Jianghua Lai

Inhibition of Histone Deacetylase in the Basolateral Amygdala Facilitates Morphine Context-Associated Memory Formation in Rats

Histone acetylation/deacetylation is a crucial mechanism in memory formation and drug addiction. There is evidence suggesting that histone H3 acetylation may contribute to the long-term neural and behavioral responses to addictive drugs. In addition, the basolateral amygdala (BLA) is critically involved in the formation of cue-associated memories. However, the behavioral effect of histone deacetylase (HDAC) inhibition in the BLA and the underlying molecular alterations at different phases of morphine-induced conditioned place preference (CPP) has not been investigated. In this study, we measured the expression, extinction, and reinstatement of morphine-induced place preference in rats pretreated with trichostatin A (TSA), an HDAC inhibitor. Intra-BLA pretreatment with TSA significantly enhanced morphine-induced CPP acquisition and expression, facilitated extinction, and reduced reinstatement of morphine-induced CPP. These behavioral changes were associated with a general increase in histone H3 lysine14 (H3K14) acetylation in the BLA together with upregulation of the brain-derived neurophic factor (BDNF) and ΔFosB and CREB activation. Collectively, our findings imply that HDAC inhibition in the BLA promotes some aspects of the memory that develops during conditioning and extinction training. Furthermore, histone H3 acetylation may play a role in learning and memory for morphine addiction in the BLA.

Genomic signatures of near-extinction and rebirth of the crested ibis and other endangered bird species

BackgroundNearly one-quarter of all avian species is either threatened or nearly threatened. Of these, 73 species are currently being rescued from going extinct in wildlife sanctuaries. One of the previously most critically-endangered is the crested ibis, Nipponia nippon. Once widespread across North-East Asia, by 1981 only seven individuals from two breeding pairs remained in the wild. The recovering crested ibis populations thus provide an excellent example for conservation genomics since every individual bird has been recruited for genomic and demographic studies.ResultsUsing high-quality genome sequences of multiple crested ibis individuals, its thriving co-habitant, the little egret, Egretta garzetta, and the recently sequenced genomes of 41 other avian species that are under various degrees of survival threats, including the bald eagle, we carry out comparative analyses for genomic signatures of near extinction events in association with environmental and behavioral attributes of species. We confirm that both loss of genetic diversity and enrichment of deleterious mutations of protein-coding genes contribute to the major genetic defects of the endangered species. We further identify that genetic inbreeding and loss-of-function genes in the crested ibis may all constitute genetic susceptibility to other factors including long-term climate change, over-hunting, and agrochemical overuse. We also establish a genome-wide DNA identification platform for molecular breeding and conservation practices, to facilitate sustainable recovery of endangered species.ConclusionsThese findings demonstrate common genomic signatures of population decline across avian species and pave a way for further effort in saving endangered species and enhancing conservation genomic efforts.

Genetic susceptibility to haemorrhagic fever with renal syndrome caused by Hantaan virus in Chinese Han population

We report a significantly higher occurrence of HLA‐DRB1*09 (51% vs. 23%, P = 0.002, OR = 3.57) and HLA‐B*46‐DRB1*09 (26% vs. 8%, P = 0.018, OR = 3.76) in patients with haemorrhagic fever with renal syndrome (HFRS) compared to the control group, suggesting Hantaan virus‐induced HFRS is associated with a genetic predisposition in the Chinese Han population.

Differential phosphorylation of GluN1-MAPKs in rat brain reward circuits following long-term alcohol exposure.

The effects of long-term alcohol consumption on the mitogen-activated protein kinases (MAPKs) pathway and N-methyl-D-aspartate-type glutamate receptor 1 (GluN1) subunits in the mesocorticolimbic system remain unclear. In the present study, rats were allowed to consume 6% (v/v) alcohol solution for 28 consecutive days. Locomotor activity and behavioral signs of withdrawal were observed. Phosphorylation and expression of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38 protein kinase and GluN1 in the nucleus accumbens, caudate putamen, amygdala, hippocampus and prefrontal cortex of these rats were also measured. Phosphorylation of ERK, but not JNK or p38, was decreased in all five brain regions studied in alcohol-drinking rats. The ratio of phospho/total-GluN1 subunit was reduced in all five brain regions studied. Those results suggest that the long-term alcohol consumption can inhibits GluN1 and ERK phosphorylation, but not JNK or p38 in the mesocorticolimbic system, and these changes may be relevant to alcohol dependence. To differentiate alcohol-induced changes in ERK and GluN1 between acute and chronic alcohol exposure, we have determined levels of phospho-ERK, phospho-GluN1 and total levels of GluN1 after acute alcohol exposure. Our data show that 30 min following a 2.5 g/kg dose of alcohol (administered intragastrically), levels of phospho-ERK are decreased while those of phospho-GluN1 are elevated with no change in total GluN1 levels. At 24 h following the single alcohol dose, levels of phospho-ERK are elevated in several brain regions while there are no differences between controls and alcohol treated animals in phospho-GluN1 or total GluN1. Those results suggest that alcohol may differentially regulate GluN1 function and ERK activation depending on alcohol dose and exposure time in the central nervous system.

