The anterior insular cortex is hypothesized to represent interoceptive effects of drug reward in the service of goal-directed behavior. The insula is richly connected, but the insula circuitry in ...addiction remains poorly characterized. We examined the involvement of the anterior insula, amygdala, and nucleus accumbens, as well as the projections of the anterior insula to the central amygdala, basolateral amygdala (BLA), and nucleus accumbens core in voluntary alcohol drinking. We trained alcohol-preferring Alko Alcohol (AA) rats to drink alcohol during intermittent 2-h sessions. We then expressed excitatory or inhibitory designer receptors designer receptors exclusively activated by designer drugs (DREADDs) in the anterior insula, nucleus accumbens, or amygdala by means of adenovirus-mediated gene transfer and activated the DREADDs with clozapine-N-oxide (CNO) prior to the drinking sessions. Next, to examine the role of specific insula projections, we expressed FLEX-DREADDs in the efferent insula → nucleus accumbens core, insula → central amygdala, and insula → BLA projections by means of a retrograde AAV-Cre vector injected into the insula projection areas. In the anterior insula and amygdala, excitatory Gq-DREADDs significantly attenuated alcohol consumption. In contrast, in the nucleus accumbens, the Gq-DREADD stimulation increased alcohol drinking, and the inhibitory Gi-DREADDs suppressed it. The Gq-DREADDs expressed in the insula → nucleus accumbens core and insula → central amygdala projections increased alcohol intake, whereas inhibition of these projections had no effect. These data demonstrate that the anterior insula, along with the amygdala and nucleus accumbens, has a key role in controlling alcohol drinking by providing excitatory input to the central amygdala and nucleus accumbens to enhance alcohol reward.
Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive.
A ...meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met).
PubMed, Embase, PsychInfo.
All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome.
A meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using "A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions".
For case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05-2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16-0.08).
A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects.
The interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis outcomes. Future additional high quality studies might change current perspectives, yet currently evidence for the interaction remains unconvincing.
The current study examines neural responses to satiety- and fasting-related volatiles and their effect on the processing of body shapes. Axillary sweat was sampled with cotton pads from 10 ...individuals after 12 h of fasting, and after having consumed a standard breakfast. Pure cotton pads served as the control. The chemosensory stimuli were presented to 20 participants (via a constant-flow olfactometer) exclusively, and additionally as context to images of overweight and underweight avatars. EEG was recorded (61 electrodes), and chemosensory (CSERPs; P1, N1, P2, P3) and visual event-related potentials (VERPs; N1, P2, P3a, P3b) were analyzed. The amplitudes of all positive CSERP components differed more strongly from cotton in response to chemosensory satiety cues as compared to fasting cues (P1: p = 0.023, P2: p = 0.083, P3: p = 0.031), paralleled by activity within the middle frontal and temporal gyrus. Overweight compared to underweight body shapes tended to elicit larger VERP P2 amplitudes (p = 0.068), and chemosensory satiety cues amplified the VERP amplitudes in response to any body shape (P2, P3a, P3b; all ps ≤ 0.017) as compared to the cotton control. The results indicate that chemosensory satiety cues transmit complex social information, overriding the processing of analogous visual input.
Halogenated natural products (HNPs) are considered to be emerging contaminants whose environmental distribution and fate are only incompletely known. Therefore, several persistent and bioaccumulative ...HNP groups, together with man-made polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), were quantified in the blubber of nine sperm whales (Physeter macrocephalus) stranded on the coast of the Mediterranean Sea in Italy. The naturally occurring polybrominated hexahydroxanthene derivatives (PBHDs; sum of TetraBHD and TriBHD) were the most prominent substance class with up to 77,000 ng/g blubber. The mean PBHD content (35,800 ng/g blubber) even exceeded the one of PCBs (28,400 ng/g blubber), although the region is known to be highly contaminated with man-made contaminants. Based on mean values, Q1 ∼ PBDEs > MeO-BDEs ∼ 2,2'-diMeO-BB 80 and several other HNPs followed with decreasing amounts. All blubber samples contained an abundant compound whose molecular formula (C16H19Br3O2) was verified using high-resolution mass spectrometry. The only plausible matching isomer was (2S,4'S,9R,9'S)-2,7-dibromo-4'-bromomethyl-1,1-dimethyl-2,3,4,4',9,9'-9,9'-hexahydro-1H-xanthen-9-ol (OH-TriBHD), a hydroxylated secondary metabolite previously detected together with TriBHD and TetraBHD in a sponge known to be a natural producer of PBHDs. The estimated mean amount of the presumed OH-TriBHD was 3000 ng/g blubber, which is unexpectedly high for hydroxylated compounds in the lipids of marine mammals.
: UV‐induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the ...skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200‐fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurin‐dependent signalling may prevent UV‐induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the ...brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-2-(methyl-2-pyridinylamino) ethyl-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.
The neurodegenerative disease X-linked adrenoleukodystrophy (X-ALD) is characterized by the abnormal accumulation of very long chain fatty acids. Mutations in the gene encoding the peroxisomal ...ATP-binding cassette half-transporter, adrenoleukodystrophy protein (ALDP), are the primary cause of X-ALD. To gain a better understanding of ALDP dysfunction, we searched for interaction partners of ALDP and identified binary interactions to proteins with functions in fatty acid synthesis (ACLY, FASN, and ACC) and activation (FATP4), constituting a thus far unknown fatty acid synthesis-transport machinery at the cytoplasmic side of the peroxisomal membrane. This machinery adds to the knowledge of the complex mechanisms of peroxisomal fatty acid metabolism at a molecular level and elucidates potential epigenetic mechanisms as regulatory processes in the pathogenesis and thus the clinical course of X-ALD.
