Supernumerary Formation of Olfactory Glomeruli Induced by Chronic Odorant Exposure: A Constructivist Expression of Neural Plasticity

It is accepted that sensory experience instructs the remodelling of neuronal circuits during postnatal development, after their specification has occurred. The story is less clear with regard to the role of experience during the initial formation of neuronal circuits, whether prenatal or postnatal, since this process is now supposed to be primarily influenced by genetic determinants and spontaneous neuronal firing. Here we evaluated this last issue by examining the effect that postnatal chronic exposure to cognate odorants has on the formation of I7 and M72 glomeruli, iterated olfactory circuits that are formed before and after birth, respectively. We took advantage of double knock-in mice whose I7 and M72 primary afferents express green fluorescent protein and β-galactosidase, correspondingly. Our results revealed that postnatal odorant chronic exposure led to the formation of permanent supernumerary I7 and M72 glomeruli in a dose and time dependent manner. Glomeruli in exposed mice were formed within the same regions of olfactory bulb and occupy small space volumes compared to the corresponding single circuits in non-exposed mice. We suggest that local reorganization of the primary afferents could participate in the process of formation of supernumerary glomeruli. Overall, our results support that sensory experience indeed instructs the permanent formation of specific glomeruli in the mouse olfactory bulb by means of constructivist processes

History and progress of antiviral drugs: from acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C

The development of antiviral drugs is a very complex process. Currently, around 50 drugs have been approved for human use against viruses such as HSV, HIV-1, the cytomegalo virus, the influenza virus, HBV and HCV. Advancements in this area have been achieved through efforts and technical breakthroughs in different scientific fields. The improvement in the treatment of HCV infection is a good example of what is needed for efficient antiviral therapy. A thorough description of the events that lead to the development of specifically targeted antiviral therapy or HCV (STAT-C) could be useful to further improve research for treating many other viral diseases in the future. Similar to HIV-1 and HBV treatment, combination therapy along with personalized medicine approaches have been necessary to successfully treat HCV patients. This review is focused on what has been done to develop a successful HCV therapy and the drawbacks along the wa

The electrophysiology of the betacell based on single transmembrane protein characteristics

The electrophysiology of betacells is at the origin of insulin secretion. Betacells exhibit a complex behaviour upon stimulation with glucose including repeated and uninterrupted bursting. Mathematical modelling is most suitable to improve knowledge about the function of various transmembrane currents provided the model is based on reliable data. This is the first attempt to build a mathematical model for the betacell-electrophysiology in a bottom-up approach which relies on single protein conductivity data. The results of previous whole-cell-based models are reconsidered. The full simulation including all prominent transmembrane proteins in betacells is used to provide a functional interpretation of their role in betacell-bursting and an updated vantage point of betacell-electrophysiology. As a result of a number of in silico knock-out- and block-experiments the novel model makes some unexpected predictions: Single-channel conductivity data imply that calcium-gated potassium currents are rather small. Thus, their role in burst interruption has to be revisited. An alternative role in high calcium level oscillations is proposed and an alternative burst interruption model is presented. It also turns out that sodium currents are more relevant than expected so far. Experiments are proposed to verify these predictions.Comment: 28 pages, 5 figures, 54 references, 14 pages supplementary materia

Epidermal growth factor increases insulin secretion and lowers blood glucose in diabetic mice

Epidermal growth factor (EGF) is synthesized in the pancreas and diabetic animals have low levels of EGF. However, the role of EGF in regulating the major function of the pancreas, insulin secretion, has not been studied. Here, we show that EGF rapidly increased insulin secretion in mouse pancreatic islets, as well as in a pancreatic beta-cell line. These events were dependent on a Ca2+ influx and phospholipase D (PLD) activity, particularly PLD2, as determined using pharmacological blockers and molecular manipulations such as over-expression and siRNA of PLD isozymes. In addition, EGF also increased plasma insulin levels and mediated glucose lowering in normal and diabetic mice. Here, for the first time, we provide evidence that EGF is a novel secretagogue that regulates plasma glucose levels and a candidate for the development of therapeutics for diabetes.open131

Restructuring of Pancreatic Islets and Insulin Secretion in a Postnatal Critical Window

Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20), insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions), and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism

Odor memory stability after reinnervation of the olfactory bulb.

