Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction

Umemori, J.; Didio, G.; Winkel, F.; Pou, M. L.; Harkki, J.; Russo, G. L.; Verie, M.; Antila, H.; Buj, C.; Taira, T.; Lauri, S. E.; Guirado, R.; Castren, E.

doi:10.1101/2021.02.14.431126

bioRxiv · 10.1101/2021.02.14.431126

Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction

Umemori, J.·Didio, G.·Winkel, F.·Pou, M. L.·Harkki, J.·Russo, G. L.·Verie, M.·Antila, H.·Buj, C.·Taira, T.·Lauri, S. E.·Guirado, R.·Castren, E.

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Abstract

Successful extinction of traumatic memories depends on neuronal plasticity in the fear extinction network. However, the mechanisms involved in the extinction process remain poorly understood. Here, we investigated the fear extinction network by using a new optogenetic technique that allows temporal and spatial control of neuronal plasticity in vivo. We optimized an optically inducible TrkB (CKII-optoTrkB), the receptor of the brain-derived neurotrophic factor, which can be activated upon blue light exposure to increase plasticity specifically in pyramidal neurons. The activation of CKII-optoTrkB facilitated the induction of LTP in Schaffer collateral-CA1 synapses after brief theta-burst stimulation and increased the expression of FosB in the pyramidal neurons of the ventral hippocampus, indicating enhanced plasticity in that brain area. We showed that optical stimulation of the CA1 region of the ventral hippocampus during fear extinction training led to an attenuated conditioned fear memory. This was a specific effect only observed when combining extinction training with CKII-optoTrkB activation, and not when using either intervention alone. Thus, TrkB activation in ventral CA1 pyramidal neurons promotes a state of neuronal plasticity that allows extinction training to guide neuronal network remodeling to overcome fear memories. Our methodology is a powerful tool to induce neuronal network remodeling in the adult brain, and can attenuate neuropsychiatric symptoms caused by malfunctioning networks.

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Umemori, J., Didio, G., Winkel, F., Pou, M. L., Harkki, J., Russo, G. L., Verie, M., Antila, H., Buj, C., Taira, T., Lauri, S. E., Guirado, R., Castren, E.. 2021-02-16. Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction. https://doi.org/10.1101/2021.02.14.431126

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