The presence of activated platelets and platelet-leukocyte aggregates in the circulation accompanies major surgical procedures and occurs in several chronic diseases. Recent findings that activated platelets contribute to the inflammatory disease atherosclerosis made us address the question whether activated platelets stimulate normal healthy endothelium. Infusion of activated platelets into young mice led to the formation of transient platelet-leukocyte aggregates and resulted in a several-fold systemic increase in leukocyte rolling 2 to 4 hours after infusion. Rolling returned to baseline levels 7 hours after infusion. Infusion of activated P-selectin ؊/؊ platelets did not induce leukocyte rolling, indicating that platelet P-selectin was involved in the endothelial activation. The endothelial activation did not require platelet CD40L. Leukocyte rolling was mediated solely by the interaction of endothelial P-selectin and leukocyte P-selectin glycoprotein ligand 1 (PSGL-1 IntroductionPlatelets are the body's defense mechanism against excessive bleeding caused by endothelial damage. Activated platelets present at the site of injury provide both a prothrombotic surface and a procoagulant surface. Excessive platelet activation occurs in coronary bypass surgery and may result in thrombotic emboli and neurologic complications. 1 Furthermore, many inflammatory diseases including sepsis, 2,3 psoriasis, 4,5 diabetes, 6-8 and cystic fibrosis 9 are associated with circulating activated platelets. These pathologies are also associated with endothelial inflammation.Platelets induce leukocyte adhesion on preactivated endothelial cells in culture. 10,11 In mouse models of atherosclerosis, the role of activated platelets in exacerbating lesion development has been clearly demonstrated. Activated platelets promote monocyte arrest on atherosclerotic lesions and atherosclerotic lesion growth. 12 Studies in our laboratory have also demonstrated the role of platelet P-selectin, in addition to endothelial P-selectin, in atherosclerotic lesion development and maturation. 13 It is important to note that P-selectin on both platelets and endothelium is expressed on the cell surface only on activation of the cells and granule secretion. 14 Early endothelial inflammation is associated with the rapid release of Weibel-Palade bodies and the consequent surface expression of Pselectin and von Willebrand factor (VWF). These molecules mediate rolling of leukocytes and platelets on endothelial cells. 15 This is followed by transcription and expression of molecules such as E-selectin, vascular-cell adhesion molecule 1 (VCAM-1), and other adhesion receptors. 16 These receptors, in turn, mediate slow rolling and adhesion of leukocytes and have been shown to be up-regulated on treatment with activated platelets in the in vitro studies. [17][18][19][20] This sequence of events leads to leukocyte rolling and extravasation at the site of injury or pathologic conditions.Recently, vascular endothelial growth factor (VEGF) secreted from ␣-granules was sh...

The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N -lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1 S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.

Sleep is a crucial biological process is regulated through complex interactions between multiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake-and sleeppromoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along the wake-promoting pathway. GABAergic sleep-promoting medications like benzodiazepines and benzodiazepine-like drugs that act more specifically on benzodiazepine receptors increase the activity of GABA, which inhibits NE and the wake-promoting pathway. Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain's circadian clock, and NE influences the synthesis of melatonin. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. Many antidepressants that affect the signaling of NE are also used for treatment of insomnia. Finally, adrenergic antagonists that are used to treat cardiovascular disorders have considerable sedative effects. Therefore, NE, long known for its role in maintaining general arousal, is also a crucial player in sleep pharmacology. The purpose of this review is to consider the role of NE in the actions of wake-and sleep-promoting drugs within the framework of the brain arousal systems.

Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.

Increased expression of the ER membrane acetyl-CoA transporter AT-1 can cause an autism-like phenotype in mice.