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Sample records for accumbens nac plays

  1. Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats.

    PubMed

    Manduca, Antonia; Servadio, Michela; Damsteegt, Ruth; Campolongo, Patrizia; Vanderschuren, Louk Jmj; Trezza, Viviana

    2016-08-01

    Social play behavior is a highly rewarding form of social interaction displayed by young mammals. Social play is important for neurobehavioral development and it has been found to be impaired in several developmental psychiatric disorders. In line with the rewarding properties of social play, we have previously identified the nucleus accumbens (NAc) as an important site of action for endocannabinoid and opioid modulation of this behavior. NAc dopamine has a well-known role in certain components of reward processes, such as incentive motivation. However, its contribution to the positive emotional aspects of social interactions is less clear. Therefore, we investigated the role of dopaminergic neurotransmission in the NAc in social play behavior in rats. We found that intra-NAc infusion of the dopamine releaser/reuptake inhibitor amphetamine increased social play behavior that was dependent on activation of both D1 and D2 dopamine receptors. This increase in social play behavior was mimicked by intra-NAc infusion of the dopamine receptor agonist apomorphine, but not of the dopamine reuptake inhibitor GBR-12909. Blockade of either D1 or D2 NAc dopamine receptors reduced social play in animals highly motivated to play as a result of longer social isolation before testing. Last, blockade of NAc dopamine receptors prevented the play-enhancing effects of endocannabinoid and opioid receptor stimulation. These findings demonstrate an important modulatory role of NAc dopaminergic neurotransmission in social play. Thus, functional activity in the mesolimbic dopamine pathway plays an important role in adaptive social development, whereas abnormal NAc dopamine function may underlie the social impairments observed in developmental psychiatric disorders such as autism, attention deficit hyperactivity disorder or early-onset schizophrenia. PMID:26860202

  2. Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats

    PubMed Central

    Trezza, Viviana; Damsteegt, Ruth; Manduca, Antonia; Petrosino, Stefania; Van Kerkhof, Linda W.M.; Pasterkamp, R. Jeroen; Zhou, Yeping; Campolongo, Patrizia; Cuomo, Vincenzo; Di Marzo, Vincenzo; Vanderschuren, Louk J.M.J.

    2012-01-01

    The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4–5 week old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signalling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats. PMID:23100412

  3. Hedonic and Nucleus Accumbens Neural Responses to a Natural Reward Are Regulated by Aversive Conditioning

    ERIC Educational Resources Information Center

    Roitman, Mitchell F.; Wheeler, Robert A.; Tiesinga, Paul H. E.; Roitman, Jamie D.; Carelli, Regina M.

    2010-01-01

    The nucleus accumbens (NAc) plays a role in hedonic reactivity to taste stimuli. Learning can alter the hedonic valence of a given stimulus, and it remains unclear how the NAc encodes this shift. The present study examined whether the population response of NAc neurons to a taste stimulus is plastic using a conditioned taste aversion (CTA)…

  4. Nucleus accumbens core lesions enhance two-way active avoidance.

    PubMed

    Lichtenberg, N T; Kashtelyan, V; Burton, A C; Bissonette, G B; Roesch, M R

    2014-01-31

    The majority of work examining the nucleus accumbens core (NAc) has focused on functions pertaining to behaviors guided by appetitive outcomes. These studies have pointed to the NAc as being critical for motivating behavior toward desirable outcomes. For example, we have recently shown that lesions of the NAc impaired performance on a reward-guided decision-making task that required rats to choose between differently valued rewards. Unfortunately, much less is known about the role that the NAc plays in motivating behavior when aversive outcomes are predicted. To address this issue we asked if NAc lesions impact performance on a two-way active avoidance task in which rats must learn to shuttle back and forth in a behavioral training box in order to avoid a footshock predicted by an auditory tone. Although bilateral NAc lesions initially impaired reward-guided decision-making, we found that the same lesions improved acquisition and retention of two-way active avoidance. PMID:24275320

  5. The Stress-Induced Soybean NAC Transcription Factor GmNAC81 Plays a Positive Role in Developmentally Programmed Leaf Senescence.

    PubMed

    Pimenta, Maiana Reis; Silva, Priscila Alves; Mendes, Giselle Camargo; Alves, Janaína Roberta; Caetano, Hanna Durso Neves; Machado, Joao Paulo Batista; Brustolini, Otavio José Bernardes; Carpinetti, Paola Avelar; Melo, Bruno Paes; Silva, José Cleydson Ferreira; Rosado, Gustavo Leão; Ferreira, Márcia Flores Silva; Dal-Bianco, Maximillir; Picoli, Edgard Augusto de Toledo; Aragao, Francisco José Lima; Ramos, Humberto Josué Oliveira; Fontes, Elizabeth Pacheco Batista

    2016-05-01

    The onset of leaf senescence is a highly regulated developmental change that is controlled by both genetics and the environment. Senescence is triggered by massive transcriptional reprogramming, but functional information about its underlying regulatory mechanisms is limited. In the current investigation, we performed a functional analysis of the soybean (Glycine max) osmotic stress- and endoplasmic reticulum (ER) stress-induced NAC transcription factor GmNAC81 during natural leaf senescence using overexpression studies and reverse genetics. GmNAC81-overexpressing lines displayed accelerated flowering and leaf senescence but otherwise developed normally. The precocious leaf senescence of GmNAC81-overexpressing lines was associated with greater Chl loss, faster photosynthetic decay and higher expression of hydrolytic enzyme-encoding GmNAC81 target genes, including the vacuolar processing enzyme (VPE), an executioner of vacuole-triggered programmed cell death (PCD). Conversely, virus-induced gene silencing-mediated silencing of GmNAC81 delayed leaf senescence and was associated with reductions in Chl loss, lipid peroxidation and the expression of GmNAC81 direct targets. Promoter-reporter studies revealed that the expression pattern of GmNAC81 was associated with senescence in soybean leaves. Our data indicate that GmNAC81 is a positive regulator of age-dependent senescence and may integrate osmotic stress- and ER stress-induced PCD responses with natural leaf senescence through the GmNAC81/VPE regulatory circuit. PMID:27016095

  6. A stress-associated NAC transcription factor (SlNAC35) from tomato plays a positive role in biotic and abiotic stresses.

    PubMed

    Wang, Guodong; Zhang, Song; Ma, Xiaocui; Wang, Yong; Kong, Fanying; Meng, Qingwei

    2016-09-01

    The NAC transcription factor family participates in responses to various kinds of environmental stimuli in plants. Responses of NAC genes to abiotic stresses have been widely studied, but their functions in response to biotic stress are little reported in plants, especially in crops. In the present study, we examined the functions of a novel tomato (Solanum lycopersicum) NAC protein (SlNAC35) in abiotic and biotic stress resistance by using transgenic tobacco. Expression analysis found that SlNAC35 expression was induced by drought stress, salt stress, bacterial pathogen, and signaling molecules, suggesting its involvement in plant responses to biotic and abiotic stimuli. Moreover, transgenic lines exhibited a greater number of lateral roots and longer root length compared with Vec lines (empty vector lines) after drought and salt treatment. These results indicate that overexpression of SlNAC35 promoted root growth and development under drought and salt stresses. Higher expressions of NtARF1, NtARF2 and NtARF8 were observed under drought and salt stresses in transgenic lines, suggesting that overexpression of SlNAC35 promoted growth and development of roots in transgenic lines possibly by involving auxin signaling and by regulating NtARF expression. In addition, SlNAC35 overexpression improved resistance to bacterial pathogen in transgenic tobacco, and reactive oxygen species may be in the upstream of salicylic acid (SA) signaling in transgenic tobacco during defense response. PMID:26991441

  7. NAC transcription factors play an important role in ethylene biosynthesis, reception and signaling of tomato fruit ripening.

    PubMed

    Kou, Xiaohong; Liu, Chen; Han, Lihua; Wang, Shuang; Xue, Zhaohui

    2016-06-01

    NAC proteins comprise a large family of transcription factors that play important roles in diverse physiological processes during development. To explore the role of NAC transcription factors in the ripening of fruits, we predicted the secondary and tertiary structure as well as regulative function of the SNAC4 (SlNAC48, Accession number: NM 001279348.2) and SNAC9 (SlNAC19, Accession number: XM 004236996.2) transcription factors in tomato. We found that the tertiary structure of SNAC9 was similar to that of ATNAP, which played an important role in the fruit senescence and was required for ethylene stimulation. Likewise, the bio-function prediction results indicated that SNAC4 and SNAC9 participated in various plant hormone signaling and senescence processes. More information about SNACs was obtained by the application of VIGS (virus-induced gene silencing). The silencing of SNAC4 and SNAC9 dramatically repressed the LeACS2, LeACS4 and LeACO1 expression, which consequently led to the inhibition of the ripening process. The silencing of SNACs down-regulated the mRNA levels of the ethylene perception genes and, at the same time, suppressed the expression of ethylene signaling-related genes except for LeERF2 which was induced by the silencing of SNAC4. The expressions of LeRIN were different in two silenced fruits. In addition, the silencing of SNAC4 reduced its mRNA level, while the silencing of SNAC9 induced its expression. Furthermore, the silencing of LeACS4, LeACO1 and LeERF2 reduced the expression of SNAC4 and SNAC9, while the silencing of NR induced the expression of all of them. In particular, these results indicate that SNAC transcription factors bind to the promoter of the ethylene synthesis genes in vitro. This experimental evidence demonstrates that SNAC4 and SNAC9 could positively regulate the tomato fruit ripening process by functioning upstream of ethylene synthesis genes. These outcomes will be helpful to provide a theoretical foundation for further

  8. Assessing Contributions of Nucleus Accumbens Shell Subregions to Reward-Seeking Behavior

    PubMed Central

    Reed, Michael D.; Hildebrand, David G. C.; Santangelo, Gabrielle; Moffa, Anthony; Pira, Ashley S.; Rycyna, Lisa; Radic, Mia; Price, Katherine; Archbold, Jonathan; McConnell, Kristi; Girard, Lauren; Morin, Kristen; Tang, Anna; Febo, Marcelo; Stellar, James R.

    2015-01-01

    Background The nucleus accumbens (NAc) plays a key role in brain reward processes including drug seeking and reinstatement. Several anatomical, behavioral, and neurochemical studies discriminate between the limbic-associated shell and the motor-associated core regions. Less studied is the fact that the shell can be further subdivided into a dorsomedial shell (NAcDMS) and an intermediate zone (NAcINT) based on differential expression of transient c-Fos and long-acting immediate-early gene ΔFosB upon cocaine sensitization. These disparate expression patterns suggest that NAc shell subregions may play distinct roles in reward-seeking behavior. In this study, we examined potential differences in the contributions of the NAcDMS and the NAcINT to reinstatement of reward-seeking behavior after extinction. Methods Rats were trained to intravenously self-administer cocaine, extinguished, and subjected to a reinstatement test session consisting of either an intracranial microinfusion of amphetamine or vehicle targeted to the NAcDMS or the NAcINT. Results Small amphetamine microinfusions targeted to the NAcDMS resulted in statistically significant reinstatement of lever pressing, whereas no statistical difference was observed for microinfusions targeted to the NAcINT. No significant difference was found for vehicle microinfusions in either case. Conclusion These results suggest heterogeneity in the behavioral relevance of NAc shell subregions, a possibility that can be tested in specific neuronal populations in the future with recently developed techniques including optogenetics. PMID:26048642

  9. Nucleus accumbens μ-opioid receptors mediate social reward.

    PubMed

    Trezza, Viviana; Damsteegt, Ruth; Achterberg, E J Marijke; Vanderschuren, Louk J M J

    2011-04-27

    Positive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05-0.1 μg) increased pinning and pouncing, characteristic elements of social play behavior in rats, and blockade of NAc opioid receptors with naloxone (0.5 μg) prevented the play-enhancing effects of systemic morphine (1 mg/kg, s.c.) administration. Thus, stimulation of opioid receptors in the NAc was necessary and sufficient for morphine to increase social play. Intra-NAc treatment with the selective μ-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) (0.1-10 ng) and the μ-opioid receptor antagonist Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (0.3-3 μg) increased and decreased social play, respectively. The δ-opioid receptor agonist DPDPE ([D-Pen(2),D-Pen(5)]-enkephalin) (0.3-3 μg) had no effects, whereas the κ-opioid receptor agonist U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide) (0.01-1 μg) decreased social play. Intra-NAc treatment with β-endorphin (0.01-1 μg) increased social play, but met-enkephalin (0.1-5 μg) and the enkephalinase inhibitor thiorphan (0.1-1 μg) were ineffective. DAMGO (0.1-10 ng) increased social play after infusion into both the shell and core subregions of the NAc. Last, intra-NAc infusion of CTAP (3 μg) prevented the development of social play-induced conditioned place preference. These findings identify NAc μ-opioid receptor stimulation as an important neural mechanism for the attribution of positive value to social interactions in adolescent rats. Altered NAc μ-opioid receptor function may underlie social impairments in psychiatric disorders such as autism

  10. Valproate Inhibits Methamphetamine Induced Hyperactivity via Glycogen Synthase Kinase 3β Signaling in the Nucleus Accumbens Core

    PubMed Central

    Xing, Bo; Liang, Xiao-ping; Liu, Peng; Zhao, Yan; Chu, Zheng; Dang, Yong-hui

    2015-01-01

    Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3β (GSK3β) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3β signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3β at serine 9 and total GSK3β levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3β activity. We further investigated whether microinjection of VPA (300 μg/0.5 μl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3β at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3β activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity. PMID:26030405

  11. Nucleus Accumbens Invulnerability to Methamphetamine Neurotoxicity

    PubMed Central

    Kuhn, Donald M.; Angoa-Pérez, Mariana; Thomas, David M.

    2016-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure. PMID:23382149

  12. Neural mechanisms of the nucleus accumbens circuit in reward and aversive learning.

    PubMed

    Hikida, Takatoshi; Morita, Makiko; Macpherson, Tom

    2016-07-01

    The basal ganglia are key neural substrates not only for motor function, but also cognitive functions including reward and aversive learning. Critical for these processes are the functional role played by two projection neurons within nucleus accumbens (NAc); the D1- and D2-expressing neurons. Recently, we have developed a novel reversible neurotransmission blocking technique that specifically blocks neurotransmission from NAc D1- and D2-expressing neurons, allowing for in vivo analysis. In this review, we outline the functional dissociation of NAc D1- and D2-expressing neurons of the basal ganglia in reward and aversive learning, as well as drug addiction. These studies have revealed the importance of activation of NAc D1 receptors for reward learning and drug addiction, and inactivation of NAc D2 receptors for aversive learning and flexibility. Based on these findings, we propose a neural mechanism, in which dopamine neurons in the ventral tegmental area that send inputs to the NAc work as a switch between D1- and D2-expressing neurons. These basal ganglia neural mechanisms will give us new insights into the pathophysiology of neuropsychiatric diseases. PMID:26827817

  13. Modulation of medial geniculate nucleus neuronal activity by electrical stimulation of the nucleus accumbens.

    PubMed

    Barry, K M; Paolini, A G; Robertson, D; Mulders, W H A M

    2015-11-12

    Dysfunctional sensory gating has been proposed to result in the generation of phantom perceptions. In agreement, it has been recently suggested that tinnitus, a phantom perception of sound commonly associated with hearing loss, is the result of a breakdown of circuitry involving the limbic system and the medial geniculate nucleus (MGN) of the thalamus. In humans with tinnitus, structural changes and abnormal activity have been found to occur in the auditory pathway as well as parts of the limbic system such as the nucleus accumbens (NAc). However, at present, no studies have been conducted on the influence of the NAc on the MGN. We investigated the functional connectivity between the NAc and MGN single neurons. Bipolar electrical stimulation was delivered to the NAc while recording single neuron activity in MGN in anesthetized Wistar rats. Histological analysis was used to confirm placement of electrodes. NAc electrical stimulation generally decreased spontaneous firing rates in MGN neurons and, in a limited number of neurons, caused an increase in firing rate. This suggests that NAc can modulate the activity of auditory neurons in the MGN and may play a role in the development of tinnitus. PMID:26349008

  14. Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats.

    PubMed

    Beloate, Lauren N; Weems, Peyton W; Casey, Graham R; Webb, Ian C; Coolen, Lique M

    2016-02-01

    Sexual experience in male rats followed by a period of abstinence causes sensitization to d-Amphetamine (Amph) reward, evidenced by an increased conditioned place preference (CPP) for low doses of Amph. Moreover, sexual experience induces neural plasticity within the nucleus accumbens (NAc), including induction of deltaFosB, which plays a key role in Amph reward cross-sensitization. The NMDA receptor subunit NR1 is also upregulated by mating, but the functional relevance of NMDA receptors in sex experience-induced effects is unknown. Here, we examined the influence of intra-NAc MK 801 infusions on sex experience-induced NAc deltaFosB and cFos expression, as well as mating- and Amph-induced CPP in adult male rats. In experiment 1, males received MK 801 or saline into the NAc during each of 4 consecutive days of mating or handling and were tested for Amph CPP and experience-induced deltaFosB 10 days later. Intra-NAc MK 801 during sexual behavior prevented experience-induced increases in Amph CPP and NAc deltaFosB expression without affecting sexual behavior. In experiment 2, the effects of intra-NAc MK 801 on mating-induced CPP were examined by intra-NAc infusion of MK 801 or saline prior to mating on conditioning days. Intra-NAc MK 801 did not affect mating-induced CPP. Next, effects of intra-NAc MK 801 on mating-induced cFos immunoreactivity were examined. MK 801 prevented mating-induced cFos expression in NAc shell and core. Together, these results provide evidence that NAc NMDA receptor activation during sexual behavior plays a key role in mating-induced cFos and deltaFosB expression and subsequent experience-induced cross-sensitization to Amph reward. PMID:26391065

  15. Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry

    PubMed Central

    Castro, Daniel C.; Cole, Shannon L.; Berridge, Kent C.

    2015-01-01

    The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact (“liking”) and motivational incentive salience (“wanting”) of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including “liking” and “wanting” for food rewards. PMID:26124708

  16. Nucleus Accumbens Core and Shell Differentially Encode Reward-Associated Cues after Reinforcer Devaluation

    PubMed Central

    West, Elizabeth A.

    2016-01-01

    Nucleus accumbens (NAc) neurons encode features of stimulus learning and action selection associated with rewards. The NAc is necessary for using information about expected outcome values to guide behavior after reinforcer devaluation. Evidence suggests that core and shell subregions may play dissociable roles in guiding motivated behavior. Here, we recorded neural activity in the NAc core and shell during training and performance of a reinforcer devaluation task. Long–Evans male rats were trained that presses on a lever under an illuminated cue light delivered a flavored sucrose reward. On subsequent test days, each rat was given free access to one of two distinctly flavored foods to consume to satiation and were then immediately tested on the lever pressing task under extinction conditions. Rats decreased pressing on the test day when the reinforcer earned during training was the sated flavor (devalued) compared with the test day when the reinforcer was not the sated flavor (nondevalued), demonstrating evidence of outcome-selective devaluation. Cue-selective encoding during training by NAc core (but not shell) neurons reliably predicted subsequent behavioral performance; that is, the greater the percentage of neurons that responded to the cue, the better the rats suppressed responding after devaluation. In contrast, NAc shell (but not core) neurons significantly decreased cue-selective encoding in the devalued condition compared with the nondevalued condition. These data reveal that NAc core and shell neurons encode information differentially about outcome-specific cues after reinforcer devaluation that are related to behavioral performance and outcome value, respectively. SIGNIFICANCE STATEMENT Many neuropsychiatric disorders are marked by impairments in behavioral flexibility. Although the nucleus accumbens (NAc) is required for behavioral flexibility, it is not known how NAc neurons encode this information. Here, we recorded NAc neurons during a training

  17. Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons.

    PubMed

    Ortinski, Pavel I; Briand, Lisa A; Pierce, R Christopher; Schmidt, Heath D

    2015-05-01

    Stimulation of D1-like dopamine receptors (D1DRs) or D2-like dopamine receptors (D2DRs) in the nucleus accumbens (NAc) shell reinstates cocaine seeking in rats, an animal model of relapse. D2DRs and D1DRs activate protein kinase C (PKC) and recent studies indicate that activation of PKC in the NAc plays an important role in the reinstatement of drug seeking induced by a systemic cocaine priming injection. In the present study, pharmacological inhibition of PKC in the NAc shell attenuated cocaine seeking induced by intra-accumbens shell microinjection of a D2DR agonist, but not a D1DR agonist. D1DRs and D2DRs are primarily expressed on different accumbens medium spiny (MSN) neurons. Neuronal signaling and activity were assessed in these two populations of NAc neurons with transgenic mice expressing fluorescent labels under the control of D1DR and D2DR promoters. Following the extinction of cocaine self-administration, bath application of a PKC inhibitor produced similar effects on single evoked excitatory and inhibitory post-synaptic currents in D1DR- and D2DR-positive MSNs in the NAc shell. However, inhibition of PKC preferentially improved the ability of excitatory, but not inhibitory, synapses to sustain responding to brief train of stimuli specifically in D2DR-positive MSNs. This effect did not appear to involve modulation of presynaptic release mechanisms. Taken together, these findings indicate that the reinstatement of cocaine seeking is at least partially due to D2DR-dependent increases in PKC signaling in the NAc shell, which reduce excitatory synaptic efficacy in D2DR-expressing MSNs. PMID:25596492

  18. Role of nucleus accumbens glutamatergic plasticity in drug addiction

    PubMed Central

    Quintero, Gabriel C

    2013-01-01

    Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance’s effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca2+-permeable AMPA receptors (CP-AMPARs) at the level of the NAc

  19. Role of nucleus accumbens glutamatergic plasticity in drug addiction.

    PubMed

    Quintero, Gabriel C

    2013-01-01

    Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance's effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca(2+)-permeable AMPA receptors (CP-AMPARs) at the level of the NAc

  20. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation.

    PubMed

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J

    2016-01-01

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1-D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated. PMID:27337658

  1. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation

    PubMed Central

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J.

    2016-01-01

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1–D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated. PMID:27337658

  2. Role of Mu and Delta Opioid Receptors in the Nucleus Accumbens in Cocaine-Seeking Behavior

    PubMed Central

    Simmons, Diana; Self, David W.

    2009-01-01

    Previous studies suggest that opioid receptors in the ventral tegmental area (VTA), but not the nucleus accumbens (NAc), play a role in relapse to drug-seeking behavior. However, environmental stimuli that elicit relapse also release the endogenous opioid β-endorphin in the NAc. Using a within–session extinction/reinstatement paradigm in rats that self-administer cocaine, we found that NAc infusions of the mu opioid receptor (MOR) agonist DAMGO moderately reinstated responding on the cocaine-paired lever at low doses (1.0–3.0 ng/side), whereas the delta opioid receptor (DOR) agonist DPDPE induced greater responding at higher doses (300–3000 ng/side) that also enhanced inactive lever responding. Using doses of either agonist that induced responding on only the cocaine-paired lever, we found that DAMGO-induced responding was blocked selectively by pretreatment with the MOR antagonist CTAP, while DPDPE-induced responding was selectively blocked by the DOR antagonist naltrindole. Cocaine-primed reinstatement was blocked by intra-NAc CTAP but not naltrindole, indicating a role for endogenous MOR-acting peptides in cocaine-induced reinstatement of cocaine-seeking behavior. In this regard, intra-NAc infusions of β-endorphin (100–1000 ng/side) induced marked cocaine-seeking behavior, an effect blocked by intra-NAc pretreatment with the MOR but not DOR antagonist. Conversely, cocaine seeking elicited by the enkephalinase inhibitor thiorphan (1–10 μg/side) was blocked by naltrindole but not CTAP. MOR stimulation in more dorsal caudate-putamen sites was ineffective, while DPDPE infusions induced cocaine seeking. Together, these findings establish distinct roles for MOR and DOR in cocaine relapse, and suggest that NAc MOR could be an important therapeutic target to neutralize the effects of endogenous β-endorphin release on cocaine relapse. PMID:19279569

  3. Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity

    PubMed Central

    Thomas, David M.; Francescutti-Verbeem, Dina M.; Kuhnt, Donald M.

    2016-01-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate–putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, L-DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure. PMID:19457119

  4. Dysregulation of AMPA receptor transmission in the nucleus accumbens in animal models of cocaine addiction

    PubMed Central

    Wolf, Marina E.

