Potassium Buffering in the Neurovascular Unit: Models and Sensitivity Analysis

AbstractAstrocytes are critical regulators of neural and neurovascular network communication. Potassium transport is a central mechanism behind their many functions. Astrocytes encircle synapses with their distal processes, which express two potassium pumps (Na-K and NKCC) and an inward rectifying potassium channel (Kir), whereas the vessel-adjacent endfeet express Kir and BK potassium channels. We provide a detailed model of potassium flow throughout the neurovascular unit (synaptic region, astrocytes, and arteriole) for the cortex of the young brain. Our model reproduces several phenomena observed experimentally: functional hyperemia, in which neural activity triggers astrocytic potassium release at the perivascular endfoot, inducing arteriole dilation; K+ undershoot in the synaptic space after periods of neural activity; neurally induced astrocyte hyperpolarization during Kir blockade. Our results suggest that the dynamics of the vascular response during functional hyperemia are governed by astrocytic Kir for the fast onset and astrocytic BK for maintaining dilation. The model supports the hypothesis that K+ undershoot is caused by excessive astrocytic uptake through Na-K and NKCC pumps, whereas the effect is balanced by Kir. We address parametric uncertainty using high-dimensional stochastic sensitivity analysis and identify possible model limitations

A partnership between academic and public librarians: “What the Health” workshop series

Background: Public librarians are in a unique position to assist the general public with health information inquiries. However, public librarians might not have the training, detailed knowledge, and confidence to provide high-quality health information. Case Presentation: The authors created and delivered three workshops to public librarians in Suffolk County, New York, highlighting several National Library of Medicine resources. Each workshop focused on a different topic: general consumer health resources, genetics health resources, and environmental/toxicology resources. At the end of each workshop, participants were asked to complete the Training Session Evaluation form provided by the National Network of Libraries of Medicine (NNLM). All participants reported that they learned a new skill or about a new tool, that their ability to locate online health information improved, and that they planned to use the knowledge they gained in the future. Online tutorials covering the major resources from each workshop were created and made accessible to the public on several organizations’ websites. Virtual reference services were initiated for public librarians who need further assistance with these resources and will continue to be provided on an ongoing basis. Financial support for the equipment and software utilized in each of these tasks was awarded by NNLM. Conclusions: Based on attendance and participant feedback, this model of health information outreach appears to have been successful in furthering the educational needs of public librarians and may be useful to others in creating a similar program in their communities

Heart development and regeneration -- a multi‐organ effort

Development of the heart, from early morphogenesis to functional maturation, as well as maintenance of its homeostasis, are tasks requiring collaborative efforts of cardiac tissue and different extra-cardiac organ systems. The brain, lymphoid organs, and gut, are among the interaction partners that can communicate with the heart through a wide array of paracrine signals acting at local or systemic level. Disturbance of cardiac homeostasis following ischemic injury also needs immediate response from these distant organs. Our hearts replace dead muscles with non-contractile fibrotic scars. We have learned from animal models capable of scarless repair that regenerative capability of the heart does not depend only on competency of the myocardium and cardiac-intrinsic factors, but also on long-range molecular signals originating in other parts of the body. Here, we provide an overview of inter-organ signals that take part in development and regeneration of the heart. We highlight recent findings and remaining questions. Finally, we discuss the potential of inter-organ modulatory approaches for possible therapeutic use

Neuromodulation and behavioral flexibility in larval zebrafish: from neurotransmitters to circuits

Animals adapt their behaviors to their ever-changing needs. Internal states, such as hunger, fear, stress, and arousal are important behavioral modulators by controlling the way an organism perceives sensory stimuli and reacts to them. The translucent zebrafish larva is an ideal model organism for studying neuronal circuits regulating brain states, owning to the possibility of easy imaging and manipulating activity of genetically identified neurons while the animal performs stereotyped and well-characterized behaviors. The main neuromodulatory circuits present in mammals can also be found in the larval zebrafish brain, with the advantage that they contain small numbers of neurons. Importantly, imaging and behavioral techniques can be combined with methods for generating targeted genetic modifications to reveal the molecular underpinnings mediating the functions of such circuits. In this review we discuss how studying the larval zebrafish brain has contributed to advance our understanding of circuits and molecular mechanisms regulating neuromodulation and behavioral flexibility

