Theta-paced stimulation of the thalamic nucleus reuniens en-trains mPFC-HPC oscillations and facilitates the acquisition of extinction memories

The nucleus reuniens (RE) is a midline thalamic nucleus interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC), structures known to be involved in aversive memory processes. Recent work indicates that the RE plays a critical role in the acquisition and retrieval of fear extinction memories. Specifically, the RE coordinates theta oscillations between the mPFC and HPC during extinction retrieval. Pharmacological inactivation of the RE impairs both mPFC-HPC theta coherence and the retrieval of extinction memory. Furthermore, theta-paced (8-Hz) optogenetic stimulation of the RE prevents fear renewal after extinction, a common form of fear relapse. However, it remains unclear whether theta-paced RE stimulation can entrain theta oscillations in the mPFC and HPC, and whether such entrainment is sufficient to facilitate the acquisition of extinction memories. To this end, we performed theta-paced optogenetic stimulation of the RE in adult male and female Long-Evans rats during extinction training. Animals underwent auditory fear conditioning, extinction, and an extinction retrieval test, each separated by 24 h. During extinction, 8-Hz stimulation of the RE was delivered concurrently with the presentation of the conditioned stimuli (CS). Theta-paced stimulation of the RE during extinction training significantly decreased freezing behavior compared to the control group. Notably, this reduction in conditioned behavior was also evident during the subsequent stimulation-free retrieval test, suggesting that RE stimulation not only suppresses conditioned fear responses acutely, but also facilitates the acquisition of long-term extinction memories. In a separate set of animals, we observed that theta-paced RE stimulation markedly enhanced both neural activity and entrained oscillations in the mPFC and dHPC at 8-Hz. This work suggests that the RE oscillatory activity is critical for the acquisition of extinction memories through the modulation of hippocampal-prefrontal network dynamics.