Retrosplenial cortex is required for the retrieval of remote memory for auditory cues

Abstract

The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent.

A critical role of hippocampus for formation of remote cued fear memory

“…It is unknown in this study how hippocampus contributes to the formation of remote cued fear memory. Considering the well-known role of hippocampus for memory consolidation through reactivation activity, our data support the idea that representation of episodic events of cued fear conditioning may be formed in the hippocampus at the time of learning and drive an internal reactivation of cells in the extra-hippocampal brain areas that needs for the time-dependent reconstruction of a memory across broad brain networks for the permanent storage [4,[21][22][23][24][25][26]. According to this view, intact hippocampal system is required at the time of learning for subsequent remote memory consolidation.…”

“…Such cortical activity during consolidation may be driven by activation of context-related representations formed in the hippocampus [ 34 , 35 ]. Several brain structures have been suggested as a remote memory storage site for cued associative fear memory such as a higher order sensory cortex [ 21 , 36 ], auditory thalamus [ 36 ], retrosplenial cortex [ 25 ], and paraventricular nucleus of thalamus [ 24 ]. Interestingly, pharmacological inactivation of temporal association cortex Te2 with TTX or muscimol 1 day following auditory fear conditioning impairs remote memory formation [ 23 ].…”

Higher-order conditioning and the retrosplenial cortex

“…First, in addition to its connections with visual cortical areas, RSC is also interconnected with regions of auditory cortex (Todd et al, in press; Vogt & Miller, 1983), thus it is entirely possible that RSC lesions could impact conditioning involving auditory cues. Consistent with this, two recent studies have demonstrated that manipulations of RSC can affect first order conditioning involving auditory cues (trace fear conditioning with an auditory CS; Kwapis et al 2015; remote retrieval of delay conditioned auditory cues, Todd et al, in press). More importantly, there is also evidence that RSC damage can impair first-order discrimination learning with auditory stimuli (Gabriel et al, 1987).…”

The retrosplenial cortex and long-term spatial memory: from the cell to the network

“…Findings from the few studies available are consistent with RSC being important for the long-term storage or retrieval of previously learnt information. Todd et al [ 12 ] showed that retrieval of auditory fear memories was disrupted when RSC lesions were made several weeks after encoding. Likewise, post-training RSC lesions impaired rats’ ability to discriminate between previously rewarded arms of a radial-arm maze (RAM), irrespective of whether the training occurred 4-weeks or one day before surgery [ 13 ].…”

“…While impairments of T-maze alternation following RSC lesions are only observed when intra-maze and extra-maze cues are put in conflict, rats infused with muscimol into the RSC show deficits even on the standard version of the task [ 16 ]. The importance of RSC for fear memory consolidation has been shown using temporary inactivation with infusates such as muscimol as well as with compounds that interfere with post-learning protein synthesis or immediate-early gene (IEG) expression [ 12 , 17 , 18 , 19 ]. The move to chemogenetic and optogenetic approaches [ 4 ] has the potential to provide next level cell-to-network analysis by enabling the selective manipulation of subpopulations of cells and specific neuronal pathways.…”