Acoustically Targeted Chemogenetics for Noninvasive Control of Neural Circuits

Abstract

Neurological and psychiatric diseases often involve the dysfunction of specific neural circuits in particular regions of the brain. Existing treatments, including drugs and implantable brain stimulators, aim to modulate the activity of these circuits, but are typically not cell type-specific, lack spatial targeting or require invasive procedures. Here, we introduce an approach to modulating neural circuits noninvasively with spatial, cell-type and temporal specificity. This approach, called acoustically targeted chemogenetics, or ATAC, uses transient ultrasonic opening of the blood brain barrier to transduce neurons at specific locations in the brain with virally-encoded engineered G-protein-coupled receptors, which subsequently respond to systemically administered bio-inert compounds to activate or inhibit the activity of these neurons. We demonstrate this concept in mice by using ATAC to noninvasively modify and subsequently activate or inhibit excitatory neurons within the hippocampus, showing that this enables pharmacological control of memory formation. This technology allows a brief, noninvasive procedure to make one or more specific brain regions capable of being selectively modulated using orally bioavailable compounds, thereby overcoming some of the key limitations of conventional brain therapies.

Biomolecular Ultrasound and Sonogenetics

“…As a noninvasive technique capable of targeting viral vectors to a specific region of the brain, FUS-BBBO creates an unprecedented opportunity for noninvasive control of neural activity with spatial, temporal, and cell-type specificity. These aspects were recently combined in a technique called acoustically targeted chemogenetics (ATAC) (115), which uses FUS-BBBO to deliver viral vectors to specific brain regions, using cell-specific promoters to target selected populations of cells within those regions and encoding chemogenetic receptors—proteins that respond exclusively to bioinert drugs (116)—to gain temporal control of the targeted cells. ATAC holds significant advantages over typical neuropsychiatric drugs, which act indiscriminately throughout the brain with limited regional and cellular specificity.…”

Achieving Spatial and Molecular Specificity with Ultrasound-Targeted Biomolecular Nanotherapeutics

“…Pioneering applications of this technology include the treatment of brain cancer 24 and neurodegenerative diseases. 25−27 To combine the spatial precision of ultrasound with the molecular, cell type, and temporal control provided by genetically engineered therapeutics, we recently developed an approach to noninvasive control of neural circuits called acoustically targeted chemogenetics, or ATAC 28 (Figure 2A, B). This technology uses FUS-BBBO to deliver adenoassociated viral (AAV) vectors into specific brain regions ( Figure 2C).…”

“…treatment and a several-week period to attain robust expression of the chemogenetic receptor that lasts for at least several months. 28 Subsequently, the transfected neurons are controlled on-demand via the simple systemic administration of the chemogenetic ligand.…”

“…In a proof-of-concept study, 28 we used ATAC to noninvasively inactivate the mouse hippocampus ( Figure 2D) and inhibit the formation of associative memories ( Figure 2E). The effect was highly specific; we did not observe off-target effects on untargeted neurons or untargeted behaviors.…”

Modulation of Brain Function and Behavior by Focused Ultrasound

“…Szablowski et al (2018) in a recent preprint showed that application of FUS allowed infection and expression of DREADDs in hippocampus of mice. Expression was limited to hippocampus and highly specific for excitatory neurons.…”