    2014-01-01

    Plasticity of glutamate transmission in neuronal circuits involving the nucleus accumbens (NAc) is now recognized to play a critical role in cocaine addiction. NAc neurons are excited primarily by AMPA-type glutamate receptors (AMPAR) and this is required for cocaine seeking. This review will briefly describe AMPAR properties and trafficking, with a focus on studies in NAc neurons, and then consider mechanisms by which cocaine may alter AMPAR transmission. Two examples will be discussed that may be important in two different stages of addiction: learning about drugs and drug-related cues during the period of drug exposure, and persistent vulnerability to craving and relapse after abstinence is achieved. The first example is drawn from studies of cultured NAc neurons. Elevation of DA levels (as would occur following cocaine exposure) facilitates activity-dependent strengthening of excitatory synapses onto medium spiny neurons, the main cell type and projection neuron of the NAc. This occurs because activation of D1-class receptors primes AMPAR for synaptic insertion, creating a temporal window in which stimuli related to cocaine-taking are more efficacious at eliciting synaptic plasticity and thus being encoded into memory. The second example involves rat models of cocaine addiction. Cell surface and synaptic expression of AMPAR on NAc neurons is persistently increased after withdrawal from repeated cocaine exposure. We hypothesize that this increases the reactivity of NAc neurons to glutamate inputs from cortex and limbic structures, facilitating the ability of these inputs to trigger cocaine seeking and thus contributing to the persistent vulnerability to relapse that characterizes addiction. PMID:20361291

  5. Influence of the hippocampus on amino acid utilizing and cholinergic neurons within the nucleus accumbens is promoted by histamine via H1 receptors

    PubMed Central

    Kraus, M M; Prast, H; Philippu, A

    2013-01-01

    Background and Purpose The influence of the neurotransmitter histamine on spontaneous and stimulation-evoked release of glutamate, aspartate, GABA and ACh in the nucleus accumbens (NAc) was investigated in vivo. Experimental Approach Using the push–pull superfusion technique, histaminergic compounds were applied to the NAc and neurotransmitter release was assessed. In some experiments, the fornix/fimbria of the hippocampus was electrically stimulated by a microelectrode and evoked potentials were monitored in the NAc. Key Results Superfusion of the NAc with the H1 receptor antagonist triprolidine (50 μM) decreased spontaneous outflow of glutamate, aspartate and ACh, while release of GABA remained unaffected. Superfusion with histamine elevated release of ACh, without influencing that of the amino acids. Electrical stimulation of the fornix/fimbria enhanced the output of amino acids and ACh within the NAc. The evoked outflow of glutamate and ACh was diminished on superfusion with triprolidine, while release of aspartate and GABA was not affected. Superfusion of the NAc with histamine intensified the stimulation-evoked release of glutamate and Ach. Histamine also elevated the stimulation-induced release of aspartate, without influencing that of GABA. Presuperfusion with triprolidine abolished the reinforced effect of histamine on stimulation-evoked transmitter release within the NAc. Conclusion and Implications Neuronal histamine activates H1 receptors and increases spontaneous release of glutamate, aspartate and ACh within the NAc. Stimulation of the hippocampal fornix/fimbria tract also enhances release of glutamate and ACh within the NAc and this effect is intensified by H1 receptor stimulation within the NAc. The latter effects, which are mediated by hippocampal afferences, might play an important role in mnemonic performance and in emotional processes such as anxiety and stress disorders. Linked Articles This article is part of a themed issue on Histamine

  6. Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose-Reinforced Cued Approach Behavior

    PubMed Central

    du Hoffmann, Johann; Nicola, Saleem M.

    2016-01-01

    Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety. PMID:27471453

  7. BDNF contributes to both rapid and homeostatic alterations in AMPA receptor surface expression in nucleus accumbens medium spiny neurons

    PubMed Central

    Reimers, Jeremy M.; Loweth, Jessica A.; Wolf, Marina E.

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in plasticity at glutamate synapses and the effects of repeated cocaine exposure. We recently showed that intracranial injection of BDNF into the rat nucleus accumbens (NAc), a key region for cocaine addiction, rapidly increases AMPA receptor (AMPAR) surface expression. To further characterize BDNF’s role in both rapid AMPAR trafficking and slower, homeostatic changes in AMPAR surface expression, we investigated the effects of acute (30 min) and long-term (24 h) treatment with BDNF on AMPAR distribution in NAc medium spiny neurons from postnatal rats co-cultured with mouse prefrontal cortex (PFC) neurons to restore excitatory inputs. Immunocytochemical studies showed that acute BDNF treatment increased cell surface GluA1 and GluA2 levels, as well as their co-localization, on NAc neurons. This effect of BDNF, confirmed using a protein crosslinking assay, was dependent on ERK but not AKT signaling. In contrast, long-term BDNF treatment decreased AMPAR surface expression on NAc neurons. Based on this latter result, we tested the hypothesis that BDNF plays a role in AMPAR “scaling down” in response to a prolonged increase in neuronal activity produced by bicuculline (24 h). Supporting this hypothesis, decreasing BDNF signaling with the extracellular BDNF scavenger TrkB-Fc prevented the scaling down of GluA1 and GluA2 surface levels in NAc neurons normally produced by bicuculline. In conclusion, BDNF exerts bidirectional effects on NAc AMPAR surface expression, depending on duration of exposure. Furthermore, BDNF’s involvement in synaptic scaling in the NAc differs from its previously described role in the visual cortex. PMID:24712995

  8. The effect of forced swim stress on morphine sensitization: Involvement of D1/D2-like dopamine receptors within the nucleus accumbens.

    PubMed

    Charmchi, Elham; Zendehdel, Morteza; Haghparast, Abbas

    2016-10-01

    Nucleus accumbens (NAc) plays an essential role in morphine sensitization and suppression of pain. Repeated exposure to stress and morphine increases dopamine release in the NAc and may lead to morphine sensitization. This study was carried out in order to investigate the effect of forced swim stress (FSS), as a predominantly physical stressor and morphine on the development of morphine sensitization; focusing on the function of D1/D2-like dopamine receptors in the NAc in morphine sensitization. Eighty-five adult male Wistar rats were bilaterally implanted with cannulae in the NAc and various doses of SCH-23390 (0.125, 0.25, 1 and 4μg/0.5μl/NAc) as a D1 receptor antagonist and sulpiride (0.25, 1 and 4μg/0.5μl/NAc) as a D2 receptor antagonist were microinjected into the NAc, during a sensitization period of 3days, 5min before the induction of FSS. After 10min, animals received subcutaneous morphine injection (1mg/kg). The procedure was followed by 5days free of antagonist, morphine and stress; thereafter on the 9th day, the nociceptive response was evaluated by tail-flick test. The results revealed that the microinjection of sulpiride (at 1 and 4μg/0.5μl/NAc) or SCH-23390 (at 0.25, 1 and 4μg/0.5μl/NAc) prior to FSS and morphine disrupts the antinociceptive effects of morphine and morphine sensitization. Our findings suggest that FSS can potentiate the effect of morphine and causes morphine sensitization which induces antinociception. PMID:27235796

  9. Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.

    PubMed

    Winters, Bradley D; Krüger, Juliane M; Huang, Xiaojie; Gallaher, Zachary R; Ishikawa, Masago; Czaja, Krzysztof; Krueger, James M; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan

    2012-10-01

    Endocannabinoid signaling critically regulates emotional and motivational states via activation of cannabinoid receptor 1 (CB1) in the brain. The nucleus accumbens (NAc) functions to gate emotional and motivational responses. Although expression of CB1 in the NAc is low, manipulation of CB1 signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders, and these effects cannot be exclusively attributed to CB1 located at afferents to the NAc. Rather, CB1-expressing neurons in the NAc, although sparse, appear to be critical for emotional and motivational responses. However, the cellular properties of these neurons remain largely unknown. Here, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein td-Tomato (tdT). Using these mice, we demonstrated that tdT-positive neurons within the NAc were exclusively fast-spiking interneurons (FSIs). These FSIs were electrically coupled with each other, and thus may help synchronize populations/ensembles of NAc neurons. CB1-expressing FSIs also form GABAergic synapses on adjacent medium spiny neurons (MSNs), providing feed-forward inhibition of NAc output. Furthermore, the membrane excitability of tdT-positive FSIs in the NAc was up-regulated after withdrawal from cocaine exposure, an effect that might increase FSI-to-MSN inhibition. Taken together with our previous findings that the membrane excitability of NAc MSNs is decreased during cocaine withdrawal, the present findings suggest that the basal functional output of the NAc is inhibited during cocaine withdrawal by multiple mechanisms. As such, CB1-expressing FSIs are targeted by cocaine exposure to influence the overall functional output of the NAc. PMID:23012412

  10. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    ERIC Educational Resources Information Center

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  11. Cloning and characterization of a novel NAC family gene CarNAC1 from chickpea (Cicer arietinum L.).

    PubMed

    Peng, Hui; Yu, Xingwang; Cheng, Huiying; Shi, Qinghua; Zhang, Hua; Li, Jiangui; Ma, Hao

    2010-01-01

    The plant-specific NAC (for NAM, ATAF1,2 and CUC2) proteins have been found to play important roles in plant development and stress responses. In this study, a NAC gene CarNAC1 (for Cicer arietinum L. NAC gene 1) was isolated from a cDNA library constructed with chickpea seedling leaves treated by polyethylene glycol. CarNAC1 encoded a putative protein with 239 amino acids and contained 3 exons and 2 introns within genomic DNA sequence. CarNAC1 had a conserved NAC domain in the N-terminus and the CarNAC1:GFP (green fluorescent protein) fusion protein was localized in the nucleus of onion epidermal cells. Additionally, CarNAC1 exhibited the trans-activation activity which was mapped to the C-terminus. The CarNAC1 transcript was detected in many chickpea organs including seedling leaves, stems, roots, flowers, and young pods, but less accumulated in young seeds. CarNAC1 was induced by leaf age and showed changes in expression during seed development and germination. Furthermore, the expression of CarNAC1 was strongly induced by drought, salt, cold, wounding, H(2)O(2), ethephon, salicylic acid, indole-3-acetic acid, and gibberellin. Our results suggest that CarNAC1 encodes a novel NAC-domain protein and may be a transcriptional activator involved in plant development and various stress responses. PMID:19669952

  12. Differential Dopamine Regulation of Ca2+ Signaling and Its Timing Dependence in the Nucleus Accumbens

    PubMed Central

    Swapna, Immani; Bondy, Brian; Morikawa, Hitoshi

    2016-01-01

    SUMMARY Dopamine action in the nucleus accumbens (NAc) is thought to drive appetitive behavior and Pavlovian reward learning. However, it remains controversial how dopamine achieves these behavioral effects by regulating medium spiny projection neurons (MSNs) of the NAc, especially on a behaviorally relevant timescale. Metabotropic glutamate receptor (mGluR)-induced Ca2+ signaling dependent on the Ca2+- releasing messenger inositol 1,4,5-triphosphate (IP3) plays a critical role in controlling neuronal excitability and synaptic plasticity. Here, we show that transient dopamine application facilitates mGluR/IP3-induced Ca2+ signals within a time window of ~2–10 s in a subpopulation of MSNs in the NAc core. Dopamine facilitation of IP3-induced Ca2+ signaling is mediated by D1 dopamine receptors. In dopamine-insensitive MSNs, activation of A2A adenosine receptors causes enhancement of IP3-evoked Ca2+ signals, which is reversed by D2 dopamine receptor activation. These results show that dopamine differentially regulates Ca2+ signaling on the order of seconds in two distinct MSN subpopulations. PMID:27068462

  13. Nucleus accumbens GLP-1 receptors influence meal size and palatability.

    PubMed

    Dossat, Amanda M; Diaz, Ryan; Gallo, Lindsay; Panagos, Alyssa; Kay, Kristen; Williams, Diana L

    2013-06-15

    Recent evidence suggests that the glucagon-like peptide-1 (GLP-1) neuronal projection to the nucleus accumbens core (NAcC) contributes to food intake control. To investigate the role of endogenous stimulation of GLP-1 receptors (GLP-1R) in NAcC, we examined the effects of the GLP-1R antagonist exendin-(9-39) (Ex9) on meal pattern and microstructure of ingestive behavior in rats. Intra-NAcC Ex9 treatment selectively increased meal size relative to vehicle in rats consuming 0.25 M sucrose solution or sweetened condensed milk. Microstructural analysis revealed effects of NAcC Ex9 on initial lick rate and the size and duration of licking bursts in rats consuming 0.1 or 0.25 M sucrose, suggesting that blockade of NAcC GLP-1R increases palatability. Because NAcC Ex9 did not affect licking for nonnutritive saccharin (0.1%), we suggest that the presence of nutrients in the gut may be required for endogenous stimulation of NAcC GLP-1R. Consistent with this, we also found that the meal size-suppressive effects of intragastric nutrient infusion were attenuated by NAcC delivery of Ex9 at a dose that had no effect when delivered alone. Analysis of licking patterns revealed that NAcC Ex9 did not reverse intragastric nutrient-induced suppression of burst number but rather blunted the effect of nutrient infusion on meal size primarily by increasing the size and duration of licking bursts. Together, our results suggest that NAcC Ex9 influences taste evaluation. We conclude that GLP-1 released in NAcC in response to gastrointestinal nutrients reduces the hedonic value of food. PMID:23612998

  14. Nucleus accumbens GLP-1 receptors influence meal size and palatability

    PubMed Central

    Dossat, Amanda M.; Diaz, Ryan; Gallo, Lindsay; Panagos, Alyssa; Kay, Kristen

    2013-01-01

    Recent evidence suggests that the glucagon-like peptide-1 (GLP-1) neuronal projection to the nucleus accumbens core (NAcC) contributes to food intake control. To investigate the role of endogenous stimulation of GLP-1 receptors (GLP-1R) in NAcC, we examined the effects of the GLP-1R antagonist exendin-(9–39) (Ex9) on meal pattern and microstructure of ingestive behavior in rats. Intra-NAcC Ex9 treatment selectively increased meal size relative to vehicle in rats consuming 0.25 M sucrose solution or sweetened condensed milk. Microstructural analysis revealed effects of NAcC Ex9 on initial lick rate and the size and duration of licking bursts in rats consuming 0.1 or 0.25 M sucrose, suggesting that blockade of NAcC GLP-1R increases palatability. Because NAcC Ex9 did not affect licking for nonnutritive saccharin (0.1%), we suggest that the presence of nutrients in the gut may be required for endogenous stimulation of NAcC GLP-1R. Consistent with this, we also found that the meal size-suppressive effects of intragastric nutrient infusion were attenuated by NAcC delivery of Ex9 at a dose that had no effect when delivered alone. Analysis of licking patterns revealed that NAcC Ex9 did not reverse intragastric nutrient-induced suppression of burst number but rather blunted the effect of nutrient infusion on meal size primarily by increasing the size and duration of licking bursts. Together, our results suggest that NAcC Ex9 influences taste evaluation. We conclude that GLP-1 released in NAcC in response to gastrointestinal nutrients reduces the hedonic value of food. PMID:23612998

  15. Play.

    ERIC Educational Resources Information Center

    Rogers, Fred; Sharapan, Hedda

    1993-01-01

    Contends that, in childhood, work and play seem to come together. Says that for young children their play is their work, and the more adults encourage children to play, the more they emphasize important lifelong resource. Examines some uses of children's play, making and building, artwork, dramatic play, monsters and superheroes, gun play, and…

  16. The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain

    PubMed Central

    Ren, Wenjie; Centeno, Maria Virginia; Berger, Sara; Wu, Ying; Na, Xiaodong; Liu, Xianguo; Kondapalli, Jyothisri; Apkarian, A Vania; Martina, Marco; Surmeier, D James

    2016-01-01

    We examined adaptations in nucleus accumbens (NAc) neurons in mouse and rat peripheral nerve injury models of neuropathic pain. Injury selectively increased excitability of NAc shell indirect pathway spiny projection neurons (iSPNs) and altered their synaptic connectivity. Moreover, injury-induced tactile allodynia was reversed by inhibiting and exacerbated by exciting iSPNs, indicating that they not only participated in the central representation of pain, but gated activity in ascending nociceptive pathways. PMID:26691834

  17. Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward.

    PubMed

    Al-Hasani, Ream; McCall, Jordan G; Shin, Gunchul; Gomez, Adrian M; Schmitz, Gavin P; Bernardi, Julio M; Pyo, Chang-O; Park, Sung Il; Marcinkiewcz, Catherine M; Crowley, Nicole A; Krashes, Michael J; Lowell, Bradford B; Kash, Thomas L; Rogers, John A; Bruchas, Michael R

    2015-09-01

    The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease. PMID:26335648

  18. Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward

    PubMed Central

    Al-Hasani, Ream; McCall, Jordan G.; Shin, Gunchul; Gomez, Adrian M.; Schmitz, Gavin P.; Bernardi, Julio M.; Pyo, Chang-O.; Park, Sung Il; Marcinkiewcz, Catherine M.; Crowley, Nicole A.; Krashes, Michael J.; Lowell, Bradford B.; Kash, Thomas L.; Rogers, John A.; Bruchas, Michael R.

    2015-01-01

    SUMMARY The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and were positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease. PMID:26335648

  19. GSK-3β inhibitors reverse cocaine-induced synaptic transmission dysfunction in the nucleus accumbens.

    PubMed

    Zhao, Rui; Chen, Jiaojiao; Ren, Zhaoxiang; Shen, Hui; Zhen, Xuechu

    2016-11-01

    Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats. By employing single-unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine-inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N-methyl-D-aspartic acid receptor (NMDAR)-mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor-mediate excitatory postsynaptic current (EPSC) were mimicked by the D1 -like receptor agonist SKF 38393 and blocked by the D1 -like receptor antagonist SCH 23390, whereas D2 -like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor-mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D1 -like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D1 receptor-GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine-induced hyperlocomotion. PMID:27377051

  20. Decreased Caffeine-Induced Locomotor Activity via Microinjection of CART Peptide into the Nucleus Accumbens Is Linked to Inhibition of the pCaMKIIa-D3R Interaction.

    PubMed

    Fu, Qiang; Zhou, Xiaoyan; Dong, Yun; Huang, Yonghong; Yang, Jianhua; Oh, Ki-Wan; Hu, Zhenzhen

    2016-01-01

    The purpose of this study was to characterize the inhibitory modulation of cocaine- and amphetamine-regulated transcript (CART) peptides, particularly with respect to the function of the D3 dopamine receptor (D3R), which is activated by its interaction with phosphorylated CaMKIIα (pCaMKIIα) in the nucleus accumbens (NAc). After repeated oral administration of caffeine (30 mg/kg) for five days, microinjection of CART peptide (0.08 μM/0.5 μl/hemisphere) into the NAc affected locomotor behavior. The pCaMKIIα-D3R interaction, D3R phosphorylation and cAMP/PKA/phosphorylated CREB (pCREB) signaling pathway activity were measured in NAc tissues, and Ca2+ influx and pCaMKIIα levels were measured in cultured NAc neurons. We found that CART attenuated the caffeine-mediated enhancement of depolarization-induced Ca2+ influx and CaMKIIα phosphorylation in cultured NAc neurons. Repeated microinjection of CART peptides into the NAc decreased the caffeine-induced enhancement of Ca2+ channels activity, pCaMKIIα levels, the pCaMKIIα-D3R interaction, D3R phosphorylation, cAMP levels, PKA activity and pCREB levels in the NAc. Furthermore, behavioral sensitization was observed in rats that received five-day administration of caffeine following microinjection of saline but not in rats that were treated with caffeine following microinjection of CART peptide. These results suggest that caffeine-induced CREB phosphorylation in the NAc was ameliorated by CART peptide due to its inhibition of D3R phosphorylation. These effects of CART peptides may play a compensatory role by inhibiting locomotor behavior in rats. PMID:27404570

  1. Decreased Caffeine-Induced Locomotor Activity via Microinjection of CART Peptide into the Nucleus Accumbens Is Linked to Inhibition of the pCaMKIIa-D3R Interaction

    PubMed Central

    Fu, Qiang; Zhou, Xiaoyan; Dong, Yun; Huang, Yonghong; Yang, Jianhua; Oh, Ki-Wan; Hu, Zhenzhen

    2016-01-01

    The purpose of this study was to characterize the inhibitory modulation of cocaine- and amphetamine-regulated transcript (CART) peptides, particularly with respect to the function of the D3 dopamine receptor (D3R), which is activated by its interaction with phosphorylated CaMKIIα (pCaMKIIα) in the nucleus accumbens (NAc). After repeated oral administration of caffeine (30 mg/kg) for five days, microinjection of CART peptide (0.08 μM/0.5 μl/hemisphere) into the NAc affected locomotor behavior. The pCaMKIIα-D3R interaction, D3R phosphorylation and cAMP/PKA/phosphorylated CREB (pCREB) signaling pathway activity were measured in NAc tissues, and Ca2+ influx and pCaMKIIα levels were measured in cultured NAc neurons. We found that CART attenuated the caffeine-mediated enhancement of depolarization-induced Ca2+ influx and CaMKIIα phosphorylation in cultured NAc neurons. Repeated microinjection of CART peptides into the NAc decreased the caffeine-induced enhancement of Ca2+ channels activity, pCaMKIIα levels, the pCaMKIIα-D3R interaction, D3R phosphorylation, cAMP levels, PKA activity and pCREB levels in the NAc. Furthermore, behavioral sensitization was observed in rats that received five-day administration of caffeine following microinjection of saline but not in rats that were treated with caffeine following microinjection of CART peptide. These results suggest that caffeine-induced CREB phosphorylation in the NAc was ameliorated by CART peptide due to its inhibition of D3R phosphorylation. These effects of CART peptides may play a compensatory role by inhibiting locomotor behavior in rats. PMID:27404570

  2. Overexpression of Shati/Nat8l, an N-acetyltransferase, in the nucleus accumbens attenuates the response to methamphetamine via activation of group II mGluRs in mice.

    PubMed

    Miyamoto, Yoshiaki; Ishikawa, Yudai; Iegaki, Noriyuki; Sumi, Kazuyuki; Fu, Kequan; Sato, Keiji; Furukawa-Hibi, Yoko; Muramatsu, Shin-Ichi; Nabeshima, Toshitaka; Uno, Kyosuke; Nitta, Atsumi

    2014-08-01

    A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment. Previously we reported that suppression of Shati/Nat8l enhanced METH-induced behavioral alterations via dopaminergic neuronal regulation. However, the physiological mechanisms of Shati/Nat8l on the dopaminergic system in the brain are unclear. In this study, we injected adeno-associated virus (AAV) vector containing Shati/Nat8l into the NAc or dorsal striatum (dS) of mice, to increase Shati/Nat8l expression. Overexpression of Shati/Nat8l in the NAc, but not in the dS, attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference in mice. Moreover, the Shati/Nat8l overexpression in the NAc attenuated the elevation of extracellular dopamine levels induced by METH in in vivo microdialysis experiments. These behavioral and neurochemical alterations due to Shati/Nat8l overexpression in the NAc were inhibited by treatment with selective group II metabotropic glutamate receptor type 2 and 3 (mGluR2/3) antagonist LY341495. In the AAV vector-injected NAc, the tissue contents of both N-acetylaspartate and N-acetylaspartylglutamate (NAAG), endogenous mGluR3 agonist, were elevated. The injection of peptidase inhibitor of NAAG or the perfusion of NAAG itself reduced the basal levels of extracellular dopamine in the NAc of naive mice. These results indicate that Shati/Nat8l in the NAc, but not in the dS, plays an important suppressive role in the behavioral responses to METH by controlling the dopaminergic system via activation of group II mGluRs. PMID:24559655

  3. AMPA/Kainate, NMDA, and Dopamine D1 Receptor Function in the Nucleus Accumbens Core: A Context-Limited Role in the Encoding and Consolidation of Instrumental Memory

    ERIC Educational Resources Information Center

    Hernandez, Pepe J.; Andrzejewski, Matthew E.; Sadeghian, Kenneth; Panksepp, Jules B.; Kelley, Ann E.

    2005-01-01

    Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of…

  4. Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation.

    PubMed

    Moradi, Marzieh; Yazdanian, Mohamadreza; Haghparast, Abbas

    2015-10-01

    Several lines of evidence have shown that stimulation of the lateral hypothalamus (LH) can induce antinociception. It has been indicated that hypothalamic orexinergic neurons send projections throughout the dopamine mesolimbic pathway. Functional interaction between the LH and the main area of the mesolimbic pathway such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc) implicates in pain modulation. Thus, in this study, we investigated the role of D2-like dopamine receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats weighing 230-280 g were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA (0.25, 1 and 4 μg/0.3 μl DMSO) and intra-accumbal (0.125, 0.25, 1 and 4 μg/0.5 μl DMSO) infusions of sulpiride as a selective D2-like receptor antagonist, prior to intra-LH carbachol (125 nM/rat) administration. In the tail-flick test, the antinociceptive effects were measured using a tail-flick algesiometer and represented as maximal possible effect (%MPE) within 5, 15, 30, 45 and 60 min after injections. Our results showed that intra-VTA and intra-accumbal sulpiride dose-dependently attenuated the LH stimulation-induced antinociception. However, the blockade of D2-like receptors within the NAc was more significant than that of the VTA. These findings show that D2-like dopamine receptors in these regions play an important role in the LH-mediated modulation of nociceptive information in the acute model of pain in the rats. It seems that this pain modulating system is more relevant to D2-like receptors in the nucleus accumbens. PMID:26166189

  5. Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor AIP induced antinociception in rats with mononeuropathy.

    PubMed

    Bian, Hui; Yu, Long-Chuan

    2015-07-10

    Calcium/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine- dependent protein kinase, which has been implicated in pain modulation at different levels of the central nervous system. The present study was performed in rats with mononeuropathy induced by left common sciatic nerve ligation. Unilateral sciatic nerve loose ligation produced decreases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation. Intra-nucleus accumbens (NAc) injection of 3 μg, 6 μg and 12 μg of myristoylated autocamtide-2-inhibitory peptide (AIP), the CaMKII inhibitor, dose-dependently increased the HWL to noxious thermal and mechanical stimulation in rats with mononeuropathy. Furthermore, intra-NAc administration of morphine, the HWL to noxious thermal and mechanical stimulation increased markedly, and there were no significant differences between morphine group and AIP group. Taken together, the results showed that intra-NAc injection of AIP induced significant antinociceptive effects in rats with mononeuropathy, indicating that CaMKII may play an important role in the transmission and/or modulation of nociceptive information in the NAc in rats with mononeuropathy. PMID:26022629

  6. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

    PubMed

    Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J; Bowles, Dawn E; Meyer, Rebecca C; Hall, Randy A; Ko, Daijin; Paladini, Carlos A; Weinshenker, David

    2016-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs. PMID:25123018

  7. The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine

    PubMed Central

    Kupchik, Yonatan M.; Moussawi, Khaled; Tang, Xing-Chun; Wang, Xiusong; Kalivas, Benjamin C.; Kolokithas, Rosalia; Ogburn, Katelyn B.; Kalivas, Peter W.

