Advances on Practical Applications of Agents and Multiagent Systems

9th International Conference on Practical Applications of Agents and Multiagent Systems, PAAMS 2011, Salamanca,Spain, 6-8 April 2011 (http://www.paams.net/paams2011/) - Proceedings: http://link.springer.com/book/10.1007%2F978-3-642-19875-5International audienceno abstrac

Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and in the anxiogenic response to ethanol withdrawal. Previously, we found that both ethanol and corticotropin releasing factor (CRF) increase GABAergic transmission in mouse and rat CeA neurons, in part by enhancing the release of GABA via activation of presynaptic CRF1 receptors. CRF1 receptors are coupled to the enzyme adenylyl cyclase (AC), which produces the second messenger cyclic AMP. There are nine isoforms of AC, but we recently found that CRF1 receptors in the pituitary were coupled to the Type 7 AC (AC7). Therefore, using an in vitro electrophysiological approach in brain slices, here we have investigated a possible role of the AC7 signaling pathway in ethanol and CRF effects on CeA GABAergic synapses of genetically modified mice with diminished brain Adcy7 activity (HET) compared to their littermate male wild-type (WT) mice. We found no significant differences in basal membrane properties, mean baseline amplitude of evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs), or paired-pulse facilitation (PPF) of GABAA-IPSPs between HET and WT mice. In CeA neurons of WT mice, ethanol superfusion significantly augmented (by 39%) GABAA-IPSPs and decreased PPF (by 25%), suggesting increased presynaptic GABA release. However, these effects were absent in HET mice. CRF superfusion also significantly augmented IPSPs (by 38%) and decreased PPF (by 23%) in WT CeA neurons, and still elicited a significant but smaller (by 13%) increase of IPSP amplitude, but no effect on PPF, in HET mice. These electrophysiological data suggest that AC7 plays an important role in ethanol and CRF modulation of presynaptic GABA release in CeA and thus may underlie ethanol-related behaviors such as anxiety and dependence

Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents

Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABAA receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABAA receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target., SIGNIFICANCE STATEMENT Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence-driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets

Reorganization of Functional Networks in Mild Cognitive Impairment

Whether the balance between integration and segregation of information in the brain is damaged in Mild Cognitive Impairment (MCI) subjects is still a matter of debate. Here we characterize the functional network architecture of MCI subjects by means of complex networks analysis. Magnetoencephalograms (MEG) time series obtained during a memory task were evaluated by synchronization likelihood (SL), to quantify the statistical dependence between MEG signals and to obtain the functional networks. Graphs from MCI subjects show an enhancement of the strength of connections, together with an increase in the outreach parameter, suggesting that memory processing in MCI subjects is associated with higher energy expenditure and a tendency toward random structure, which breaks the balance between integration and segregation. All features are reproduced by an evolutionary network model that simulates the degenerative process of a healthy functional network to that associated with MCI. Due to the high rate of conversion from MCI to Alzheimer Disease (AD), these results show that the analysis of functional networks could be an appropriate tool for the early detection of both MCI and AD

A conflict monitoring account of the control mechanisms involved in dual-tasking

The present study investigates the cognitive mechanism underlying the control of interference during dual-task coordination. Partially inspired by the Conflict Monitoring Hypothesis (Botvinick et al., 2001), we test the assumption that dual-task interference is resolved by a top-down adaptation mechanism that is responsible for behavioral adjustments in the prioritization of the coordinated tasks. In a series of two experiments, we measured conflict adaptation to the so-called Gratton effect—the decrease in dual-task interference following incompatible trials. In Experiment 1 the primary task was a low demand choice discrimination task, while in Experiment 2 the primary task was an updating task that imposes a continuous load on working memory. The secondary task was a tone discrimination task. Both experiments consistently showed that the response conflict of previous trial triggers top-down behavioral adjustments that reduce interference. We conclude that dual-task interference shows strong similarities to Stroop-like types of cognitive interference, namely in the way that suboptimal performance is dealt with by the cognitive system

