ArticlebioRxiv : the preprint server for biology2025
Theta-paced stimulation of the thalamic nucleus reuniens entrains mPFC-HPC oscillations and facilitates the acquisition of extinction memories.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: 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. Functional inactivation of the RE impairs both mPFC-HPC coherence and extinction memory. Here we examine whether imposing theta activity on the RE entrains oscillations in the mPFC and HPC and facilitates extinction learning. Methods: To deliver theta-paced (8 Hz) optogenetic stimulation, we expressed an excitatory opsin, (channelrhodopsin; AAV9-CaMKIIa-hChR2(H134R)-mCherry) or control virus (AAV9-CaMKIIa-mCherry) in the RE in male and female rats. A single optic fiber targeting the RE was implanted during the same surgery. After recovery, animals underwent auditory fear conditioning, extinction training, and an extinction retrieval test, each separated by 24-h. During extinction training, conditioned stimuli (CS) presentations were paired with 8-Hz sinusoidal optostimulation (473 nM, 10 mW) of the RE. In another experiment, we recorded local field potentials (LFPs) from the mPFC and dorsal HPC during using these behavioral procedures. Results: Theta-paced stimulation of the RE during extinction training significantly decreased freezing behavior compared to the control group. Notably, the reduction in conditioned behavior was evident during the subsequent stimulation-free retrieval test. This reveals that RE stimulation during extinction not only suppresses conditioned fear responses acutely, but also facilitates the acquisition of long-term extinction memories. Theta-paced RE stimulation markedly enhanced both neural activity and entrained theta oscillations in the mPFC and dHPC. Conclusion: This work suggests that the RE oscillatory activity is critical for the acquisition of extinction memories through the modulation of hippocampal-prefrontal network dynamics. In the future, RE theta-paced stimulation can be an important therapeutic tool by strengthening extinction memories.
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