    2011-01-01

    Background Relapse to cocaine-seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine-seeking and depotentiate PFC-NAcore synapses. Here we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors (mGluRs) mGluR2/3 and mGluR5. Methods Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, prior to inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures. Results NAC microinjection into the NAcore inhibited the reinstatement of cocaine-seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in a mGluR2/3-dependent manner, while high doses of NAC increased amplitude in a mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine-seeking by NAC was potentiated. Conclusions The effect of NAC on relapse to cocaine-seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5. PMID:22137594

  8. The Miscanthus NAC transcription factor MlNAC9 enhances abiotic stress tolerance in transgenic Arabidopsis.

    PubMed

    Zhao, Xun; Yang, Xuanwen; Pei, Shengqiang; He, Guo; Wang, Xiaoyu; Tang, Qi; Jia, Chunlin; Lu, Ying; Hu, Ruibo; Zhou, Gongke

    2016-07-15

    NAC (NAM, ATAF1/2, and CUC2) transcription factors are known to play important roles in responses to abiotic stresses in plants. Currently, little information regarding the functional roles of NAC genes in stress tolerance is available in Miscanthus lutarioriparius, a promising bioenergy plant for cellulosic ethanol production. In this study, we carried out the functional characterization of MlNAC9 in abiotic stresses. MlNAC9 was shown to act as a nuclear localized transcription activator with the activation domain in its C-terminus. The overexpression of MlNAC9 in Arabidopsis conferred hypersensitivity to abscisic acid (ABA) at seed germination and root elongation stages. In addition, the overexpression of MlNAC9 led to increased seed germination rate and root growth under salt (NaCl) treatment. Meanwhile, the transgenic Arabidopsis overexpressing MlNAC9 showed enhanced tolerance to drought and cold stresses. The expression of stress-responsive marker genes was significantly increased in MlNAC9 overexpression lines compared to that of WT under ABA, drought, salt, and cold stresses. Correspondingly, the activities of antioxidant enzymes superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were significantly increased and the malondialdehyde (MDA) content was lower accumulated in MlNAC9 overexpression lines under drought and salt treatments. These results indicated that the overexpression of MlNAC9 improved the tolerance to abiotic stresses via an ABA-dependent pathway, and the enhanced tolerance of transgenic plants was mainly attributed to the increased expression of stress-responsive genes and the enhanced scavenging capability of reactive oxygen species (ROS). PMID:27085481

  9. Serotonin2C receptors modulate dopamine transmission in the nucleus accumbens independently of dopamine release: behavioral, neurochemical and molecular studies with cocaine.

    PubMed

    Cathala, Adeline; Devroye, Céline; Maitre, Marlène; Piazza, Pier Vincenzo; Abrous, Djoher Nora; Revest, Jean-Michel; Spampinato, Umberto

    2015-05-01

    In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5-HT2C R) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5-HT2C R agonists on cocaine-induced responses have suggested that 5-HT2C Rs can modulate mesoaccumbens DA pathway activity independently of accumbal DA release, thereby controlling DA transmission in the nucleus accumbens (NAc). In the present study, we assessed this hypothesis by studying the influence of the 5-HT2C R agonist Ro 60-0175 on cocaine-induced behavioral, neurochemical and molecular responses. The i.p. administration of 1 mg/kg Ro 60-0175 inhibited hyperlocomotion induced by cocaine (15 mg/kg, i.p.), had no effect on cocaine-induced DA outflow in the shell, and increased it in the core subregion of the NAc. Furthermore, Ro 60-0175 inhibited the late-onset locomotion induced by the subcutaneous administration of the DA-D2 R agonist quinpirole (0.5 mg/kg), as well as cocaine-induced increase in c-Fos immunoreactivity in NAc subregions. Finally, Ro 60-0175 inhibited cocaine-induced phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine residues in the NAc core, this effect being reversed by the selective 5-HT2C R antagonist SB 242084 (0.5 mg/kg, i.p.). Altogether, these findings demonstrate that 5-HT2C Rs are capable of modulating mesoaccumbens DA pathway activity at post-synaptic level by specifically controlling DA signaling in the NAc core subregion. In keeping with the tight relationship between locomotor activity and NAc DA function, this interaction could participate in the inhibitory control of cocaine-induced locomotor activity. PMID:24661380

  10. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens.

    PubMed

    Albaugh, Daniel L; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action. PMID:27601003

  11. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens

    PubMed Central

    Albaugh, Daniel L.; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D.; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action. PMID:27601003

  12. Play

    NASA Astrophysics Data System (ADS)

    Harteveld, Casper

    Designing a game with a serious purpose involves considering the worlds of Reality and Meaning yet it is undeniably impossible to create a game without a third world, one that is specifically concerned with what makes a game a game: the play elements. This third world, the world of people like designers and artists, and disciplines as computer science and game design, I call the world of Play and this level is devoted to it. The level starts off with some of the misperceptions people have of play. Unlike some may think, we play all the time, even when we grow old—this was also very noticeable in designing the game Levee Patroller as the team exhibited very playful behavior at many occasions. From there, I go into the aspects that characterize this world. The first concerns the goal of the game. This relates to the objectives people have to achieve within the game. This is constituted by the second aspect: the gameplay. Taking actions and facing challenges is subsequently constituted by a gameworld, which concerns the third aspect. And all of it is not possible without the fourth and final aspect, the type of technology that creates and facilitates the game. The four aspects together make up a “game concept” and from this world such a concept can be judged on the basis of three closely interrelated criteria: engagement, immersion, and fun.

  13. Synaptic and Behavioral Profile of Multiple Glutamatergic Inputs to the Nucleus Accumbens

    PubMed Central

    Britt, Jonathan P.; Benaliouad, Faiza; McDevitt, Ross A.; Stuber, Garret D.; Wise, Roy A.; Bonci, Antonello

    2013-01-01

    SUMMARY Excitatory afferents to the nucleus accumbens (NAc) are thought to facilitate reward seeking by encoding reward-associated cues. Selective activation of different glutamatergic inputs to the NAc can produce divergent physiological and behavioral responses, but mechanistic explanations for these pathway-specific effects are lacking. Here, we compared the innervation patterns and synaptic properties of ventral hippocampus, basolateral amygdala, and prefrontal cortex input to the NAc. Ventral hippocampal input was found to be uniquely localized to the medial NAc shell, where it was predominant and selectively potentiated following cocaine exposure. In vivo, bidirectional optogenetic manipulations of this pathway attenuated and enhanced cocaine-induced locomotion. Challenging the idea that any of these inputs encode motivationally-neutral information, activation of each discrete pathway reinforced instrumental behaviors. Finally, direct optical activation of medium spiny neurons proved to be capable of supporting self-stimulation, demonstrating that behavioral reinforcement is an explicit consequence of strong excitatory drive to the NAc. PMID:23177963

  14. Cocaine Exposure Reorganizes Cell-Type and Input-Specific Connectivity in the Nucleus Accumbens

    PubMed Central

    MacAskill, Andrew F.; Cassel, John M.; Carter, Adam G.

    2014-01-01

    Exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the Nucleus Accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we use whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine alters connectivity in the mouse NAc medial shell. We first determine that cocaine selectively enhances amygdala innervation of D1-MSNs relative to D2-MSNs. We then show that amygdala activity is required for cocaine-induced changes to behavior and connectivity. Finally, we establish how heightened amygdala innervation can explain the structural and functional changes induced by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell-type and input-specific connectivity in the NAc. PMID:25108911

  15. Protein complex formation and intranuclear dynamics of NAC1 in cancer cells.

    PubMed

    Nakayama, Naomi; Kato, Hiroaki; Sakashita, Gyosuke; Nariai, Yuko; Nakayama, Kentaro; Kyo, Satoru; Urano, Takeshi

    2016-09-15

    Nucleus accumbens-associated protein 1 (NAC1) is a cancer-related transcription regulator protein that is also involved in the pluripotency and differentiation of embryonic stem cells. NAC1 is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. NAC1 knock-down was previously shown to result in the apoptosis of ovarian cancer cell lines and to rescue their sensitivity to chemotherapy, suggesting that NAC1 may be a potential therapeutic target, but protein complex formation and the dynamics of intranuclear NAC1 in cancer cells remain poorly understood. In this study, analysis of HeLa cell lysates by fast protein liquid chromatography (FPLC) on a sizing column showed that the NAC1 peak corresponded to an apparent molecular mass of 300-500 kDa, which is larger than the estimated molecular mass (58 kDa) of the protein. Furthermore, live cell photobleaching analyses with green fluorescent protein (GFP)-fused NAC1 proteins revealed the intranuclear dynamics of NAC1. Collectively our results demonstrate that NAC1 forms a protein complex to function as a transcriptional regulator in cancer cells. PMID:27424155

  16. ZmNAC55, a maize stress-responsive NAC transcription factor, confers drought resistance in transgenic Arabidopsis.

    PubMed

    Mao, Hude; Yu, Lijuan; Han, Ran; Li, Zhanjie; Liu, Hui

    2016-08-01

    Abiotic stress has been shown to significantly limit the growth and productivity of crops. NAC transcription factors play essential roles in response to various abiotic stresses. However, only little information regarding stress-related NAC genes is available in maize. Here, we cloned a maize NAC transcription factor ZmNAC55 and identified its function in drought stress. Transient expression and transactivation assay demonstrated that ZmNAC55 was localized in the nucleus and had transactivation activity. Expression analysis of ZmNAC55 in maize showed that this gene was induced by drought, high salinity and cold stresses and by abscisic acid (ABA). Promoter analysis demonstrated that multiple stress-related cis-acting elements exist in promoter region of ZmNAC55. Overexpression of ZmNAC55 in Arabidopsis led to hypersensitivity to ABA at the germination stage, but enhanced drought resistence compared to wild-type seedlings. Transcriptome analysis identified a number of differentially expressed genes between 35S::ZmNAC55 transgenic and wild-type plants, and many of which are involved in stress response, including twelve qRT-PCR confirmed well-known drought-responsive genes. These results highlight the important role of ZmNAC55 in positive regulates of drought resistence, and may have potential applications in transgenic breeding of drought-tolerant crops. PMID:27085597

  17. Rapid changes in extracellular glutamate induced by natural arousing stimuli and intravenous cocaine in the nucleus accumbens shell and core

    PubMed Central

    Wakabayashi, Ken T.

    2012-01-01

    Glutamate (Glu) is a major excitatory neurotransmitter, playing a crucial role in the functioning of the nucleus accumbens (NAc), a critical area implicated in somatosensory integration and regulation of motivated behavior. In this study, high-speed amperometry with enzyme-based biosensors was used in freely moving rats to examine changes in extracellular Glu in the NAc shell and core induced by a tone, tail pinch (TP), social interaction with a male conspecific (SI), and intravenous (iv) cocaine (1 mg/kg). To establish the contribution of Glu to electrochemical signal changes, similar recordings were conducted with null (Glu0) sensors, which were exposed to the same chemical and physical environment but were insensitive to Glu. TP, SI, and cocaine, but not a tone, induced relatively large and prolonged current increases detected by both Glu and Glu0 sensors. However, current differentials revealed very rapid, much smaller, and transient increases in extracellular Glu levels, more predominantly in the NAc shell than core. In contrast to monophasic responses with natural stimuli, cocaine induced a biphasic Glu increase in the shell, with a transient peak during the injection and a slower postinjection peak. Therefore, Glu is phasically released in the NAc after exposure to natural arousing stimuli and cocaine; this release is rapid, stimulus dependent, and structure specific, suggesting its role in triggering neural and behavioral activation induced by these stimuli. This study also demonstrates the need for multiple in vitro and in vivo controls to reveal relatively small, highly phasic, and transient fluctuations in Glu levels occurring under behaviorally relevant conditions. PMID:22496525

  18. A Shift in the Role of Glutamatergic Signaling in the Nucleus Accumbens Core with the Development of an Addicted Phenotype

    PubMed Central

    Doyle, Susan E.; Ramôa, Carolina; Garber, Garrett; Newman, Joshua; Toor, Shaun; Lynch, Wendy J.

    2014-01-01

    Background While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early “non-addicted” stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug-seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a “non-addicted” or an “addicted” phenotype. Methods Following acquisition, male and female Sprague Dawley rats were given either short access (3 fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hr access (10 days; 4 trials/hr; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate AMPA/KA receptor antagonist CNQX (0.0, 0.01, 0.03, 0.1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short versus extended access self-administration. Results Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended versus short access self-administration confirming the development of an addicted phenotype in the extended access group. CNQX dose-dependently reduced motivation for cocaine in the extended access group, but was without effect in the short access group. Conclusions These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in “non-addicted” stages, becomes critical once addiction has developed. PMID:24629536

  19. Surface expression of GABAA receptors in the rat nucleus accumbens is increased in early but not late withdrawal from extended-access cocaine self-administration.

    PubMed

    Purgianto, Anthony; Loweth, Jessica A; Miao, Julia J; Milovanovic, Mike; Wolf, Marina E

    2016-07-01

    It is well established that cocaine-induced changes in glutamate receptor expression in the nucleus accumbens (NAc) play a significant role in animal models of cocaine addiction. Far less is known about cocaine-induced changes in GABA transmission, despite its importance in regulating NAc output via local interneurons and medium spiny neuron (MSN) axon collaterals (GABA 'microcircuit'). Here we investigated whether GABAA receptor surface or total expression is altered following an extended-access cocaine self-administration regimen that produces a time-dependent intensification (incubation) of cue-induced cocaine craving in association with strengthening of AMPA receptor (AMPAR) transmission onto MSN. Rats self-administered cocaine or saline (control condition) 6h/day for 10 days. NAc tissue was obtained and surface proteins biotinylated on three withdrawal days (WD) chosen to span incubation of craving and associated AMPAR plasticity: WD2, WD25 and WD48. Immunoblotting was used to measure total and surface expression of three GABAA receptor subunits (α1, α2, and α4) that are strongly expressed in the NAc. We found a transient increase in surface, but not total, expression of the α2 subunit on WD2 from cocaine self-administration, an effect that was no longer observed by WD25. The expression of α1 and α4 subunits was not altered at these withdrawal times. On WD48, when AMPAR transmission is significantly potentiated, we did not find any alteration in GABAA receptor surface or total expression. Our findings suggest that the strengthening of AMPAR-mediated glutamate transmission in the NAc is not accompanied by compensatory strengthening of GABAergic transmission through insertion of additional GABAA receptors. PMID:27060767

  20. Novel NAC Transcription Factor TaNAC67 Confers Enhanced Multi-Abiotic Stress Tolerances in Arabidopsis

    PubMed Central

    Mao, Xinguo; Chen, Shuangshuang; Li, Ang; Zhai, Chaochao; Jing, Ruilian

    2014-01-01

    Abiotic stresses are major environmental factors that affect agricultural productivity worldwide. NAC transcription factors play pivotal roles in abiotic stress signaling in plants. As a staple crop, wheat production is severely constrained by abiotic stresses whereas only a few NAC transcription factors have been characterized functionally. To promote the application of NAC genes in wheat improvement by biotechnology, a novel NAC gene designated TaNAC67 was characterized in common wheat. To determine its role, transgenic Arabidopsis overexpressing TaNAC67-GFP controlled by the CaMV-35S promoter was generated and subjected to various abiotic stresses for morphological and physiological assays. Gene expression showed that TaNAC67 was involved in response to drought, salt, cold and ABA treatments. Localization assays revealed that TaNAC67 localized in the nucleus. Morphological analysis indicated the transgenics had enhanced tolerances to drought, salt and freezing stresses, simultaneously supported by enhanced expression of multiple abiotic stress responsive genes and improved physiological traits, including strengthened cell membrane stability, retention of higher chlorophyll contents and Na+ efflux rates, improved photosynthetic potential, and enhanced water retention capability. Overexpression of TaNAC67 resulted in pronounced enhanced tolerances to drought, salt and freezing stresses, therefore it has potential for utilization in transgenic breeding to improve abiotic stress tolerance in crops. PMID:24427285

  1. Accumbens dopamine-acetylcholine balance in approach and avoidance.

    PubMed

    Hoebel, Bartley G; Avena, Nicole M; Rada, Pedro

    2007-12-01

    Understanding systems for approach and avoidance is basic for behavioral neuroscience. Research on the neural organization and functions of the dorsal striatum in movement disorders, such as Huntington's and Parkinson's Disease, can inform the study of the nucleus accumbens (NAc) in motivational disorders, such as addiction and depression. We propose opposing roles for dopamine (DA) and acetylcholine (ACh) in the NAc in the control of GABA output systems for approach and avoidance. Contrary to DA, which fosters approach, ACh release is a correlate or cause of meal satiation, conditioned taste aversion and aversive brain stimulation. ACh may also counteract excessive DA-mediated approach behavior as revealed during withdrawal from drugs of abuse or sugar when the animal enters an ACh-mediated state of anxiety and behavioral depression. This review summarizes evidence that ACh is important in the inhibition of behavior when extracellular DA is high and the generation of an anxious or depressed state when DA is relatively low. PMID:18023617

  2. Cocaine-induced dendritic remodeling occurs in both D1 and D2 dopamine receptor-expressing neurons in the nucleus accumbens.

    PubMed

    Li, Juan; Liu, Nuyun; Lu, Kangrong; Zhang, Lei; Gu, Jingjing; Guo, Fukun; An, Shengli; Zhang, Lin; Zhang, Lu

    2012-05-31

    Repeated exposure to cocaine can induce persistent alterations in the brain's reward system, including increases in the number of dendrites and spine density on medium-sized spiny neurons (MSNs) in the nucleus accumbens (NAc). The structural remodeling of dendrites and spines in the NAc is thought to play a critical role in cocaine addiction. MSNs in the NAc can be classified by expression of either D1 or D2 dopamine receptors, which are localized to the direct and indirect pathway, respectively. It is unknown whether the dendritic changes induced by repeated cocaine treatment occur in MSNs of the direct or indirect pathway. Because the traditional Golgi-Cox impregnation of neurons precludes identifying particular subpopulations of MSNs, we performed dendritic morphology analysis after biocytin-labeling and Golgi-Cox impregnation. We found that the biocytin staining MSNs showed higher dendritic spine density and higher number of dendrites than that in Golgi impregnation group. In addition, we found that the increasing spine density induced by repeated cocaine treatment in female mice was higher than that in male mice. Next we used biocytin staining and dynorphin/D2 receptor colocalization to determine which cell type(s) displayed dendritic changes after repeated cocaine treatment. We found that cocaine-induced changes in dendritic parameters occurred in MSNs of both the direct (D1-expressing) and indirect (D2-expressing) pathways. PMID:22561554

  3. The role of D-serine as co-agonist of NMDA receptors in the nucleus accumbens: relevance to cocaine addiction.

    PubMed

    D'Ascenzo, Marcello; Podda, Maria Vittoria; Grassi, Claudio

    2014-01-01

    Cocaine addiction is characterized by compulsive drug use despite adverse consequences and high rate of relapse during periods of abstinence. Increasing consensus suggests that addiction to drugs of abuse usurps learning and memory mechanisms normally related to natural rewards, ultimately producing long-lasting neuroadaptations in the mesocorticolimbic system. This system, formed in part by the ventral tegmental area and nucleus accumbens (NAc), has a central role in the development and expression of addictive behaviors. In addition to a broad spectrum of changes that affect morphology and function of NAc excitatory circuits in cocaine-treated animals, impaired N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity is a typical feature. D-serine, a D-amino acid that has been found at high levels in mammalian brain, binds with high affinity the co-agonist site of NMDAR and mediates, along with glutamate, several important processes including synaptic plasticity. Here we review recent literature focusing on cocaine-induced impairment in synaptic plasticity mechanisms in the NAc and on the fundamental role of D-serine as co-agonist of NMDAR in functional and dysfunctional synaptic plasticity within this nucleus. The emerging picture is that reduced D-serine levels play a crucial role in synaptic plasticity relevant to cocaine addiction. This finding opens new perspectives for therapeutic approaches to treat this addictive state. PMID:25076900

  4. The role of D-serine as co-agonist of NMDA receptors in the nucleus accumbens: relevance to cocaine addiction

    PubMed Central

    D’Ascenzo, Marcello; Podda, Maria Vittoria; Grassi, Claudio

    2014-01-01

    Cocaine addiction is characterized by compulsive drug use despite adverse consequences and high rate of relapse during periods of abstinence. Increasing consensus suggests that addiction to drugs of abuse usurps learning and memory mechanisms normally related to natural rewards, ultimately producing long-lasting neuroadaptations in the mesocorticolimbic system. This system, formed in part by the ventral tegmental area and nucleus accumbens (NAc), has a central role in the development and expression of addictive behaviors. In addition to a broad spectrum of changes that affect morphology and function of NAc excitatory circuits in cocaine–treated animals, impaired N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity is a typical feature. D-serine, a D-amino acid that has been found at high levels in mammalian brain, binds with high affinity the co-agonist site of NMDAR and mediates, along with glutamate, several important processes including synaptic plasticity. Here we review recent literature focusing on cocaine-induced impairment in synaptic plasticity mechanisms in the NAc and on the fundamental role of D-serine as co-agonist of NMDAR in functional and dysfunctional synaptic plasticity within this nucleus. The emerging picture is that reduced D-serine levels play a crucial role in synaptic plasticity relevant to cocaine addiction. This finding opens new perspectives for therapeutic approaches to treat this addictive state. PMID:25076900

  5. Dissociable contribution of nucleus accumbens and dorsolateral striatum to the acquisition of risk choice behavior in the rat.

    PubMed

    Yang, Jen-Hau; Liao, Ruey-Ming

    2015-12-01

    While a growing body of research has suggested that the mesocorticolimbic dopamine systems play a key role in decision making under risk, how the nucleus accumbens (NAC) is involved in the acquisition of risk choice behavior remains unclear. This study used a T-maze task to assess risk-based decision making in which the rat was required to assess the risk by choosing to enter either a small and certain reward arm or a large but uncertain reward arm of the maze. The latter option, when chosen, resulted in provision of 2, 4, or 8 sweeten pellets with a probability (p) of 0.5, 0.25, or 0.125, respectively. Thus the latter arm provided three different conditions of reward ratio, compared to the choice of former arm, which always provided 1 pellet with p=1. This risk choice task was then run with the expected value being equality between the binary choice options. The experimental rats first received an excitoneurotoxic lesion affecting either the NAC or the dorsolateral striatum (DLS) and this was followed by post-lesion behavioral examination. The sham lesion control rats acquired a stable risk choice with regard to each reward ratio over a 10-day test. The pattern of choice behavior appeared in risk-seeking when p=0.5 to obtain 2 pellets, and was risk-averse when larger reward resulted in lower p. The NAC lesion significantly disrupted the acquisition of the aforementioned risk choice behavior and apparently shifted the choice into a risk-averse style for all three reward ratios. No such effect was observed in the rats with DLS lesions. Neither the gross motor action nor the discrimination of different reward magnitudes was impaired by the lesions affecting either the NAC or DLS as assessed by an additional experiment. These findings suggest that firstly there is heterogeneity between NAC and DLS with respect to risk-based decision making, and that secondly the NAC is involved and critical to the acquisition of behavioral choice under risk, specially when the

  6. Nucleus accumbens shell, but not core, tracks motivational value of salt.

    PubMed

    Loriaux, Amy L; Roitman, Jamie D; Roitman, Mitchell F

    2011-09-01

    To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state. PMID:21697439

  7. Relief learning is dependent on NMDA receptor activation in the nucleus accumbens

    PubMed Central

    Mohammadi, Milad; Fendt, Markus

    2015-01-01

    Background and Purpose Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning. Experimental Approach The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested. Key Results Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections. Conclusion and Implication The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory. PMID:25572550

  8. Histone arginine methylation in cocaine action in the nucleus accumbens.

    PubMed

    Damez-Werno, Diane M; Sun, HaoSheng; Scobie, Kimberly N; Shao, Ningyi; Rabkin, Jaclyn; Dias, Caroline; Calipari, Erin S; Maze, Ian; Pena, Catherine J; Walker, Deena M; Cahill, Michael E; Chandra, Ramesh; Gancarz, Amy; Mouzon, Ezekiell; Landry, Joseph A; Cates, Hannah; Lobo, Mary-Kay; Dietz, David; Allis, C David; Guccione, Ernesto; Turecki, Gustavo; Defilippi, Paola; Neve, Rachael L; Hurd, Yasmin L; Shen, Li; Nestler, Eric J

    2016-08-23

    Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. PMID:27506785

  9. Identification and expression pattern of one stress-responsive NAC gene from Solanum lycopersicum.

    PubMed

    Han, Qinqin; Zhang, Junhong; Li, Hanxia; Luo, Zhidan; Ziaf, Khurram; Ouyang, Bo; Wang, Taotao; Ye, Zhibiao

    2012-02-01

    NAC (for NAM, ATAF1, 2, and CUC2) family genes have been found to play an important role in diversified developmental processes and environmental responses. A new NAC-type transcription factor SlNAC3 was primarily identified and isolated from the cDNA libraries of tomato cultivar Ailsa Craig. It contains three exons and two introns within genomic DNA sequence and encodes a polypeptide of 329 amino acids. A plant-specific and conserved NAC domain is located in the N-terminus of SlNAC3. The protein SlNAC3 is subcellularly localized in the nucleus of onion epidemical cells and it has a transcriptional activation domain in the C-terminal region which shows extremely divergent among NACs. Phylogenetic analysis showed that SlNAC3 belonged to the OsNAC3 subgroup of the NAC protein family. Tissue expression profile analysis revealed that SlNAC3 was expressed mainly in flower, fruit and root. The transcription expression of SlNAC3 was inhibited by salt, drought stress and ABA treatment. These data demonstrate that SlNAC3 might interact with environmental and endogenous stimuli and probably function when plants response to salt and drought stresses through ABA signaling pathways as a transcriptional activator. PMID:21637957

  10. TaNAC2, a NAC-type wheat transcription factor conferring enhanced multiple abiotic stress tolerances in Arabidopsis

    PubMed Central

    Mao, Xinguo; Zhang, Hongying; Qian, Xueya; Li, Ang; Zhao, Guangyao; Jing, Ruilian

    2012-01-01

    Environmental stresses such as drought, salinity, and cold are major factors that significantly limit agricultural productivity. NAC transcription factors play essential roles in response to various abiotic stresses. However, the paucity of wheat NAC members functionally characterized to date does not match the importance of this plant as a world staple crop. Here, the function of TaNAC2 was characterized in Arabidopsis thaliana. A fragment of TaNAC2 was obtained from suppression subtractive cDNA libraries of wheat treated with polyethylene glycol, and its full-length cDNA was obtained by searching a full-length wheat cDNA library. Gene expression profiles indicated that TaNAC2 was involved in response to drought, salt, cold, and abscisic acid treatment. To test its function, transgenic Arabidopsis lines overexpressing TaNAC2–GFP controlled by the cauliflower mosaic virus 35S promoter were generated. Overexpression of TaNAC2 resulted in enhanced tolerances to drought, salt, and freezing stresses in Arabidopsis, which were simultaneously demonstrated by enhanced expression of abiotic stress-response genes and several physiological indices. Therefore, TaNAC2 has potential for utilization in transgenic breeding to improve abiotic stress tolerances in crops. PMID:22330896

  11. Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing

    PubMed Central

    Nelson, AJD; Thur, KE; Marsden, CA; Cassaday, HJ

    2011-01-01

    Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to-be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0 mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0 µg/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates. PMID:21262855

  12. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression

    PubMed Central

    Bagot, Rosemary C.; Parise, Eric M.; Peña, Catherine J.; Zhang, Hong-Xing; Maze, Ian; Chaudhury, Dipesh; Persaud, Brianna; Cachope, Roger; Bolaños-Guzmán, Carlos A.; Cheer, Joseph; Deisseroth, Karl; Han, Ming-Hu; Nestler, Eric J.

