ABSTRACT
Connecting neural circuit output to behaviour can be facilitated by the precise chemical manipulation of specific cell populations1,2. Engineered receptors exclusively activated by designer small molecules enable manipulation of specific neural pathways3,4. However, their application to studies of behaviour has thus far been hampered by a trade-off between the low temporal resolution of systemic injection versus the invasiveness of implanted cannulae or infusion pumps2. Here, we developed a remotely controlled chemomagnetic modulation-a nanomaterials-based technique that permits the pharmacological interrogation of targeted neural populations in freely moving subjects. The heat dissipated by magnetic nanoparticles (MNPs) in the presence of alternating magnetic fields (AMFs) triggers small-molecule release from thermally sensitive lipid vesicles with a 20 s latency. Coupled with the chemogenetic activation of engineered receptors, this technique permits the control of specific neurons with temporal and spatial precision. The delivery of chemomagnetic particles to the ventral tegmental area (VTA) allows the remote modulation of motivated behaviour in mice. Furthermore, this chemomagnetic approach activates endogenous circuits by enabling the regulated release of receptor ligands. Applied to an endogenous dopamine receptor D1 (DRD1) agonist in the nucleus accumbens (NAc), a brain area involved in mediating social interactions, chemomagnetic modulation increases sociability in mice. By offering a temporally precise control of specified ligand-receptor interactions in neurons, this approach may facilitate molecular neuroscience studies in behaving organisms.
Subject(s)
Delayed-Action Preparations/chemistry , Drug Delivery Systems , Magnetite Nanoparticles/chemistry , Nerve Net/drug effects , Neurotransmitter Agents/administration & dosage , Animals , Behavior, Animal/drug effects , Cells, Cultured , Liposomes/chemistry , Magnetic Fields , Male , Mice , Mice, Inbred C57BL , Nerve Net/physiology , Neurotransmitter Agents/pharmacology , Rats , Temperature , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/physiologyABSTRACT
Kava (Piper methysticum) is an ethnomedicinal shrub native to the Polynesian islands with well-established anxiolytic and analgesic properties. Its main psychoactive principles, kavalactones, form a unique class of polyketides that interact with the human central nervous system through mechanisms distinct from those of conventional psychiatric drugs. However, an unknown biosynthetic machinery and difficulty in chemical synthesis hinder the therapeutic use of kavalactones. In addition, kava also produces flavokavains, which are chalconoids with anticancer properties structurally related to kavalactones. Here, we report de novo elucidation of the key enzymes of the kavalactone and flavokavain biosynthetic network. We present the structural basis for the evolutionary development of a pair of paralogous styrylpyrone synthases that establish the kavalactone scaffold and the catalytic mechanism of a regio- and stereo-specific kavalactone reductase that produces a subset of chiral kavalactones. We further demonstrate the feasibility of engineering styrylpyrone production in heterologous hosts, thus opening a way to develop kavalactone-based non-addictive psychiatric therapeutics through synthetic biology.