Vasculo-neuronal coupling and neurovascular coupling at the neurovascular unit: impact of hypertension

Components of the neurovascular unit (NVU) establish dynamic crosstalk that regulates cerebral blood flow and maintain brain homeostasis. Here, we describe accumulating evidence for cellular elements of the NVU contributing to critical physiological processes such as cerebral autoregulation, neurovascular coupling, and vasculo-neuronal coupling. We discuss how alterations in the cellular mechanisms governing NVU homeostasis can lead to pathological changes in which vascular endothelial and smooth muscle cell, pericyte and astrocyte function may play a key role. Because hypertension is a modifiable risk factor for stroke and accelerated cognitive decline in aging, we focus on hypertension-associated changes on cerebral arteriole function and structure, and the molecular mechanisms through which these may contribute to cognitive decline. We gather recent emerging evidence concerning cognitive loss in hypertension and the link with vascular dementia and Alzheimer’s disease. Collectively, we summarize how vascular dysfunction, chronic hypoperfusion, oxidative stress, and inflammatory processes can uncouple communication at the NVU impairing cerebral perfusion and contributing to neurodegeneration.Fil: Presa, Jessica Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Augusta University Medical Center. Medical College of Georgia; Estados UnidosFil: Saravia, Flavia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bagi, Zsolt. Augusta University Medical Center. Medical College of Georgia; Estados UnidosFil: Filosa, Jessica A.. Augusta University Medical Center. Medical College of Georgia; Estados Unido

Buccal mucosa is a promising graft in Peyronie's disease surgery. Our experience and a brief literature review on autologous grafting materials

AIM: Peyronie's Disease (PD) is an under reported acquired benign condition that, at the moment, is not curable with medical therapy. Surgery represent the gold standard of treatment. Surgical approaches are several and they consist in "plication techniques" or plaque incision/excision with grafting of resulting albuginea defect. Among grafting procedures, albuginea defect substitution with autologous materials demonstrated over the years not inferior results respect to heterologous grafts. Buccal mucosa graft (BMG) is not usually emphasized in many review articles and clinical series are yet limited. METHODS: We present our experience with seventeen plaque incision procedures and BMG in surgical correction of complex penile curvatures due to PD performed in a period of 30 months. Our analyses was focused on buccal mucosa graft characteristics as major determinant of the surgical success. We also conducted a brief literature review on autologous grafting materials used in reconstructive penile surgery for PD. RESULTS: Our cosmetics and functional results consists in a 100% of functional penile straightening with no relapses and 5,8% of de novo erectile dysfunction. Mean age was 56.4 years, mean follow-up of 22.5 (6-36) months. No complications graft related were observed. Operative time was 115.3 minutes in mean. Over 94% of patients referred they were "really much better" and "much better" satisfied based on PGI-I questionnaire administrated at the last follow- up visit. CONCLUSION: BMG is revealing as an optimal choice for reconstructive surgery in PD. Anatomical characteristics consisting in the great elasticity, the quick integration time and the easy harvesting technique lead to high cosmetics and functional success rate, without omitting economical and invasiveness aspects

Glucose-6-phosphate dehydrogenase plays a crucial role in the protection from redox-stress induced apoptosis.

