A Molecular Calcium Integrator Reveals a Striatal Cell Type Driving Aversion

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Analyzing heterogeneous cell populations requires methods to record transient cellular events.
• Genetic tagging of active cells is crucial for understanding cellular function and reprogramming.

Purpose of the Study:

• To develop a molecular technology for stable genetic tagging of cells based on activity-related calcium increases.
• To demonstrate the utility of this technology in identifying and manipulating specific neural ensembles.

Main Methods:

• Developed FLiCRE (Fluorescent Ligand-Induced Calcium-Responsive Element) for genetic tagging.
• Utilized FLiCRE to label activated neural ensembles in the mouse nucleus accumbens.
• Employed single-cell RNA sequencing to detect FLiCRE transcripts and analyze cell-type specific activation.
• Used optogenetics to manipulate the identified cell population.

Main Results:

• FLiCRE successfully labeled activated neural ensembles in response to aversive stimuli.
• Single-cell RNA sequencing confirmed FLiCRE transcript presence, enabling simultaneous cell-type and activation history readout.
• Identified a novel cell type in the nucleus accumbens activated by long-range excitatory projections.
• Selective optogenetic recruitment of this cell type elicited behavioral aversion.

Conclusions:

• FLiCRE provides a powerful tool for molecularly informed characterization and manipulation of activated cellular ensembles.
• This technology enables precise analysis and reprogramming of heterogeneous cell populations.
• FLiCRE advances the ability to study and control specific cell types based on their activity history.