Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms.DOI: http://dx.doi.org/10.7554/eLife.18247.001

Capabilities for recording neural activity in behaving mammals have greatly expanded our understanding of brain function. Some of the most sophisticated approaches use light delivered by an implanted fiber-optic cable to optically excite genetically encoded calcium indicators and to record the resulting changes in fluorescence. Physical constraints induced by the cables and the bulk, size, and weight of the associated fixtures complicate studies on natural behaviors, including social interactions and movements in environments that include obstacles, housings, and other complex features. Here, we introduce a wireless, injectable fluorescence photometer that integrates a miniaturized light source and a photodetector on a flexible, needle-shaped polymer support, suitable for injection into the deep brain at sites of interest. The ultrathin geometry and compliant mechanics of these probes allow minimally invasive implantation and stable chronic operation. In vivo studies in freely moving animals demonstrate that this technology allows high-fidelity recording of calcium fluorescence in the deep brain, with measurement characteristics that match or exceed those associated with fiber photometry systems. The resulting capabilities in optical recordings of neuronal dynamics in untethered, freely moving animals have potential for widespread applications in neuroscience research.

Highlights d Pain recruits the dynorphin-kappa opioid receptor system in the nucleus accumbens d Inhibitory inputs onto dynorphin cells are reduced during inflammatory pain d Increase in dynorphin tone mediates inflammatory paininduced negative affect

Highlights d pnVTA Pnoc neurons project locally onto VTA dopamine neurons d pnVTA Pnoc neurons become active when animals are demotivated to seek rewards d Stimulation of pnVTA Pnoc neurons reduces breakpoint and promotes avoidance behavior d VTA dopamine neuron NOPR expression is necessary to limit reward-seeking behavior Authors

Optogenetic methods to modulate cells and signaling pathways via targeted expression and activation of light-sensitive proteins have greatly accelerated the process of mapping complex neural circuits and defining their roles in physiological and pathological contexts. Recently demonstrated technologies based on injectable, microscale inorganic light-emitting diodes (μ-ILEDs) with wireless control and power delivery strategies offer important functionality in such experiments, by eliminating the external tethers associated with traditional fiber optic approaches. Existing wireless μ-ILED embodiments allow, however, illumination only at a single targeted region of the brain with a single optical wavelength and over spatial ranges of operation that are constrained by the radio frequency power transmission hardware. Here we report stretchable, multiresonance antennas and battery-free schemes for multichannel wireless operation of independently addressable, multicolor μ-ILEDs with fully implantable, miniaturized platforms. This advance, as demonstrated through in vitro and in vivo studies using thin, mechanically soft systems that separately control as many as three different μ-ILEDs, relies on specially designed stretchable antennas in which parallel capacitive coupling circuits yield several independent, well-separated operating frequencies, as verified through experimental and modeling results. When used in combination with active motion-tracking antenna arrays, these devices enable multichannel optogenetic research on complex behavioral responses in groups of animals over large areas at low levels of radio frequency power (<1 W). Studies of the regions of the brain that are involved in sleep arousal (locus coeruleus) and preference/aversion (nucleus accumbens) demonstrate the unique capabilities of these technologies.wireless optogenetics | stretchable electronics | wireless power transmission | deep brain stimulation | antenna O ptogenetics exploits a toolbox of light-sensitive proteins for optical manipulation of neural networks as a powerful means for the study of circuit-level mechanisms that underlie psychiatric diseases (1-4). Canonical optogenetic experiments in the brain require cranial insertion of an optical fiber to illuminate a region of interest (5, 6). Although this approach permits simple behavior modeling, constraints in animal motion and alterations in natural behaviors due to fiber tethering and external fixation complicate use in chronic longitudinal models and in experiments that assess complex responses. Many of these limitations can be bypassed with optoelectronic technologies and wireless receivers, as recently demonstrated in optogenetic stimulation of the brain, the peripheral nerves, and the spinal cord (4, 7-13). Systems that offer soft, compliant mechanical properties and thin, fully implantable designs are particularly advantageous (7). These systems, however, have still not been optimized to fully take advantage of the power of combining mouse genetics/optogentics with long-term beha...