A thalamic-hippocampal CA1 signal for contextual fear memory suppression, extinction, and discrimination.

The adaptive regulation of fear memories is a crucial neural function that prevents inappropriate fear expression. Fear memories can be acquired through contextual fear conditioning (CFC) which relies on the hippocampus. The thalamic nucleus reuniens (NR) is necessary to extinguish contextual fear and innervates hippocampal CA1. However, the role of the NR-CA1 pathway in contextual fear is unknown. We developed a head-restrained virtual reality CFC paradigm, and demonstrate that mice can acquire and extinguish context-dependent fear responses. We found that inhibiting the NR-CA1 pathway following CFC lengthens the duration of fearful freezing epochs, increases  fear generalization, and delays fear extinction. Using in vivo imaging, we recorded NR-axons innervating CA1 and found that NR-axons become tuned to fearful freezing following CFC. We conclude that the NR-CA1 pathway actively suppresses fear by disrupting contextual fear memory retrieval in CA1 during fearful freezing behavior, a process that also reduces fear generalization and accelerates extinction.

Direct Thalamic Inputs to Hippocampal CA1 Transmit a Signal That Suppresses Ongoing Contextual Fear Memory Retrieval.

Memory retrieval of fearful experiences is essential for survival but can be maladaptive if not appropriately suppressed. Fear memories can be acquired through contextual fear conditioning (CFC) which relies on the hippocampus. The thalamic subregion Nucleus Reuniens (NR) is necessary for contextual fear extinction and strongly projects to hippocampal subregion CA1. However, the NR-CA1 pathway has not been investigated during behavior, leaving unknown its role in contextual fear memory retrieval. We implement a novel head-restrained virtual reality CFC paradigm and show that inactivation of the NR-CA1 pathway prolongs fearful freezing epochs, induces fear generalization, and delays extinction. We use in vivo sub-cellular imaging to specifically record NR-axons innervating CA1 before and after CFC. We find NR-axons become selectively tuned to freezing only after CFC, and this activity is well-predicted by an encoding model. We conclude that the NR-CA1 pathway actively suppresses fear responses by disrupting ongoing hippocampal-dependent contextual fear memory retrieval.

Direct Thalamic Inputs to Hippocampal CA1 Transmit a Signal That Suppresses Ongoing Contextual Fear Memory Retrieval.

Memory retrieval of fearful experiences is essential for survival but can be maladaptive if not appropriately suppressed. Fear memories can be acquired through contextual fear conditioning (CFC) which relies on the hippocampus. The thalamic subregion Nucleus Reuniens (NR) is necessary for contextual fear extinction and strongly projects to hippocampal subregion CA1. However, the NR-CA1 pathway has not been investigated during behavior, leaving unknown its role in contextual fear memory retrieval. We implement a novel head-restrained virtual reality CFC paradigm and show that inactivation of the NR-CA1 pathway prolongs fearful freezing epochs, induces fear generalization, and delays extinction. We use in vivo sub-cellular imaging to specifically record NR-axons innervating CA1 before and after CFC. We find NR-axons become selectively tuned to freezing only after CFC, and this activity is well-predicted by an encoding model. We conclude that the NR-CA1 pathway actively suppresses fear responses by disrupting ongoing hippocampal-dependent contextual fear memory retrieval.