    2015-01-01

    Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression. PMID:25952660

  13. Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action

    PubMed Central

    Ferguson, Deveroux; Koo, Ja Wook; Feng, Jian; Heller, Elizabeth; Rabkin, Jacqui; Heshmati, Mitra; Renthal, William; Neve, Rachael; Liu, Xiaochuan; Shao, Ningyi; Sartorelli, Vittorio; Shen, Li

    2013-01-01

    Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological conditions remains poorly understood. Here, we establish an essential role for SIRT1 and SIRT2 in regulating behavioral responses to cocaine and morphine through actions in the nucleus accumbens (NAc), a key brain reward region. We show that chronic cocaine administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor ΔFosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocaine and morphine. In contrast, the local knockdown of SIRT1 from the NAc of floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point toward novel signaling pathways involved in drug action. PMID:24107942

  14. Music and the nucleus accumbens.

    PubMed

    Mavridis, Ioannis N

    2015-03-01

    Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA. PMID:25102783

  15. O-GlcNAc inhibits interaction between Sp1 and Elf-1 transcription factors

    SciTech Connect

    Lim, Kihong; Chang, Hyo-Ihl

    2009-03-13

    The novel protein modification, O-linked N-acetylglucosamine (O-GlcNAc), plays an important role in various aspects of cell regulation. Although most of nuclear transcription regulatory factors are modified by O-GlcNAc, O-GlcNAc effects on transcription remain largely undefined yet. In this study, we show that O-GlcNAc inhibits a physical interaction between Sp1 and Elf-1 transcription factors, and negatively regulates transcription of placenta and embryonic expression oncofetal protein gene (Pem). These findings suggest that O-GlcNAc inhibits Sp1-mediated gene transcription possibly by interrupting Sp1 interaction with its cooperative factor.

  16. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens

    PubMed Central

    Gangarossa, Giuseppe; Espallergues, Julie; de Kerchove d'Exaerde, Alban; El Mestikawy, Salah; Gerfen, Charles R.; Hervé, Denis; Girault, Jean-Antoine; Valjent, Emmanuel

    2012-01-01

    The nucleus accumbens (NAc) is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs) constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP) or the Cre-recombinase (Cre) under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific extracellular signal-regulated kinase (ERK) phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist), quinpirole (a D2 receptors (D2R)-like agonist), apomorphine (a non-selective DA receptor agonist), raclopride (a D2R-like antagonist), and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study. PMID:23423476

  17. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens.

    PubMed

    Gangarossa, Giuseppe; Espallergues, Julie; de Kerchove d'Exaerde, Alban; El Mestikawy, Salah; Gerfen, Charles R; Hervé, Denis; Girault, Jean-Antoine; Valjent, Emmanuel

    2013-01-01

    The nucleus accumbens (NAc) is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs) constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP) or the Cre-recombinase (Cre) under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific extracellular signal-regulated kinase (ERK) phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist), quinpirole (a D2 receptors (D2R)-like agonist), apomorphine (a non-selective DA receptor agonist), raclopride (a D2R-like antagonist), and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study. PMID:23423476

  18. Glucocorticoid receptor mediated the propofol self-administration by dopamine D1 receptor in nucleus accumbens.

    PubMed

    Wu, Binbin; Liang, Yuyuan; Dong, Zhanglei; Chen, Zhichuan; Zhang, Gaolong; Lin, Wenxuan; Wang, Sicong; Wang, Benfu; Ge, Ren-Shan; Lian, Qingquan

    2016-07-22

    Propofol, a widely used anesthetic, can cause addictive behaviors in both human and experimental animals. In the present study, we examined the involvement of glucocorticoid receptor (GR) signaling in the molecular process by which propofol may cause addiction. The propofol self-administration model was established by a fixed ratio 1 (FR1) schedule of reinforced dosing over successive 14days in rats. On day 15, the rats were treated with dexamethasone, a GR agonist (10-100μg/kg), or RU486, a GR antagonist (10-100μg/kg) at 1h prior to the last training. The animal behaviors were recorded automatically by the computer. The expression of dopamine D1 receptor in the nucleus accumbens (NAc) was examined by Western blot and the concentrations of plasma corticosterone were measured by enzyme-linked immunosorbent assay (ELISA). To further examine the specificity of GR in the process, mineralocorticoid receptor (MR) antagonist, spironolactone, and dexamethasone plus MR agonist, aldosterone, were also tested. Administration of dexamethasone (100μg/kg) or RU486 (⩾10mg/kg) significantly attenuated the rate of propofol maintained active nose-poke responses and infusions, which were accompanied by reductions in both plasma corticosterone level and the expression of D1 receptor in the NAc. Neither spironolactone alone nor dexamethasone combined with aldosterone affected the propofol-maintaining self-administrative behavior, indicating GR, but not MR, modulates the propofol reward in rats. In addition, neither the food-maintaining sucrose responses under FR1 schedule nor the locomotor activity was affected by any doses of dexamethasone or RU486 tested. These findings provide evidence that GR signaling may play an important role in propofol reward. PMID:27126557

  19. Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

    PubMed Central

    Cacciapaglia, Fabio; Wightman, R. Mark; Carelli, Regina M.

    2015-01-01

    Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. SIGNIFICANCE STATEMENT Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have

  20. Activation of p38 signaling in the microglia in the nucleus accumbens contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

    PubMed

    Zhang, Xue-Qin; Cui, Yu; Cui, Yue; Chen, Yu; Na, Xiao-Dong; Chen, Feng-Ying; Wei, Xu-Hong; Li, Yong-Yong; Liu, Xian-Guo; Xin, Wen-Jun

    2012-02-01

    Several lines of evidence have suggested that activated glia contributes to morphine-induced reward (conditioned place preference, CPP). Compared to well-defined roles of astrocyte in morphine CPP, the role of microglia in the nucleus accumbens (NAc) remains poorly characterized. The aim of the present study was to investigate the distinct role of microglia in morphine-induced CPP. Systemic administration of morphine (7.5 mg/kg for 5 days) induced significant preference for the morphine-paired compartment in rats, which lasted for at least 6 days after cessation of morphine treatment. Immunohistochemistry results showed that activation of p38 in the NAc microglia induced by chronic morphine treatment maintained on day 11. Bilateral intra-NAc injection of minocycline, a putative microglia inhibitor, or SB203580, an inhibitor of p38, prior to morphine administration not only inhibited p38 activation in the microglia but impaired the acquisition of CPP. On the day following the acquisition of morphine CPP, a single injection of minocycline or SB203580 failed to block the expression of CPP. Notably, pretreatment with minocycline or SB203580 for 5 days following the acquisition of morphine CPP significantly suppressed the activation of p38 and attenuated the maintenance of morphine CPP. Collectively, our present study indicates that the p38 signaling in the NAc microglia may play an important role in the acquisition and maintenance but not the expression of morphine CPP, and provides new evidence that microglia might be a potential target for the therapy of morphine addiction. PMID:22004988

  1. The Spontaneously Hypertensive and Wistar Kyoto Rat Models of ADHD Exhibit Sub-Regional Differences in Dopamine Release and Uptake in the Striatum and Nucleus Accumbens

    PubMed Central

    Miller, Erin M.; Pomerleau, Francois; Huettl, Peter; Russell, Vivienne A.; Gerhardt, Greg A.; Glaser, Paul E.A.

    2012-01-01

    The most widely used animal model of attention-deficit/hyperactivity disorder (ADHD) is the spontaneously hypertensive rat (SHR/NCrl), which best represents the combined subtype (ADHD-C). Recent evidence has revealed that a progenitor strain, the Wistar Kyoto from Charles River Laboratories (WKY/NCrl), is useful as a model of the inattentive subtype (ADHD-PI) and the Wistar Kyoto from Harlan Laboratories (WKY/NHsd) and the Sprague Dawley (SD) have been suggested as controls. Dopamine (DA) dysfunction in the striatum (Str) and nucleus accumbens core (NAc) is thought to play a significant role in the pathophysiology of ADHD but data obtained with the SHR is equivocal. Using high-speed chronoamperometric recordings with carbon fiber microelectrodes, we found that the SHR/NCrl displayed decreased KCl-evoked DA release versus the WKY/NCrl model of ADHD-PI in the dorsal Str. The WKY/NCrl and the WKY/NHsd control did not differ from each other; however, the control SD released less DA than the WKY/NCrl model of ADHD-PI in the dorsal Str and less than the control WKY/NHsd in the intermediate Str. The SHR/NCrl had faster DA uptake in the ventral Str and NAc versus both control strains, while the WKY/NCrl model of ADHD-PI exhibited faster DA uptake in the NAc versus the SD control. These results suggest that increased surface expression of DA transporters may explain the more rapid uptake of DA in the Str and NAc of these rodent models of ADHD. PMID:22960443

  2. Characterization of a chickpea (Cicer arietinum L.) NAC family gene, CarNAC5, which is both developmentally- and stress-regulated.

    PubMed

    Peng, Hui; Cheng, Hui-Ying; Yu, Xin-Wang; Shi, Qing-Hua; Zhang, Hua; Li, Jian-Gui; Ma, Hao

    2009-01-01

    It has been documented that the plant-specific NAC (for NAM, ATAF1,2 and CUC2) transcription factors play an important role in plant development and stress responses. In this study, a chickpea NAC gene CarNAC5 (for Cicer arietinum L. NAC gene 5) was isolated from a cDNA library from chickpea leaves treated by polyethylene glycol (PEG). CarNAC5, as a single/low copy gene, contained three exons and two introns within genomic DNA sequence and encoded a polypeptide with 291 amino acids. CarNAC5 protein had a conserved NAC domain in the N-terminus and showed high similarity to other NACs, especially ATAF subgroup members. The CarNAC5:GFP fusion protein was localized in the nucleus of onion epidermal cells. Furthermore, CarNAC5 protein activated the reporter genes LacZ and HIS3 in yeast. The transactivation activity was mapped to the C-terminal region. The transcripts of CarNAC5 appeared in many chickpea tissues including seedling leaves, stems, roots, flowers, seeds and pods, but mostly accumulated in flowers. Meanwhile, CarNAC5 was strongly expressed during seed maturation and in embryos of the early germinating seeds. It was also significantly induced by drought, heat, wounding, salicylic acid (SA), and indole-3-acetic acid (IAA) treatments. Our results suggest that CarNAC5 encodes a novel NAC-domain protein and acts as a transcriptional activator involved in plant developmental regulation and various stress responses. PMID:19800808

  3. Extinction and Reinstatement of Phasic Dopamine Signals in the Nucleus Accumbens Core during Pavlovian Conditioning

    PubMed Central

    Sunsay, Ceyhun; Rebec, George V.

    2014-01-01

    The prediction-error model of dopamine (DA) signaling has largely been confirmed with various appetitive Pavlovian conditioning procedures and has been supported in tests of Pavlovian extinction. Studies have repeatedly shown, however, that extinction does not erase the original memory of conditioning as the prediction-error model presumes, putting the model at odds with contemporary views that treat extinction as an episode of learning rather than unlearning of conditioning. Here, we combined fast-scan cyclic voltammetry (FSCV) with appetitive Pavlovian conditioning to assess DA release directly during extinction and reinstatement. DA was monitored in the nucleus accumbens core (NAc), which plays a key role in reward processing. Following at least 4 daily sessions of 16 tone-food pairings, FSCV was performed while rats received additional tone-food pairings followed by tone alone presentations (i.e., extinction). Acquisition memory was reinstated with non-contingent presentations of reward and then tested with cue presentation. Tone-food pairings produced transient (1–3 s) DA release in response to tone. During extinction, the amplitude of the DA response decreased significantly. Following presentation of two non-contingent food pellets, subsequent tone presentation reinstated the DA signal. Our results support the prediction-error model for appetitive Pavlovian extinction but not for reinstatement. PMID:25111335

  4. δ-Opioid and Dopaminergic Processes in Accumbens Shell Modulate the Cholinergic Control of Predictive Learning and Choice

    PubMed Central

    Laurent, Vincent; Bertran-Gonzalez, Jesus; Chieng, Billy C.

    2014-01-01

    Decision-making depends on the ability to extract predictive information from the environment to guide future actions. Outcome-specific Pavlovian-instrumental transfer (PIT) provides an animal model of this process in which a stimulus predicting a particular outcome biases choice toward actions earning that outcome. Recent evidence suggests that cellular adaptations of δ-opioid receptors (DORs) on cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) are necessary for PIT. Here we found that modulation of DORs in CINs critically influences D1-receptor (D1R)-expressing projection neurons in the NAc-S to promote PIT. First, we assessed PIT-induced changes in signaling processes in dopamine D1- and D2-receptor-expressing neurons using drd2-eGFP mice, and found that PIT-related signaling was restricted to non-D2R-eGFP-expressing neurons, suggesting major involvement of D1R-neurons. Next we confirmed the role of D1Rs pharmacologically: the D1R antagonist SCH-23390, but not the D2R antagonist raclopride, infused into the NAc-S abolished PIT in rats, an effect that depended on DOR activity. Moreover, asymmetrical infusion of SCH-23390 and the DOR antagonist naltrindole into the NAc-S also abolished PIT. DOR agonists were found to sensitize the firing responses of CINs in brain slices prepared immediately after the PIT test. We confirmed the opioid-acetylcholinergic influence over D1R-neurons by selectively blocking muscarinic M4 receptors in the NAc-S, which tightly regulate the activity of D1Rs, a treatment that rescued the deficit in PIT induced by naltrindole. We describe a model of NAc-S function in which DORs modulate CINs to influence both D1R-neurons and stimulus-guided choice between goal-directed actions. PMID:24453326

  5. δ-Opioid receptors in the accumbens shell mediate the influence of both excitatory and inhibitory predictions on choice

    PubMed Central

    Laurent, Vincent; Wong, Felix L; Balleine, Bernard W

    2015-01-01

    BACKGROUND AND PURPOSE Stimuli that predict rewarding events can control choice between future actions, and this control could be mediated by δ-opioid receptors in the nucleus accumbens shell (NAc-S). Stimuli predicting the absence of important events can also guide choice, although it remains unknown whether they do so via changes in an accumbal δ-opioid receptor-related process. EXPERIMENTAL APPROACH δ-opioid receptor-eGFP mice were trained to perform two instrumental actions that delivered different food outcomes. Choice between the two actions was then tested in the presence of stimuli paired with either the delivery or the non-delivery of each of the two outcomes. Bilateral infusions of the δ-opioid receptor antagonist naltrindole into the NAc-S were used to determine the role of these receptors at the time of choice and δ-opioid receptor expression in the NAc-S used to assess functional activity. KEY RESULTS A stimulus predicting a specific outcome biased choice performance towards the action previously earning that same outcome. In contrast, a stimulus signalling the absence of that outcome biased performance away from the action that delivered that outcome towards actions associated with the absence of that outcome. Both effects were associated with increased δ-opioid receptor expression on the membrane of cholinergic interneurons within the NAc-S. Furthermore, both effects were blocked by naltrindole infused into the NAc-S. CONCLUSIONS AND IMPLICATIONS These findings suggest that δ-opioid receptors in the NAc-S were involved in the effects of predictive learning on choice between actions, whether those predictions involve the presence or absence of specific rewarding events. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24758591

  6. NMR-based metabonomic in hippocampus, nucleus accumbens and prefrontal cortex of methamphetamine-sensitized rats.

    PubMed

    Bu, Qian; Lv, Lei; Yan, Guangyan; Deng, Pengchi; Wang, Yanli; Zhou, Jiaqing; Yang, Yanzhu; Li, Yan; Cen, Xiaobo

    2013-05-01

    (1)H NMR spectroscopy was applied to investigate the changes of cerebral metabolites in brain hippocampus, nucleus accumbens (NAC) and prefrontal cortex (PFC) of the rats subjected to subcutaneous twice-daily injections of 2.5mg/kg methamphetamine (MAP) for 7 days. The results indicated that MAP exposure induced significant behavioral sensitization and altered cerebral metabolites in rats. The neurotransmitters glutamate, glutamine and GABA significantly decreased in hippocampus, NAC and PFC. Specifically, increased succinic acid semialdehyde, a metabolism product of GABA, was observed in hippocampus. Additionally, decreased serotonin was observed in both NAC and PFC, whereas decreased dopamine was only observed in NAC after repeated MAP treatment. Glutathione obviously decreased in above brain regions, whereas acetylcysteine declined in hippocampus and NAC, and taurine declined in NAC and PFC. Homocysteic acid was elevated in hippocampus and NAC by repeated MAP administration. Membrane ingredients like phosphocholine elevated in response to MAP administration in NAC and PFC. N-Acetyl-aspartate, a marker of neuronal viability, decreased in the three regions; however, myo-inositol, a glial cell marker, increased in hippocampus and PFC. Tricarboxylic acid cycle intermediate products, such as α-ketoglutarate, succinate, citrate and the methionine significantly decreased in above three brain regions after MAP administration; however, ADP decreased in hippocampus. These results indicate that repeated MAP treatment causes neurotransmitters disturbance, imbalance between oxidative stress and antioxidants, and gliosis in hippocampus, NAC and PFC. Profound metabolic changes detected across brain regions provide the first evidence of metabonomic changes in MAP-induced sensitized rats. PMID:23462569

  7. A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

    PubMed

    McCairn, Kevin W; Nagai, Yuji; Hori, Yukiko; Ninomiya, Taihei; Kikuchi, Erika; Lee, Ju-Young; Suhara, Tetsuya; Iriki, Atsushi; Minamimoto, Takafumi; Takada, Masahiko; Isoda, Masaki; Matsumoto, Masayuki

    2016-01-20

    Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT. PMID:26796690

  8. D2R DNA Transfer Into the Nucleus Accumbens Attenuates Cocaine Self-Administration in Rats

    PubMed Central

    THANOS, PANAYOTIS K.; MICHAELIDES, MICHAEL; UMEGAKI, HIROYUKI; VOLKOW, NORA D.

    2009-01-01

    Dopamine (DA) D2 receptor (D2R) agonists and antagonists can modulate self-administration behavior, conditioned place preference, and locomotor responses to cocaine. Low levels of D2R have also been observed in cocaine addicted subjects and in non human primates after chronic cocaine exposures. Prior studies had shown that D2R upregulation in the nucleus accumbens (NAc) in rodents trained to self-administer alcohol markedly attenuated alcohol preference and intake. Here we assess the effects of D2R upregulation in the NAc on cocaine intake in rats trained to self-administer cocaine. Following 2 weeks of i.v. cocaine self-administration (CSA), rats were stereotaxically treated with an adenovirus that carried the D2R gene to upregulate D2R in the NAc. D2R vector treatment resulted in a significant decrease (75%) in cocaine infusions and lever presses (70%) for cocaine. This effect lasted 6 days before cocaine consumption returned to baseline levels, which corresponds roughly to the time it takes D2R to return to baseline levels. These findings show that CSA and D2R in the NAc are negatively correlated and suggest that cocaine intake is modulated in part by D2R levels in NAc. Thus strategies aimed at increasing D2R expression in NAc may be beneficial in treating cocaine abuse and addiction. PMID:18418874

  9. Dopamine invigorates reward seeking by promoting cue-evoked excitation in the nucleus accumbens.

    PubMed

    du Hoffmann, Johann; Nicola, Saleem M

    2014-10-22

    Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior. PMID:25339748

  10. Dual Function of NAC072 in ABF3-Mediated ABA-Responsive Gene Regulation in Arabidopsis

    PubMed Central

    Li, Xiaoyun; Li, Xiaoling; Li, Meijuan; Yan, Youcheng; Liu, Xu; Li, Ling

    2016-01-01

    The NAM, ATAF1/2, and CUC2 (NAC) domain proteins play various roles in plant growth and stress responses. Arabidopsis NAC transcription factor NAC072 has been reported as a transcriptional activator in Abscisic acid (ABA)-responsive gene expression. However, the exact function of NAC072 in ABA signaling is still elusive. In this study, we present evidence for the interrelation between NAC072 and ABA-responsive element binding factor 3 (ABF3) that act as a positive regulator of ABA-responsive gene expression in Arabidopsis. The transcript of NAC072 is up-regulated by ABF3 in ABA response, and NAC072 protein interacts with ABF3. Enhanced ABA sensitivity occurs in nac072 mutant plants that overexpressed ABF3. However, overexpression of NAC072 weakened the ABA sensitivity in the abf3 mutant plants, but instead of recovering the ABA sensitivity of abf3. NAC072 and ABF3 cooperate to regulate RD29A expression, but are antagonistic when regulating RD29B expression. Therefore, NAC072 displays a dual function in ABF3-mediated ABA-responsive gene regulation. PMID:27486475

  11. Role of Nucleus Accumbens in Neuropathic Pain: Linked Multi-Scale Evidence in the Rat Transitioning to Neuropathic Pain

    PubMed Central

    Chang, Pei-Ching; Pollema-Mays, Sarah Lynn; Centeno, Maria Virginia; Procissi, Daniel; Contini, Massimos; Baria, Alex Tomas; Martina, Macro; Apkarian, Apkar Vania

    2015-01-01

    Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury, SNI). We observed inter-related changes: 1) In resting-state fMRI, functional connectivity of the NAc to dorsal striatum and cortex was reduced 28 days (but not 5 days) after SNI; 2) contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28 days after SNI; 3) In SNI (but not sham) covariance of gene expression was upregulated at 5 days and settled to a new state at 28 days; and 4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior. PMID:24607959

  12. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

    ERIC Educational Resources Information Center

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  13. Modulation of Memory Consolidation by the Basolateral Amygdala or Nucleus Accumbens Shell Requires Concurrent Dopamine Receptor Activation in Both Brain Regions

    ERIC Educational Resources Information Center

    LaLumiere, Ryan T.; Nawar, Erene M.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the…

  14. Genome-Wide Identification and Expression Analysis of the NAC Transcription Factor Family in Cassava

    PubMed Central

    Yan, Yan; Hou, Xiaowan; Zou, Meiling; Lu, Cheng; Wang, Wenquan; Peng, Ming

    2015-01-01

    NAC [no apical meristem (NAM), Arabidopsis transcription activation factor [ATAF1/2] and cup-shaped cotyledon (CUC2)] proteins is one of the largest groups of plant specific transcription factors and plays a crucial role in plant growth, development, and adaption to the environment. Currently, no information is known about the NAC family in cassava. In this study, 96 NAC genes (MeNACs) were identified from the cassava genome. Phylogenetic analysis of the NACs from cassava and Arabidopsis showed that MeNAC proteins can be clustered into 16 subgroups. Gene structure analysis found that the number of introns of MeNAC genes varied from 0 to 5, with the majority of MeNAC genes containing two introns, indicating a small gene structure diversity of cassava NAC genes. Conserved motif analysis revealed that all of the identified MeNACs had the conserved NAC domain and/or NAM domain. Global expression analysis suggested that MeNAC genes exhibited different expression profiles in different tissues between wild subspecies and cultivated varieties, indicating their involvement in the functional diversity of different accessions. Transcriptome analysis demonstrated that MeNACs had a widely transcriptional response to drought stress and that they had differential expression profiles in different accessions, implying their contribution to drought stress resistance in cassava. Finally, the expression of twelve MeNAC genes was analyzed under osmotic, salt, cold, ABA, and H2O2 treatments, indicating that cassava NACs may represent convergence points of different signaling pathways. Taken together, this work found some excellent tissue-specific and abiotic stress-responsive candidate MeNAC genes, which would provide a solid foundation for functional investigation of the NAC family, crop improvement and improved understanding of signal transduction in plants. These data bring new insight on the complexity of the transcriptional control of MeNAC genes and support the hypothesis that

  15. Molecular characterization of banana NAC transcription factors and their interactions with ethylene signalling component EIL during fruit ripening.

