The dopamine neuron synaptic map in the striatum.

Dopamine neurons project to the striatum to control movement, cognition, and motivation via slower volume transmission as well as faster dopamine, glutamate, and GABA synaptic actions capable of conveying the temporal information in dopamine neuron firing. To define the scope of these synaptic actions, recordings of dopamine-neuron-evoked synaptic currents were made in four major striatal neuron types, spanning the entire striatum. This revealed that inhibitory postsynaptic currents are widespread, while excitatory postsynaptic currents are localized to the medial nucleus accumbens and the anterolateral-dorsal striatum, and that all synaptic actions are weak in the posterior striatum. Synaptic actions in cholinergic interneurons are the strongest, variably mediating inhibition throughout the striatum and excitation in the medial accumbens, capable of controlling their activity. This mapping shows that dopamine neuron synaptic actions extend throughout the striatum, preferentially target cholinergic interneurons, and define distinct striatal subregions.

Single Dose of Amphetamine Induces Delayed Subregional Attenuation of Cholinergic Interneuron Activity in the Striatum.

Psychostimulants such as amphetamine (AMPH) target dopamine (DA) neuron synapses to engender drug-induced plasticity. While DA neurons modulate the activity of striatal (Str) cholinergic interneurons (ChIs) with regional heterogeneity, how AMPH affects ChI activity has not been elucidated. Here, we applied quantitative fluorescence imaging approaches to map the dose-dependent effects of a single dose of AMPH on ChI activity at 2.5 and 24 h after injection across the mouse Str using the activity-dependent marker phosphorylated ribosomal protein S6 (p-rpS6240/244). AMPH did not affect the distribution or morphology of ChIs in any Str subregion. While AMPH at either dose had no effect on ChI activity after 2.5 h, ChI activity was dose dependently reduced after 24 h specifically in the ventral Str/nucleus accumbens (NAc), a critical site of psychostimulant action. AMPH at either dose did not affect the spontaneous firing of ChIs. Altogether this work demonstrates that a single dose of AMPH has delayed regionally heterogeneous effects on ChI activity, which most likely involves extra-Str synaptic input.

Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.

OBJECTIVE: Autophagy is a physiological self-eating process that can promote cell survival or activate cell death in eukaryotic cells. In skeletal muscle, it is important for maintaining muscle mass and function that is critical to sustain mobility and regulate metabolism. The UV radiation resistance-associated gene (UVRAG) regulates the early stages of autophagy and autophagosome maturation and plays a key role in endosomal trafficking. This study investigated the essential in vivo role of UVRAG in skeletal muscle biology. METHODS: To determine the role of UVRAG in skeletal muscle in vivo, we generated muscle-specific UVRAG knockout mice using the Cre-loxP system driven by Myf6 promoter that is exclusively expressed in skeletal muscle. Myf6-Cre+ UVRAGfl/fl (M-UVRAG-/-) mice were compared to littermate Myf6-Cre+ UVRAG+/+ (M-UVRAG+/+) controls under basal conditions on a normal chow diet. Body composition, muscle function, and mitochondria morphology were assessed in muscles of the WT and KO mice at 24 weeks of age. RESULTS: M-UVRAG-/- mice developed accelerated sarcopenia and impaired muscle function compared to M-UVRAG+/+ littermates at 24 weeks of age. Interestingly, these mice displayed improved glucose tolerance and increased energy expenditure likely related to upregulated Fgf21, a marker of muscle dysfunction. Skeletal muscle of the M-UVRAG-/- mice showed altered mitochondrial morphology with increased mitochondrial fission and EGFR accumulation reflecting defects in endosomal trafficking. To determine whether increased EGFR signaling had a causal role in muscle dysfunction, the mice were treated with an EGFR inhibitor, gefitinib, which partially restored markers of muscle and mitochondrial deregulation. Conversely, constitutively active EGFR transgenic expression in UVRAG-deficient muscle led to further detrimental effects with non-overlapping distinct defects in muscle function, with EGFR activation affecting the muscle fiber type whereas UVRAG deficiency impaired mitochondrial homeostasis. CONCLUSIONS: Our results show that both UVRAG and EGFR signaling are critical for maintaining muscle mass and function with distinct mechanisms in the differentiation pathway.

Systematic review of the incidence of herbal drug-induced liver injury in Korea.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal drugs have been generally believed to be safe, based on the natural sources and long clinical experience. With the increasing use of herbal medicine worldwide, the potential toxicity of herbal drugs, especially drug-induced liver injury (DILI), frequently becomes a medical issue. This study was aimed to estimate the incidence of DILI following herbal drug consumption in Korea METHODS AND MATERIALS: A literature search for herbal DILI in eight databases, including PubMed, Medline, the Cochrane Library, EMBASE, and four Korean electronic databases. RESULTS: Six studies (three prospective and three retrospective) met the necessary criteria for assessment of the risk of DILI following herbal medicine exposure. The total number of participants in the six studies was 1699 (756 males and 943 females), and the incidence of herbal DILI varied from 0 to 1.92 among them. Total incidence of herbal DILI was 0.71% (12 patients with herbal DILI), and it was significantly higher in male (1.32%) than female (0.21%) respectively (p<0.01). All of the patients that experienced DILI concomitantly ingested herbal medicine and conventional drugs. CONCLUSIONS: This result showed the comprehensive data indicating the incident risk of hepatotoxicity in patients using herbal drugs in Korea, and presented the possibility of increased risk for the DILI by concurrent administration of herbal and conventional medicines.

Preventing the dissolution of lithium polysulfides in lithium-sulfur cells by using Nafion-coated cathodes.

The principal drawback of lithium-sulfur batteries is the dissolution of long-chain lithium polysulfides into the electrolyte, which limits cycling performance. To overcome this problem, we focused on the development of a novel cathode as well as anode material and designed Nafion-coated NiCrAl/S as a cathode and lithium powder as an anode. Nafion-coated NiCrAl/S cathode was synthesized using a two-step dip-coating technique. The lithium-powder anode was used instead of a lithium-foil anode to prohibit dendrite growth and to improve on the electrochemical behaviors. The cells showed an initial discharge capacity of about 900 mA g(-1) and a final discharge capacity of 772 mA g(-1) after 100 cycles at 0.1 C-rate. Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) demonstrate that using the Nafion-coated NiCrAl/S cathode can suppress the dissolution of long-chain lithium polysulfides.