Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine

Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response.Fil: Dobbs, Lauren K.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados UnidosFil: Kaplan, Alanna R.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados UnidosFil: Lemos, Julia C.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados UnidosFil: Matsui, Aya. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Michigan State University; Estados UnidosFil: Alvarez, Veronica A.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados Unido

Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer), while existing at a nearly undetectable level in the surrounding normal tissue.</p> <p>Methods</p> <p>H19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH) using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer.</p> <p>Results</p> <p>H19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth.</p> <p>Conclusion</p> <p>These observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.</p

Genetics of focal segmental glomerulosclerosis

The recent advances in understanding the pathophysiology of focal segmental glomerulosclerosis (FSGS) and molecular function of glomerular filtration barrier come directly from genetic linkage and positional cloning studies. The exact role and function of the newly discovered genes and proteins are being investigated by in vitro and in vivo mechanistic studies. Those genes and proteins interactions seem to change susceptibility to kidney disease progression. Better understanding of their exact role in the development of FSGS may influence future therapies and outcomes in this complex disease

Population Attributable Fraction of Smoking and Metabolic Syndrome on Cardiovascular Disease Mortality in Japan: a 15-Year Follow Up of NIPPON DATA90

<p>Abstract</p> <p>Background</p> <p>Smoking and metabolic syndrome are known to be related to cardiovascular diseases (CVD) risk. In Asian countries, prevalence of obesity has increased and smoking rate in men is still high. We investigated the attribution of the combination of smoking and metabolic syndrome (or obesity) to excess CVD deaths in Japan.</p> <p>Methods</p> <p>A cohort of nationwide representative Japanese samples, a total of 6650 men and women aged 30-70 at baseline without history of CVD was followed for 15 years. Multivariate-adjusted hazard ratio for CVD death according to the combination of smoking status and metabolic syndrome (or obesity) was calculated using Cox proportional hazard model. Population attributable fraction (PAF) of CVD deaths was calculated using the hazard ratios.</p> <p>Results</p> <p>During the follow-up period, 87 men and 61 women died due to CVD. The PAF component of CVD deaths in non-obese smokers was 36.8% in men and 11.3% in women, which were higher than those in obese smokers (9.1% in men and 5.2% in women). The PAF component of CVD deaths in smokers without metabolic syndrome was 40.9% in men and 11.9% in women, which were also higher than those in smokers with metabolic syndrome (7.1% in men and 3.9% in women).</p> <p>Conclusion</p> <p>Our results indicated that a large proportion of excess CVD deaths was observed in smokers without metabolic syndrome or obesity, especially in men. These findings suggest that intervention targeting on smokers, irrespective of the presence of metabolic syndrome, is still important for the prevention of CVD in Asian countries.</p

Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats

BACKGROUND: Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care. METHODOLOGY/PRINCIPAL FINDINGS: We examine here using high-density oligonucleotide array the state of DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18 containing the NR3C1 gene in the hippocampus of adult rats. Natural variations in maternal care are associated with coordinate epigenetic changes spanning over a hundred kilobase pairs. The adult offspring of high compared to low maternal care mothers show epigenetic changes in promoters, exons, and gene ends associated with higher transcriptional activity across many genes within the locus examined. Other genes in this region remain unchanged, indicating a clustered yet specific and patterned response. Interestingly, the chromosomal region containing the protocadherin-α, -β, and -γ (Pcdh) gene families implicated in synaptogenesis show the highest differential response to maternal care. CONCLUSIONS/SIGNIFICANCE: The results suggest for the first time that the epigenetic response to maternal care is coordinated in clusters across broad genomic areas. The data indicate that the epigenetic response to maternal care involves not only single candidate gene promoters but includes transcriptional and intragenic sequences, as well as those residing distantly from transcription start sites. These epigenetic and transcriptional profiles constitute the first tiling microarray data set exploring the relationship between epigenetic modifications and RNA expression in both protein coding and non-coding regions across a chromosomal locus in the mammalian brain