    PubMed

    Shan, Wei; Kuang, Jian-fei; Chen, Lei; Xie, Hui; Peng, Huan-huan; Xiao, Yun-yi; Li, Xue-ping; Chen, Wei-xin; He, Quan-guang; Chen, Jian-ye; Lu, Wang-jin

    2012-09-01

    The plant-specific NAC (NAM, ATAF1/2, and CUC2) transcription factors (TFs) play important roles in plant growth, development, and stress responses. However, the precise role of NAC TFs in relation to fruit ripening is poorly understood. In this study, six NAC genes, designated MaNAC1-MaNAC6, were isolated and characterized from banana fruit. Subcellular localization showed that MaNAC1-MaNAC5 proteins localized preferentially to the nucleus, while MaNAC6 was distributed throughout the entire cell. A transactivation assay in yeast demonstrated that MaNAC4 and MaNAC6, as well as their C-terminal regions, possessed trans-activation activity. Gene expression profiles in fruit with four different ripening characteristics, including natural, ethylene-induced, 1-methylcyclopropene (1-MCP)-delayed, and a combination of 1-MCP with ethylene treatment, revealed that the MaNAC genes were differentially expressed in peel and pulp during post-harvest ripening. MaNAC1 and MaNAC2 were apparently upregulated by ethylene in peel and pulp, consistent with the increase in ethylene production. In contrast, MaNAC3 in peel and pulp and MaNAC5 in peel were constitutively expressed, and transcripts of MaNAC4 in peel and pulp and MaNAC6 in peel decreased, while MaNAC5 or MaNAC6 in pulp increased slightly during fruit ripening. Furthermore, the MaNAC2 promoter was activated after ethylene application, further enhancing the involvement of MaNAC2 in fruit ripening. More importantly, yeast two-hybrid and bimolecular fluorescence complementation analyses confirmed that MaNAC1/2 physically interacted with a downstream component of ethylene signalling, ethylene insensitive 3 (EIN3)-like protein, termed MaEIL5, which was downregulated during ripening. Taken together, these results suggest that MaNACs such as MaNAC1/MaNAC2, may be involved in banana fruit ripening via interaction with ethylene signalling components. PMID:22888129

  16. Vitrification of NAC process residue

    SciTech Connect

    Merrill, R.A.; Whittington, K.F.; Peters, R.D.

    1995-12-31

    Vitrification tests have been performed with simulated waste compositions formulated to represent the residue which would be obtained from the treatment of low-level, nitrate wastes from Hanford and Oak Ridge by the nitrate to ammonia and ceramic (NAC) process. The tests were designed to demonstrate the feasibility of vitrifying NAC residue and to quantify the impact of the NAC process on the volume of vitrified waste. The residue from NAC treatment of low-level nitrate wastes consists primarily of oxides of aluminum and sodium. High alumina glasses were formulated to maximize the waste loading of the NAC product. Transparent glasses with up to 35 wt% alumina, and even higher contents in opaque glasses, were obtained at melting temperatures of 1,200 C to 1,400 C. A modified TCLP leach test showed the high alumina glasses to have good chemical durability, leaching significantly less than either the ARM-1 or the DWPF-EA high-level waste reference glasses. A significant increase in the final waste volume would be a major result of the NAC process on LLW vitrification. For Hanford wastes, NAC-treatment of nitrate wastes followed by vitrification of the residue will increase the final volume of vitrified waste by 50% to 90%; for Melton Valley waste from Oak Ridge, the increase in final glass volume will be 260% to 280%. The increase in volume is relative to direct vitrification of the waste in a 20 wt% Na{sub 2}O glass formulation. The increase in waste volume directly affects not only disposal costs, but also operating and/or capital costs. Larger plant size, longer operating time, and additional energy and additive costs are direct results of increases in waste volume. Such increases may be balanced by beneficial impacts on the vitrification process; however, those effects are outside the scope of this report.

  17. Vitrification of NAC process residue

    SciTech Connect

    Merrill, R.A.; Whittington, K.F.; Peters, R.D.

    1995-09-01

    Vitrification tests have been performed with simulated waste compositions formulated to represent the residue which would be obtained from the treatment of low-level, nitrate wastes from Hanford and Oak Ridge by the nitrate to ammonia and ceramic (NAC) process. The tests were designed to demonstrate the feasibility of vitrifying NAC residue and to quantify the impact of the NAC process on the volume of vitrified waste. The residue from NAC treatment of low-level nitrate wastes consists primarily of oxides of aluminum and sodium. High alumina glasses were formulated to maximize the waste loading of the NAC product. Transparent glasses with up to 35 wt% alumina, and even higher contents in opaque glasses, were obtained at melting temperatures of 1200{degrees}C to 1400{degrees}C. A modified TCLP leach test showed the high alumina glasses to have good chemical durability, leaching significantly less than either the ARM-1 or the DWPF-EA high-level waste reference glasses. A significant increase in the final waste volume would be a major result of the NAC process on LLW vitrification. For Hanford wastes, NAC-treatment of nitrate wastes followed by vitrification of the residue will increase the final volume of vitrified waste by 50% to 90%; for Melton Valley waste from Oak Ridge, the increase in final glass volume will be 260% to 280%. The increase in volume is relative to direct vitrification of the waste in a 20 wt% Na{sub 2}O glass formulation. The increase in waste volume directly affects not only disposal costs, but also operating and/or capital costs. Larger plant size, longer operating time, and additional energy and additive costs are direct results of increases in waste volume. Such increases may be balanced by beneficial impacts on the vitrification process; however, those effects are outside the scope of this report.

  18. Behavioral Flexibility Is Increased by Optogenetic Inhibition of Neurons in the Nucleus Accumbens Shell during Specific Time Segments

    ERIC Educational Resources Information Center

    Aquili, Luca; Liu, Andrew W.; Shindou, Mayumi; Shindou, Tomomi; Wickens, Jeffery R.

    2014-01-01

    Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus-reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity…

  19. NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats.

    PubMed

    De Giovanni, Laura N; Guzman, Andrea S; Virgolini, Miriam B; Cancela, Liliana M

    2016-12-15

    Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue-induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP. PMID:27506656

  20. [The role of the nucleus accumbens in psychiatric disorders].

    PubMed

    Mavridis, I

    2015-01-01

    The nucleus accumbens is the most inferior part of the striatum and is mainly connected to the limbic system. It is neurochemically and immunohistochemically divided into a shell laterally and a core medially. As a functionally central structure between amygdala, basal ganglia, mesolimbic dopaminergic regions, mediodorsal thalamus and prefrontal cortex, the nucleus accumbens appears to play a modulative role in the flow of the information from the amygdaloid complex to these regions. Dopamine is a major neurotransmitter of the nucleus accumbens and this nucleus has a modulative function to the amygdala-basal ganglia-prefrontal cortex circuit. Together with the prefrontal cortex and amygdala, nucleus accumbens consists a part of the cerebral circuit which regulates functions associated with effort. It is anatomically located in a unique way to serve emotional and behavioral components of feelings. It is considered as a neural interface between motivation and action, having a key-role in food intake, sexual behavior, reward-motivated behavior, stress-related behavior and substance-dependence. It is involved in several cognitive, emotional and psychomotor functions, altered in some psychopathology. Moreover it is involved in some of the commonest and most severe psychiatric disorders, such as depression, schizophrenia, obsessive-compulsive disorder and other anxiety disorders, as well as in addiction, including drugs abuse, alcoholism and smoking. Nucleus accumbens has also a role in other psychiatric disorders such as bipolar disorder, attention deficit/ hyperactivity disorder and post-traumatic stress disorder. Because of its rich dopaminergic projections, this nucleus has been subject of many studies in animals as well as in humans, connecting its malfunction with the disturbed reward process observed in depression. Neuromodulation interventions targeting the nucleus accumbens are nowadays applied in strictly selected patients suffering from treatment

  1. Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal-Accumbens Plasticity After Stress.

    PubMed

    Segev, Amir; Akirav, Irit

    2016-03-01

    Acute stress results in release of glucocorticoids, which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors have a key role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Growing attention has been focused on nucleus accumbens (NAc) plasticity, which regulates mood and motivation. The NAc integrates affective and context-dependent input from the BLA and ventral subiculum (vSub), respectively. As our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity. Bilateral, ipsilateral, and contralateral BLA administration of RU or WIN reversed the stress-induced impairment in vSub-NAc long-term potentiation (LTP) and the decrease in cAMP response element-binding protein (CREB) activity in the NAc. BLA CB1 receptors were found to mediate the preventing effects of WIN on plasticity, but not the preventing effects of RU, after stress. Inactivating the ipsilateral BLA, but not the contralateral BLA, impaired LTP. The possible mechanisms underlying the effects of BLA on NAc plasticity are discussed; the data suggest that BLA-induced changes in the NAc may be mediated through neural pathways in the brain's stress circuit rather than peripheral pathways. The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may have a central role in the treatment of a variety of stress-related disorders. PMID:26289146

  2. Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens

    PubMed Central

    Zhao, Changjiu; Eisinger, Brian Earl; Driessen, Terri M.; Gammie, Stephen C.

    2014-01-01

    Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. PMID:25414651

  3. Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection.

    PubMed

    Neumann, Peter A; Wang, Yicun; Yan, Yijin; Wang, Yao; Ishikawa, Masago; Cui, Ranji; Huang, Yanhua H; Sesack, Susan R; Schlüter, Oliver M; Dong, Yan

    2016-08-01

    Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine self-administration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short- and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal. PMID:27074816

  4. NAC Transcription Factors in Senescence: From Molecular Structure to Function in Crops

    PubMed Central

    Podzimska-Sroka, Dagmara; O’Shea, Charlotte; Gregersen, Per L.; Skriver, Karen

    2015-01-01

    Within the last decade, NAC transcription factors have been shown to play essential roles in senescence, which is the focus of this review. Transcriptome analyses associate approximately one third of Arabidopsis NAC genes and many crop NAC genes with senescence, thereby implicating NAC genes as important regulators of the senescence process. The consensus DNA binding site of the NAC domain is used to predict NAC target genes, and protein interaction sites can be predicted for the intrinsically disordered transcription regulatory domains of NAC proteins. The molecular characteristics of these domains determine the interactions in gene regulatory networks. Emerging local NAC-centered gene regulatory networks reveal complex molecular mechanisms of stress- and hormone-regulated senescence and basic physiological steps of the senescence process. For example, through molecular interactions involving the hormone abscisic acid, ArabidopsisNAP promotes chlorophyll degradation, a hallmark of senescence. Furthermore, studies of the functional rice ortholog, OsNAP, suggest that NAC genes can be targeted to obtain specific changes in lifespan control and nutrient remobilization in crop plants. This is also exemplified by the wheat NAM1 genes which promote senescence and increase grain zinc, iron, and protein content. Thus, NAC genes are promising targets for fine-tuning senescence for increased yield and quality. PMID:27135336

  5. The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.

    PubMed

    Scofield, M D; Heinsbroek, J A; Gipson, C D; Kupchik, Y M; Spencer, S; Smith, A C W; Roberts-Wolfe, D; Kalivas, P W

    2016-07-01

    The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances. PMID:27363441

  6. Alcohol-seeking behavior is associated with increased glutamate transmission in basolateral amygdala and nucleus accumbens as measured by glutamate-oxidase coated biosensors

    PubMed Central

    Gass, Justin T.; Sinclair, Courtney M.; Cleva, Richard M.; Widholm, John J.; Olive, M. Foster

    2010-01-01

    Relapse is one of the most problematic aspects in the treatment of alcoholism and is often triggered by alcohol-associated environmental cues. Evidence indicates that glutamate neurotransmission plays a critical role in cue-induced relapse-like behavior, as inhibition of glutamate neurotransmission can prevent reinstatement of alcohol-seeking behavior. However, few studies have examined specific changes in extracellular glutamate levels in discrete brain regions produced by exposure to alcohol-associated cues. The purpose of this study was to use glutamate oxidase (GluOx)-coated biosensors to monitor changes in extracellular glutamate in specific brain regions during cue-induced reinstatement of alcohol-seeking behavior. Male Wistar rats were implanted with indwelling jugular vein catheters and intracerebral guide cannula aimed at the basolateral amygdala (BLA) or nucleus accumbens (NAc) core, and then trained to self-administer alcohol intravenously. A separate group of animals was trained to self-administer food pellets. Each reinforcer was accompanied by the presentation of a light/tone stimulus. Following stabilization of responding for alcohol or food reinforcement and subsequent extinction training, animals were implanted with precalibrated biosensors and then underwent a 1 hr cue-induced reinstatement testing period. As determined by GluOx-coated biosensors, extracellular levels of glutamate were increased in the BLA and NAc core during cue-induced reinstatement of alcohol-seeking behavior. The cumulative change in extracellular glutamate in both regions was significantly greater for cue-induced reinstatement of alcohol-seeking behavior versus that of food-seeking behavior. These results indicate that increases in glutamate transmission in the BLA and NAc core may be a neurochemical substrate of cue-evoked alcohol-seeking behavior. PMID:21054692

  7. Role of orexin-2 receptors in the nucleus accumbens in antinociception induced by carbachol stimulation of the lateral hypothalamus in formalin test.

    PubMed

    Yazdi, Fatemeh; Jahangirvand, Mahboubeh; Ezzatpanah, Somayeh; Haghparast, Abbas

    2016-08-01

    Orexins, which are mainly produced by orexin-expressing neurons in the lateral hypothalamus (LH), play an important role in pain modulation. Previously, it has been established that the nucleus accumbens (NAc) is involved in the modulation of formalin-induced nociceptive responses, a model of tonic pain. In this study, the role of intra-accumbal orexin-2 receptors (OX2rs) in the mediation of formalin-induced pain was investigated. A volume of 0.5 μl of 10, 20, and 40 nmol/l solutions of TCS OX2 29, an OX2r antagonist, were unilaterally microinjected into the NAc 5 min before an intra-LH carbachol microinjection (0.5 μl of 250 nmol/l solution). After 5 min, animals received a subcutaneous injection of formalin 2.5% (50 μl) into the hind paw. Pain-related behaviors were assessed at 5 min intervals during a 60-min test period. The findings showed that TCS OX2 29 administration dose dependently blocked carbachol-induced antinociception during both phases of formalin-induced pain. The antianalgesic effect of TCS OX2 29 was greater during the late phase compared with the early phase. These observations suggest that the NAc, as a part of a descending pain-modulatory circuitry, partially mediates LH-induced analgesia in the formalin test through recruitment of OX2rs. This makes the orexinergic system a good potential therapeutic target in the control of persistent inflammatory pain. PMID:26871404

  8. Appetitive changes during salt deprivation are paralleled by widespread neuronal adaptations in nucleus accumbens, lateral hypothalamus, and central amygdala.

    PubMed

    Tandon, Shashank; Simon, Sidney A; Nicolelis, Miguel A L

    2012-08-01

    Salt appetite is a goal-directed behavior in which salt-deprived animals ingest high salt concentrations that they otherwise find aversive. Because forebrain areas such as the lateral hypothalamus (LH), central amygdala (CeA), and nucleus accumbens (NAc) are known to play an important role in this behavior, we recorded from these areas while water-deprived (WD) and salt-deprived (SD) rats performed a two-bottle choice test between 0.5 M salt (NaCl) and 0.4 M sucrose. In the SD state, the preference ratio for high molar salt markedly increased. Electrophysiological recordings analyzed with respect to the onset of licking clusters revealed the presence of both excitatory and inhibitory neuronal responses during salt and/or sucrose consumption. In the NAc, putative medium spiny neurons and tonically active neurons exhibited excitatory and inhibitory responses. In all areas, compared with those recorded during the WD state, neurons recorded during the SD state showed an increase in the percentage of salt-evoked excitatory responses and a decrease in the percentage of sucrose-evoked inhibitory responses, suggesting that a subset of the neuronal population in these areas codes for the increased motivational and/or hedonic value of the salt solution. In addition, in the SD state, the firing of excitatory neurons in LH and CeA became more synchronized, indicating a greater functional connectivity between salt-responsive neurons in these areas. We propose that plastic changes in the feeding-related neuronal populations of these forebrain areas arise when changes in metabolic state alter the hedonic and motivational value of a particular taste stimulus. PMID:22572944

  9. Accumbens dopamine-acetylcholine balance in approach and avoidance

    PubMed Central

    Hoebel, Bartley G.; Avena, Nicole M.; Rada, Pedro

    2008-01-01

    Summary Understanding systems for approach and avoidance is basic for behavioral neuroscience. Research on the neural organization and functions of the dorsal striatum in movement disorders, such as Huntington's and Parkinson's Disease, can inform the study of the nucleus accumbens (NAc) in motivational disorders, such as addiction and depression. We propose opposing roles for dopamine (DA) and acetylcholine (ACh) in the NAc in the control of GABA output systems for approach and avoidance. Contrary to DA, which fosters approach, ACh release is a correlate or cause of meal satiation, conditioned taste aversion and aversive brain stimulation. ACh may also counteract excessive DA-mediated approach behavior as revealed during withdrawal from drugs of abuse or sugar, when the animal enters an ACh-mediated state of anxiety and behavioral depression. This review summarizes evidence that ACh is important in the inhibition of behavior when extracellular DA is high and the generation of an anxious or depressed state when DA is relatively low. PMID:18023617

  10. Gene expression analysis of heat shock proteins in the nucleus accumbens of rats with different morphine seeking behaviours.

    PubMed

    Salas, Elisabet; Bocos, Carlos; Del Castillo, Carmen; Pérez-García, Carmen; Morales, Lidia; Alguacil, Luis F

    2011-11-20

    Heat-shock proteins play functional roles on brain regulatory processes which are deeply involved in drug addiction, such as synaptic plasticity. However, few studies have been focused on gene expression of heat-shock proteins (Hsp) as potential diagnostic tools for addiction risk. This work tries to provide new knowledge on this field by using two rat models of differential vulnerability to morphine addiction in order to study differential gene expression of a selected group of Hsp genes in the nucleus accumbens (NAc). Hsp70-1A, 84, 86 and 105 genes were similarly regulated by an acute injection of morphine in two subpopulations of Sprague Dawley (SD) rats showing different rates of extinction of morphine conditioned preference. However, Lewis and Fischer rats, two strains that differ in many aspects of drug seeking behaviours, exhibited marked differences in their expression patterns of Hsp84, 86 and 105. These results suggest that differential Hsp gene expression could be related to addiction vulnerability and recommend further work to validate these proteins as potential markers for drug addiction risk. PMID:21763353

  11. Identification of an NAC Transcription Factor Family by Deep Transcriptome Sequencing in Onion (Allium cepa L.).

    PubMed

    Zheng, Xia; Tang, Shouwei; Zhu, Siyuan; Dai, Qiuzhong; Liu, Touming

    2016-01-01

    Although onion has been used extensively in the past for cytogenetic studies, molecular analysis has been lacking because the availability of genetic resources is limited. NAM, ATAF, and CUC (NAC) transcription factors (TFs) are plant-specific proteins, and they play key roles in plant growth, development, and stress tolerance. However, none of the onion NAC (CepNAC) genes had been identified thus far. In this study, the transcriptome of onion leaves was analyzed by Illumina paired-end sequencing. Approximately 102.9 million clean sequence reads were produced and used for de novo assembly, which generated 117,189 non-redundant transcripts. Of these transcripts, 39,472 were annotated for their function. In order to mine the CepNAC TFs, CepNAC genes were searched from the transcripts assembled, resulting in the identification of all 39 CepNAC genes. These 39 CepNAC proteins were subjected to phylogenetic analysis together with 47 NAC proteins of known function that were previously identified in other species. The results showed that they can be divided into five groups (NAC-I-V). Interestingly, the NAC-IV and -V groups were found to be likely related to the processes of secondary wall synthesis and stress response, respectively. The transcriptome analysis generated a substantial amount of transcripts, which will aid immensely in identifying important genes and accelerating our understanding of onion growth and development. Moreover, the discovery of 39 CepNAC TFs and the identification of the sequence conservation between them and NAC proteins published will provide a basis for further characterization and validation of their functions in the future. PMID:27331904

  12. Identification of an NAC Transcription Factor Family by Deep Transcriptome Sequencing in Onion (Allium cepa L.)

    PubMed Central

    Zhu, Siyuan; Dai, Qiuzhong; Liu, Touming

    2016-01-01

    Although onion has been used extensively in the past for cytogenetic studies, molecular analysis has been lacking because the availability of genetic resources is limited. NAM, ATAF, and CUC (NAC) transcription factors (TFs) are plant-specific proteins, and they play key roles in plant growth, development, and stress tolerance. However, none of the onion NAC (CepNAC) genes had been identified thus far. In this study, the transcriptome of onion leaves was analyzed by Illumina paired-end sequencing. Approximately 102.9 million clean sequence reads were produced and used for de novo assembly, which generated 117,189 non-redundant transcripts. Of these transcripts, 39,472 were annotated for their function. In order to mine the CepNAC TFs, CepNAC genes were searched from the transcripts assembled, resulting in the identification of all 39 CepNAC genes. These 39 CepNAC proteins were subjected to phylogenetic analysis together with 47 NAC proteins of known function that were previously identified in other species. The results showed that they can be divided into five groups (NAC-I–V). Interestingly, the NAC-IV and -V groups were found to be likely related to the processes of secondary wall synthesis and stress response, respectively. The transcriptome analysis generated a substantial amount of transcripts, which will aid immensely in identifying important genes and accelerating our understanding of onion growth and development. Moreover, the discovery of 39 CepNAC TFs and the identification of the sequence conservation between them and NAC proteins published will provide a basis for further characterization and validation of their functions in the future. PMID:27331904

  13. Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens

    PubMed Central

    Jean, Alexandra; Conductier, Grégory; Manrique, Christine; Bouras, Constantin; Berta, Philippe; Hen, René; Charnay, Yves; Bockaert, Joël; Compan, Valérie

    2007-01-01

    Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT4R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT4R antagonist or siRNA-mediated 5-HT4R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT4R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT4R. Using 5-HT4R knockout mice, we demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT4R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT4R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy. PMID:17913892

  14. NOS1AP O-GlcNAc Modification Involved in Neuron Apoptosis Induced by Excitotoxicity.

    PubMed

    Zhu, Liang; Tao, Tao; Zhang, Dongmei; Liu, Xiaojuan; Ke, Kaifu; Shen, Aiguo

    2015-01-01

    O-Linked N-acetylglucosamine, or O-GlcNAc, is a dynamic post-translational modification that cycles on and off serine and threonine residues of nucleocytoplasmic and mitochondrial proteins. In addition to cancer and inflammation diseases, O-GlcNAc modification appears to play a critical role during cell apoptosis and stress response, although the precise mechanisms are still not very clear. Here we found that nitric oxide synthase adaptor (NOS1AP), which plays an important part in glutamate-induced neuronal apoptosis, carries the modification of O-GlcNAc. Mass spectrometry analysis identified Ser47, Ser183, Ser204, Ser269, Ser271 as O-GlcNAc sites. Higher O-GlcNAc of NOS1AP was detected during glutamate-induced neuronal apoptosis. Furthermore, with O-GlcNAc sites of NOS1AP mutated, the interaction of NOS1AP and neuronal nitric oxide syntheses (nNOS) decreases. Finally, during glutamate-induced neuronal apoptosis, decreasing the O-GlcNAc modification of NOS1AP results in more severe neuronal apoptosis. All these results suggest that O-GlcNAc modification of NOS1AP exerts protective effects during glutamate-induced neuronal apoptosis. PMID:26197318

  15. Activity of D1/2 Receptor Expressing Neurons in the Nucleus Accumbens Regulates Running, Locomotion, and Food Intake

    PubMed Central

    Zhu, Xianglong; Ottenheimer, David; DiLeone, Ralph J.

    2016-01-01

    While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The nucleus accumbens (NAc) is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure. Specific manipulation of D1 vs. D2 neurons was done in both low expenditure and high expenditure (wheel running) conditions to assess behavioral effects in these different states. Direct control of neural activity was achieved using a designer receptors exclusively activated by designer drugs (DREADD) strategy. Activation of NAc D1 neurons increased food intake, wheel running and locomotor activity. In contrast, activation of D2 neurons in the NAc reduced running and locomotion while D2 neuron inhibition had opposite effects. These results highlight the importance of considering both intake and expenditure in the analysis of D1 and D2 neuronal manipulations. Moreover, the behavioral outcomes from NAc D1 neuronal manipulations depend upon the activity state of the animals (wheel running vs. non-running). The data support and complement the hypothesis of specific NAc dopamine pathways facilitating energy expenditure and suggest a potential strategy for human weight control. PMID:27147989

  16. ¹H NMR-based metabonomics in brain nucleus accumbens and striatum following repeated cocaine treatment in rats.

    PubMed

    Li, Y; Yan, G-Y; Zhou, J-Q; Bu, Q; Deng, P-C; Yang, Y-Z; Lv, L; Deng, Y; Zhao, J-X; Shao, X; Zhu, R-M; Huang, Y-N; Zhao, Y-L; Cen, X-B

    2012-08-30

    Studies have shown a few cerebral metabolites modified by cocaine in brain regions; however, endogenous metabolic profiling has been lacking. Ex vivo (1)H NMR (hydrogen-1 nuclear magnetic resonance) spectroscopy-based metabonomic approach coupled with partial least squares was applied to investigate the changes of cerebral metabolites in nucleus accumbens (NAc) and striatum of rats subjected to cocaine treatment. Our results showed that both single and repeated cocaine treatment can induce significant changes in a couple of cerebral metabolites. The increase of neurotransmitters glutamate and gamma-amino butyric acid (GABA) were observed in NAc and striatum from the rats repeatedly treated with cocaine. Creatine and taurine increased in NAc whereas taurine increased and creatine decreased in striatum after repeated cocaine treatment. Elevation of N-acetylaspartate in NAc and striatum and decrease of lactate in striatum were observed, which may reflect the mitochondria dysregulation caused by cocaine; moreover, alterations of choline, phosphocholine and glycerol in NAc and striatum could be related to membrane disruption. Moreover, groups of rats with and without conditioned place preference (CPP) apparatus are presenting difference in metabolites. Collectively, our results provide the first evidence of metabonomic profiling of NAc and striatum in response to cocaine, exhibiting a regionally-specific alteration patterns. We find that repeated cocaine administration leads to significant metabolite alterations, which are involved in neurotransmitter disturbance, oxidative stress, mitochondria dysregulation and membrane disruption in brain. PMID:22609933

  17. Abnormal resting-state functional connectivity of the nucleus accumbens in multi-year abstinent heroin addicts.

    PubMed

    Zou, Feng; Wu, Xinhuai; Zhai, Tianye; Lei, Yu; Shao, Yongcong; Jin, Xiao; Tan, Shuwen; Wu, Bing; Wang, Lubin; Yang, Zheng

    2015-11-01

    Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross-sectional study, whole-brain resting-state functional magnetic resonance images (8 min) were collected from 30 heroin-addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting-state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse-related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin-dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long-term-abstinent heroin-dependent individuals. PMID:26280556

  18. Activity of D1/2 Receptor Expressing Neurons in the Nucleus Accumbens Regulates Running, Locomotion, and Food Intake.

