Rheumatoid arthritis is a common chronic inflammatory disorder and a major cause of disability. Despite the progress made with recent clinical use of anti-cytokine biologics, the response rate of rheumatoid arthritis treatment remains unsatisfactory, owing largely to the complexity of cytokine interactions and the multiplicity of cytokine targets. Here, we show a nanoparticle-based broad-spectrum anti-inflammatory strategy for rheumatoid arthritis management. By fusing neutrophil membrane onto polymeric cores, we prepare neutrophil membrane-coated nanoparticles that inherit the antigenic exterior and associated membrane functions of the source cells, which makes them ideal decoys of neutrophil-targeted biological molecules. It is shown that these nanoparticles can neutralize proinflammatory cytokines, suppress synovial inflammation, target deep into the cartilage matrix, and provide strong chondroprotection against joint damage. In a mouse model of collagen-induced arthritis and a human transgenic mouse model of arthritis, the neutrophil membrane-coated nanoparticles show significant therapeutic efficacy by ameliorating joint damage and suppressing overall arthritis severity.

Dopamine (DA) release varies within subregions and local environments of the striatum, suggesting that controls intrinsic and extrinsic to the DA fibers and terminals regulate release. While applying fast-scan cyclic voltammetry and using tonic and phasic stimulus trains, we investigated the regulation of DA release in the dorsolateral to ventral striatum. The ratio of phasic-to-tonic-evoked DA signals varied with the average ongoing firing frequency, and the ratio was generally higher in the nucleus accumbens (NAc) compared with the dorsolateral striatum. At the normal average firing frequency, burst stimulation produces a larger increase in the DA response in the NAc than the dorsolateral striatum. This finding was comparable whether the DA measurements were made using in vitro brain slices or were recorded in vivo from freely moving rodents. Blockade of the dopamine transporters and dopamine D 2 receptors particularly enhanced the tonic DA signals. Conversely, blockade of nicotinic acetylcholine receptors (nAChRs) containing the ␤ 2 subunit (␤ 2 *) predominantly suppressed tonic DA signals. The suppression of tonic DA release increased the contrast between phasic and tonic DA signals, and that made the frequencydependent DA dynamics between the dorsolateral striatum and NAc more similar. The results indicate that intrinsic differences in the DA fibers that innervate specific regions of the striatum combine with (at least) DA transporters, DA receptors, and nAChRs to regulate the frequency dependence of DA release. A combination of mechanisms provides specific local control of DA release that underlies pathway-specific information associated with motor and reward-related functions. Dopamine (DA) neurons operate in distinct tonic and phasic timescales to differentiate behaviorally relevant information (Schultz, 2007). DA neurons discharge tonically at low frequencies that consist of individual action potentials without bursts . Periodically, DA neurons fire in phasic bursts of near 20 Hz and greater (Hyland et al., 2002;Robinson et al., 2004). Evidence indicates that phasic or burst firing induces greater extracellular DA release compared with tonic, single-spike firing activity (Gonon, 1988;Grace, 1991;Floresco et al., 2003). Those tonic and phasic signals arise from midbrain DA neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) that innervate the whole dorsal to ventral extent of the striatum. Although the DA neurons that project to the prefrontal cortex may have higher discharge rates (Chiodo et al., 1984;Lammel et al., 2008), many midbrain DA neurons often exhibit similar overall firing properties (Schultz, 1986;Clark and Chiodo, 1988;Gariano et al., 1989;Robinson et al., 2004). Reward-related sensory input, however, such as that initiated by an addictive drug, enhances DA release to varying degrees depending on the dopaminergic pathway and target region (Pontieri et al., 1996;Nisell et al., 1997;Shi et al., 2000;Di Chiara et al., 2004;Janhunen and Ahtee, 2007). Th...

The dorsal striatum and the nucleus accumbens (NAc) shell of the ventral striatum have similar cellular components and are both richly innervated by dopamine neurons. Despite similarities that extend throughout the striatum, only the NAc shell has a conspicuous increase in basal dopamine upon the initial administration of psychostimulant drugs such as nicotine. As measured by microdialysis, the elevated dopamine in the NAc shell is considered an identifying functional characteristic of addictive drugs. To examine this general functional difference between nicotine's action on the dorsolateral striatum and NAc shell, we directly monitored dopamine release in rat striatal slices using fast-scan cyclic voltammetry. In addition, we separately monitored the in vivo unit firing activity of putative midbrain dopamine neurons from freely moving rats using chronic multiple tetrodes. Nicotine administration increased the firing frequency of dopamine neurons and specifically increased the number and the length of phasic burst firing. The frequency dependence for dopamine release in the dorsolateral striatum and NAc shell is fundamentally different, enabling mainly the NAc shell to capitalize on the nicotineinduced phasic burst firing by dopamine neurons. Although nicotine decreased low-frequency (tonic) dopamine release in both areas, the increased ratio of phasic bursts relative to tonic firing caused by nicotine boosted the basal dopamine concentration predominantly in the NAc shell. By favoring release from bursts while depressing release from tonic signals, nicotine spreads the range of dopamine signaling and effectively increases the signal-to-noise relationship along dopamine afferents.

The striatum receives rich dopaminergic and more moderate serotonergic innervation. After vesicular release, dopamine and serotonin (5-hydroxytryptamine, 5-HT) signaling is controlled by transporter-mediated reuptake. Dopamine is taken up by dopamine transporters (DATs), which are expressed at the highest density in the striatum. Although DATs also display a low affinity for 5-HT, that neurotransmitter is normally efficiently taken up by the 5-HT transporters. We found that when extracellular 5-HT is elevated by exogenous application or by using antidepressants (e.g., fluoxetine) to inhibit the 5-HT transporters, the extremely dense striatal DATs uptake 5-HT into dopamine terminals. Immunohistochemical results and measurements using fast cyclic voltammetry showed that elevated 5-HT is taken up by DATs into striatal dopamine terminals that subsequently release 5-HT and dopamine together. These results suggest that antidepressants that block serotonin transporters or other factors that elevate extracellular 5-HT alter the temporal and spatial relationship between dopamine and 5-HT signaling in the striatum.

This work developed the first example of PET-ATRP using a reductive pathway, which provides new opportunities for the synthesis of well-controlled polymer architectures through a photochemical approach.