The olfactory system, particularly the olfactory epithelium, presents a unique opportunity to study the regenerative capabilities of the brain, because of its ability to recover after damage. In this study, we ablated olfactory sensory neurons with methimazole and followed the anatomical and functional recovery of circuits expressing genetic markers for I7 and M72 receptors (M72-IRES-tau-LacZ and I7-IRES-tau-GFP). Our results show that 45 days after methimazole-induced lesion, axonal projections to the bulb of M72 and I7 populations are largely reestablished. Furthermore, regenerated glomeruli are re-formed within the same areas as those of control, unexposed mice. This anatomical regeneration correlates with functional recovery of a previously learned odorant-discrimination task, dependent on the cognate ligands for M72 and I7. Following regeneration, mice also recover innate responsiveness to TMT and urine. Our findings show that regeneration of neuronal circuits in the olfactory system can be achieved with remarkable precision and underscore the importance of glomerular organization to evoke memory traces stored in the brain

The largest glomeruli displayed primary afferent reorganization within a restricted space during chronic odorant exposure.

<p>The figure shows the expression of I7tauGFP glomeruli in non-exposed mice and mice exposed to heptaldehyde. Notice that primary afferents redistribute in variable ways between the largest and supernumerary glomeruli (arrows) in exposed mice. The effect was seen in all half bulbs analyzed (n = 10 for each condition) when mice were exposed from postnatal day (PD) 0 to PD5. In mice exposed from PD10 to PD15 the effect was seen in 8 out of 10 total half bulbs analyzed. Scale bar 100 µm; inset square is 2× magnification.</p

Priming of Hypothalamic Ghrelin Signaling and Microglia Activation Exacerbate Feeding in Rats’ Offspring Following Maternal Overnutrition

Maternal overnutrition during pregnancy leads to metabolic alterations, including obesity, hyperphagia, and inflammation in the offspring. Nutritional priming of central inflammation and its role in ghrelin sensitivity during fed and fasted states have not been analyzed. The current study aims to identify the effect of maternal programming on microglia activation and ghrelin-induced activation of hypothalamic neurons leading to food intake response. We employed a nutritional programming model exposing female Wistar rats to a cafeteria diet (CAF) from pre-pregnancy to weaning. Food intake in male offspring was determined daily after fasting and subcutaneous injection of ghrelin. Hypothalamic ghrelin sensitivity and microglia activation was evaluated using immunodetection for Iba-1 and c-Fos markers, and Western blot for TBK1 signaling. Release of TNF-alpha, IL-6, and IL-1&beta; after stimulation with palmitic, oleic, linoleic acid, or C6 ceramide in primary microglia culture were quantified using ELISA. We found that programmed offspring by CAF diet exhibits overfeeding after fasting and peripheral ghrelin administration, which correlates with an increase in the hypothalamic Iba-1 microglia marker and c-Fos cell activation. Additionally, in contrast to oleic, linoleic, or C6 ceramide stimulation in primary microglia culture, stimulation with palmitic acid for 24 h promotes TNF-alpha, IL-6, and IL-1&beta; release and TBK1 activation. Notably, intracerebroventricular (i.c.v.) palmitic acid or LPS inoculation for five days promotes daily increase in food intake and food consumption after ghrelin administration. Finally, we found that i.c.v. palmitic acid substantially activates hypothalamic Iba-1 microglia marker and c-Fos. Together, our results suggest that maternal nutritional programing primes ghrelin sensitivity and microglia activation, which potentially might mirror hypothalamic administration of the saturated palmitic acid