    PubMed

    Zhu, Xianglong; Ottenheimer, David; DiLeone, Ralph J

    2016-01-01

    While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The nucleus accumbens (NAc) is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure. Specific manipulation of D1 vs. D2 neurons was done in both low expenditure and high expenditure (wheel running) conditions to assess behavioral effects in these different states. Direct control of neural activity was achieved using a designer receptors exclusively activated by designer drugs (DREADD) strategy. Activation of NAc D1 neurons increased food intake, wheel running and locomotor activity. In contrast, activation of D2 neurons in the NAc reduced running and locomotion while D2 neuron inhibition had opposite effects. These results highlight the importance of considering both intake and expenditure in the analysis of D1 and D2 neuronal manipulations. Moreover, the behavioral outcomes from NAc D1 neuronal manipulations depend upon the activity state of the animals (wheel running vs. non-running). The data support and complement the hypothesis of specific NAc dopamine pathways facilitating energy expenditure and suggest a potential strategy for human weight control. PMID:27147989

  19. Neuroelectric signatures of reward learning and decision-making in the human nucleus accumbens.

    PubMed

    Cohen, Michael X; Axmacher, Nikolai; Lenartz, Doris; Elger, Christian E; Sturm, Volker; Schlaepfer, Thomas E

    2009-06-01

    Learning that certain actions lead to risky rewards is critical for biological, social, and economic survival, but the precise neural mechanisms of such reward-guided learning remain unclear. Here, we show that the human nucleus accumbens plays a key role in learning about risks by representing reward value. We recorded electrophysiological activity directly from the nucleus accumbens of five patients undergoing deep brain stimulation for treatment of refractory major depression. Patients engaged in a simple reward-learning task in which they first learned stimulus-outcome associations (learning task), and then were able to choose from among the learned stimuli (choosing task). During the learning task, nucleus accumbens activity reflected potential and received reward values both during the cue stimulus and during the feedback. During the choosing task, there was no nucleus accumbens activity during the cue stimulus, but feedback-related activity was pronounced and similar to that during the learning task. This pattern of results is inconsistent with a prediction error response. Finally, analyses of cross-correlations between the accumbens and simultaneous recordings of medial frontal cortex suggest a dynamic interaction between these structures. The high spatial and temporal resolution of these recordings provides novel insights into the timing of activity in the human nucleus accumbens, its functions during reward-guided learning and decision-making, and its interactions with medial frontal cortex. PMID:19092783

  20. An investigation of interactions between hypocretin/orexin signaling and glutamate receptor surface expression in the rat nucleus accumbens under basal conditions and after cocaine exposure

    PubMed Central

    Plaza-Zabala, Ainhoa; Li, Xuan; Milovanovic, Mike; Loweth, Jessica A.; Maldonado, Rafael; Berrendero, Fernando; Wolf, Marina E.

    2013-01-01

    Hypocretin peptides are critical for the effects of cocaine on excitatory synaptic strength in the ventral tegmental area (VTA). However, little is known about their role in cocaine-induced synaptic plasticity in the nucleus accumbens (NAc). First, we tested whether hypocretin-1 by itself could acutely modulate glutamate receptor surface expression in the NAc, given that hypocretin-1 in the VTA reproduces cocaine’s effects on glutamate transmission. We found no effect of hypocretin-1 infusion on AMPA or NMDA receptor surface expression in the NAc, measured by biotinylation, either 30 min or 3 h after the infusion. Second, we were interested in whether changes in hypocretin receptor-2 (Hcrtr-2) expression contribute to cocaine-induced plasticity in the NAc. As a first step towards addressing this question, Hcrtr-2 surface expression was compared in the NAc after withdrawal from extended-access self-administration of saline (control) versus cocaine. We found that surface Hcrtr-2 levels remain unchanged following 14, 25 or 48 days of withdrawal from cocaine, a time period in which high conductance GluA2-lacking AMPA receptors progressively emerge in the NAc. Overall, our results fail to support a role for hypocretins in acute modulation of glutamate receptor levels in the NAc or a role for altered Hcrtr-2 expression in withdrawal-dependent synaptic adaptations in the NAc following cocaine self-administration. PMID:24262606

  1. Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking.

    PubMed

    Lei, Kelly; Wegner, Scott A; Yu, Ji Hwan; Mototake, Arisa; Hu, Bing; Hopf, Frederic W

    2016-01-01

    Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs) promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc) and anterior insular cortex (aINS) in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle. Inhibition of OX1Rs with the widely used SB-334867 within the medial NAc Shell (mNAsh) significantly reduced drinking of alcohol, with no effect on saccharin intake, and no effect on alcohol consumption when infused above the mNAsh. In contrast, intra-mNAsh infusion of the orexin-2 receptor TCS-OX2-29 had no impact on alcohol drinking. In addition, OX1R inhibition within the aINS had no effect on excessive drinking, which was surprising given the importance of aINS-NAc circuits in promoting alcohol consumption and the role for aINS OX1Rs in driving nicotine intake. However, OX1R inhibition within the mPFC did reduce alcohol drinking, indicating cortical OXR involvement in promoting intake. Also, in support of the critical role for mNAsh OX1Rs, SB within the mNAsh also significantly reduced operant alcohol self-administration in rats. Finally, orexin ex vivo enhanced firing in mNAsh neurons from alcohol-drinking mice, with no effect on evoked EPSCs or input resistance; a similar orexin increase in firing without a change in input resistance was observed in alcohol-naïve mice. Taken together, our results suggest that OX1Rs within the mNAsh and mPFC, but not the aINS, play a central role in

  2. Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

    PubMed Central

    Lei, Kelly; Wegner, Scott A.; Yu, Ji Hwan; Mototake, Arisa; Hu, Bing; Hopf, Frederic W.

    2016-01-01

    Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs) promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc) and anterior insular cortex (aINS) in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle. Inhibition of OX1Rs with the widely used SB-334867 within the medial NAc Shell (mNAsh) significantly reduced drinking of alcohol, with no effect on saccharin intake, and no effect on alcohol consumption when infused above the mNAsh. In contrast, intra-mNAsh infusion of the orexin-2 receptor TCS-OX2-29 had no impact on alcohol drinking. In addition, OX1R inhibition within the aINS had no effect on excessive drinking, which was surprising given the importance of aINS-NAc circuits in promoting alcohol consumption and the role for aINS OX1Rs in driving nicotine intake. However, OX1R inhibition within the mPFC did reduce alcohol drinking, indicating cortical OXR involvement in promoting intake. Also, in support of the critical role for mNAsh OX1Rs, SB within the mNAsh also significantly reduced operant alcohol self-administration in rats. Finally, orexin ex vivo enhanced firing in mNAsh neurons from alcohol-drinking mice, with no effect on evoked EPSCs or input resistance; a similar orexin increase in firing without a change in input resistance was observed in alcohol-naïve mice. Taken together, our results suggest that OX1Rs within the mNAsh and mPFC, but not the aINS, play a central role in

  3. Dynamic changes in accumbens dopamine correlate with learning during intracranial self-stimulation

    PubMed Central

    Owesson-White, Catarina A.; Cheer, Joseph F.; Beyene, Manna; Carelli, Regina M.; Wightman, R. Mark

    2008-01-01

    Dopamine in the nucleus accumbens (NAc) is an important neurotransmitter for reward-seeking behaviors such as intracranial self-stimulation (ICSS), although its precise role remains unclear. Here, dynamic fluctuations in extracellular dopamine were measured during ICSS in the rat NAc shell with fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Rats were trained to press a lever to deliver electrical stimulation to the substantia nigra (SNc)/ventral tegmental area (VTA) after the random onset of a cue that predicted reward availability. Latency to respond after cue onset significantly declined across trials, indicative of learning. Dopamine release was evoked by the stimulation but also developed across trials in a time-locked fashion to the cue. Once established, the cue-evoked dopamine transients continued to grow in amplitude, although they were variable from trial to trial. The emergence of cue-evoked dopamine correlated with a decline in electrically evoked dopamine release. Extinction of ICSS resulted in a significant decline in goal-directed behavior coupled to a significant decrease in cue-evoked phasic dopamine across trials. Subsequent reinstatement of ICSS was correlated with a return to preextinction transient amplitudes in response to the cue and reestablishment of ICSS behavior. The results show the dynamic nature of chemical signaling in the NAc during ICSS and provide new insight into the role of NAc dopamine in reward-related behaviors. PMID:18689678

  4. AUTS2 in the nucleus accumbens is essential for heroin-induced behavioral sensitization.

    PubMed

    Zhu, Yongsheng; Xing, Bo; Dang, Wei; Ji, Yuanyuan; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Lai, Jianghua

    2016-10-01

    Autism susceptibility candidate 2 (AUTS2) is a gene associated with autism and mental retardation. Recent studies have suggested an association of the AUTS2 gene with heroin dependence, and reduced AUTS2 gene expression may confer increased susceptibility to heroin dependence. However, the functional role of the AUTS2 protein in regulating enduring neuroadaptations in response to heroin exposure has not been established. Here, we investigated the effects of acute and chronic heroin exposure on AUTS2 mRNA and protein expression in the nucleus accumbens (NAc) and caudate-putamen (CPu) to determine whether changes in AUTS2 expression are associated with heroin-induced locomotor sensitization in mice. Moreover, we explored whether AUST2 knockdown affects heroin-induced locomotor sensitization. AUTS2 mRNA and protein expression in the NAc, but not the CPu, was decreased after chronic heroin (1mg/kg) administration. In the NAc, the expression of heroin-induced locomotor sensitization was enhanced through the lentiviral-AUTS2-shRNA-mediated knockdown of AUTS2, while the overexpression of AUTS2 attenuated the locomotor-stimulant effects of heroin. Together, these results indicate that AUTS2 in the NAc, but not the CPu, suppresses the initiation and expression of heroin-induced behavioral sensitization, suggesting that AUST2 may be a potential target for the treatment of heroin dependence. PMID:27423627

  5. Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration.

    PubMed

    Chong, Samuel L; Claussen, Catherine M; Dafny, Nachum

    2012-03-10

    Methylphenidate (MPD) is a psychostimulant that enhances dopaminergic neurotransmission in the central nervous system by using mechanisms similar to cocaine and amphetamine. The mode of action of brain circuitry responsible for an animal's neuronal response to MPD is not fully understood. The nucleus accumbens (NAc) has been implicated in regulating the rewarding effects of psychostimulants. The present study used permanently implanted microelectrodes to investigate the acute and chronic effects of MPD on the firing rates of NAc neuronal units in freely behaving rats. On experimental day 1 (ED1), following a saline injection (control), a 30 min baseline neuronal recording was obtained immediately followed by a 2.5 mg/kg i.p. MPD injection and subsequent 60 min neuronal recording. Daily 2.5 mg/kg MPD injections were given on ED2 through ED6 followed by 3 washout days (ED7 to ED9). On ED10, neuronal recordings were resumed from the same animal after a saline and MPD (rechallenge) injection exactly as obtained on ED1. Sixty-seven NAc neuronal units exhibited similar wave shape, form and amplitude on ED1 and ED10 and their firing rates were used for analysis. MPD administration on ED1 elicited firing rate increases and decreases in 54% of NAc units when compared to their baselines. Six consecutive MPD administrations altered the neuronal baseline firing rates of 85% of NAc units. MPD rechallenge on ED10 elicited significant changes in 63% of NAc units. These alterations in firing rates are hypothesized to be through mechanisms that include D1 and D2-like DA receptor induced cellular adaptation and homeostatic adaptations/deregulation caused by acute and chronic MPD administration. PMID:22248440

  6. κ Opioid Receptors in the Nucleus Accumbens Shell Mediate Escalation of Methamphetamine Intake

    PubMed Central

    Schlosburg, Joel E.; Wee, Sunmee; Gould, Adam; George, Olivier; Grant, Yanabel; Zamora-Martinez, Eva R.; Edwards, Scott; Crawford, Elena; Vendruscolo, Leandro F.; Koob, George F.

    2015-01-01

    Given that the κ opioid receptor (KOR) system has been implicated in psychostimulant abuse, we evaluated whether the selective KOR antagonist norbinaltorphimine dihydrochloride (nor-BNI) would attenuate the escalation of methamphetamine (METH) intake in an extended-access self-administration model. Systemic nor-BNI decreased the escalation of intake of long-access (LgA) but not short-access (ShA) self-administration. nor-BNI also decreased elevated progressive-ratio (PR) breakpoints in rats in the LgA condition and continued to decrease intake after 17 d of abstinence, demonstrating that the effects of a nor-BNI injection are long lasting. Rats with an ShA history showed an increase in prodynorphin immunoreactivity in both the nucleus accumbens (NAc) core and shell, but LgA animals showed a selective increase in the NAc shell. Other cohorts of rats received nor-BNI directly into the NAc shell or core and entered into ShA or LgA. nor-BNI infusion in the NAc shell, but not NAc core, attenuated escalation of intake and PR responding for METH in LgA rats. These data indicate that the development and/or expression of compulsive-like responding for METH under LgA conditions depends on activation of the KOR system in the NAc shell and suggest that the dynorphin–KOR system is a central component of the neuroplasticity associated with negative reinforcement systems that drive the dark side of addiction. PMID:25762676

  7. κ Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake.

    PubMed

    Whitfield, Timothy W; Schlosburg, Joel E; Wee, Sunmee; Gould, Adam; George, Olivier; Grant, Yanabel; Zamora-Martinez, Eva R; Edwards, Scott; Crawford, Elena; Vendruscolo, Leandro F; Koob, George F

    2015-03-11

    Given that the κ opioid receptor (KOR) system has been implicated in psychostimulant abuse, we evaluated whether the selective KOR antagonist norbinaltorphimine dihydrochloride (nor-BNI) would attenuate the escalation of methamphetamine (METH) intake in an extended-access self-administration model. Systemic nor-BNI decreased the escalation of intake of long-access (LgA) but not short-access (ShA) self-administration. nor-BNI also decreased elevated progressive-ratio (PR) breakpoints in rats in the LgA condition and continued to decrease intake after 17 d of abstinence, demonstrating that the effects of a nor-BNI injection are long lasting. Rats with an ShA history showed an increase in prodynorphin immunoreactivity in both the nucleus accumbens (NAc) core and shell, but LgA animals showed a selective increase in the NAc shell. Other cohorts of rats received nor-BNI directly into the NAc shell or core and entered into ShA or LgA. nor-BNI infusion in the NAc shell, but not NAc core, attenuated escalation of intake and PR responding for METH in LgA rats. These data indicate that the development and/or expression of compulsive-like responding for METH under LgA conditions depends on activation of the KOR system in the NAc shell and suggest that the dynorphin-KOR system is a central component of the neuroplasticity associated with negative reinforcement systems that drive the dark side of addiction. PMID:25762676

  8. Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues.

    PubMed

    Aitken, Tara J; Greenfield, Venuz Y; Wassum, Kate M

    2016-03-01

    Environmental reward-predictive stimuli provide a major source of motivation for instrumental reward-seeking activity and this has been linked to dopamine signaling in the nucleus accumbens (NAc) core. This cue-induced incentive motivation can be quite general, not restricted to instrumental actions that earn the same unique reward, and is also typically regulated by one's current need state, such that cues only motivate actions when this is adaptive. But it remains unknown whether cue-evoked dopamine signaling is similarly regulated by need state. Here, we used fast-scan cyclic voltammetry to monitor dopamine concentration changes in the NAc core of rats during a Pavlovian-to-instrumental transfer task in which the motivating influence of two cues, each signaling a distinct food reward (sucrose or food pellets), over an action earning a third unique food reward (polycose) was assessed in a state of hunger and of satiety. Both cues elicited a robust NAc dopamine response when hungry. The magnitude of the sucrose cue-evoked dopamine response correlated with the Pavlovian-to-instrumental transfer effect that was selectively induced by this stimulus. Satiety attenuated these cue-evoked dopamine responses and behavioral responding, even though rats had never experienced the specific food rewards in this state. These data demonstrate that cue-evoked NAc core responses are sensitive to current need state, one critical variable that determines the current adaptive utility of cue-motivated behavior. Food-predictive stimuli motivate food-seeking behavior. Here, we show that food cues evoke a robust nucleus accumbens core dopamine response when hungry that correlates with the cue's ability to invigorate general food seeking. This response is attenuated when sated, demonstrating that food cue-evoked accumbens dopamine responses are sensitive to the need state information that determines the current adaptive utility of cue-motivated action. PMID:26715366

  9. The role of the nucleus accumbens shell in the mediation of the reinforcing properties of a safety signal in free-operant avoidance: dopamine-dependent inhibitory effects of d-amphetamine.

    PubMed

    Fernando, Anushka B P; Urcelay, Gonzalo P; Mar, Adam C; Dickinson, Tony A; Robbins, Trevor W

    2014-05-01

    Safety signals (SSs) have been shown to reinforce instrumental avoidance behavior due to their ability to signal the absence of an aversive event; however, little is known of their neural mediation. This study investigated whether infusions of d-amphetamine in the nucleus accumbens (Nac), previously shown to potentiate responding for appetitive conditioned reinforcers (CRfs), also regulate avoidance responding for a SS. Rats were trained on a free-operant task in which lever-press responses avoided shock and were reinforced with an auditory SS. Rats were then cannulated in the Nac core (NacC) or shell (NacS) and infused with d-amphetamine and, in separate NacS groups, other drugs, before extinction sessions with the SS present or absent following responding. Selective effects of d-amphetamine were found in the NacS, but not in the NacC, when the SS was present in the session. A significant increase in response rate during the presentation of the SS reflected a disruption of its fear-inhibiting properties. In parallel, a decrease in avoidance response rate reflected the reduced influence of the SS as a CRf. Inactivation of the NacS reduced avoidance responding only when the SS was present in the session, whereas the D1-D2 DA receptor antagonist α-flupenthixol reduced responding both before and during the SS regardless of the presence of the SS. Atomoxetine (ATO), a selective noradrenaline reuptake inhibitor, had no effect on responding. These results indicate a role for the NacS in the mediation of the conditioned reinforcing properties of a SS. These effects appear to be modulated by dopaminergic mechanisms but seem distinct from those previously reported with food-related CRfs. PMID:24336447

  10. Nucleus accumbens stimulation in pathological obesity.

    PubMed

    Harat, Marek; Rudaś, Marcin; Zieliński, Piotr; Birska, Julita; Sokal, Paweł

    2016-01-01

    One of the potential treatment methods of obesity is deep brain stimulation (DBS) of nucleus accumbens. We describe the case of 19 years old woman with hypothalamic obesity. She weighted 151.4 kg before DBS and the non-surgical methods proved to be inefficient. She was treated with implantation of DBS electrode to nucleus accumbens bilaterally. Results were measured with body mass index and neuropsychological tests. Follow-up was 14 months. Fourteen months after surgery weight was 138 kg, BMI was 48.3. Neuropsychological test results were intact. The presented case supports the thesis of treatment of obesity with nucleus accumbens stimulation. PMID:27154450

  11. Identification of 7 stress-related NAC transcription factor members in maize (Zea mays L.) and characterization of the expression pattern of these genes.

    PubMed

    Lu, Min; Sun, Qing-Peng; Zhang, Deng-Feng; Wang, Tian-Yu; Pan, Jin-Bao

    2015-06-26

    NAC proteins are plant-specific transcription factors that play essential roles in plant development and various abiotic stress responses. A comprehensive analysis of maize NAC genes was performed in this study. A total of 157 non-redundant maize NAC genes including seven membrane-bound members were identified and found to be unevenly distributed on 10 maize chromosomes. Motif composition analysis indicated that the maize NAC proteins share three relatively conserved motifs in the NAC domain within the N-terminal region. Phylogenetic analysis of 157 maize NAC proteins accompanied by 117 NAC proteins from Arabidopsis and 151 from rice were presented. The NAC proteins evaluated were divided into two large groups including 18 subgroups. Gene duplication analysis indicated that gene loss occurred during maize evolution. Seven NAC members that belong to the same clade of maize NAC domain genes were isolated, and overlapping expression patterns were observed under various abiotic stresses, including low temperature, high salinity and dehydration, and phytohormone abscisic acid treatments. This suggested that NAC members function as stress-responsive transcription factors in ABA-dependent signaling pathways. Relatively higher expression levels of these selected maize NAC genes were detected in roots. The stress responsive NAC genes may have applications in molecular breeding to improve crop stress tolerance. PMID:25937463

  12. Interactions between brainstem noradrenergic neurons and the nucleus accumbens shell in modulating memory for emotionally arousing events

    PubMed Central

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-β-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these mnemonic effects are mediated by norepinephrine (NE) release from NTS terminals onto NAC neurons. The present studies approached this question by examining the contribution of NAC α-noradrenergic receptors in mediating this effect and assessed whether glutamatergic activation of the NTS alters NE concentrations in the NAC. Rats were trained for 6 d to drink from a water spout located at the end of an inhibitory avoidance chamber. On day 7, a 0.35-mA footshock was initiated once the rat approached the spout and remained active until it escaped into the neutral compartment. Blockade of α-noradrenergic receptors in the NAC with phentolamine (0.5 µg/0.5 µL) attenuated memory enhancement produced by glutamatergic (50 ng/0.5 µL) infusion on NTS neurons (P < 0.01). Experiment 2 used in vivo microdialysis to assess whether glutamate activation of NTS alters NAC NE concentrations. NE levels were unchanged by NTS infusion of phosphate-buffered saline (PBS) or low dose glutamate (50 ng/0.5 µL) but elevated significantly (P < 0.05) by combining the same dose with the footshock (0.35 mA, 2 sec) given in Study 1 or infusion of (100 ng/0.5 µL) glutamate alone. Findings demonstrate that NE released from NTS terminals enhances representations in memory by acting on α-noradrenergic receptors within the NAC. PMID:21602321

  13. Lesions of nucleus accumbens affect morphine-induced release of ascorbic acid and GABA but not of glutamate in rats.

    PubMed

    Sun, Ji Y; Yang, Jing Y; Wang, Fang; Wang, Jian Y; Song, Wu; Su, Guang Y; Dong, Ying X; Wu, Chun F

    2011-10-01

    Our previous studies have shown that local perfusion of morphine causes an increase of extracellular ascorbic acid (AA) levels in nucleus accumbens (NAc) of freely moving rats. Lines of evidence showed that glutamatergic and GABAergic were associated with morphine-induced effects on the neurotransmission of the brain, especially on the release of AA. In the present study, the effects of morphine on the release of extracellular AA, γ-aminobutyric acid (GABA) and glutamate (Glu) in the NAc following bilateral NAc lesions induced by kainic acid (KA) were studied by using the microdialysis technique, coupled to high performance liquid chromatography with electrochemical detection (HPLC-ECD) and fluorescent detection (HPLC-FD). The results showed that local perfusion of morphine (100 µM, 1 mM) in NAc dose-dependently increased AA and GABA release, while attenuated Glu release in the NAc. Naloxone (0.4 mM) pretreated by local perfusion to the NAc, significantly blocked the effects of morphine. After NAc lesion by KA (1 µg), morphine-induced increase in AA and GABA were markedly eliminated, while decrease in Glu was not affected. The loss effect of morphine on AA and GABA release after KA lesion could be recovered by GABA agonist, musimol. These results indicate that morphine-induced AA release may be mediated at least by µ-opioid receptor. Moreover, this effect of morphine possibly depend less on the glutamatergic afferents, but more on the GABAergic circuits within this nucleus. Finally, AA release induced by local perfusion of morphine may be GABA-receptor mediated and synaptically localized in the NAc. PMID:20731632

  14. Reduced dopamine function within the medial shell of the nucleus accumbens enhances latent inhibition

    PubMed Central

    Nelson, A.J.D.; Thur, K.E.; Horsley, R.R.; Spicer, C.; Marsden, C.A.; Cassaday, H.J.

    2011-01-01

    Latent inhibition (LI) manifests as poorer conditioning to a CS that has previously been presented without consequence. There is some evidence that LI can be potentiated by reduced mesoaccumbal dopamine (DA) function but the locus within the nucleus accumbens of this effect is as yet not firmly established. Experiment 1 tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of DA terminals within the core and medial shell subregions of the nucleus accumbens (NAc) would enhance LI under conditions that normally disrupt LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures (to a noise CS) and 2 conditioning trials. The vehicle-injected and core-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the medial shell, however, produced potentiation of LI, demonstrated across two extinction tests. In a subsequent experiment, haloperidol microinjected into the medial shell prior to conditioning similarly enhanced LI. These results underscore the dissociable roles of core and shell subregions of the NAc in mediating the expression of LI and indicate that reduced DA function within the medial shell leads to enhanced LI. PMID:21146557

  15. Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose

    PubMed Central

    Wakabayashi, Ken T.; Ren, Suelynn E.; Kiyatkin, Eugene A.

