Wireless closed-loop optogenetics across the entire dorsoventral spinal cord in mice.

Optoelectronic systems can exert precise control over targeted neurons and pathways throughout the brain in untethered animals, but similar technologies for the spinal cord are not well established. In the present study, we describe a system for ultrafast, wireless, closed-loop manipulation of targeted neurons and pathways across the entire dorsoventral spinal cord in untethered mice. We developed a soft stretchable carrier, integrating microscale light-emitting diodes (micro-LEDs), that conforms to the dura mater of the spinal cord. A coating of silicone-phosphor matrix over the micro-LEDs provides mechanical protection and light conversion for compatibility with a large library of opsins. A lightweight, head-mounted, wireless platform powers the micro-LEDs and performs low-latency, on-chip processing of sensed physiological signals to control photostimulation in a closed loop. We use the device to reveal the role of various neuronal subtypes, sensory pathways and supraspinal projections in the control of locomotion in healthy and spinal-cord injured mice.

Epineural optogenetic activation of nociceptors initiates and amplifies inflammation.

Activation of nociceptor sensory neurons by noxious stimuli both triggers pain and increases capillary permeability and blood flow to produce neurogenic inflammation1,2, but whether nociceptors also interact with the immune system remains poorly understood. Here we report a neurotechnology for selective epineural optogenetic neuromodulation of nociceptors and demonstrate that nociceptor activation drives both protective pain behavior and inflammation. The wireless optoelectronic system consists of sub-millimeter-scale light-emitting diodes embedded in a soft, circumneural sciatic nerve implant, powered and driven by a miniaturized head-mounted control unit. Photostimulation of axons in freely moving mice that express channelrhodopsin only in nociceptors resulted in behaviors characteristic of pain, reflecting orthodromic input to the spinal cord. It also led to immune reactions in the skin in the absence of inflammation and potentiation of established inflammation, a consequence of the antidromic activation of nociceptor peripheral terminals. These results reveal a link between nociceptors and immune cells, which might have implications for the treatment of inflammation.

Optical cuff for optogenetic control of the peripheral nervous system.

OBJECTIVE: Nerves in the peripheral nervous system (PNS) contain axons with specific motor, somatosensory and autonomic functions. Optogenetics offers an efficient approach to selectively activate axons within the nerve. However, the heterogeneous nature of nerves and their tortuous route through the body create a challenging environment to reliably implant a light delivery interface. APPROACH: Here, we propose an optical peripheral nerve interface-an optocuff-, so that optogenetic modulation of peripheral nerves become possible in freely behaving mice. MAIN RESULTS: Using this optocuff, we demonstrate orderly recruitment of motor units with epineural optical stimulation of genetically targeted sciatic nerve axons, both in anaesthetized and in awake, freely behaving animals. Behavioural experiments and histology show the optocuff does not damage the nerve thus is suitable for long-term experiments. SIGNIFICANCE: These results suggest that the soft optocuff might be a straightforward and efficient tool to support more extensive study of the PNS using optogenetics.

Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses.

Potentially harmful stimuli are detected at the skin by nociceptor sensory neurons that drive rapid protective withdrawal reflexes and pain. We set out to define, at a millisecond timescale, the relationship between the activity of these sensory neurons and the resultant behavioral output. Brief optogenetic activation of cutaneous nociceptors was found to activate only a single action potential in each fiber. This minimal input was used to determine high-speed behavioral responses in freely behaving mice. The localized stimulus generated widespread dynamic repositioning and alerting sub-second behaviors whose nature and timing depended on the context of the animal and its position, activity, and alertness. Our findings show that the primary response to injurious stimuli is not limited, fixed, or localized, but is dynamic, and that it involves recruitment and gating of multiple circuits distributed throughout the central nervous system at a sub-second timescale to effectively both alert to the presence of danger and minimize risk of harm.

Correlation between muscular and nerve signals responsible for hand grasping in non-human primates.

Neuroprosthetic devices that interface with the nervous system to restore functional motor activity offer a viable alternative to nerve regeneration, especially in proximal nerve injuries like brachial plexus injuries where muscle atrophy may set in before nerve re-innervation occurs. Prior studies have used control signals from muscle or cortical activity. However, nerve signals are preferred in many cases since they permit more natural and precise control when compared to muscle activity, and can be accessed with much lower risk than cortical activity. Identification of nerve signals that control the appropriate muscles is essential for the development of such a `bionic link'. Here we examine the correlation between muscle and nerve signals responsible for hand grasping in the M. fascicularis. Simultaneous recordings were performed using a 4-channel thin-film longitudinal intra-fascicular electrode (tf-LIFE) and 9 bipolar endomysial muscle electrodes while the animal performed grasping movements. We were able to identify a high degree of correlation (r > 0.6) between nerve signals from the median nerve and movement-dependent muscle activity from the flexor muscles of the forearm, with a delay that corresponded to 25 m/s nerve conduction velocity. The phase of the flexion could be identified using a wavelet approximation of the ENG. This result confirms this approach for a future neuroprosthetic device for the treatment of peripheral nerve injuries.