Background: Dysfunction of the peroxisomal ABC transporter ALDP and elevated very long chain fatty acids are the hallmark of X-ALD.
Results: Peroxisomal ABC transporters interact with proteins functioning in fatty acid synthesis and activation.
Conclusion: We identified a new fatty acid synthesis-transport machinery adapted to different chain lengths and metabolic conditions.
Significance: This machinery extends the knowledge on peroxisomal β-oxidation and X-ALD pathogenesis.
Patients belonging to xeroderma pigmentosum (XP) complementation group C comprise one‐third of all XP patients. Only four major reports compiled larger groups of XP‐C patients from southern Europe ...(12 pts), North America (16 pts) and Africa (14 and 56 pts) as well as their genetic background (46 XPC mutations). We identified 16 XP‐C patients from Germany. Interestingly, only five patients exhibited severe sun sensitivity. The mean age of XP diagnosis was 9.4 years, and the median age of the first skin cancer was 7 years. Neurological symptoms were absent in all but two patients. Primary fibroblasts from all 16 patients showed reduced post‐UV cell survival (mean: 50% vs 93% in normal cells) and reduced reactivation of an UV‐treated luciferase reporter gene (mean: 6.4% vs 30.7% in normal cells). XPC mRNA expression was also greatly reduced compared with normal cells (mean: 14.3%; range 8.3–25.7%) except in XP47MA (274.1%). All patients carried homozygous XPC mutations. Four mutations have been described previously: c.1747_1748delTG (found in 4/16), c.567 C>T (4/16), c.1839 C>T (1/16) and a complex insertion/deletion mutation in exon 9 (1/16). The novel frameshift mutations c.446_447delAG (2/16), c.1525insA (1/16) and c.2271delC (1/16) lead to truncated XPC proteins as does the novel nonsense mutation c.843C>T (1/16). XP47MA carries an interesting mutation (c.2538_2540delATC; p.Ile812del) resulting in an in‐frame single amino acid deletion. This mutation results in a classical XP phenotype, a non‐functional XPC protein, but elevated XPC mRNA expression. Our study indicates that extrinsic factors may contribute to XP‐C symptom severity due to nonsense‐mediated message decay.
Purpose
Whilst childhood trauma (CT) is a known risk factor across the spectrum of psychosis expression, little is known about possible interplay with genetic liability.
Methods
The TwinssCan Study ...collected data in general population twins, focussing on expression of psychosis at the level of subthreshold psychotic experiences. A multilevel mixed-effects linear regression analysis was performed including 745 subjects to assess the interaction between genetic liability and CT. The Symptom Checklist-90 (SCL-90-R) score of the co-twin was used as an indirect measure of genetic liability to psychopathology, while the Childhood Trauma Questionnaire Short-Form (CTQ-SF) was used to assess CT in the domains of physical, emotional and sexual abuse, as well as physical and emotional neglect. The Community Assessment of Psychic Experience (CAPE) questionnaire was used to phenotypically characterize psychosis expression.
Results
In the model using the CAPE total score, the interaction between CT and genetic liability was close to statistical significance (
χ
2
= 5.6,
df
= 2,
p
= 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (
χ
2
= 8.8,
df
= 2,
p
= 0.012) for the CAPE-negative symptoms subscale, but not for the other two subscales (i.e. positive and depressive).
Conclusion
The results suggest that the impact of CT on subthreshold expression of psychosis, particularly in the negative subdomain, may be larger in the co-presence of significant genetic liability for psychopathology.
Declarative and probabilistic feedback-based learning was evaluated in 8-12-year-old school-age children with developmental language disorder (DLD;
= 14) and age-matched children with typical ...development (TD;
= 15). Children performed a visual two-choice word-learning task and a visual probabilistic classification task while their electroencephalogram (EEG) was recorded non-invasively from the scalp. Behavioral measures of accuracy and response to feedback, and electrophysiological responses to feedback were collected and compared between the two groups. While behavioral data indicated poorer performance by children with DLD in both learning paradigms, and similar response patterns to positive and negative feedback, electrophysiological data highlighted processing patterns in the DLD group that differed by task. More specifically, in this group, feedback processing in the context of declarative learning, which is known to be dominated by the medial temporal lobe (MTL), was associated with enhanced N170, an event-related brain potential (ERP) associated with MTL activation. The N170 amplitude was found to be correlated with declarative task performance in the DLD group. During probabilistic learning, known to be governed by the striatal-based learning system, the feedback-related negativity (FRN) ERP, which is the product of the cortico-striatal circuit dominated feedback processing. Within the context of probabilistic learning, enhanced N170 was associated with poor learning in the TD group, suggesting that MTL activation during probabilistic learning disrupts learning. These results are interpreted within the context of a proposed feedback parity hypothesis suggesting that in children with DLD, the system that dominates learning (i.e., MTL during declarative learning and the striatum during probabilistic learning) dominates and supports feedback processing.
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