Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction

Abstract

Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear.

Fear renewal activates cyclic adenosine monophosphate signaling in the dentate gyrus

“…Although cannula placements in these studies included the DG, they also contained adjacent areas, not targeting the DG. However, these data appear to contradict at least one recent study demonstrating a role for DG in the retrieval of contextual fear extinction (Bernier et al, 2017). It is speculated that this discrepancy is due to the DG contributes to contextual fear extinction retrieval or auditory fear extinction retrieval through a different mechanism.…”

“…In our study, inactivation of the DG resulted in the disruption of fear renewal, and the rats exhibited extinction memory. Previous studies revealed that extinction is a process that requires both the retrieval of hippocampally stored information and the acquisition of new learning that may be hippocampal-dependent, at least in part (Bernier et al, 2017). The animals may require two memories for extinction retrieval: a fear conditioning memory and an extinction memory.…”

“…A number of studies have demonstrated that suppression or lesions of the DG interferes with memory acquisition but not with the expression of previously learned memories (Kheirbek, Klemenhagen, Sahay, & Hen, 2012;Lassalle, Bataille, & Halley, 2000;Madroňal et al, 2016). However, other studies concluded that the DG contributes to both memory acquisition and retrieval (Bernier et al, 2017). These studies suggest that the contribution of the DG to stress and emotional processing, especially whether the DG participates in memory retrieval is still debated.…”

“…The dentate gyrus (DG) region of the hippocampal formation is considered to play a role in encoding spatial and contextual information, particularly in pattern separation and novel information (Bernier et al, ). A number of studies have demonstrated that suppression or lesions of the DG interferes with memory acquisition but not with the expression of previously learned memories (Kheirbek, Klemenhagen, Sahay, & Hen, ; Lassalle, Bataille, & Halley, ; Madroňal et al, ).…”

Propranolol can induce PTSD‐like memory impairments in rats

“…The DG plays an important role in the discrimination of a similar context from a fearful one (Wu & Hen, ). Inhibition of dorsal DG increases the generalization of fear to an unfamiliar context that was similar to a feared context and impairs fear expression in the conditioned context when it was similar to a neutral context (Bernier et al., ). However, all subregions of the hippocampus are highly interconnected.…”