Glucose-6-phosphate dehydrogenase-deleted embryonic stem (ES) cells (G6pdD) proliferate in vitro without special requirements, but when challenged with oxidants fail to sustain glutathione disulphide reconversion to reduced glutathione (GSH), entering a condition of oxidative stress. Here, we investigate the signalling events downstream of GSH oxidation in G6pdD and wild-type (wt) ES cells. We found that G6pdD ES cells are very sensitive to oxidants, activating an apoptotic pathway at oxidant concentrations otherwise sublethal for wt ES cells. We show that the apoptotic pathway activated by low oxidant concentrations is accompanied by mitochondria dysfunction, and it is therefore blocked by the overexpression of Bcl-XL. Bcl-XL does not inhibit the decrease in cellular GSH and reactive oxygen species formation following oxidant treatment. We also found that oxidant treatment in ES cells is followed by the activation of the MEK/ extracellular signal-regulated kinase (ERK) pathway. Interest¬ingly, ERK activation has opposite outcomes in G6pdD ES cells compared to wt, which has a proapoptotic function in the first and a prosurvival function in the latter. We show that this phenomenon can be regulated by the cellular GSH level

Using pERK immunostaining to quantify neuronal activity induced by stress in zebrafish larvae

The larval zebrafish has emerged as a very useful model organism to study the neuronal circuits controlling neuroendocrine and behavioral responses to stress. This protocol describes how to expose zebrafish larvae to hyperosmotic stress and test whether candidate populations of neurons are activated or inhibited by the stressor using a relatively rapid immunofluorescence staining approach. This approach takes advantage of the phosphorylation of the extracellular signal-regulated kinase (ERK) upon neuronal activation. For complete details on the use and execution of this protocol, please refer to Corradi et al. (2022)

Perception of Time-Discrete Haptic Feedback on the Waist is Invariant with Gait Events

The effectiveness of haptic feedback devices highly depends on the perception of tactile stimuli, which differs across body parts and can be affected by movement. In this study, a novel wearable sensory feedback apparatus made of a pair of pressure-sensitive insoles and a belt equipped with vibrotactile units is presented; the device provides time-discrete vibrations around the waist, synchronized with biomechanically-relevant gait events during walking. Experiments with fifteen healthy volunteers were carried out to investigate users' tactile perception on the waist. Stimuli of different intensities were provided at twelve locations, each time synchronously with one pre-defined gait event (i.e. heel strike, flat foot or toe off), following a pseudo-random stimulation sequence. Reaction time, detection rate and localization accuracy were analyzed as functions of the stimulation level and site and the effect of gait events on perception was investigated. Results revealed that above-threshold stimuli (i.e. vibrations characterized by acceleration amplitudes of 1.92g and 2.13g and frequencies of 100 Hz and 150 Hz, respectively) can be effectively perceived in all the sites and successfully localized when the intertactor spacing is set to 10 cm. Moreover, it was found that perception of time-discrete vibrations was not affected by phase-related gating mechanisms, suggesting that the waist could be considered as a preferred body region for delivering haptic feedback during walking

Goosecoid and HNF-3beta genetically interact to regulate neural tube patterning during mouse embryogenesis

The homeobox gene goosecoid (gsc) and the winged-helix gene Hepatic Nuclear Factor-3beta (HNF-3beta) are co-expressed in all three germ layers in the anterior primitive streak and at the rostral end of mouse embryos during gastrulation. In this paper, we have tested the possibility of functional synergism or redundancy between these two genes during embryogenesis by generating double-mutant mice for gsc and HNF-3beta. Double-mutant embryos of genotype gsc(-/-);HNF-3beta(+/-) show a new phenotype as early as embryonic days 8.75. Loss of Sonic hedgehog (Shh) and HNF-3beta expression was observed in the notochord and ventral neural tube of these embryos. These results indicate that gsc and HNF-3beta interact to regulate Shh expression and consequently dorsal-ventral patterning in the neural tube. In the forebrain of the mutant embryos, severe growth defects and absence of optic vesicles could involve loss of expression of fibroblast growth factor-8, in addition to Shh. Our results also suggest that interaction between gsc and HNF-3beta regulates other signalling molecules required for proper development of the foregut, branchial arches and heart