A Chemogenetic Tool that Enables Functional Neural Circuit Analysis.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Chemogenetics offers neuronal activity control but doesn't reveal antecedent circuit drivers.
• Current methods are limited as activating molecules are not genetically encoded.
• The insect allatostatin/allatostatin receptor system is a specific, inhibitory chemogenetic approach where the peptide ligand is genetically encoded.

Purpose of the Study:

• To develop and validate a novel chemogenetic system for neuronal inhibition using a genetically encoded ligand.
• To enable investigation of antecedent circuits driving neuronal activity.
• To demonstrate the utility of this system in a physiological context.

Main Methods:

• Development of viral vector-based systems to express biologically active allatostatin in neurons in vivo.
• Expression of allatostatin receptors in subpopulations of postsynaptic neurons.
• Demonstration of activity-dependent allatostatin release and subsequent inhibition of target neurons.

Main Results:

• Successful expression of functional allatostatin and its receptors using viral vectors.
• Activity-dependent release of allatostatin effectively inhibited allatostatin receptor-expressing neurons.
• Validation in the vagal viscerosensory system showed inhibitory input led to decreased baroreceptor reflex sensitivity and body weight.

Conclusions:

• A novel, genetically encoded chemogenetic system for neuronal inhibition has been developed.
• This system allows for the study of antecedent circuits by enabling activity-dependent inhibition.
• The approach is validated in a physiological system, demonstrating its potential for neuroscience research.