Dopamine D3 receptor regulates basal but not amphetamine-induced changes in pain sensitivity in mice

Pain is a complex and subjective experience that involves not only the transduction of noxious stimuli by nociceptive fibers, but also the cognitive and emotional processing by the brain. Previous studies on the transmission of nociception suggest that the activation of mesolimbic dopamine (DA) system plays an important role in mediating the suppression of tonic pain. The aim of the current study was to examine the role of DA D3 receptor in modulating basal and amphetamine-induced changes in pain sensitivity in mice. We used wild-type and D3 receptor mutant mice and determined allodynia induced by both noxious heat (radiant heat) and mechanical (von Frey hair) stimuli. We show that D3 receptor mutant mice exhibit hypoalgesia in both the tail-flick test and von Frey hair test compared to wild-type mice. Amphetamine-induced hyperalgesia in both D3 receptor mutant and wild-type mice in the tail-flick test and von Frey hair test. There was no significantly difference in the relative change in pain sensitivity between wild-type and D3 receptor mutant mice in both the tail-flick test and von Frey hair test following amphetamine administration. These results suggest that the D3 receptor regulates the transmission of nociception. Moreover, amphetamine can lower pain threshold in mice.

Analysis of Variations in the Glutamate Receptor, N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA) receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs) with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT)26 repeats (rs3219790) in the heroin addiction group was significantly higher than that in the control group (χ2 = 5.360, P = 0.021). The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3) were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction). Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487) had nominally significant P values for association (P<0.05), but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6) and T-T (block 10) haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003). These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.

Differential phosphorylation of NMDAR1–CaMKII–MAPKs in the rat nucleus accumbens following chronic ethanol exposure

Previous studies suggest that the nucleus accumbens shell (AcbSh) and core (AcbC) regions may have distinct roles in ethanol consumption. N-Methyl-d-aspartate receptor 1 (NMDAR1), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases (ERKs) have been demonstrated to contribute to and possibly interact in the molecular mechanism underlying ethanol dependence and relapse. However, little is known regarding the mechanisms underlying the effects of ethanol exposure, withdrawal, and re-exposure, particularly with regard to NMDAR1-CaMKII-ERK signaling in accumbens subregions. In the present study, rats were provided with a 6% ethanol solution as their only drinking source. We found that ethanol exerted locomotor stimulant and anxiolytic effects in open field behaviors. Phosphorylation of NMDAR1, CaMKII and ERK was significantly decreased in the AcbSh and AcbC following chronic ethanol exposure. Ethanol withdrawal increased phospho-NMDAR1 and phospho-CaMKII expression in the AcbSh. Ethanol withdrawal also induced an increase of phospho-ERK1/2 in both the AcbSh and AcbC, while ethanol re-exposure decreased phospho-ERK in the AcbSh. These results indicated that the activation of NMDAR1-CaMKII-ERK signaling in the AcbSh but not the AcbC would contribute more to ethanol drinking and chronic ethanol-related negative emotional states.

5-Aza-2’-deoxycytidine in the medial prefrontal cortex regulates alcohol-related behavior and Ntf3-TrkC expression in rats

Recent studies have indicated that DNA methylation plays an important role in the development of alcohol abuse. 5-Aza-2’-deoxycytidine (5-Aza-dc), an inhibitor of DNA methyltransferases, was FDA approved for myelodysplastic syndrome treatment. However, it is unclear whether 5-Aza-dc is involved in alcohol abuse. In this study, using a chronic alcohol exposure model in rats, 5-Aza-dc was injected into the medial prefrontal cortex (mPFC). Alcohol-drinking behavior and the anxiety related behavior were evaluated by two-bottle choice and open field test. We found that 5-Aza-dc injection into the mPFC significantly decreased alcohol consumption and alcohol preference in alcohol-exposure rats, corresponding to the reduced blood alcohol levels. Although 5-Aza-dc potentiated the anxiety-like behavior of alcohol-exposure rats, it had no effect on the locomotor activity. Moreover, both of the mRNA and protein levels of DNA Methyltransferase 3A (DNMT3A) and DNMT3B in the mPFC were upregulated after 35 days of alcohol exposure and this upregulation could be reversed by 5-Aza-dc treatment. Additionally, 5-Aza-dc reversed the alcohol-induced downregulation of neurotrophin-3 (Ntf3), correspondingly the expression of its receptor-TrkC was reduced. These findings identified a functional role of 5-Aza-dc in alcohol-related behavioral phenotypes and one of the potential target genes, Ntf3. We also provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcohol abuse.

