Rasgrf2 controls noradrenergic involvement in the acute and subchronic effects of alcohol in the brain

Rationale

Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2^?/? mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT).

Objective

In order to further investigate how Rasgrf2 modifies the acute and subchronic effects of alcohol in the brain, we investigated its effects on the noradrenergic and serotonergic systems.

Methods

We measured noradrenaline and serotonin activity in the brain by in vivo microdialysis and RNA expression by chip analysis and RT-PCR after acute and sub-chronic alcohol exposure in Rasgrf2^?/? and WT mice.

Results

In vivo microdialysis showed a significantly reduced noradrenergic response and an absent serotonergic response in the nucleus accumbens (NAcc) and caudate putamen (CPu) after an alcohol challenge in Rasgrf2^?/? mice. A co-expression analysis showed that there is a high correlation between Rasgrf2 and α2 adrenoceptor RNA expression in the ventral striatum in naïve animals. Accordingly, we further assessed the role of Rasgrf2 in the response of the noradrenergic system to subchronic alcohol exposure. A decrease in β1 adrenoceptor gene expression was seen in Rasgrf2^+/+, but not Rasgrf2^?/? mice following alcohol exposure. Conversely, alcohol resulted in a decrease in both β2 and α2 adrenoceptor gene expression in knockout but not WT Rasgrf2 mice.

Conclusions

These findings suggest that adaptations in the noradrenergic system contribute to the Rasgrf2 enhanced risk of alcoholism.     

From gene to brain to behavior: schizophrenia‐associated variation in AMBRA1 alters impulsivity‐related traits

Recently, genome‐wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level‐dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity‐related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory‐Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito‐frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia‐related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.     

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

The α-Ca²⁺/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a ‘molecular memory'' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKII^T286A mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in αCaMKII^T286A mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that αCaMKII^T286A mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in αCaMKII^T286A mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA–5-HT balance as a putative mechanism.     

Inter-observer agreement and clinical diagnosis of leprosy for prophylaxis studies

Clinical diagnosis is still the most useful tool for detecting early cases of leprosy in field research. In prophylaxis studies accuracy of clinical diagnosis of leprosy is important during intake as well as for measuring efficacy of the intervention. This paper reports our observations regarding the extent of inter-observer variations in clinical diagnosis of leprosy and its implications for a prophylaxis study. Information on 225 suspects and cases of leprosy, each examined independently by three senior workers after initial standardization, was used for this purpose. Agreement among the examiners regarding the presence of skin patch, thickened nerve trunk and sensory deficit was fairly high (Kappa = 0.7). Agreement on the presence of infiltration in a skin patch was not satisfactory (Kappa = 0.4-0.5). It was observed that in clinical diagnosis of leprosy, presence of skin patch and sensory deficit, as well as thickened nerve trunk and related anaesthesia were correlated observations. The influence of inter-observer variations on defining leprosy problem in the community can be quite large. The paper suggests some ways of overcoming the problem.     

Mitochondrial dysfunction and immune activation are detectable in early Alzheimer's disease blood

Alzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood.     

Reducing depression among community-dwelling older adults using life-story review: A pilot study

A life-story review can serve as an effective intervention to express one's inner feelings and provide emotional catharsis. The research aim was to examine the effects of life-story review on depression levels in community-dwelling older adults in Singapore. This pilot experimental pre-post-follow-up study was conducted from July 2012 to February 2013. Twenty-nine older Malays aged 60 and above, with mild to moderate depression, were randomly allocated to the life-story review (intervention) group (n = 15) or the non life-story review (control) group (n = 14). Depressive symptoms were measured by the Geriatric Depression Scale-15 and collected five times over eight weeks. Generalized estimating equations were used to examine the effects of the intervention on the elders' depression levels, controlled for age, gender, medication use, existence of chronic disease, and diary writing experience. Reductions in depression scores were found in the intervention group from week 1 (Mean ± SD 5.9 ± 2.3) to week 8 (1.9 ± 1.6) compared with the control group (week 1: 5.0 ± 1.3; week 8: 3.5 ± 1.5). At week 8, the intervention group showed a significantly lower level of depression than the control group (χ² = 14.61, p < 0.001). This study adds to prior research supporting the use of life story review in improving depression levels in cognitively intact community dwelling older adults.     

Biomarkers in bile-complementing advanced endoscopic imaging in the diagnosis of indeterminate biliary strictures

Biliary strictures present a diagnostic challenge and a conundrum, particularly when an initial work up including abdominal imaging and endoscopic retrograde cholangiopancreatography based sampling are nondiagnostic. Advances in endoscopic imaging have helped us diagnose these strictures better. However, even with modern technology, some strictures remain a diagnostic challenge. The proximity of bile fluid to the bile duct epithelia makes it an attractive option to investigate for bio-markers, which might be representative of the functions/abnormal changes taking place in the biliary system. A number of biomarkers in bile have been discovered recently in approaching biliary strictures with their potential future diagnostic utility, further supported by the immunohistochemical analysis of the resected tissue specimens. Novel biliary biomarkers especially carcinoembryonic cell adhesion molecule 6 and neutrophil gelatinase-associated lipocalin seem promising in differentiating malignant from benign biliary strictures. Recent developments in lipidomic profiling of bile are also very promising. Biliary biomarkers appear to complement endoscopic imaging in diagnosing malignant etiologies of biliary stricture. Future studies addressing these biomarkers need to be incorporated to the current endoscopic techniques to determine the best approach in determining the etiology of biliary strictures.