Figure 1.

Principles of precision neuromodulation through chemogenetics

(A) Using either site-directed mutagenesis or directed evolution, candidate signaling receptors are modified to exhibit elevated or diminished affinities for cognate ligands. Ligands are either exogenous, pharmacologically inert small molecules or endogenous signaling molecules. (B) Chemogenetic receptors are delivered to the brain using viral vectors. Receptor expression is restricted by the localized infusion of the viral vector and tissue-specific regulatory elements of gene expression. (C) Therapeutic neuromodulation is achieved through reversible and titratable signaling events mediated by the chemogenetic receptors in the presence of cognate chemogenetic ligands, with therapeutic efficacy and safety contingent upon neuromodulation of specific brain regions, cell types, and/or circuits. Receptor expression is non-invasively and longitudinally monitored by positron emission tomography.