Distribution of human leukocyte antigen alleles and haplotypes in Oroqen and Ewenki nationality minority in Inner Mongolia Autonomous Region of China

The frequencies of the human leukocyte antigen alleles HLA‐A,‐B, DRB1 and the A‐B, A‐DRB1, B‐DRB1, A‐B‐DRB1 haplotypes were investigated through means of PCR‐based reverse line‐strip sequence specific oligonucleotide hybridization on 108 Oroqen and 104 Ewenki nationality unrelated healthy individuals from the Inner Mongolia Autonomous Region of China. A total of thirteen different HLA‐A alleles, 21 different HLA‐B alleles and 13 different HLA‐DRB1 alleles were detected in the Oroqen ethnic group and the most frequent HLA alleles found were A*24(35.65%), B*15(17.92%), and DRB1*09(17.59%), respectively. The common HLA‐A‐B‐DRB1 haplotypes were A*24‐B*40‐DRB1*09(5.09%), A*24‐B*48‐DRB1*12(2.78%) and A*24‐B*51‐DRB1*04(2.78%); and the HLA‐A*33‐B*58, A*30‐B*13, A*01‐B*37, A*33‐DRB1*03, A*01‐DRB1*10, A*30‐DRB1*07, B*37‐DRB1*10, B*58‐DRB1*03, B*38‐DRB1*08, B*13‐DRB1*07 were significant positive linkage disequilibrium in the Oroqen nationality group. In total, 14 different HLA‐A alleles, 27 B alleles and 12 DRB1 alleles were found in Ewenki nationality group, and the most frequent HLA alleles found were A*24(24.49%), B*40(17.35%), and DRB1*04(14.80%), respectively. The common HLA‐A‐B‐DRB1 haplotypes were A*33‐B*58‐DRB1*03(6.25%), A*01‐B*51‐DRB1*11(2.88%) and A*24‐B*40‐DRB1*09(2.88%); the HLA‐A*33‐B*58, A*29‐B*44, A*03‐B*52, A*33‐DRB1*03, A*29‐DRB1*07, A*24‐DRB1*09, B*58‐DRB1*03, B*08‐DRB1*03, B*46‐DRB1*09 were significant positive linkage disequilibrium in Ewenki nationality group. The distribution of HLA A,‐B, DRB1, alleles haplotypes frequencies and phylogenetic tree indicated that the Oroqen and Ewenki population groups belongs to northern group of China, together as a group cluster.

Opiate-associated contextual memory formation and retrieval are differentially modulated by dopamine D1 and D2 signaling in hippocampal–prefrontal connectivity

Contextual memory driven by abused drugs such as opiates has a central role in maintenance and relapse of drug-taking behaviors. Although dopamine (DA) signaling favors memory storage and retrieval via regulation of hippocampal–prefrontal connectivity, its role in modulating opiate-associated contextual memory is largely unknown. Here, we report roles of DA signaling within the hippocampal–prefrontal circuit for opiate-related memories. Combining-conditioned place preference (CPP) with molecular analyses, we investigated the DA D1 receptor (D1R) and extracellular signal-regulated kinase (ERK)-cAMP-response element binding protein (CREB) signaling, as well as DA D2 receptor (D2R) and protein kinase B (PKB or Akt)/glycogen synthase kinase 3 (GSK3) signaling in the ventral hippocampus (vHip) and medial prefrontal cortex (mPFC) during the formation of opiate-related associative memories. Morphine-CPP acquisition increased the activity of the D1R–ERK–CREB pathway in both the vHip and mPFC. Morphine-CPP reinstatement was associated with the D2R-mediated hyperactive GSK3 via Akt inhibition in the vHip and PFC. Furthermore, integrated D1R–ERK–CREB and D2R–Akt–GSK3 pathways in the vHip–mPFC circuit are required for the acquisition and retrieval of the morphine contextual memory, respectively. Moreover, blockage of D1R or D2R signaling could alleviate normal Hip-dependent spatial memory. These results suggest that D1R and D2R signaling are differentially involved in the acquisition and retrieval of morphine contextual memory, and DA signaling in the vHip–mPFC connection contributes to morphine-associated and normal memory, largely depending on opiate exposure states.