BrightFocus Alzheimer's Fast Track 2019.

The 3 day workshop "Alzheimer's Fast Track" is a unique opportunity for graduate students, postdoctoral fellows, or other early-career scientists, focused on Alzheimer's disease research, to gain new knowledge and become an expert in where this emerging scientific field is moving. In addition, it is not only about receiving a good overview, but also learning to write and defend a successful application for securing funding for Alzheimer's disease research projects.

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1beta administration.

Loss of appetite and cachexia is an obstacle in the treatment of chronic infection and cancer. Proinflammatory cytokines released from activated immune cells and acting in the central nervous system (CNS) are prime candidates for mediating these metabolic changes, potentially affecting both energy intake as well as energy expenditure. The effect of intravenous administration of two proinflammatory cytokines, interleukin (IL)-1beta (15 microg/kg) and tumor necrosis factor (TNF)-alpha (10 microg/kg), on food and water intake, locomotor activity, oxygen consumption (VO2), and respiratory exchange ratio (RER) was evaluated. The two cytokines elicited a comparable decrease in food intake and activated similar numbers of cells in the paraventricular nucleus of the hypothalamus (PVH), a region that plays a critical role in the regulation of appetite and metabolism (determined via expression of the immediate early gene, c-fos). However, only IL-1beta reduced locomotion and RER, and increased VO2, while TNF-alpha was without effect. To examine the role of the melanocortins in mediating IL-1beta- induced metabolic changes, animals were pretreated centrally with a melanocortin receptor antagonist, HS014. Pretreatment with HS014 blocked the effect of IL-1beta on food intake and RER at later time points (beyond 8 h post injection), as well as the hypoactivity and increased metabolic rate. Further, HS014 blocked the induction of Fos-ir in the PVH. These data highlight the importance of the melanocortin system, particularly within the PVH, in mediating a broad range of metabolic responses to IL-1beta.

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors.

Stroke is the leading cause of disability in adults. Drug treatments that target stroke-induced pathological mechanisms and promote recovery are desperately needed. In the brain, an ischemic event triggers major inflammatory responses that are mediated by the resident microglial cells. In this review, we focus on the microglia activation after ischemic brain injury as a target of immunomodulatory therapeutics. We divide the microglia-mediated events following ischemic stroke into three categories: acute, subacute, and long-term events. This division encompasses the spatial and temporal dynamics of microglia as they participate in the pathophysiological changes that contribute to the symptoms and sequela of a stroke. The importance of Toll-like receptor (TLR) signaling in the outcomes of these pathophysiological changes is highlighted. Increasing evidence shows that microglia have a complex role in stroke pathophysiology, and they mediate both detrimental and beneficial effects on stroke outcome. So far, most of the pharmacological studies in experimental models of stroke have focused on neuroprotective strategies which are impractical for clinical applications. Post-ischemic inflammation is long lasting and thus, could provide a therapeutic target for novel delayed drug treatment. However, more studies are needed to elucidate the role of microglia in the recovery process from an ischemic stroke and to evaluate the therapeutic potential of modulating post-ischemic inflammation to promote functional recovery.

Step Sequence Is a Critical Gait Parameter of Unilateral 6-OHDA Parkinson's Rat Models.

Parkinson's disease is a progressive neurological disorder, marked by the loss of dopaminergic neurons in the nigrostriatal pathway that leads to abnormal gait, rigidity, slowness of movement, and tremor. The ability to recapitulate and measure the neurological sequelae in rodent models of Parkinson's disease is important for studying and evaluating potential therapeutics. Individual variability in lesion severity and injury progression are key factors in the 6-hydroxydopamine model that require normalization when evaluating therapeutic effects. The gait parameters that were found to be affected by 6-hydroxydopamine lesioning of the nigrostriatal pathway in rats may be used to study novel transgenic models of Parkinson's disease as well as to test novel therapeutics. Previously, studies have used a video-based system to analyze gait abnormalities in the 6-hydroxydopamine model of Parkinson's disease, but these studies did not account for individual variability on reported gait parameters. By analyzing the ratio of parameters from the injured to uninjured sides and correcting for speed in related parameters, hindpaw step cycle parameters, hindpaw print area, and step sequence are significantly altered in different ways for each type of lesion, when compared to saline-injected controls. These findings enable new metrics for evaluating therapeutic efficacy of drug-, gene-, or cell-based therapies in rat models of Parkinson's disease.

Near-infrared fluorescent protein iRFP713 as a reporter protein for optogenetic vectors, a transgenic Cre-reporter rat, and other neuronal studies.

BACKGROUND: The use of genetically-encoded fluorescent reporters is essential for the identification and observation of cells that express transgenic modulatory proteins. Near-infrared (NIR) fluorescent proteins have superior light penetration through biological tissue, but are not yet widely adopted. NEW METHOD: Using the near-infrared fluorescent protein, iRFP713, improves the imaging resolution in thick tissue sections or the intact brain due to the reduced light-scattering at the longer, NIR wavelengths used to image the protein. Additionally, iRFP713 can be used to identify transgenic cells without photobleaching other fluorescent reporters or affecting opsin function. We have generated a set of adeno-associated vectors in which iRFP713 has been fused to optogenetic channels, and can be expressed constitutively or Cre-dependently. RESULTS: iRFP713 is detectable when expressed in neurons both in vitro and in vivo without exogenously supplied chromophore biliverdin. Neuronally-expressed iRFP713 has similar properties to GFP-like fluorescent proteins, including the ability to be translationally fused to channelrhodopsin or halorhodopsin, however, it shows superior photostability compared to EYFP. Furthermore, electrophysiological recordings from iRFP713-labeled cells compared to cells labeled with mCherry suggest that iRFP713 cells are healthier and therefore more stable and reliable in an ex vivo preparation. Lastly, we have generated a transgenic rat that expresses iRFP713 in a Cre-dependent manner. CONCLUSIONS: Overall, we have demonstrated that iRFP713 can be used as a reporter in neurons without the use of exogenous biliverdin, with minimal impact on viability and function thereby making it feasible to extend the capabilities for imaging genetically-tagged neurons in slices and in vivo.

Usability of four commercially-oriented EEG systems.

Electroencephalography (EEG) holds promise as a neuroimaging technology that can be used to understand how the human brain functions in real-world, operational settings while individuals move freely in perceptually-rich environments. In recent years, several EEG systems have been developed that aim to increase the usability of the neuroimaging technology in real-world settings. Here, the usability of three wireless EEG systems from different companies are compared to a conventional wired EEG system, BioSemi's ActiveTwo, which serves as an established laboratory-grade 'gold standard' baseline. The wireless systems compared include Advanced Brain Monitoring's B-Alert X10, Emotiv Systems' EPOC and the 2009 version of QUASAR's Dry Sensor Interface 10-20. The design of each wireless system is discussed in relation to its impact on the system's usability as a potential real-world neuroimaging system. Evaluations are based on having participants complete a series of cognitive tasks while wearing each of the EEG acquisition systems. This report focuses on the system design, usability factors and participant comfort issues that arise during the experimental sessions. In particular, the EEG systems are assessed on five design elements: adaptability of the system for differing head sizes, subject comfort and preference, variance in scalp locations for the recording electrodes, stability of the electrical connection between the scalp and electrode, and timing integration between the EEG system, the stimulus presentation computer and other external events.