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PLoS ONE (1)
Schizophrenia research (1)
The Journal of neuroscience : the official journal of the Society for Neuroscience (1)
Yiannoulos, Georgia (3)
Bitsios, Panos (1)
Blau, Justin (1)
Buchsbaum, Anna M. (1)
Byne, William (1)
Cyran, Shawn A. (1)
Hurd, Yasmin L. (1)
Jacobs, Michelle M. (1)
Jutras-Aswad, Didier (1)
Liu, Xun (1)
Marcus, Sue (1)
Nomura, Yoko (1)
Roussos, Panos (1)
Saez, Lino (1)
Tatusov, Alex (1)
Young, Michael W. (1)
Year of Publication
Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study
Jacobs, Michelle M.
Hurd, Yasmin L.
Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown.
Healthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect.
Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.
Effects of Mental Illness and Aging in Two Thalamic Nuclei
We previously reported a schizophrenia associated reduction of neuronal and oligodendrocyte number in the anterior principal thalamic nucleus (APN) in a cohort of severely impaired elderly subjects with schizophrenia (SZ) relative to age matched nonpsychiatric controls (NCs). The present study was undertaken to determine 1) if those findings could be replicated in an independent sample of less chronically impaired subjects with SZ and NCs stratified across a broader age range; 2) if the findings are specific to SZ or are also seen in unipolar major depressive (MDD) or bipolar disorder (BPD); and 3) if the findings are specific to the APN or also seen in another thalamic nucleus. Computer assisted stereological methods were employed to determine the number of neurons and oligodendrocytes in the APN and centromedian nucleus (CMN) of the Nissl-stained thalamic sections maintained by the Stanley Foundation Brain Bank. This collection includes specimens from NCs and age matched subjects with diagnoses of SZ, MDD, or BPD who died between the ages of 25 and 68. Data were analyzed by mixed-effects linear regressions adjusting for demographic variables and known history of exposure to psychotropic medications.
Oligodendrocyte number was decreased in both nuclei relative to NCs in subjects with SZ and in that subset of subjects with BPD who had experienced psychotic episodes. Compared to NCs both of these patient groups also exhibited an attenuation of an age-related increase in the number of oligodendrocytes. Contrary to our previous report, we did not detect a SZ-associated deficit in neuronal number in the APN. A history of exposure to neuroleptics, however, was associated with a decrease in neuronal number in both nuclei, but this decrease did not vary in relation to cumulative lifetime neuroleptic exposure in fluphenazine equivalents. Among subjects with psychiatric diagnoses, exposure to lithium was associated with an increase in the number of oligodendrocytes. No effects were detected for exposure to anticonvulsants or for abuse of alcohol or other substances.
The DOUBLE-TIME protein kinase regulates the subcellular localization of the Drosophila clock protein PERIOD
Cyran, Shawn A.
Buchsbaum, Anna M.
Young, Michael W.
The Journal of neuroscience : the official journal of the Society for Neuroscience
The PERIOD (PER), TIMELESS (TIM) and DOUBLE-TIME (DBT) proteins are essential components of one feedback loop in the Drosophila circadian molecular clock. PER and TIM physically interact. Co-expression of PER and TIM promotes their nuclear accumulation and influences the activity of DBT: although DBT phosphorylates and destabilizes PER, this is suppressed by TIM. Experiments using Drosophila cells in culture have indicated that PER can translocate to the nucleus without TIM and will repress transcription in a DBT-potentiated manner. In this study we examined the control of PER subcellular localization in Drosophila clock cells in vivo. We found that PER can translocate to the nucleus in tim01 null mutants – but only if DBT kinase activity is inhibited. We also found that nuclear PER is a potent transcriptional repressor in dbt mutants in vivo without TIM. Thus, in vivo, DBT regulates PER subcellular localization, in addition to its previously documented role as a mediator of PER stability, while DBT does not seem essential for transcriptional repression by PER. It was previously reported that over-expression of a second kinase, SHAGGY/GLYCOGEN SYNTHASE KINASE 3 (SGG) accelerates PER nuclear accumulation. Here we show that these effects of SGG on PER nuclear accumulation require TIM. We propose a revised clock model that incorporates this tight kinase regulation of PER and TIM nuclear entry.
Circadian; Period; Double-time; Timeless; Nuclear entry; Drosophila
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