    2015-01-01

    Methylenedioxypyrovalerone (MDPV) is generally considered to be a more potent cocaine-like psychostimulant, as it shares a similar pharmacological profile with cocaine and induces similar physiological and locomotor responses. Recently, we showed that intravenous cocaine induces rapid rise in nucleus accumbens (NAc) glucose and established its relation to neural activation triggered by the peripheral drug actions. This study was conducted to find out whether MDPV, at a behaviorally equivalent dose, shares a similar pattern of NAc glucose dynamics. Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine. By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose. While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose. These results imply that cocaine-users may be more susceptible to addiction than MDPV-users due to the presence of an interoceptive signal (i.e., sensory cue), which may result in earlier and more direct reward detection. Additionally, while health complications arising from acute cocaine use are typically cardiovascular related, MDPV may be more dangerous to the brain due to uncompensated cerebral vasoconstriction. PMID:26441499

  16. Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose.

    PubMed

    Wakabayashi, Ken T; Ren, Suelynn E; Kiyatkin, Eugene A

    2015-01-01

    Methylenedioxypyrovalerone (MDPV) is generally considered to be a more potent cocaine-like psychostimulant, as it shares a similar pharmacological profile with cocaine and induces similar physiological and locomotor responses. Recently, we showed that intravenous cocaine induces rapid rise in nucleus accumbens (NAc) glucose and established its relation to neural activation triggered by the peripheral drug actions. This study was conducted to find out whether MDPV, at a behaviorally equivalent dose, shares a similar pattern of NAc glucose dynamics. Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine. By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose. While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose. These results imply that cocaine-users may be more susceptible to addiction than MDPV-users due to the presence of an interoceptive signal (i.e., sensory cue), which may result in earlier and more direct reward detection. Additionally, while health complications arising from acute cocaine use are typically cardiovascular related, MDPV may be more dangerous to the brain due to uncompensated cerebral vasoconstriction. PMID:26441499

  17. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving

    PubMed Central

    Lee, Brian R.; Ma, Yao-ying; Huang, Yanhua H.; Wang, Xiusong; Otaka, Mami; Ishikawa, Masago; Neumann, Peter A.; Graziane, Nicolas M.; Brown, Travis E.; Suska, Anna; Guo, Changyong; Lobo, Mary Kay; Sesack, Susan R.; Wolf, Marina E.; Nestler, Eric J.; Shaham, Yavin; Schlüter, Oliver M.; Dong, Yan

    2013-01-01

    In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after drug withdrawal. This ‘incubation of cocaine craving’ is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens. However, the circuit-level adaptations mediating this plasticity remain elusive. Here we studied silent synapses—often regarded as immature synapses that express stable NMDA receptors with AMPA receptors either absent or labile—in basolateral amygdala-to-accumbens projection in incubation of cocaine craving. Silent synapses were detected within this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became ‘unsilenced’, a process involving synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased cocaine incubation. Our finding indicates that silent synapse-based reorganization of the amygdala-to-accumbens projection is critical for persistent cocaine craving and relapse after withdrawal. PMID:24077564

  18. Dynamic risk control by human nucleus accumbens.

    PubMed

    Nachev, Parashkev; Lopez-Sosa, Fernando; Gonzalez-Rosa, Javier Jesus; Galarza, Ana; Avecillas, Josue; Pineda-Pardo, Jose Angel; Lopez-Ibor, Juan José; Reneses, Blanca; Barcia, Juan Antonio; Strange, Bryan

    2015-12-01

    Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established. PMID:26428667

  19. Methamphetamine-induced enhancement of hippocampal long-term potentiation is modulated by NMDA and GABA receptors in the shell-accumbens.

    PubMed

    Heysieattalab, Soomaayeh; Naghdi, Nasser; Hosseinmardi, Narges; Zarrindast, Mohammad-Reza; Haghparast, Abbas; Khoshbouei, Habibeh

    2016-08-01

    Addictive drugs modulate synaptic transmission in the meso-corticolimbic system by hijacking normal adaptive forms of experience-dependent synaptic plasticity. Psychostimulants such as METH have been shown to affect hippocampal synaptic plasticity, albeit with a less understood synaptic mechanism. METH is one of the most addictive drugs that elicit long-term alterations in the synaptic plasticity in brain areas involved in reinforcement learning and reward processing. Dopamine transporter (DAT) is one of the main targets of METH. As a substrate for DAT, METH decreases dopamine uptake and increases dopamine efflux via the transporter in the target brain regions such as nucleus accumbens (NAc) and hippocampus. Due to cross talk between NAc and hippocampus, stimulation of NAc has been shown to alter hippocampal plasticity. In this study, we tested the hypothesis that manipulation of glutamatergic and GABA-ergic systems in the shell-NAc modulates METH-induced enhancement of long term potentiation (LTP) in the hippocampus. Rats treated with METH (four injections of 5 mg/kg) exhibited enhanced LTP as compared to saline-treated animals. Intra-NAc infusion of muscimol (GABA receptor agonist) decreased METH-induced enhancement of dentate gyrus (DG)-LTP, while infusion of AP5 (NMDA receptor antagonist) prevented METH-induced enhancement of LTP. These data support the interpretation that reducing NAc activity can ameliorate METH-induced hippocampal LTP through a hippocampus-NAc-VTA circuit loop. Synapse 70:325-335, 2016. © 2016 Wiley Periodicals, Inc. PMID:27029021

  20. A high-fat meal, or intraperitoneal administration of a fat emulsion, increases extracellular dopamine in the nucleus accumbens.

    PubMed

    Rada, Pedro; Avena, Nicole M; Barson, Jessica R; Hoebel, Bartley G; Leibowitz, Sarah F

    2012-01-01

    Evidence links dopamine (DA) in the nucleus accumbens (NAc) shell to the ingestion of palatable diets. Less is known, however, about the specific relation of DA to dietary fat and circulating triglycerides (TG), which are stimulated by fat intake and promote overeating. The present experiments tested in Sprague-Dawley rats whether extracellular levels of NAc DA increase in response to acute access to fat-rich food or peripheral injection of a fat emulsion and, if so, whether this is related to caloric intake or elevated circulating lipids. When rats consumed more calories of a high-fat meal compared with a low-fat meal, there was a significant increase in extracellular accumbens DA (155% vs. 119%). Systemic injection of a fat emulsion, which like a high-fat diet raises circulating TG but eliminates the factor of taste and allows for the control of caloric intake, also significantly increased extracellular levels of DA (127%) compared to an equicaloric glucose solution (70%) and saline (85%). Together, this suggests that a rise in circulating TG may contribute to the stimulatory effect of a high-fat diet on NAc DA. PMID:24962774

  1. A High-Fat Meal, or Intraperitoneal Administration of a Fat Emulsion, Increases Extracellular Dopamine in the Nucleus Accumbens

    PubMed Central

    Rada, Pedro; Avena, Nicole M.; Barson, Jessica R.; Hoebel, Bartley G.; Leibowitz, Sarah F.

    2012-01-01

    Evidence links dopamine (DA) in the nucleus accumbens (NAc) shell to the ingestion of palatable diets. Less is known, however, about the specific relation of DA to dietary fat and circulating triglycerides (TG), which are stimulated by fat intake and promote overeating. The present experiments tested in Sprague-Dawley rats whether extracellular levels of NAc DA increase in response to acute access to fat-rich food or peripheral injection of a fat emulsion and, if so, whether this is related to caloric intake or elevated circulating lipids. When rats consumed more calories of a high-fat meal compared with a low-fat meal, there was a significant increase in extracellular accumbens DA (155% vs. 119%). Systemic injection of a fat emulsion, which like a high-fat diet raises circulating TG but eliminates the factor of taste and allows for the control of caloric intake, also significantly increased extracellular levels of DA (127%) compared to an equicaloric glucose solution (70%) and saline (85%). Together, this suggests that a rise in circulating TG may contribute to the stimulatory effect of a high-fat diet on NAc DA. PMID:24962774

  2. Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens.

    PubMed

    Sun, Haosheng; Maze, Ian; Dietz, David M; Scobie, Kimberly N; Kennedy, Pamela J; Damez-Werno, Diane; Neve, Rachael L; Zachariou, Venetia; Shen, Li; Nestler, Eric J

    2012-11-28

    Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, whereas downregulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive chromatin immunoprecipitation followed by massively parallel sequencing analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise. PMID:23197736

  3. Dopamine Receptor Blockade Modulates the Rewarding and Aversive Properties of Nicotine via Dissociable Neuronal Activity Patterns in the Nucleus Accumbens

    PubMed Central

    Sun, Ninglei; Laviolette, Steven R

    2014-01-01

    The mesolimbic pathway comprising the ventral tegmental area (VTA) and projection terminals in the nucleus accumbens (NAc) has been identified as a critical neural system involved in processing both the rewarding and aversive behavioral effects of nicotine. Transmission through dopamine (DA) receptors functionally modulates these effects directly within the NAc. Nevertheless, the neuronal mechanisms within the NAc responsible for these bivalent behavioral effects are presently not known. Using an unbiased conditioned place preference procedure combined with in vivo neuronal recordings, we examined the effects of nicotine reward and aversion conditioning on intra-NAc neuronal sub-population activity patterns. We report that intra-VTA doses of nicotine that differentially produce rewarding or aversive behavioral effects produce opposite effects on sub-populations of fast-spiking interneurons (FSIs) or medium spiny neurons (MSNs) within the shell region of the NAc (NAshell). Thus, while the rewarding effects of intra-VTA nicotine were associated with inhibition of FSI and activation of MSNs, the aversive effects of nicotine produced the opposite pattern of NAshell neuronal population activity. Blockade of DA transmission with a broad-spectrum DA receptor antagonist, α-flupenthixol, strongly inhibited the spontaneous activity of NAshell FSIs, and reversed the conditioning properties of intra-VTA nicotine, switching nicotine-conditioned responses from aversive to rewarding. Remarkably, DA receptor blockade switched intra-NAshell neuronal population activity from an aversion to a reward pattern, concomitant with the observed switch in behavioral conditioning effects. PMID:24896614

  4. A high-fat diet or galanin in the PVN decreases phosphorylation of CREB in the nucleus accumbens.

    PubMed

    Bocarsly, M E; Avena, N M

    2013-09-17

    A high-fat diet (HFD) can increase hypothalamic galanin (GAL). GAL has recently been shown to inhibit opiate reward, which in turn, decreases cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc). We hypothesized that injection of GAL into the paraventricular nucleus (PVN), or consumption of a HFD, would be associated with a decrease in NAc CREB. In Exp. 1, GAL in the PVN of naïve rats decreased phosphorylated-CREB (pCREB) which is the activated form of CREB, in the NAc compared to saline-injected controls. In Exp. 2, rats fed ad libitum HFD for 4 weeks had reduced NAc pCREB levels compared to rats with sporadic tastes of the HFD. Body weight, serum triglyceride and leptin levels were also raised in the chronic HFD-fed rats. These data suggest that PVN GAL or chronic intake of a HFD can decrease NAc pCREB. The implications of these findings may help to explain the lack of opiate-like withdrawal that has been reported in response to overeating a HFD, thereby providing a potential mechanism underlying behavioral differences seen with addiction-like overconsumption of different types of palatable foods. PMID:23747305

  5. A high-fat diet or galanin in the PVN decreases phosphorylation of CREB in the nucleus accumbens

    PubMed Central

    Bocarsly, Miriam E.; Avena, Nicole M.

    2013-01-01

    A high-fat diet (HFD) can increase hypothalamic galanin (GAL). GAL has recently been shown to inhibit opiate reward, which in turn, decreases cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc). We hypothesized that injection of GAL into the PVN, or consumption of a HFD, would be associated with a decrease in NAc CREB. In Exp. 1, GAL in the paraventricular nucleus (PVN) of naïve rats decreased phosphorylated-CREB (pCREB) in the NAc compared to saline injected controls. In Exp. 2, rats fed ad libitum HFD for 4 wks had reduced NAc pCREB levels compared to rats with sporadic tastes of the HFD. Body weight, serum triglyceride and leptin levels were also raised in the chronic HFD-fed rats. These data suggest that PVN GAL or chronic intake of a HFD can decrease NAc pCREB. The implications of these findings may help to explain the lack of opiate-like withdrawal that has been reported in response to overeating a high fat diet, thereby providing a potential mechanism underlying behavioral differences seen with addiction-like overconsumption of different types of palatable foods. PMID:23747305

  6. Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens

    PubMed Central

    Sun, HaoSheng; Maze, Ian; Dietz, David M.; Scobie, Kimberly N.; Kennedy, Pamela J.; Damez-Werno, Diane; Neve, Rachael L.; Zachariou, Venetia; Shen, Li; Nestler, Eric J.

    2012-01-01

    Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has recently been implicated in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, while down-regulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive ChIP-seq analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine, and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise. PMID:23197736

  7. Injection of Cocaine-Amphetamine Regulated Transcript (CART) peptide into the nucleus accumbens does not inhibit caffeine-induced locomotor activity: Implications for CART peptide mechanism.

    PubMed

    Job, Martin O

    2016-09-01

    Much evidence suggests that intra-nucleus accumbens (NAc) CART peptide (CART 55-102) injection inhibits locomotor activity (LMA) when there is an increase in the release and activity of dopamine (DA) in the NAc. However, this hypothesis has not been fully tested. One way to examine this is to determine if there is a lack of effect of intra-NAc CART peptide on LMA that does not involve increases in DA release in the NAc. Several studies have suggested that caffeine-induced LMA does not involve extracellular DA release in the NAc core. Therefore, in this study, we have examined the effect of injections of CART peptide (2.5μg) into the NAc core on the locomotor effects of caffeine in male Sprague-Dawley rats. Several LMA relevant doses of caffeine were used (0, 10, 20mg/kg i.p.), and an inverted U response curve was found as expected. We determined, in the same animals, that intra-NAc CART peptide had no effect on caffeine-induced LMA whereas it blunted cocaine-mediated LMA, as shown by other reports. We also extended a previous observation in mice by showing that at a LMA activating dose of caffeine there is no alteration of CART peptide levels in the NAc of rats. Our study supports the hypothesis that the inhibitory effects of CART peptide in the NAc may be exerted only under conditions of increased extracellular DA release and activity in this region. Our results also suggest that intra-NAc CART 55-102 does not generally inhibit increases in LMA due to all drugs, but has a more specific inhibitory effect on dopaminergic neurotransmission. PMID:27168116

  8. Role of dopamine D1-like receptor within the nucleus accumbens in acute food deprivation- and drug priming-induced reinstatement of morphine seeking in rats.

    PubMed

    Sadeghzadeh, Fatemeh; Babapour, Vahab; Haghparast, Abbas

    2015-01-01

    Dopamine is a predominant neurotransmitter in the nervous system, which plays an important role in both drug priming- and cue-induced reinstatement of cocaine and heroin seeking. Therefore, in the present study, the conditioned place preference (CPP) paradigm was used to evaluate the effects of intra-accumbal administration of SCH23390 as a dopamine D1-like receptor antagonist on food deprivation (FD) and drug priming-induced reinstatement. Sixty-eight adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannulae into the nucleus accumbens (NAc). For induction of the CPP, subcutaneous (sc) administration of morphine (5mg/kg) was used daily during a three-day conditioning phase. The conditioning score and locomotor activity were recorded by using the Ethovision software. Under extinction conditions, rats were given an 'off' period and were tested for FD-induced reinstatement following the 24-h or 48-h FD condition, and for drug priming-induced reinstatement under the sated condition following an injection of 0.5 and 1mg/kg (sc) morphine. In the next experiments, animals received different doses of intra-accumbal SCH23390 (0.25, 1 and 4 μg/0.5 μl saline) bilaterally and were subsequently tested for FD- and morphine priming-induced reinstatement. Our findings indicated that only a dose of 1mg/kg and not 0.5mg/kg of morphine induced the reinstatement of morphine. 24-h FD similar to 48-h FD induced the reinstatement of seeking behaviors facilitated by an ineffective dose of morphine (0.5mg/kg). Furthermore, the D1-like receptor antagonist attenuated FD- and drug priming-induced reinstatement dose-dependently. It is concluded that FD- and drug priming-induced reinstatement may be mediated, at least in some way, by activation of dopamine D1-like receptors in the NAc. PMID:25835321

  9. Enhanced Upregulation of CRH mRNA Expression in the Nucleus Accumbens of Male Rats after a Second Injection of Methamphetamine Given Thirty Days Later

    PubMed Central

    Cadet, Jean Lud; Brannock, Christie; Ladenheim, Bruce; McCoy, Michael T.; Krasnova, Irina N.; Lehrmann, Elin; Becker, Kevin G.; Jayanthi, Subramaniam

    2014-01-01

    Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; P<0.01) in the expression of 412 (352 upregulated, 60 down-regulated) transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (Crh), oxytocin (Oxt), and vasopressin (Avp) that were upregulated. Injection of METH (10 mg/kg) altered the expression of 503 (338 upregulated, 165 down-regulated) transcripts measured one month later (MS group). These genes also included Cart and Crh. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated) transcripts including Avp, Cart, and Crh. The METH-induced increased Crh expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crh, Cart, and Avp mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug. PMID:24475032

  10. Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning

    PubMed Central

    Yamaguchi, Takashi; Goto, Akihiro; Nakahara, Ichiro; Yawata, Satoshi; Hikida, Takatoshi; Matsuda, Michiyuki; Funabiki, Kazuo; Nakanishi, Shigetada

    2015-01-01

    The nucleus accumbens (NAc) serves as a key neural substrate for aversive learning and consists of two distinct subpopulations of medium-sized spiny neurons (MSNs). The MSNs of the direct pathway (dMSNs) and the indirect pathway (iMSNs) predominantly express dopamine (DA) D1 and D2 receptors, respectively, and are positively and negatively modulated by DA transmitters via Gs- and Gi-coupled cAMP-dependent protein kinase A (PKA) signaling cascades, respectively. In this investigation, we addressed how intracellular PKA signaling is involved in aversive learning in a cell type-specific manner. When the transmission of either dMSNs or iMSNs was unilaterally blocked by pathway-specific expression of transmission-blocking tetanus toxin, infusion of PKA inhibitors into the intact side of the NAc core abolished passive avoidance learning toward an electric shock in the indirect pathway-blocked mice, but not in the direct pathway-blocked mice. We then examined temporal changes in PKA activity in dMSNs and iMSNs in behaving mice by monitoring Förster resonance energy transfer responses of the PKA biosensor with the aid of microendoscopy. PKA activity was increased in iMSNs and decreased in dMSNs in both aversive memory formation and retrieval. Importantly, the increased PKA activity in iMSNs disappeared when aversive memory was prevented by keeping mice in the conditioning apparatus. Furthermore, the increase in PKA activity in iMSNs by aversive stimuli reflected facilitation of aversive memory retention. These results indicate that PKA signaling in iMSNs plays a critical role in both aversive memory formation and retention. PMID:26305972

  11. Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour

    PubMed Central

    Roberts, Michael D; Toedebusch, Ryan G; Wells, Kevin D; Company, Joseph M; Brown, Jacob D; Cruthirds, Clayton L; Heese, Alexander J; Zhu, Conan; Rottinghaus, George E; Childs, Thomas E; Booth, Frank W

    2014-01-01

    We compared the nucleus accumbens (NAc) transcriptomes of generation 8 (G8), 34-day-old rats selectively bred for low (LVR) versus high voluntary running (HVR) behaviours in rats that never ran (LVRnon-run and HVRnon-run), as well as in rats after 6 days of voluntary wheel running (LVRrun and HVRrun). In addition, the NAc transcriptome of wild-type Wistar rats was compared. The purpose of this transcriptomics approach was to generate testable hypotheses as to possible NAc features that may be contributing to running motivation differences between lines. Ingenuity Pathway Analysis and Gene Ontology analyses suggested that ‘cell cycle’-related transcripts and the running-induced plasticity of dopamine-related transcripts were lower in LVR versus HVR rats. From these data, a hypothesis was generated that LVR rats might have less NAc neuron maturation than HVR rats. Follow-up immunohistochemistry in G9–10 LVRnon-run rats suggested that the LVR line inherently possessed fewer mature medium spiny (Darpp-32-positive) neurons (P < 0.001) and fewer immature (Dcx-positive) neurons (P < 0.001) than their G9–10 HVR counterparts. However, voluntary running wheel access in our G9–10 LVRs uniquely increased their Darpp-32-positive and Dcx-positive neuron densities. In summary, NAc cellularity differences and/or the lack of running-induced plasticity in dopamine signalling-related transcripts may contribute to low voluntary running motivation in LVR rats. PMID:24665095

  12. The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning.

    PubMed

    Boschen, Suelen Lucio; Wietzikoski, Evellyn Claudia; Winn, Philip; Da Cunha, Claudio

    2011-09-01

    The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((-)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences. PMID:21619938

  13. Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour.

    PubMed

    Roberts, Michael D; Toedebusch, Ryan G; Wells, Kevin D; Company, Joseph M; Brown, Jacob D; Cruthirds, Clayton L; Heese, Alexander J; Zhu, Conan; Rottinghaus, George E; Childs, Thomas E; Booth, Frank W

    2014-05-15

    We compared the nucleus accumbens (NAc) transcriptomes of generation 8 (G8), 34-day-old rats selectively bred for low (LVR) versus high voluntary running (HVR) behaviours in rats that never ran (LVR(non-run) and HVR(non-run)), as well as in rats after 6 days of voluntary wheel running (LVR(run) and HVR(run)). In addition, the NAc transcriptome of wild-type Wistar rats was compared. The purpose of this transcriptomics approach was to generate testable hypotheses as to possible NAc features that may be contributing to running motivation differences between lines. Ingenuity Pathway Analysis and Gene Ontology analyses suggested that 'cell cycle'-related transcripts and the running-induced plasticity of dopamine-related transcripts were lower in LVR versus HVR rats. From these data, a hypothesis was generated that LVR rats might have less NAc neuron maturation than HVR rats. Follow-up immunohistochemistry in G9-10 LVR(non-run) rats suggested that the LVR line inherently possessed fewer mature medium spiny (Darpp-32-positive) neurons (P < 0.001) and fewer immature (Dcx-positive) neurons (P < 0.001) than their G9-10 HVR counterparts. However, voluntary running wheel access in our G9-10 LVRs uniquely increased their Darpp-32-positive and Dcx-positive neuron densities. In summary, NAc cellularity differences and/or the lack of running-induced plasticity in dopamine signalling-related transcripts may contribute to low voluntary running motivation in LVR rats. PMID:24665095

  14. Metabotropic Glutamate Receptor 5 within Nucleus Accumbens Shell modulates environment-elicited cocaine conditioning expression

    PubMed Central

    Martínez-Rivera, Arlene; Rodríguez-Borrero, Enrique; Matías-Alemán, Maria; Montalvo-Acevedo, Alexandra; Guerrero-Figuereo, Kathleen; Febo-Rodriguez, Liz. J; Morales-Rivera, Amarilys; Maldonado-Vlaar, Carmen S.

    2014-01-01

    The metabotropic glutamate receptors 5 (mGluRs5) within the Nucleus Accumbens (NAc) have been implicated in the modulation of psychostimulant reward. We hypothesized that blockade of mGluR5 within the NAc shell would impair cocaine conditioning in rats. For this study, animals were implanted with cannulae within the NAc shell, and separate groups were exposed to a multimodal environment within activity chambers that signaled cocaine (cocaine-paired) or saline (controls, cocaine-unpaired) injections. Prior to placing the animals in the chambers, rats received systemic intraperitoneal injections of saline or cocaine for 10 consecutive sessions. In the test session (D12), animals were exposed to the multimodal environment without any cocaine or saline pre-treatment. Before placing the rats in the chambers, separate groups of animals were infused within the NAc shell with 2.5, 12 or 25nmol/0.5μl/side of 2-methyl-6- (phenylethynyl) pyridine (MPEP), an antagonist of mGluR5 or with vehicle. Blockade of the mGluR5 subtype at a 2.5nmol dose showed no significant difference in either the ambulatory distance (AD) or the vertical plane move time (VPT). In contrast, mGluR5 blockade at 12nmol and 25nmol decreased conditioned locomotion in the cocaine-paired groups. An association of the environmental cues with the effects of cocaine implies the involvement of memory process during the conditioning response. Our results suggest that mGluR5 within the NAc shell could be modulating the expression of memory related to the association of environmental cues with the effects of cocaine. We suggest that mGluR5 could be taking into account to further studies related with cocaine exposure and cocaine addiction treatments. PMID:23850523

  15. Nucleus accumbens responses differentiate execution and restraint in reward-directed behavior

    PubMed Central

    Loriaux, Amy L.

    2013-01-01

    Our behavior is powerfully driven by environmental cues that signal the availability of rewarding stimuli. We frequently encounter stimuli—a bowl of candy or an alert from our smartphone—that trigger actions to obtain those rewards, even though there may be positive outcomes associated with not acting. The inability to restrain one's action in the presence of reward-associated cues is one type of impulsive behavior and a component of such maladaptive behaviors as overeating, gambling, and substance abuse. The nucleus accumbens (NAc) is ideally situated to integrate multiple cognitive and affective inputs to bias action via outputs through the basal ganglia. NAc neurons have been shown to respond to cues that predict reward availability, goal-directed behaviors aimed at obtaining them, and delivery of the reward itself. As these processes are typically associated, it is difficult to discern whether signals in the NAc are more closely related to processing reward-predictive aspects of goal-directed behavior or selection of behavioral response. To dissociate these possibilities, we recorded the activity of NAc neurons while rats performed a task in which two different cues both informed rats of reward availability but required them to either press a lever (Go) or withhold pressing (NoGo) to obtain the reward. Individual cue-responsive neurons showed either increases or decreases in activity at cue onset. Increases in activity were larger, and decreases smaller, when rats withheld lever pressing, whether correctly for NoGo trials or in error on Go trials. Thus NAc cue responses correlated with action, regardless of cue type or accuracy. PMID:24174652

  16. Identification and characterization of plant-specific NAC gene family in canola (Brassica napus L.) reveal novel members involved in cell death.

