplenial neurons in layer V project directly to CA1 of the dorsal hippocampus in mice (Tsai et al, 2022). These projections may help retrieve remotely acquired contextual fear memory, demonstrating a bidirectional interdependence between regions (Tsai et al, 2022).…”

Sharp cell-type-identity changes differentiate the retrosplenial cortex from the neocortex

“…Our results demonstrate a gRSC/dRSC specificity in cell type composition, as well as uncover differences between the gRSC and the neocortex (Figure 6). This may provide insight into clarifying functional differences between the gRSC and dRSC 10,[28][29][30][31] , as well as revealing differences in RSC information processing relative to the neocortex.…”