Tagging active neurons by soma-targeted Cal-Light
Jung Ho Hyun, Kenichiro Nagahama, Ho Namkung, Neymi Mignocchi, Seung‐Eon Roh, Patrick Hannan, Sarah Krüssel, Chuljung Kwak, Abigail McElroy, Bian Liu, Mingguang Cui, Seung-Hwan Lee, Dongmin Lee, Richard L. Huganir, Paul F. Worley, Akira Sawa, Hyung‐Bae Kwon
Abstract
Verifying causal effects of neural circuits is essential for proving a direct circuit-behavior relationship. However, techniques for tagging only active neurons with high spatiotemporal precision remain at the beginning stages. Here we develop the soma-targeted Cal-Light (ST-Cal-Light) which selectively converts somatic calcium rise triggered by action potentials into gene expression. Such modification simultaneously increases the signal-to-noise ratio of reporter gene expression and reduces the light requirement for successful labeling. Because of the enhanced efficacy, the ST-Cal-Light enables the tagging of functionally engaged neurons in various forms of behaviors, including context-dependent fear conditioning, lever-pressing choice behavior, and social interaction behaviors. We also target kainic acid-sensitive neuronal populations in the hippocampus which subsequently suppress seizure symptoms, suggesting ST-Cal-Light's applicability in controlling disease-related neurons. Furthermore, the generation of a conditional ST-Cal-Light knock-in mouse provides an opportunity to tag active neurons in a region- or cell-type specific manner via crossing with other Cre-driver lines. Thus, the versatile ST-Cal-Light system links somatic action potentials to behaviors with high temporal precision, and ultimately allows functional circuit dissection at a single cell resolution.