Remotely Controlled Chemomagnetic Modulation of Targeted Neural Circuits

Abstract

Connecting neural circuit output to behaviour can be facilitated by precise chemical manipulation of specific cell populations1,2. Engineered receptors exclusively activated by designer small molecules enable manipulation of specific neural pathways3,4. Their application to studies of behaviour has thus far been hampered by a trade-off between low temporal resolution of systemic injection versus invasiveness of implanted cannulas or infusion pumps2. Here, we develop remotely controlled chemomagnetic modulation – a nanomaterials-based technique that permits pharmacological interrogation of targeted neural populations in freely moving subjects. The heat dissipated by magnetic nanoparticles in the presence of alternating magnetic fields triggers small molecule release from thermally sensitive lipid vesicles with 20 s latency. Coupled with chemogenetic activation of engineered receptors, this technique permits the control of specific neurons with temporal and spatial precision. Delivery of chemomagnetic particles to the ventral tegmental area allows remote modulation of motivated behaviour in mice. Furthermore, this chemomagnetic approach activates endogenous circuits by enabling regulated release of receptor ligands. Applied to an endogenous dopamine receptor D1 agonist in the nucleus accumbens, a brain area involved in mediating social interactions, chemomagnetic modulation increases sociability in mice. By offering temporally precise control of specified ligand-receptor interactions in neurons, this approach may facilitate molecular neuroscience studies in behaving organisms.