Reducing falls in Parkinson’s disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson’s disease (PD), the leading levodopa‐insensitive cause of hospitalization and long‐term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic–dopaminergic losses (“DL rats”) and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5‐HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro‐cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle‐treated group, the combined treatment greatly reduced (Cohen’s d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall‐prone moments suggested that this treatment improved the efficacy and speed of re‐instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.Following short freezes, rats with dual cortical cholinergic and striatal dopaminergic deafferentation resumed forward movement relatively slowly, generally with the tail positioned relatively low and with a slouched posture, yielding slips and falls. When treated with donepezil and idalopirdine (DON + IDL), such rats resumed forward movement, sometimes starting with a hop, they quickly regaining regular traversal speed and fluid forward movement, with high and firm tail position and upright posture, thereby preventing slips and falls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135976/1/ejn13354_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135976/2/ejn13354.pd

Deterministic functions of cortical acetylcholine

Traditional descriptions of the basal forebrain cholinergic projection system to the cortex have focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing. Through presynaptic receptors expressed on cholinergic terminals, thalamocortical and corticocortical projections can evoke brief cholinergic release events. These acetylcholine ( AC h) release events occur on a fast, sub‐second to seconds‐long time scale (‘transients’). In rats performing a task requiring the detection of cues as well as the report of non‐cue events cholinergic transients mediate the detection of cues specifically in trials that involve a shift from a state of monitoring for cues to cue‐directed responding. Accordingly, ill‐timed cholinergic transients, generated using optogenetic methods, force false detections in trials without cues. We propose that the evidence is consistent with the hypothesis that cholinergic transients reduce detection uncertainty in such trials. Furthermore, the evidence on the functions of the neuromodulatory component of cholinergic neurotransmission suggests that higher levels of neuromodulation favor staying‐on‐task over alternative action. In other terms, higher cholinergic neuromodulation reduces opportunity costs. Evidence indicating a similar integration of other ascending projection systems, including noradrenergic and serotonergic systems, into cortical circuitry remains sparse, largely because of the limited information about local presynaptic regulation and the limitations of current techniques in measuring fast and transient neurotransmitter release events in these systems. Traditional descriptions of the basal forebrain cholinergic projection system to the cortex focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107385/1/ejn12515.pd

Structural analysis of a genetically encoded fret biosensor by SAXS and MD simulations

Inspired by the modular architecture of natural signaling proteins, ligand binding proteins are equipped with two fluorescent proteins (FPs) in order to obtain Förster resonance energy transfer (FRET)-based biosensors. Here, we investigated a glucose sensor where the donor and acceptor FPs were attached to a glucose binding protein using a variety of different linker sequences. For three resulting sensor constructs the corresponding glucose induced conformational changes were measured by small angle X-ray scattering (SAXS) and compared to recently published single molecule FRET results (Höfig et al., ACS Sensors, 2018). For one construct which exhibits a high change in energy transfer and a large change of the radius of gyration upon ligand binding, we performed coarse-grained molecular dynamics simulations for the ligand-free and the ligand-bound state. Our analysis indicates that a carefully designed attachment of the donor FP is crucial for the proper transfer of the glucose induced conformational change of the glucose binding protein into a well pronounced FRET signal change as measured in this sensor construct. Since the other FP (acceptor) does not experience such a glucose induced alteration, it becomes apparent that only one of the FPs needs to have a well-adjusted attachment to the glucose binding protein

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

We thank Manuel Kulagin for technical help, Pierre Bonnaventure for portal vein blood sampling, Francisco Sepulveda for technical assistance in GS-MS acquisition, and Dorothee Hahne (Metabolomics Australia, University of Western Australia) for human samples SCFA isolation, acquisition, and analysis. We also thank Cristina Cartoni (Phenotyping Unit, EPFL) for Milliplex analysis, Jessica Dessimoz and her team from the Histology Core Facility (EPFL), Miguel Garcia and his team from the Flow Cytometry Core Facility (EPFL), and staff from the EPFL CPG animal house for excellent animal care. The computations were partially performed at the Vital-IT Center for high-performance computing of the SIB Swiss Institute of Bioinformatics (http://www.vital-it.ch). The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 310948. Funding for A.W.W. and a subset of the 16S rRNA gene sequencing was provided by the Wellcome Trust (grant number WT 098051). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Diminished trk A receptor signaling reveals cholinergic‐attentional vulnerability of aging

The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of tropomyosin‐related kinase A (trk A ) receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata ( nMB / SI ) of adult and aged rats. Suppression of trk A receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trk A levels in the nMB / SI . trk A knockdown neither affected nMB / SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trk A suppression augmented an age‐related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release acetylcholine ( AC h). The capacity of cortical synapses to release AC h in vivo was also lower in aged/trk A ‐ AAV ‐infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age‐related increases in cortical pro NGF and p75 receptor levels interacted with the vector‐induced loss of trk A receptors to shift NGF signaling toward p75‐mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early A lzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling. The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of trk A receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata (n MB / SI ) of adult and aged rats. This study provides novel evidence that reduced trkA receptors is not sufficient to trigger cholinergic dysfunction. Rather, aging interacts with disrupted trkA signaling to escalate the vulnerability of BF cholinergic neurons and the manifestation of age‐related attentional impairments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/1/ejn12090-sup-0001-SupportingInformation.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/2/ejn12090.pd

