Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The striatum is a critical brain region involved in motor control, reward, and habit formation.
• Precise tools are needed to access and manipulate specific striatal cell types and their circuits for functional studies.
• Existing transgenic models have limitations in specificity and versatility across species.

Purpose of the Study:

• To develop and validate a toolbox of enhancer-driven adeno-associated virus (AAV) vectors for cell-type-specific access to striatal populations.
• To enable targeted perturbation of striatal circuits and detailed cellular analysis.
• To provide a versatile tool for studying striatal function in diverse mammalian species.

Main Methods:

• Curated and validated a collection of best-in-class enhancer-AAV vectors.
• Evaluated vector specificity using molecular validation, multiple delivery routes, and diverse transgene cargos.
• Demonstrated optogenetic perturbation of behavior and multiplex labeling of striatal interneurons.

Main Results:

• Achieved reliable cell-type-specific labeling of major striatal neuron populations, including medium spiny neurons (MSNs) and interneurons.
• Demonstrated successful optogenetic control of behavior via direct pathway circuit perturbation.
• Showcased conserved in vivo activity of MSN enhancers in rats and macaques, extending beyond mouse models.

Conclusions:

• The enhancer-AAV toolbox provides enhanced versatility for targeting striatal cell types and circuits compared to transgenic lines.
• This resource facilitates cell-type and circuit-specific studies in diverse mammalian species.
• The developed vectors are crucial for advancing our understanding of striatal function and dysfunction.