Dopamine in the dorsal hippocampus impairs the late-consolidation of cocaine-associated memory

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.Fil: Kramar, Cecilia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Chefer, Vladimir I.. National Institutes of Health; Estados UnidosFil: Wise, Roy A.. National Institutes of Health; Estados UnidosFil: Medina, Jorge Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Barbano, María Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

QTL Mapping of Combining Ability and Heterosis of Agronomic Traits in Rice Backcross Recombinant Inbred Lines and Hybrid Crosses

BACKGROUND: Combining ability effects are very effective genetic parameters in deciding the next phase of breeding programs. Although some breeding strategies on the basis of evaluating combining ability have been utilized extensively in hybrid breeding, little is known about the genetic basis of combining ability. Combining ability is a complex trait that is controlled by polygenes. With the advent and development of molecular markers, it is feasible to evaluate the genetic bases of combining ability and heterosis of elite rice hybrids through QTL analysis. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we first developed a QTL-mapping method for dissecting combining ability and heterosis of agronomic traits. With three testcross populations and a BCRIL population in rice, biometric and QTL analyses were conducted for ten agronomic traits. The significance of general combining ability and special combining ability for most of the traits indicated the importance of both additive and non-additive effects on expression levels. A large number of additive effect QTLs associated with performance per se of BCRIL and general combining ability, and dominant effect QTLs associated with special combining ability and heterosis were identified for the ten traits. CONCLUSIONS/SIGNIFICANCE: The combining ability of agronomic traits could be analyzed by the QTL mapping method. The characteristics revealed by the QTLs for combining ability of agronomic traits were similar with those by multitudinous QTLs for agronomic traits with performance per se of BCRIL. Several QTLs (1-6 in this study) were identified for each trait for combining ability. It demonstrated that some of the QTLs were pleiotropic or linked tightly with each other. The identification of QTLs responsible for combining ability and heterosis in the present study provides valuable information for dissecting genetic basis of combining ability

Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals

Low Level of Low-Density Lipoprotein Receptor-Related Protein 1 Predicts an Unfavorable Prognosis of Hepatocellular Carcinoma after Curative Resection

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC). METHODS: LRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens. RESULTS: Low LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set. CONCLUSIONS: LRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy

A Dynamic and Complex Network Regulates the Heterosis of Yield-Correlated Traits in Rapeseed (Brassica napus L.)

Although much research has been conducted, the genetic architecture of heterosis remains ambiguous. To unravel the genetic architecture of heterosis, a reconstructed F2 population was produced by random intercross among 202 lines of a double haploid population in rapeseed (Brassica napus L.). Both populations were planted in three environments and 15 yield-correlated traits were measured, and only seed yield and eight yield-correlated traits showed significant mid-parent heterosis, with the mean ranging from 8.7% (branch number) to 31.4% (seed yield). Hundreds of QTL and epistatic interactions were identified for the 15 yield-correlated traits, involving numerous variable loci with moderate effect, genome-wide distribution and obvious hotspots. All kinds of mode-of-inheritance of QTL (additive, A; partial-dominant, PD; full-dominant, D; over-dominant, OD) and epistatic interactions (additive × additive, AA; additive × dominant/dominant × additive, AD/DA; dominant × dominant, DD) were observed and epistasis, especially AA epistasis, seemed to be the major genetic basis of heterosis in rapeseed. Consistent with the low correlation between marker heterozygosity and mid-parent heterosis/hybrid performance, a considerable proportion of dominant and DD epistatic effects were negative, indicating heterozygosity was not always advantageous for heterosis/hybrid performance. The implications of our results on evolution and crop breeding are discussed

In vitro nuclear interactome of the HIV-1 Tat protein

<p>Abstract</p> <p>Background</p> <p>One facet of the complexity underlying the biology of HIV-1 resides not only in its limited number of viral proteins, but in the extensive repertoire of cellular proteins they interact with and their higher-order assembly. HIV-1 encodes the regulatory protein Tat (86–101aa), which is essential for HIV-1 replication and primarily orchestrates HIV-1 provirus transcriptional regulation. Previous studies have demonstrated that Tat function is highly dependent on specific interactions with a range of cellular proteins. However they can only partially account for the intricate molecular mechanisms underlying the dynamics of proviral gene expression. To obtain a comprehensive nuclear interaction map of Tat in T-cells, we have designed a proteomic strategy based on affinity chromatography coupled with mass spectrometry.</p> <p>Results</p> <p>Our approach resulted in the identification of a total of 183 candidates as Tat nuclear partners, 90% of which have not been previously characterised. Subsequently we applied <it>in silico </it>analysis, to validate and characterise our dataset which revealed that the Tat nuclear interactome exhibits unique signature(s). First, motif composition analysis highlighted that our dataset is enriched for domains mediating protein, RNA and DNA interactions, and helicase and ATPase activities. Secondly, functional classification and network reconstruction clearly depicted Tat as a polyvalent protein adaptor and positioned Tat at the nexus of a densely interconnected interaction network involved in a range of biological processes which included gene expression regulation, RNA biogenesis, chromatin structure, chromosome organisation, DNA replication and nuclear architecture.</p> <p>Conclusion</p> <p>We have completed the <it>in vitro </it>Tat nuclear interactome and have highlighted its modular network properties and particularly those involved in the coordination of gene expression by Tat. Ultimately, the highly specialised set of molecular interactions identified will provide a framework to further advance our understanding of the mechanisms of HIV-1 proviral gene silencing and activation.</p