Regional vesicular acetylcholine transporter distribution in human brain: A [18F]fluoroethoxybenzovesamicol positron emission tomography study

Prior efforts to image cholinergic projections in human brain in vivo had significant technical limitations. We used the vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) and positron emission tomography to determine the regional distribution of VAChT binding sites in normal human brain. We studied 29 subjects (mean age 47 [range 20–81] years; 18 men; 11 women). [18F]FEOBV binding was highest in striatum, intermediate in the amygdala, hippocampal formation, thalamus, rostral brainstem, some cerebellar regions, and lower in other regions. Neocortical [18F]FEOBV binding was inhomogeneous with relatively high binding in insula, BA24, BA25, BA27, BA28, BA34, BA35, pericentral cortex, and lowest in BA17–19. Thalamic [18F]FEOBV binding was inhomogeneous with greatest binding in the lateral geniculate nuclei and relatively high binding in medial and posterior thalamus. Cerebellar cortical [18F]FEOBV binding was high in vermis and flocculus, and lower in the lateral cortices. Brainstem [18F]FEOBV binding was most prominent at the mesopontine junction, likely associated with the pedunculopontine–laterodorsal tegmental complex. Significant [18F]FEOBV binding was present throughout the brainstem. Some regions, including the striatum, primary sensorimotor cortex, and anterior cingulate cortex exhibited age‐related decreases in [18F]FEOBV binding. These results are consistent with prior studies of cholinergic projections in other species and prior postmortem human studies. There is a distinctive pattern of human neocortical VChAT expression. The patterns of thalamic and cerebellar cortical cholinergic terminal distribution are likely unique to humans. Normal aging is associated with regionally specific reductions in [18F]FEOBV binding in some cortical regions and the striatum.Using [18F]FEOBV PET, we describe the distribution of cholinergic terminals in human brain. The distribution of cholinergic terminals is similar to that found in other mammals with some distinctive features in cortex, thalamus, and cerebellum. There are regionally specific age‐related changes in cholinergic terminal density.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146604/1/cne24541.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146604/2/cne24541_am.pd

Moving towards more sustainable aquaculture practices: a meta-analysis on the potential of plant-enriched diets to improve fish growth, immunity and disease resistance

Aquatic animal diseases are one of the major limiting factors in aquaculture development, with disease emergence forecast to increase with global change. However, in order to treat increasing diseases in a context of global emergence of antimicrobial resistance and strengthening regulations on antimicrobial use, sustainable alternatives are urgently needed. The use of plant supplements to increase fish immunity and disease resistance has gained much popularity within the last decades. The use of functional supplements, such as plants, can also improve growth and feed assimilation, contributing to a better optimization of aquaculture resources (e.g. fish meal inclusion). We conducted a systematic review and meta-analysis in order to identify the research gaps in the use of plant-enriched diets in fish aquaculture and estimate, for the first time, the overall efficacy of plant-enriched diets on fish growth, immunity and disease resistance as well as the effect of intrinsic parameters (fish trophic level, type of plant material, dosage, treatment duration and pathogen species) on the treatment efficacy. We found that plant-enriched diets significantly enhanced growth, immunity and disease survival of treated fish, regardless of the fish trophic level, treatment duration and type of material used. We also show that plant supplements are a versatile alternative that can benefit different aquaculture sectors (from small-scale fish farmers to intensive productions). Finally, we observed that studies need to improve the information reported about the plant material used (e.g. origin, identification, chemical composition), in order to allow the comparison of different experiments and improve their repeatability

The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study

Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut–joint axis in animal models. In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease. At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis. Given this association, we performed a feasibility study in RA patients using high-fiber dietary supplementation with the objective to restore microbial homeostasis and promote the secretion of beneficial immunomodulatory microbial metabolites. RA patients (n = 36) under routine care received daily high-fiber bars or cereals for 28 days. Clinical assessments and laboratory analysis of immune parameters in blood and stool samples from RA patients were done before and after the high-fiber dietary supplementation. We observed an increase in circulating regulatory T cell numbers, favorable Th1/Th17 ratios, as well as decreased markers of bone erosion in RA patients after 28 days of dietary intervention. Furthermore, patient-related outcomes of RA improved. Based on these results, we conclude that controlled clinical studies of high-fiber dietary interventions could be a viable approach to supplement or complement current pharmacological treatment strategies

Free Fatty Acids in Bone Pathophysiology of Rheumatic Diseases

Obesity—in which free fatty acid (FFA) levels are chronically elevated—is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and β-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways