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Crucial role for CA2 inputs in the sequential organization of CA1 time cells supporting memory.

ABSTRACT: There is considerable evidence for hippocampal time cells that briefly activate in succession to represent the temporal structure of memories. Previous studies have shown that time cells can be disrupted while leaving place cells intact, indicating that spatial and temporal information can be coded in parallel. However, the circuits in which spatial and temporal information are coded have not been clearly identified. Here we investigated temporal and spatial coding by dorsal hippocampal CA1 (dCA1) neurons in mice trained on a classic spatial working-memory task. On each trial, the mice approached the same choice point on a maze but were trained to alternate between traversing one of two distinct spatial routes (spatial coding phase). In between trials, there was a 10-s mnemonic delay during which the mouse continuously ran in a fixed location (temporal coding phase). Using cell-type-specific optogenetic methods, we found that inhibiting dorsal CA2 (dCA2) inputs into dCA1 degraded time cell coding during the mnemonic delay and impaired the mouse's subsequent memory-guided choice. Conversely, inhibiting dCA2 inputs during the spatial coding phase had a negligible effect on place cell activity in dCA1 and no effect on behavior. Collectively, our work demonstrates that spatial and temporal coding in dCA1 is largely segregated with respect to the dCA2-dCA1 circuit and suggests that CA2 plays a critical role in representing the flow of time in memory within the hippocampal network.

SUBMITTER: MacDonald CJ

PROVIDER: S-EPMC7826404 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Social recognition memory (SRM) is the ability to distinguish familiar from novel conspecifics and is crucial for survival and reproductive success across social species. We previously reported that oxytocin (OXT) receptor (OXTR) signaling in the CA2/CA3a of dorsal hippocampus is essential to promote the persistence of long-term SRM, yet how the endogenous OXT system influences CA2 outputs to regulate long-term SRM formation remains unclear. Methods To achieve a selective deletion of CA2 OXTRs, we crossed Amigo2-Cre mice with Oxtr-floxed mice to generate CA2-specific Oxtr conditional knockout (Oxtr−/−) mice. A three-chamber paradigm test was used for studying SRM in mice. Chemogenetic and optogenetic targeting strategies were employed to manipulate neuronal activity. Results We show that selective ablation of Oxtr in the CA2 suffices to impair the persistence of long-term SRM but has no effect on sociability and social novelty preference in the three-chamber paradigm test. We find that cell-type specific activation of OXT neurons within the hypothalamic paraventricular nucleus enhances long-term SRM and this enhancement is blocked by local application of OXTR antagonist L-368,899 into dorsal hippocampal CA2 (dCA2) region. In addition, chemogenetic neuronal silencing in dCA2 demonstrated that neuronal activity is essential for forming long-term SRM. Moreover, chemogenetic terminal-specific inactivation reveals a crucial role for dCA2 outputs to ventral CA1 (vCA1), but not dorsal lateral septum, in long-term SRM. Finally, targeted activation of the dCA2-to-vCA1 circuit effectively ameliorates long-term SRM deficit observed in Oxtr−/− mice. Conclusions These findings highlight the importance of hippocampal CA2 OXTR signaling in governing the persistence of long-term SRM and identify a hippocampal circuit linking dCA2 to vCA1 necessary for controlling long-term SRM formation. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00834-x.

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Crucial role for CA2 inputs in the sequential organization of CA1 time cells supporting memory.

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