Sex-dependent factors of alcohol and neuroimmune mechanisms

Excessive alcohol use disrupts neuroimmune signaling across various cell types, including neurons, microglia, and astrocytes. The present review focuses on recent, albeit limited, evidence of sex differences in biological factors that mediate neuroimmune responses to alcohol and underlying neuroimmune systems that may influence alcohol drinking behaviors. Females are more vulnerable than males to the neurotoxic and negative consequences of chronic alcohol drinking, reflected by elevations of pro-inflammatory cytokines and inflammatory mediators. Differences in cytokine, microglial, astrocytic, genomic, and transcriptomic evidence suggest females are more reactive than males to neuroinflammatory changes after chronic alcohol exposure. The growing body of evidence supports that innate immune factors modulate synaptic transmission, providing a mechanistic framework to examine sex differences across neurocircuitry. Targeting neuroimmune signaling may be a viable strategy for treating AUD, but more research is needed to understand sex-specific differences in alcohol drinking and neuroimmune mechanisms

9th International Conference on Practical Applications of Agents and Multiagent Systems

PAAMS, the International Conference on Practical Applications of Agents and Multi-Agent Systems is the international yearly tribune to present, to discuss, and to disseminate the latest developments and the most important outcomes related to real-world applications. It provides a unique opportunity to bring multi-disciplinary experts, academics and practitioners together to exchange their experience in the development of Agents and Multi-Agent Systems. This volume presents the papers that have been accepted for the 2011 edition. These articles capture the most innovative results and this year’s trends: Finance and Trading, Information Systems and Organisations, Leisure Culture and Interactions, Medicine and Cloud Computing, Platforms and Adaptation, Robotics and Manufacturing, Security and Privacy, Transports and Optimisation paper

Chronic alcohol exposure disrupts CB₁ regulation of GABAergic transmission in the rat basolateral amygdala

The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse. The endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB(1)) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB(1) activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB(1) is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here we investigated the potential disruption of eCB/CB(1) signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2–3 weeks intermittent ethanol. In the naïve rat BLA, the CB(1) agonist WIN 55,212-2 (WIN) decreased GABA release and this effect was prevented by the CB(1) antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity. This retrograde tonic eCB/CB(1) signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB(1) system. In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both pre- and postsynaptic mechanisms. Notably, CB(1) activation impaired ethanol’s facilitation of GABAergic transmission across both groups, but the AM251- and ethanol-induced facilitation of GABA release were additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB(1) influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and thus, may contribute to the alcohol dependent state

Chronic ethanol exposure decreases CB₁ receptor function at GABAergic synapses in the rat central amygdala

The endogenous cannabinoids (eCBs) influence the acute response to ethanol and the development of tolerance, dependence and relapse. Chronic alcohol exposure alters eCB levels and type 1 cannabinoid receptor (CB(1)) expression and function in brain regions associated with addiction. CB(1) inhibits GABA release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB(1) signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naïve rats, CB(1) agonist WIN 55,212-2 (WIN) decreased the frequency of spontaneous and miniature GABA(A) receptor-mediated inhibitory postsynaptic currents (s/mIPSCs). This effect was prevented by CB(1) antagonism, but not type 2 cannabinoid receptor (CB(2)) antagonism. After 2–3 weeks of intermittent ethanol exposure, these WIN inhibitory effects were attenuated, suggesting ethanol-induced impairments in CB(1) function. The CB(1) antagonist AM251 revealed a tonic eCB/CB(1) control of GABAergic transmission in the alcohol-naïve CeA that was occluded by calcium chelation in the postsynaptic cell. Chronic ethanol exposure abolished this tonic CB(1) influence on mIPSC, but not sIPSC, frequency. Finally, acute ethanol increased CeA GABA release in both naïve and ethanol exposed rats. Although CB(1) activation prevented this effect, the AM251- and ethanol-induced GABA release were additive, ruling out a direct participation of CB(1) signaling in the ethanol effect. Collectively, these observations demonstrate an important CB(1) influence on CeA GABAergic transmission and indicate that the CeA is particularly sensitive to alcohol-induced disruptions of CB(1) signaling