Thalamic nucleus reuniens coordinates prefrontal-hippocampal synchrony to suppress extinguished fear

Abstract

Traumatic events result in vivid and enduring fear memories. Suppressing the retrieval of these memories is central to behavioral therapies for pathological fear. The medial prefrontal cortex (mPFC) and hippocampus (HPC) have been implicated in retrieval suppression, but how mPFC-HPC activity is coordinated during extinction retrieval is unclear. Here we show that after extinction training, coherent theta oscillations (6-9 Hz) in the HPC and mPFC are correlated with the suppression of conditioned freezing in male and female rats. Inactivation of the nucleus reuniens (RE), a thalamic hub interconnecting the mPFC and HPC, reduces extinction-related Fos expression in both the mPFC and HPC, dampens mPFC-HPC theta coherence, and impairs extinction retrieval. Conversely, theta-paced optogenetic stimulation of RE augments fear suppression and reduces relapse of extinguished fear. Collectively, these results demonstrate a novel role for RE in coordinating mPFC-HPC interactions to suppress fear memories after extinction.

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

“…Our findings expand on a previous canon of work that indicates both the mPFC-NR projection and NR itself are required for contextual fear extinction and preventing fear overgeneralization 29,33–35 . Our results suggest that in addition to these roles, NR reduces time spent freezing following CFC by suppressing CFMR as it is occurring during freezing epochs.…”

“…NR stimulation reduces contextual fear-induced immediate early gene expression in both mPFC and CA1 35,36 . While the roles of the mPFC-NR pathway and NR itself have been explored during CFMR, the role of the NR-CA1 pathway is unknown.…”

“…The mPFC-NR projection and NR itself is necessary for both fear extinction and for preventing fear generalization to a neutral context, a process in which mice fail to form context-specific memory and additionally associate a non-shocked context with fear 29–35 . NR stimulation reduces contextual fear-induced immediate early gene expression in both mPFC and CA1 35,36 . While the roles of the mPFC-NR pathway and NR itself have been explored during CFMR, the role of the NR-CA1 pathway is unknown.…”

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

“…Our findings expand on a previous canon of work that indicates both the mPFC-NR projection and NR itself are required for contextual fear extinction and preventing fear overgeneralization 29,[33][34][35] . Our results suggest that in addition to these roles, NR reduces time spent freezing following CFC by suppressing CFMR as it is occurring during freezing epochs.…”

“…The mPFC-NR projection and NR itself is necessary for both fear extinction and for preventing fear generalization to a neutral context, a process in which mice fail to form context-specific memory and additionally associate a non-shocked context with fear [29][30][31][32][33][34][35] .…”