Front Psychiatry

The rate of individuals with addiction who are currently treated are low, and this can be explained by barriers such as stigma, desire to cope alone, and difficulty to access treatment. These barriers could be overcome by mobile technologies. EMI (Ecological Momentary Intervention) is a treatment procedure characterized by the delivery of interventions (messages on smartphones) to people in their daily lives. EMI presents opportunities for treatments to be available to people during times and in situations when they are most needed. Craving is a strong predictor of relapse and a key target for addiction treatment. Studies using Ecological Momentary Assessment (EMA) method have revealed that, in daily life, person-specific cues could precipitate craving, that in turn, is associated with a higher probability to report substance use and relapse in the following hours. Assessment and management of these specific situations in daily life could help to decrease addictive use and avoid relapse. The Craving-Manager smartphone app has been designed to diagnose addictive disorders, and assess and manage craving as well as individual predictors of use/relapse. It delivers specific and individualized interventions (counseling messages) composed of evidence-based addiction treatments approaches (cognitive behavioral therapy and mindfulness). The Craving-Manager app can be used for any addiction (substance or behavior). The objective of this protocol is to evaluate the efficacy of the Craving-Manager app in decreasing use (of primary substance(s)/addictive behavior(s)) over 4 weeks, among individuals on a waiting list for outpatient addiction treatment. This multicenter double-blind randomized controlled trial (RCT) will compare two parallel groups: experimental group (full interventional version of the app, 4 weeks, EMA + EMI), versus control group (restricted version of the app, 4 weeks, only EMA). Two hundred and seventy-four participants will be recruited in 6 addiction treatment centers in France. This RCT will provide indication on how the Craving-Manager app will reduce addictive use (e.g., better craving management, better stimulus control) in both substance and behavioral addictions. If its efficacy is confirmed, the app could offer the possibility of an easy to use and personalized intervention accessible to the greatest number of individuals with addiction. ClinicalTrials.gov: NCT04732676

Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

OBJECTIVE: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. METHODS: PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). RESULTS: The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. INTERPRETATION: Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD

Predominant Functional Expression of Kv1.3 by Activated Microglia of the Hippocampus after Status epilepticus

BACKGROUND:Growing evidence indicates that the functional state of microglial cells differs according to the pathological conditions that trigger their activation. In particular, activated microglial cells can express sets of Kv subunits which sustain delayed rectifying potassium currents (Kdr) and modulate differently microglia proliferation and ability to release mediators. We recently reported that hippocampal microglia is in a particular activation state after a status epilepticus (SE) and the present study aimed at identifying which of the Kv channels are functionally expressed by microglia in this model. METHODOLOGY/PRINCIPAL FINDINGS:SE was induced by systemic injection of kainate in CX3CR1(eGFP/+) mice and whole cell recordings of fluorescent microglia were performed in acute hippocampal slices prepared 48 h after SE. Microglia expressed Kdr currents which were characterized by a potential of half-maximal activation near -25 mV, prominent steady-state and cumulative inactivations. Kdr currents were almost abolished by the broad spectrum antagonist 4-Aminopyridine (1 mM). In contrast, tetraethylammonium (TEA) at a concentration of 1 mM, known to block Kv3.1, Kv1.1 and 1.2 subunits, only weakly reduced Kdr currents. However, at a concentration of 5 mM which should also affect Kv1.3 and 1.6, TEA inhibited about 30% of the Kdr conductance. Alpha-dendrotoxin, which selectively inhibits Kv1.1, 1.2 and 1.6, reduced only weakly Kdr currents, indicating that channels formed by homomeric assemblies of these subunits are not important contributors of Kdr currents. Finally, agitoxin-2 and margatoxin strongly inhibited the current. CONCLUSIONS/SIGNIFICANCE:These results indicate that Kv1.3 containing channels predominantly determined Kdr currents in activated microglia after SE

Repetitive Immunization Enhances the Susceptibility of Mice to Peripherally Administered Prions

The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease

Physiopathologie de la tremblante naturelle et expérimentale (neuroinvasion et activation gliale)

Les maladies à prions, pathologies neurodégénératives, requièrent l'expression de la protéine prion de l'hôte (PrPc) qui s'accumule sous une isoforme pathologique (PrPsc). La sensibilité des ovins à la tremblante est caractérisée par une forte composante génétique. Notre travail a confirmé par immunohistochimie le rôle chez les moutons sensibles des tissus lymphoïdes du tube digestif dans la propagation de l'agent vers le système nerveux central, via le système nerveux entérique autonome. La cinétique d'accumulation de la PrPsc dans le névraxe a également été définie. Dans un modèle expérimental murin, l'apparition de PrPsc dans le cerveau a été corrélée avec certains processus pathologiques, dont un stress oxydatif ciblant les astrocytes. La réponse inflammatoire gliale a été analysée par immunohistochimie et RT-PCR. Le rôle de cette réponse dans le processus neuropathologique et les voies de dissémination de l'agent à l'interface neuroimmune restent à définir.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

