2016 Acta Physiologica  
Synaptic connectivity and molecular composition provide a blueprint for information processing in neural circuits. Detailed structural analysis of neural circuits requires nanometer resolution, which can be obtained with serial-section electron microscopy. However, this technique remains challenging for reconstructing molecularly defined synapses. We used a genetically encoded synaptic marker for electron microscopy (GESEM) based on intra-vesicular generation of electron-dense labeling in
more » ... boutons. This approach allowed the identification of synapses from Cre recombinase-expressing or GAL4-expressing neurons in the mouse and fly with excellent preservation of ultrastructure. We applied this tool to visualize long-range connectivity of AGRP and POMC neurons in the mouse, two molecularly defined hypothalamic populations that are important for feeding behavior. Combining selective ultrastructural reconstruction of neuropil with functional and viral circuit mapping, we characterized some basic features of circuit organization for axon projections of these cell types. Our findings demonstrate that GESEM labeling enables long-range connectomics with molecularly defined cell types. Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical due to the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic, agouti-related protein-secreting neurons (AgRP neurons) represent primary orexigenic drives of homeostatic feeding. Using a models of neuronal inhibition or ablation we demonstrate that the feeding response to a fast, ghrelin or serotonin receptor agonist relies on AgRP neurons; however, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intakea hallmark of comfort feeding. These results demonstrate that hedonic circuitry can solely operate feeding and override the homeostatic circuitry especially in conditions where positive response to energy demands is chronically defective. Exercise tolerance is determined by the ability to minimize the rate at which metabolic acidaemia and related contributors to fatigue develop. Minimizing the H + production rate depends on an aerobic energytransfer system with rapid dynamics and high capacity; constraining the consequent degree of acidaemia, however, depends on the ventilatory (V 0 E ) system (with its associated perceptual sequellae) clearing the additional CO 2 released by bicarbonate-buffering mechanisms and effecting compensatory hypocapnia ('respiratory compensation'). The determinants of an 'appropriate' exercise V 0 E response are pulmonary CO 2 output (V 0 CO 2 ) ('metabolic' component), arterial PCO 2 (PaCO 2 ) (control 'set-point'), and the dead space fraction of the breath (V D /V T ) ('gas-exchange A molecular pathway inhibiting ectopic calcification is initiated by ABCC6, a membrane transporter primarily expressed in liver. ABCC6 facilitates the efflux of ATP from hepatocytes, what is rapidly converted into pyrophosphate (PPi) in the liver vasculature. PPi is the major inhibitor of calcification. Mutations in ABCC6 are responsible for the currently incurable calcification disorder pseudoxanthoma elasticum (PXE) and some cases of generalized arterial calcification of infancy (GACI). Most mutations in ABCC6 are missense, many of which have preserved transport activity but are retained intracellular. We have shown that the chemical chaperone 4-phenylbutyrate (4-PBA) can reorient ABCC6 mutants into the plasma membrane. In a humanized mouse model transiently expressing human ABCC6 mutants in the liver, we addressed whether treatment with 4-PBA could rescue the physiological function of ABCC6 in vivo by restoring its potential to inhibit calcification. We used the dystrophic cardiac calcification phenotype as a marker in Abcc6 -/mice to determine the effect of 4-PBA on mineralization. Introduction of human wtABCC6 to the livers of Abcc6 À/À mice restored hepatic PPi release. Administration of 4-PBA to Abcc6-deficient mice expressing human ABCC6 mutants in their livers restored the calcification inhibitory capacity of the protein. As 75% of patients are with at least one missense allele, the potential of 4-PBA (an FDA-approved drug) seems to be a promising strategy for allele-specific therapy of ABCC6-associated calcification disorders and plasma PPi as a useful indicator of ABCC6 activity. When FEPS was founded, physiology had been sidelined as irrelevant to the foundations of biology. The central theory of biology, i.e. the neo-Darwinist interpretation of evolution, had concluded that physiological adaptation to environmental challenges could not directly influence the germline or inheritance. I came to doubt this view through experiments and computational models on the cardiac pacemaker, showing that knock-out experiments could not accurately reveal gene function without reverse engineering the Oxytocin receptor (OTR) antagonists (ORAs) are used as tocolytic agents for women in preterm labour (PTL). However, OT can also activate the three vasopressin receptors (AVPRs) subtypes, including AVPR1a, which is highly expressed in myometrium throughout gestation. It is not clear if AVPR antagonism is also required for effective tocolysis. We used OTR-and AVPR subtype-selective peptides and expression studies to determine the importance of AVPR subtypes in human myometrium. Astrocytes have a prominent role in brain (patho)physiology. They can signal to adjacent neurons by releasing glutamate via process of regulated Considerable efforts have been devoted to understanding the cellular events underlying changes in cerebral blood flow (CBF) driven by increases in neuronal activity, that is, neurovascular coupling (NVC). However, less is understood about the mechanisms defining basal CBF and resting neuronal brain activity, and how these factors influence NVC. Here we addressed the cellular mechanisms by which changes in steadystate vascular tone, and thus perfusion, affect Obesity alters the behavior of the meso-limbic reward network that ultimately impacts on the activity of the Purpose: Increased H + and hyperactivation of Na + -H + exchanger1 (NHE1) are the causes contracture and cell deaths induced by ischemia reperfusion (I/R) injury. The aim of this study is to investigate the effect of the NHE inhibitor (cariporide, CRP) on the Objective: The aim of our study is to determine the effect of an hydroalcoholic extract of barks of
doi:10.1111/apha.12712 pmid:27329970 fatcat:imcxhh3singqdlh7umt4tcj54y