jULIEs: extracellular probes for recordings and stimulation in the structurally and functionally intact mouse brain

High signal-to-noise, scalable and minimally invasive recording and stimulation of the nervous system in intact animals is of fundamental importance to advance the understanding of brain function. Extracellular electrodes are among the most powerful tools capable of interfacing with large neuronal populations 1-3 . Neuronal tissue damage remains a major limiting factor in scaling electrode arrays, and has been found to correlate with electrode diameter across different electrode materials, such as microfabricated Michigan and Utah-style arrays 4 , MEMS and microsystems 5 , soft polymer or tungsten electrodes 6 and Parylene C probes 7 . Small diameter ultramicroelectrodes (UMEs), while highly desirable, pose significant technical challenges such as reaching sufficient electrolyte-electrode coupling and limiting stray signal loss. To overcome these challenges, we have designed juxtacellular Ultra-Low Impedance Electrodes (jULIEs), a scalable technique for achieving high signal-to-noise electrical recordings as well as stimulation with UMEs. jULIEs are metal-glass composite UMEs thermally drawn to outer diameters (OD) of <25 µm, with metal core diameters (ID) of as little as 1 µm. We introduce a two-step electrochemical modification strategy that reduces UME coupling impedances by two orders of magnitude. Modifications enabled high signal-to-noise neural recordings in vivo through wires with micrometer scale core diameters. Histological and imaging experiments indicated that local vascular damage is minimal. Spikes reached amplitudes over 1 mV in vivo , indicating that recordings are possible in close proximity to intact neurons. Recording sites can be arranged in arbitrary patterns tailored to various neuroanatomical target structures and allowing parallel penetrations. jULIEs thus represent a versatile platform that allows for reliable recording and manipulation of neural activity in any areas of the functionally intact mammalian brain.