Localization of Mineralocorticoid Receptors at Mammalian Synapses

In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids

Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain

Antidepressant effects of valproic acid in an animal model of depression

Valproic acid, beside its anticonvulsant action, is widely used as a mood stabilizer in the therapy of bipolar disorder. The potential antidepressant action of valproic acid has not been sufficiently characterized so far. The aim of the present study was to evaluate the antidepressant effect of valproic acid in an aldosterone model of depression. Subchronic treatment with valproic acid resulted in a reduction of the time spent in immobility in the forced swim test. In conclusion, the present study provides evidence on antidepressant effects of valproic acid using a classical behavioral approach for testing the efficacy of antidepressant drug in animal models

Effects of Vortioxetine On Biomarkers Associated with Glutamatergic Activity in An SSRI Insensitive Model of Depression in Female Rats

The aim of this study was to investigate the antidepressant activity of vortioxetine in a tryptophan (TRP) depletion female rat model of depression and compare it to that of paroxetine using doses that fully occupy the serotonin transporter (SERT). We evaluated the effects of vortioxetine on potential biomarkers associated with TRP depletion including serum aldosterone, corticosterone and IL-6 levels together with indirect indicators of glutamate neurotransmission. Female Sprague-Dawley rats were randomized to control, low TRP, low TRP/paroxetine or low TRP/vortioxetine groups. Vortioxetine and paroxetine were administered via diet (10 mg/kg/day) and drinking water (10 mg/kg/day) respectively for 14 days. Vortioxetine but not paroxetine reversed TRP depletion-induced depressive-like behavior. Vortioxetine reduced TRP depletion-induced increases of serum corticosterone, aldosterone, IL-6 and N-methyl-D-aspartate and α7-nicotinic acetylcholine receptor expression in the amygdala and hippocampus, respectively. Paroxetine demonstrated little effect except a reduction of aldosterone. Vortioxetine but not paroxetine reversed TRP depletion-induced reductions of serum and brain kynurenic acid. In conclusion, vortioxetine, but not paroxetine, enabled reversals of TRP depletion-induced changes of depression-like behavior and markers of glutamatergic activity. These observations support the hypothesis that vortioxetine\u27s antidepressant activity may involve mechanisms beyond SERT inhibition

Oxytocin levels in the posterior pituitary and in the heart are modified by voluntary wheel running

We hypothesized that voluntary wheel running results in increased secretion of oxytocin, a peptide involved in the stress response. An additional hypothesis was that prolonged exercise affects oxytocin levels in the heart, which is in line with the potential role of oxytocin in cardiovascular functions. Voluntary wheel running lasted 3 weeks and daily running distances increased progressively reaching maximum levels about 8 km (Sprague-Dawley rats) and 4 km (Lewis strain). The exercise resulted in significant reduction of epididymal fat, slight increase in glucose transporter GLUT4 mRNA levels and significant enhancement of plasma density. Voluntary exercise failed to influence plasma oxytocin levels either in Lewis or Sprague-Dawley rats, but it resulted in a significant decrease of oxytocin concentrations in the posterior pituitary. Plasma oxytocin concentrations were not modified even if the measurements were made in the dark phase of the day. In voluntary wheel running Sprague-Dawley rats, the content of oxytocin in the right heart atrium was lower than in controls. Thus, the present findings demonstrate that prolonged voluntary wheel running results in a decrease in pituitary oxytocin content without evident changes in hormone concentrations in peripheral blood. However, prolonged exercise used has a significant impact on oxytocin levels in the heart. (c) 2006 Elsevier B.V. All rights reserved

Experimental Infection of Sand Flies by Massilia Virus and Viral Transmission by Co-Feeding on Sugar Meal

Background: Massilia virus (MASV) is a phlebovirus isolated from Phlebotomus perniciosus in various regions of southwestern Europe. It is closely related to human pathogens such as Toscana virus and sandfly fever Naples virus. The natural cycle of phleboviruses is poorly understood. Indeed, experimental studies demonstrate that transovarial and sexual transmission are not efficient enough for the maintenance of the virus in nature and to date there is no convincing evidence that a species of vertebrates is the reservoir of the virus. Here, we studied various transmission routes of MASV taking advantage of experimental colonies representing different species of sand flies. Methodology/Principal findings: In P. perniciosus, four sources of infection were compared: (i) Virus-seeded larval food to the first instar larvae (L1), or (ii) to the fourth instar larvae (L4), (iii) virus-seeded blood meal to adult females, and (iv) virus-seeded sugar meal to adults of both sexes. From 875 adults emerged from infected L1 and L4, only three were positive. In females infected by bloodmeal the infection rate was high before defecation, then it decreased drastically; MASV RNA was detected in only 5 out of 27 post-defecation. Surprisingly, the most efficient route of infection was observed after intake of virus-seeded sugar meal: 72% of females (79/110) and 52% of males (51/99) were found to be MASV RNA-positive. In addition, MASV-infected sandflies regurgitated virus particules into the sugar drop and MASV RNA was detectable in this drop for at least 24 h after regurgitation. MASV RNA was detected in about one third of the P. perniciosus exposed to this sugar drop contaminated by regurgitation. Sugar meal infection was also tested with six other species of sand flies. In males, there were no significant differences in infection rates when compared to P. perniciosus. In females, most species tested showed high infection rate at the beginning but then significant gradual decrease in infection rate during the experiment. Conclusions/Significance: We present the first description of arboviral infection of a dipteran vector using sugar meal. In all seven sand fly species tested, MASV was detected for two weeks post-infection. Our results showed that MASV can be transmitted between P. perniciosus either through co-feeding or via an infected sugar source such as plant sap. These newly described routes of horizontal transmission may play an important role in the circulation of phleboviruses in nature