In vitro Modeling of Prion Strain Tropism

Prions are atypical infectious agents lacking genetic material. Yet, various strains have been isolated from animals and humans using experimental models. They are distinguished by the resulting pattern of disease, including the localization of PrPsc deposits and the spongiform changes they induce in the brain of affected individuals. In this paper, we discuss the emerging use of cellular and acellular models to decipher the mechanisms involved in the strain-specific targeting of distinct brain regions. Recent studies suggest that neuronal cultures, protein misfolding cyclic amplification, and combination of both approaches may be useful to explore this under-investigated but central domain of the prion field

Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling.: Activated microglia in the epileptic hippocampus

International audienceMicroglia cells are the resident macrophages of the CNS, and their activation plays a critical role in inflammatory reactions associated with many brain disorders, including ischemia, Alzheimer's and Parkinson's diseases, and epilepsy. However, the changes of microglia functional properties in epilepsy have rarely been studied. Here, we used a model of status epilepticus (SE) induced by intraperitoneal kainate injections to characterize the properties of microglial cells in hippocampal slices from CX3CR1(eGFP/+) mice. SE induced within 3 h an increased expression of inflammatory mediators in the hippocampus, followed by a modification of microglia morphology, a microglia proliferation, and a significant neurodegeneration in CA1. Changes in electrophysiological intrinsic membrane properties of hippocampal microglia were detected at 24-48 h after SE with, in particular, the appearance of new voltage-activated potassium currents. Consistent with the observation of an upregulation of purinergic receptor mRNAs in the hippocampus, we also provide pharmacological evidence that microglia membrane currents mediated by the activation of P2 receptors, including P2X(7), P2Y(6), and P2Y(12), were increased 48 h after SE. As a functional consequence of this modification of purinergic signaling, motility of microglia processes toward a source of P2Y(12) receptor agonist was twice as fast in the epileptic hippocampus. This study is the first functional description of microglia activation in an in vivo model of inflammation and provides evidence for the existence of a particular microglial activation state after a status epilepticus

Chemtob S: Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 2006

PURPOSE. The role of microglia, present in the retina early in development before vascularization, remains ill defined. The authors investigated whether microglia are implicated in retinal blood vessel formation. METHODS. The microglia and vasculature of developing human fetal and rodent retinas were examined by labeling the endothelial cells with lectin and the microglia with CD18 antibody or green fluorescent protein driven by the promoter of the chemokine receptor CX 3 CR1. Rodent ischemic proliferative retinopathy induced by hyperoxia or hypercapnia, which model retinopathy of prematurity, and ex vivo retinal explants were used to assess microglial involvement in vascular pathology. Microglial participation in developmental retinal vessel formation was further studied in neonatal rats after pharmacologic macrophage depletion with the use of clodronate liposomes and subsequent intravitreal injection of microglia. RESULTS. Microglia intimately appose developing vessels of human and murine retinas. Ischemic retinopathy models exhibit decreased microglia concomitant with the characteristic reductions in vasculature observed in these retinopathies. Retinal explants exposed to conditions resulting in ischemic retinopathies (in vivo) reveal that antioxidants protect against microglial loss. Depletion of resident retinal microglia, but not systemic macrophages, reduced developmental vessel growth and density, which were restored by intravitreal microglial injection. CONCLUSIONS. These observations suggest that proper retinal blood vessel formation requires an adequate resident microglial population because diminished microglia are associated with decreased vascularity in models of ischemic retinopathy and retinal vascular development. In light of these findings, the traditional definition of microglia as merely immunocompetent cells should be reconsidered to encompass this new function related to blood vessel formation. (Invest Ophthalmol Vis Sci

Effects of broad spectrum blockers of potassium channels on the outward rectifying current expressed by microglia 48 h after the induction of <i>status epilepticus</i>.

<p>A Example of the current (left panel) induced by a voltage step from −70 to +30 mV in control (black trace) and after perfusion of 4-AP (1 mM, red trace), and the I/V relationships in the same cell (right panel). Note that 4-AP almost completely abolished the outward rectifying currents without affecting the inward currents. B–C Examples of leak subtracted currents induced by a voltage step from −70 to +40 mV in control (black trace) and after 4-AP 1 mM (B, red trace) or TEA 5 mM (C). The leak conductances of the cells in B and C were 585 and 256 pS, respecitively. The graphs on the right represent the conductance, normalized to its maximum value, as a function of membrane potential and its inhibition induced by 4-AP (B, n = 8), TEA (C) 1 mM (n = 9) and 5 mM (n = 7).</p

Summary of the effects induced by the different drugs tested on the outward rectifying potassium current evoked by a voltage step from −70 to +30 mV.

<p>The histogram represents the average of the leak subtracted current after drug application and normalized to its pre-drug value. The “time matched control” bar corresponds to experiments in which the current was measured during 10 to 15 minutes without any drug application to control for the absence of any significant run-down of the current. Statistical tests were done on raw data (paired <i>t test</i>, **p<0.01; the number of tested cells for each condition is that given in the legends of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006770#pone-0006770-g003" target="_blank">figures 3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006770#pone-0006770-g004" target="_blank">4</a>).</p