Acoustically targeted chemogenetics for the non-invasive 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.

Consistent opening of the blood brain barrier using focused ultrasound with constant intravenous infusion of microbubble agent

“…Such increased concentration after several injections can cause enhancement rates to elevate unintentionally. To avoid this issue, many groups have implemented delays between microbubble injections to allow for clearance 14,18,36 . Our results clearly show that even 15 min after delivery stopped there were enough circulating microbubbles for substantial BBB opening to occur (Fig.…”

Chemogenetic ligands for translational neurotheranostics

“…It is important to point out that such considerations are not unique to chemogenetics but are shared by conventional brain-targeted gene therapies. New technologies such as acoustically-targeted chemogenetics 15 and systemically administered genetically-targeted vectors 16 offer further promise for minimizing invasiveness of such practices. Chemogenetics and related technologies are already greatly facilitating identification of disease-relevant neuron types and circuits at the preclinical level, and tools such as those reported here hold great promise for helping translate these groundbreaking studies into clinical strategies.…”

Sonogenetics for noninvasive and cellular-level neuromodulation in rodent brain

“…in clinical trials, and new genome editing technologies have brought safe gene delivery a step closer to clinical practice 32 . Recently, several preclinical studies have shown that FUS in combination with microbubbles can transiently enhance the blood-brain barrier permeability for the noninvasive and localized delivery of intravenously injected AAVs to the mouse brain for optogenetics 33 and chemogenetics 34 . Currently, clinical trials are evaluating the feasibility and safety of the FUS technique for drug delivery to the brain [35][36][37] .…”