Midbrain stimulation in freely behaving mice by photothermal transducers actuated via widefield near-infrared II light

Invasive brain implants and tethered optical fibres are typically used in restrained or motion-impaired animals, limiting the control and the decoding of the neural circuitry in freely behaving ones. Here we report the implant- and tether-free optical neurostimulation of deep brain regions by locally injected and untargeted photothermal transducers. The macromolecular transducers, comprising a semiconducting polymer core and an amphiphilic polymer shell, have an average diameter of 40 nanometres and achieve a photothermal conversion of 71% (at 1064 nm), activating the transient receptor potential cation channel subfamily V member 1 (TRPV1) ectopically expressed by an adeno-associated virus in dopaminergic neurons of tyrosine hydroxylase-driven Cre recombinase transgenic mice. The near-transparency of biological tissue in the second near-infrared window enabled the light source to be placed at 50 centimetres above the mouse, at a low incident power density of 10 milliwatt/square millimetre, resulting in the activation, through the scalp and skull, of the dopaminergic neurons in the ventral tegmental area, with minimal thermal damage. The approach is suitable for the neurostimulation of socially interacting mice.