Functional networks and network perturbations in rodents

Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed

Granger causal connectivity dissociates navigation networks that subserve allocentric and egocentric path integration

Studies on spatial navigation demonstrate a significant role of the retrosplenial complex (RSC) in the transformation of egocentric and allocentric information into complementary spatial reference frames (SRFs). The tight anatomical connections of the RSC with a wide range of other cortical regions processing spatial information support its vital role within the human navigation network. To better understand how different areas of the navigational network interact, we investigated the dynamic causal interactions of brain regions involved in solving a virtual navigation task. EEG signals were decomposed by independent component analysis (ICA) and subsequently examined for information flow between clusters of independent components (ICs) using direct short-time directed transfer function (sdDTF). The results revealed information flow between the anterior cingulate cortex and the left prefrontal cortex in the theta (4-7 Hz) frequency band and between the prefrontal, motor, parietal, and occipital cortices as well as the RSC in the alpha (8-13 Hz) frequency band. When participants prefered to use distinct reference frames (egocentric vs. allocentric) during navigation was considered, a dominant occipito-parieto-RSC network was identified in allocentric navigators. These results are in line with the assumption that the RSC, parietal, and occipital cortices are involved in transforming egocentric visual-spatial information into an allocentric reference frame. Moreover, the RSC demonstrated the strongest causal flow during changes in orientation, suggesting that this structure directly provides information on heading changes in humans

Cerebro-Cerebellar Pathways for Verbal Working Memory

The current study examined the structural and functional connectivity of the cerebro-cerebellar network of verbal working memory as proposed by Chen and Desmond (2005a). Diffusion spectrum imaging was employed to establish structural connectivity between cerebro-cerebellar regions co-activated during a verbal working memory task. The inferior frontal gyrus, inferior parietal lobule, pons, thalamus, superior cerebellum and inferior cerebellum were used as regions of interest to reconstruct and segment the contralateral white matter cerebro-cerebellar circuitry. The segmented pathways were examined further to establish the relationship between structural and effective connectivity as well as the relationship between structural connectivity and verbal working memory performance. No direct relationship between structural and effective connectivity was found but the results demonstrated that structural connectivity is indirectly related to effective connectivity as DCM models that resembled more closely with underlying white matter pathways had a higher degree of model inference confidence. Additionally, it was demonstrated that the structural connectivity of the ponto-cerebellar tract was associated with individual differences in response time for verbal working memory. The findings of the study contribute to further our understanding of the relationship between structural and functional connectivity and the impact of variability in verbal working memory performance

Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo

The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal death in vitro and in vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivation in vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP-p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration

An Overview of Regional Experiments on Biomass Burning Aerosols and Related Pollutants in Southeast Asia: From BASE-ASIA and the Dongsha Experiment to 7-SEAS

By modulating the Earth-atmosphere energy, hydrological and biogeochemical cycles, and affecting regional-to-global weather and climate, biomass burning is recognized as one of the major factors affecting the global carbon cycle. However, few comprehensive and wide-ranging experiments have been conducted to characterize biomass-burning pollutants in Southeast Asia (SEA) or assess their regional impact on meteorology, the hydrological cycle, the radiative budget, or climate change. Recently, BASEASIA (Biomass-burning Aerosols in South-East Asia: Smoke Impact Assessment) and the 7-SEAS (7- South-East Asian Studies) Dongsha Experiment were conducted during the spring seasons of 2006 and 2010 in northern SEA, respectively, to characterize the chemical, physical, and radiative properties of biomass-burning emissions near the source regions, and assess their effects. This paper provides an overview of results from these two campaigns and related studies collected in this special issue, entitled Observation, modeling and impact studies of biomass burning and pollution in the SE Asian Environment. This volume includes 28 papers, which provide a synopsis of the experiments, regional weatherclimate, chemical characterization of biomass-burning aerosols and related pollutants in source and sink regions, the spatial distribution of air toxics (atmospheric mercury and dioxins) in source and remote areas, a characterization of aerosol physical, optical, and radiative properties, as well as modeling and impact studies. These studies, taken together, provide the first relatively complete dataset of aerosol chemistry and physical observations conducted in the sourcesink region in the northern SEA, with particular emphasis on the marine boundary layer and lower free troposphere (LFT). The data, analysis and modeling included in these papers advance our present knowledge of source characterization of biomass-burning pollutants near the source regions as well as the physical and chemical processes along transport pathways. In addition, we raise key questions to be addressed by a coming deployment during springtime 2013 in northern SEA, named 7-SEASBASELInE (Biomass-burning Aerosols Stratocumulus Environment: Lifecycles and Interactions Experiment). This campaign will include a synergistic approach for further exploring many key atmospheric processes (e.g., complex aerosol-cloud interactions) and impacts of biomass burning on the surface-atmosphere energy budgets during the lifecycles of biomass burning emissions

A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: The iESRD study

Background: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of the immune system. Nevertheless, the etiology and impact of these changes in ESRD patients remain unknown. Results: Compared to healthy individuals, ESRD patients exhibit accelerated immunosenescence in both T cell and monocyte compartments, characterized by a dramatic reduction in naïve CD4+ and CD8+ T cell numbers but increase in CD8+ TEMRA cell and proinflammatory monocyte numbers. Notably, within ESRD patients, aging-related immune changes positively correlated not only with increasing age but also with longer dialysis vintage. In multivariable-adjusted logistic regression models, the combination of high terminally differentiated CD8+ T cell level and high intermediate monocyte level, as a composite predictive immunophenotype, was independently associated with prevalent coronary artery disease as well as cardiovascular disease, after adjustment for age, sex, systemic inflammation and presence of diabetes. Levels of terminally differentiated CD8+ T cells also positively correlated with the level of uremic toxin p-cresyl sulfate. Conclusions: Aging-associated adaptive and innate immune changes are aggravated in ESRD and are associated with cardiovascular diseases. For the first time, our study demonstrates the potential link between immunosenescence in ESRD and duration of exposure to the uremic milieu

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field