Tapered Drug delivery, Optical stimulation, and Electrophysiology (T-DOpE) probes reveal the importance of cannabinoid signaling in hippocampal CA1 oscillations in behaving mice.

Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. Here we developed a thermal tapering process (TTP) which enables the fabrication of novel, low-cost, flexible probes that combine ultrafine features of dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly of the probes. We demonstrate that our T-DOpE ( apered rug delivery, tical stimulation, and lectrophysiology) probe achieves in a single neuron-scale device (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. With a tapered geometry, the device tip can be minimized (as small as 50 μm) to ensure minimal tissue damage while the backend is ~20 times larger allowing for direct integration with industrial-scale connectorization. Acute and chronic implantation of the probes in mouse hippocampus CA1 revealed canonical neuronal activity at the level of local field potentials and spiking. Taking advantage of the triple-functionality of the T-DOpE probe, we monitored local field potentials with simultaneous manipulation of endogenous type 1 cannabinoid receptors (CB1R; via microfluidic agonist delivery) and CA1 pyramidal cell membrane potential (optogenetic activation). Electro-pharmacological experiments revealed that focal infusion of CB1R agonist CP-55,940 in dorsal CA1 downregulated theta and sharp wave-ripple oscillations. Furthermore, using the full electro-pharmacological-optical feature set of the T-DOpE probe we found that CB1R activation reduces sharp wave-ripples (SPW-Rs) by impairing the innate SPW-R-generating ability of the CA1 circuit.