    PubMed

    Wang, Boya; Guo, Xiaohua; Wang, Chen; Ma, Jieyu; Niu, Fangfang; Zhang, Hanfeng; Yang, Bo; Liang, Wanwan; Han, Feng; Jiang, Yuan-Qing

    2015-03-01

    NAC transcription factors are plant-specific and play important roles in plant development processes, response to biotic and abiotic cues and hormone signaling. However, to date, little is known about the NAC genes in canola (or oilseed rape, Brassica napus L.). In this study, a total of 60 NAC genes were identified from canola through a systematical analysis and mining of expressed sequence tags. Among these, the cDNA sequences of 41 NAC genes were successfully cloned. The translated protein sequences of canola NAC genes with the NAC genes from representative species were phylogenetically clustered into three major groups and multiple subgroups. The transcriptional activities of these BnaNAC proteins were assayed in yeast. In addition, by quantitative real-time RT-PCR, we further observed that some of these BnaNACs were regulated by different hormone stimuli or abiotic stresses. Interestingly, we successfully identified two novel BnaNACs, BnaNAC19 and BnaNAC82, which could elicit hypersensitive response-like cell death when expressed in Nicotiana benthamiana leaves, which was mediated by accumulation of reactive oxygen species. Overall, our work has laid a solid foundation for further characterization of this important NAC gene family in canola. PMID:25616736

  17. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

    PubMed

    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors. PMID:27421228

  18. Localization of O-GlcNAc-modified proteins in neuromuscular diseases.

    PubMed

    Nakamura, Seika; Nakano, Satoshi; Nishii, Makoto; Kaneko, Satoshi; Kusaka, Hirofumi

    2012-06-01

    O-linked N-acetylglucosamine (O-GlcNAc) is a ubiquitous post-translational modification of nucleocytoplasmic proteins that induces the attachment of N-acetylglucosamine to serine or threonine residues of a protein. In contrast to other protein glycosylations, this modification is highly reversible and, similar to phosphorylation, it plays important roles in various cell signals. Here, we immunolocalized O-GlcNAc-modified proteins in muscle biopsy specimens from 40 patients with neuromuscular diseases and controls. In normal muscle fibers, O-GlcNAc was found along plasma membranes and in nuclei. Diffuse and increased cytoplasmic staining of O-GlcNAc was detected in (1) regenerating muscle fibers in muscular dystrophy, myositis, and rhabdomyolysis; (2) a proportion of atrophic fibers in myositis, such as those found in perifascicular regions in dermatomyositis; and (3) vacuolated fibers in sporadic inclusion body myositis (s-IBM) and distal myopathy with rimmed vacuoles (DMRV). Target formations in neurogenic muscular atrophy were O-GlcNAc positive. Increase of O-GlcNAc glycosylation could be associated with the stress response, as these lesions have been shown to be positive for several stress markers. Vacuolar rims in s-IBM and DMRV were sometimes sharply lined by O-GlcNAc-positive deposits, which reflects myonuclear breakdown occurring from the disease. PMID:22718293

  19. GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma.

    PubMed

    Kwon, Ok-Seon; Oh, Ensel; Park, Jeong-Rak; Lee, Ji-Seon; Bae, Gab-Yong; Koo, Jae-Hyung; Kim, Hyongbum; Choi, Yoon L; Choi, Young Soo; Kim, Jhingook; Cha, Hyuk-Jin

    2015-12-01

    While metastasis, the main cause of lung cancer-related death, has been extensively studied, the underlying molecular mechanism remains unclear. A previous clinicogenomic study revealed that expression of N-acetylgalactosaminyltransferase (GalNAc-T14), is highly inversely correlated with recurrence-free survival in those with non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism(s) has not been determined. Here, we showed that GalNAc-T14 expression was positively associated with the invasive phenotype. Microarray and biochemical analyses revealed that HOXB9, the expression of which was increased in a GalNAc-T14-dependent manner, played an important role in metastasis. GalNAc-T14 increased the sensitivity of the WNT response and increased the stability of the β-catenin protein, leading to induced expression of HOXB9 and acquisition of an invasive phenotype. Pharmacological inhibition of β-catenin in GalNAc-T14-expressing cancer cells suppressed HOXB9 expression and invasion. A meta-analysis of clinical genomics data revealed that expression of GalNAc-T14 or HOXB9 was strongly correlated with reduced recurrence-free survival and increased hazard risk, suggesting that targeting β-catenin within the GalNAc-T14/WNT/HOXB9 axis may be a novel therapeutic approach to inhibit metastasis in NSCLC. PMID:26544896

  20. NAC transcription factors in plant multiple abiotic stress responses: progress and prospects

    PubMed Central

    Shao, Hongbo; Wang, Hongyan; Tang, Xiaoli

    2015-01-01

    Abiotic stresses adversely affect plant growth and agricultural productivity. According to the current climate prediction models, crop plants will face a greater number of environmental stresses, which are likely to occur simultaneously in the future. So it is very urgent to breed broad-spectrum tolerant crops in order to meet an increasing demand for food productivity due to global population increase. As one of the largest families of transcription factors (TFs) in plants, NAC TFs play vital roles in regulating plant growth and development processes including abiotic stress responses. Lots of studies indicated that many stress-responsive NAC TFs had been used to improve stress tolerance in crop plants by genetic engineering. In this review, the recent progress in NAC TFs was summarized, and the potential utilization of NAC TFs in breeding abiotic stress tolerant transgenic crops was also be discussed. In view of the complexity of field conditions and the specificity in multiple stress responses, we suggest that the NAC TFs commonly induced by multiple stresses should be promising candidates to produce plants with enhanced multiple stress tolerance. Furthermore, the field evaluation of transgenic crops harboring NAC genes, as well as the suitable promoters for minimizing the negative effects caused by over-expressing some NAC genes, should be considered. PMID:26579152

  1. Behavioral flexibility is increased by optogenetic inhibition of neurons in the nucleus accumbens shell during specific time segments

    PubMed Central

    Aquili, Luca; Liu, Andrew W.; Shindou, Mayumi; Shindou, Tomomi; Wickens, Jeffery R.

    2014-01-01

    Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus–reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity in behavioral flexibility, we used light-activated halorhodopsin to inhibit nucleus accumbens shell neurons during specific time segments of a bar-pressing task requiring a win–stay/lose–shift strategy. We found that optogenetic inhibition during action selection in the time segment preceding a lever press had no effect on performance. However, inhibition occurring in the time segment during feedback of results—whether rewards or nonrewards—reduced the errors that occurred after a change in contingency. Our results demonstrate critical time segments during which nucleus accumbens shell neurons integrate feedback into subsequent responses. Inhibiting nucleus accumbens shell neurons in these time segments, during reinforced performance or after a change in contingencies, increases lose–shift behavior. We propose that the activity of nucleus shell accumbens shell neurons in these time segments plays a key role in integrating knowledge of results into subsequent behavior, as well as in modulating lose–shift behavior when contingencies change. PMID:24639489

  2. Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene.

    PubMed

    Beckley, Jacob T; Randall, Patrick K; Smith, Rachel J; Hughes, Benjamin A; Kalivas, Peter W; Woodward, John J

    2016-05-01

    Abused inhalants are voluntarily inhaled at high concentrations to produce intoxicating effects. Results from animal studies show that the abused inhalant toluene triggers behaviors, such as self-administration and conditioned place preference, which are commonly associated with addictive drugs. However, little is known about how toluene affects neurons within the nucleus accumbens (NAc), a brain region within the basal ganglia that mediates goal-directed behaviors and is implicated in the development and maintenance of addictive behaviors. Here we report that toluene inhibits a component of the after-hyperpolarization potential, and dose-dependently inhibits N-methyl-D-aspartate (NMDA)-mediated currents in rat NAc medium spiny neurons (MSN). Moreover, using the multivariate statistical technique, partial least squares discriminative analysis to analyze electrophysiological measures from rat NAc MSNs, we show that toluene induces a persistent depression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated currents in one subtype of NAc MSNs, and that the electrophysiological features of MSN neurons predicts their sensitivity to toluene. The CB1 receptor antagonist AM281 blocked the toluene-induced long-term depression of AMPA currents, indicating that this process is dependent on endocannabinoid signaling. The neuronal identity of recorded cells was examined using dual histochemistry and shows that toluene-sensitive NAc neurons are dopamine D2 MSNs that express preproenkephalin mRNA. Overall, the results from these studies indicate that physiological characteristics obtained from NAc MSNs during whole-cell patch-clamp recordings reliably predict neuronal phenotype, and that the abused inhalant toluene differentially depresses excitatory neurotransmission in NAc neuronal subtypes. PMID:25752326

  3. Roles of Nucleus Accumbens CREB and Dynorphin in Dysregulation of Motivation

    PubMed Central

    Muschamp, John W.; Carlezon, William A.

    2013-01-01

    Psychostimulants such as amphetamine and cocaine are believed to produce dependence by causing rapid, supraphysiological elevations in synaptic dopamine (DA) within the nucleus accumbens (NAc) (Volkow et al. 2009, Neuropharmacology 56: 3–8). These changes in forebrain DA transmission are similar to those evoked by natural reinforcers (Louilot et al. 1991, Brain Res 553: 313–317; Roitman et al. 2004, J Neurosci 24: 1265–1271), but are of greater magnitude and longer duration. Repeated drug exposure causes compensatory neuroadaptations in neurons of the NAc, some of which may modulate excess DA in a homeostatic fashion. One such adaptation is the activation of the transcription factor CREB (cAMP response element-binding protein) within neurons of the NAc. Although elevated levels of transcriptionally active CREB appear to attenuate DA transmission by increasing expression of the endogenous κ opioid receptor (KOR) ligand dynorphin, increased dynorphin transmission may ultimately have undesirable effects that contribute to drug withdrawal states as well as comorbid psychiatric illnesses such as depression. This state may prompt a return to drug use to mitigate the adverse effects of withdrawal. This article summarizes our current understanding of how CREB and dynorphin contribute to the dysregulation of motivation and describes novel therapeutic strategies that derive from preclinical research in this area. PMID:23293139

  4. Cocaine- and morphine-induced synaptic plasticity in the nucleus accumbens.

    PubMed

    Alcantara, Adriana A; Lim, Helen Y; Floyd, Christopher E; Garces, Juanita; Mendenhall, John M; Lyons, Chelsea L; Berlanga, Monica L

    2011-04-01

    The critical brain areas and molecular mechanisms involved in drug abuse and dependence have been extensively studied. Drug-induced persistent behaviors such as sensitization, tolerance, or relapse, however, far outlast any previously reported mechanisms. A challenge in the field of addiction, therefore, has been to identify drug-induced changes in brain circuitry that may subserve long-lasting changes in behavior. This study examined behavioral changes and electron microscopic evidence of altered synaptic connectivity within the nucleus accumbens (NAc) following repeated administration of cocaine or morphine. The unbiased quantitative stereological physical disector method was used to estimate the number of synapses per neuron. Increases in the synapse-to-neuron ratio were found in the NAc shell of cocaine-treated (49.1%) and morphine-treated (55.1%) rats and in the NAc core of cocaine-treated animals (49.1%). This study provides direct ultrastructural evidence of drug-induced synaptic plasticity and identifies synaptic remodeling as a potential neural substrate underlying drug-induced behavioral sensitization. PMID:20730804

  5. AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine

    PubMed Central

    Wolf, Marina E.; Ferrario, Carrie R.

    2010-01-01

    This review focuses on cocaine-induced postsynaptic plasticity in the nucleus accumbens (NAc) involving changes in AMPA receptor (AMPAR) transmission. First, fundamental properties of AMPAR in the NAc are reviewed. Then, we provide a detailed and critical analysis of literature demonstrating alterations in AMPAR transmission in association with behavioral sensitization to cocaine and cocaine self-administration. We conclude that cocaine exposure leads to changes in AMPAR transmission that depend on many factors including whether exposure is contingent or non-contingent, the duration of withdrawal, and whether extinction training has occurred. The relationship between changes in AMPAR transmission and responding to cocaine or cocaine-paired cues can also be affected by these variables. However, after prolonged withdrawal in the absence of extinction training, our findings and others lead us to propose that AMPAR transmission is enhanced, resulting in stronger responding to drug-paired cues. Finally, many results indicate that the state of synaptic transmission in the NAc after cocaine exposure is associated with impairment of AMPAR-dependent plasticity. This may contribute to a broad range of addiction-related behavioral changes. PMID:20109488

  6. Circadian genes Period 1 and Period 2 in the nucleus accumbens regulate anxiety-related behavior

    PubMed Central

    Spencer, Sade; Falcon, Edgardo; Kumar, Jaswinder; Krishnan, Vaishnav; Mukherjee, Shibani; Birnbaum, Shari G.; McClung, Colleen A.

    2013-01-01

    It has been suggested for some time that circadian rhythm abnormalities underlie the development of multiple psychiatric disorders. However, it is unclear how disruptions in individual circadian genes might regulate mood and anxiety. Here we found that mice lacking functional mPeriod 1 (mPer1) or mPeriod 2 (mPer2) individually did not have consistent behavioral abnormalities in measures of anxiety-related behavior. However, mice deficient in both mPer1 and mPer2 had an increase in levels of anxiety-like behavior in multiple measures. Moreover, we found that mPer1 and mPer2 expression was reduced in the nucleus accumbens (NAc) after exposure to chronic social defeat stress, a paradigm that led to increased anxiety-related behavior. Following social defeat, chronic treatment with fluoxetine normalized Per gene expression towards wild-type levels. Knockdown of both mPer1 and mPer2 expression via RNA interference specifically in the NAc led to a similar increase in anxiety-like behavior as seen in the mutant animals. Taken together, these results implicate the Per genes in the NAc in response to stress and the development of anxiety. PMID:23039899

  7. OGA inhibition by GlcNAc-selenazoline

    PubMed Central

    Kim, Eun Ju; Love, Dona C.; Darout, Etzer; Abdo, Mohannad; Rempel, Brian; Withers, Stephen G.; Rablen, Paul R.; Hanover, John A.; Knapp, Spencer

    2010-01-01

    The title compound, which differs from the powerful O-GlcNAcase (OGA) inhibitor GlcNAc-thiazoline only at the chalcogen atom (Se for S), is a much weaker inhibitor in a direct OGA assay. In human cells, however, the selenazoline shows comparable ability to induce hyper-O-GlcNAc-ylation, and the two show similar reduction of insulin-stimulated translocation of glucose transporter 4 in differentiated 3T3 adipocytes. PMID:20822912

  8. Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence.

    PubMed

    Zan, Gui-Ying; Wang, Qian; Wang, Yu-Jun; Liu, Yao; Hang, Ai; Shu, Xiao-Hong; Liu, Jing-Gen

    2015-09-15

    The association between morphine withdrawal and depressive-like symptoms is well documented, however, the role of dynorphin/κ opioid receptor system and the underlying neural substrates have not been fully understood. In the present study, we found that four weeks morphine abstinence after a chronic escalating morphine regimen significantly induced depressive-like behaviors in mice. Prodynorphin mRNA and protein levels were increased in the nucleus accumbens (NAc) after four weeks of morphine withdrawal. Local injection of κ opioid receptor antagonist nor-Binaltorphimine (norBNI) in the NAc significantly blocked the expression of depressive-like behaviors without influencing general locomotor activity. Thus, the present study extends previous findings by showing that prolonged morphine withdrawal-induced depressive-like behaviors are regulated by dynorphin/κ opioid receptor system, and shed light on the κ opioid receptor antagonists as potential therapeutic agents for the treatment of depressive-like behaviors induced by opiate withdrawal. PMID:26049060

  9. Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the nucleus accumbens of cocaine-treated rats

    PubMed Central

    Mitrano, D.A.; Arnold, C.; Smith, Y.

    2008-01-01

    There is significant pharmacological and behavioral evidence that group I metabotropic glutamate receptors (mGluR1a and mGluR5) in the nucleus accumbens play an important role in the neurochemical and pathophysiological mechanisms that underlie addiction to psychostimulants. To further address this issue, we undertook a detailed ultrastructural analysis to characterize changes in the subcellular and subsynaptic localization of mGluR1a and mGluR5 in the core and shell of nucleus accumbens following acute or chronic cocaine administration in rats. After a single cocaine injection (30mg/kg) and 45 minutes withdrawal, there was a significant decrease in the proportion of plasma membrane-bound mGluR1a in accumbens shell dendrites. Similarly, the proportion of plasma membrane-bound mGluR1a was decreased in large dendrites of accumbens core neurons following chronic cocaine exposure (i.e. 1 week treatment followed by three weeks withdrawal). However, neither acute nor chronic cocaine treatments induced significant change in the localization of mGluR5 in accumbens core and shell, which is in contrast with the significant reduction of plasma membrane-bound mGluR1a and mGluR5 induced by local intra-accumbens administration of the group I mGluR agonist, DHPG. In conclusion, these findings demonstrate that cocaine-induced glutamate imbalance (Smith et al., 1995; Pierce et al., 1996; Reid et al., 1997) has modest effects on the trafficking of group I mGluRs in the nucleus accumbens. These results provide valuable information on the neuroadaptive mechanisms of accumbens group I mGluRs in response to cocaine administration. PMID:18479833

  10. Functional characterization of NAC55 transcription factor from oilseed rape (Brassica napus L.) as a novel transcriptional activator modulating reactive oxygen species accumulation and cell death.

    PubMed

    Niu, Fangfang; Wang, Chen; Yan, Jingli; Guo, Xiaohua; Wu, Feifei; Yang, Bo; Deyholos, Michael K; Jiang, Yuan-Qing

    2016-09-01

    NAC transcription factors (TFs) are plant-specific and play important roles in development, responses to biotic and abiotic cues and hormone signaling. So far, only a few NAC genes have been reported to regulate cell death. In this study, we identified and characterized a NAC55 gene isolated from oilseed rape (Brassica napus L.). BnaNAC55 responds to multiple stresses, including cold, heat, abscisic acid (ABA), jasmonic acid (JA) and a necrotrophic fungal pathogen Sclerotinia sclerotiorum. BnaNAC55 has transactivation activity and is located in the nucleus. BnaNAC55 is able to form homodimers in planta. Unlike ANAC055, full-length BnaNAC55, but not either the N-terminal NAC domain or C-terminal regulatory domain, induces ROS accumulation and hypersensitive response (HR)-like cell death when expressed both in oilseed rape protoplasts and Nicotiana benthamiana. Furthermore, BnaNAC55 expression causes obvious nuclear DNA fragmentation. Moreover, quantitative reverse transcription PCR (qRT-PCR) analysis identified that the expression levels of multiple genes regulating ROS production and scavenging, defense response as well as senescence are significantly induced. Using a dual luciferase reporter assay, we further confirm that BnaNAC55 could activate the expression of a few ROS and defense-related gene expression. Taken together, our work has identified a novel NAC TF from oilseed rape that modulates ROS accumulation and cell death. PMID:27312204

  11. Dopamine in the nucleus accumbens modulates the memory of social defeat in Syrian hamsters (Mesocricetus auratus).

    PubMed

    Gray, C L; Norvelle, A; Larkin, T; Huhman, K L

    2015-06-01

    Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Experiment 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 μg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24h later in response to a non-aggressive intruder. In Experiment 2, infusion of 3.75 μg cis-(Z)-flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Experiment 3, we found that the effect of cis-(Z)-flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat. PMID:25721736

  12. Dopamine in the nucleus accumbens modulates the memory of social defeat in Syrian hamsters (Mesocricetus auratus)

    PubMed Central

    Gray, C.L.; Norvelle, A.; Larkin, T.; Huhman, K.L..

    2015-01-01

    Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Exp. 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 μg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24 hr later in response to a non-aggressive intruder. In Exp. 2, infusion of 3.75 μg cis(z)flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Exp. 3, we found that the effect of cis(z)flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat. PMID:25721736

  13. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens.

    PubMed

    White, André O; Kramár, Enikö A; López, Alberto J; Kwapis, Janine L; Doan, John; Saldana, David; Davatolhagh, M Felicia; Alaghband, Yasaman; Blurton-Jones, Mathew; Matheos, Dina P; Wood, Marcelo A

    2016-01-01

    Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long-term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations. PMID:27226355

  14. Administration of the Glial Condition Medium in the Nucleus Accumbens Prolong Maintenance and Intensify Reinstatement of Morphine-Seeking Behavior.

    PubMed

    Arezoomandan, Reza; Khodagholi, Fariba; Haghparast, Abbas

    2016-04-01

    Accumulating evidence suggested that glial cells are involved in synaptic plasticity and behavioral changes induced by drugs abuse. The role of these cells in maintenance and reinstatement of morphine (MRP) conditioned place preference (CPP) remains poorly characterized. The aim of present study was to investigate the direct role of glial cells in nucleus accumbens (NAc) in the maintenance and reinstatement of MRP-seeking behavior. CPP induced with injection of MRP (5 mg/kg, s.c. for 3 days), lasted for 7 days after cessation of MRP treatment and priming dose of MRP (1 mg/kg, s.c.) reinstated the extinguished MRP-induced CPP. The astrocyte-conditioned medium (ACM) and neuroglia conditioned medium (NCM) exposed to MRP (10 and 100 µM) have been microinjected into the NAc. Intra-NAc administration of ACM during extinction period failed to change the maintenance of MRP-CPP, but MRP 100-treated ACM could slightly increase the magnitude of reinstatement. In contrast to ACM, intra-NAc administration of MRP 100-treated NCM caused slower extinction by 3 days and significantly increased the magnitude of reinstatement. Our findings suggest the involvement of glial cells activation in the maintenance and reinstatement of MRP-seeking behaviors, and provides new evidence that these cells might be a potential target for the treatment of MRP addiction. PMID:26547198

  15. Molecular changes in the medial prefrontal cortex and nucleus accumbens are associated with blocking the behavioral sensitization to cocaine

    PubMed Central

    Zhang, Yi; Zhu, Xiongzhao; Huang, Can; Zhang, Xiuwu

    2015-01-01

    Previous studies have demonstrated that cocaine-induced behavioral sensitization is associated with persistent functional and structural alterations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc); however, the molecular mechanisms underlying these changes have not been elucidated. In this study, the behavioral sensitization to cocaine was established in Sprague Dawley rats and was measured by locomotion and behavioral rating. The brain tissue homogenization was used for measuring the level of brain-derived neurotrophic factor (BDNF), the expression and activity of integrin-linked kinase (ILK), level of protein kinase B (Akt) phosphorylation at serine 473 and threonine 308, and the expression of p75NTR, TrkA, and TrkB protein. The Results showed that cocaine sensitization was associated with increased BDNF, ILK activity, phospho-Akt Ser473, p75NTR, and TrkB protein levels in the mPFC and NAc core. The combination of pergolide and ondansetron normalized not only behavioral sensitization, but also the increases in these molecular markers. Dual immunofluoresence staining showed that ILK expression is co-distributed with p75NTR and TrkA expression in both the mPFC and NAc core. Results suggested that the BDNF-TrkA/p75NTR-ILK-Akt signaling pathway may be active in cocaine sensitization and associated neural plasticity in the mPFC and NAc core. PMID:26538265

  16. Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines.

    PubMed

    Uys, Joachim D; McGuier, Natalie S; Gass, Justin T; Griffin, William C; Ball, Lauren E; Mulholland, Patrick J

    2016-05-01

    Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown. Using an unbiased proteomic approach, we investigated the effects of chronic intermittent ethanol (CIE) exposure on neuroadaptations in postsynaptic density (PSD)-enriched proteins in the NAc of ethanol-dependent mice. Compared with controls, CIE exposure significantly changed expression levels of 50 proteins in the PSD-enriched fraction. Systems biology and functional annotation analyses demonstrated that the dysregulated proteins are expressed at tetrapartite synapses and critically regulate cellular morphology. To confirm this latter finding, the density and morphology of dendritic spines were examined in the NAc core of ethanol-dependent mice. We found that CIE exposure and withdrawal differentially altered dendrite diameter and dendritic spine density and morphology. Through the use of quantitative proteomics and functional annotation, these series of experiments demonstrate that ethanol dependence produces neuroadaptations in proteins that modify dendritic spine morphology. In addition, these studies identified novel PSD-related proteins that contribute to the neurobiological mechanisms of ethanol dependence that drive maladaptive structural plasticity of NAc neurons. PMID:25787124

  17. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens

    PubMed Central

    White, André O.; Kramár, Enikö A.; López, Alberto J.; Kwapis, Janine L.; Doan, John; Saldana, David; Davatolhagh, M. Felicia; Alaghband, Yasaman; Blurton-Jones, Mathew; Matheos, Dina P.; Wood, Marcelo A.

    2016-01-01

    Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long-term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations. PMID:27226355

  18. Observational learning in mice can be prevented by medial prefrontal cortex stimulation and enhanced by nucleus accumbens stimulation.

    PubMed

    Jurado-Parras, M Teresa; Gruart, Agnès; Delgado-García, José M

    2012-03-01

    The neural structures involved in ongoing appetitive and/or observational learning behaviors remain largely unknown. Operant conditioning and observational learning were evoked and recorded in a modified Skinner box provided with an on-line video recording system. Mice improved their acquisition of a simple operant conditioning task by observational learning. Electrical stimulation of the observer's medial prefrontal cortex (mPFC) at a key moment of the demonstration (when the demonstrator presses a lever in order to obtain a reward) cancels out the benefits of observation. In contrast, electrical stimulation of the observer's nucleus accumbens (NAc) enhances observational learning. Ongoing cognitive processes in the demonstrator could also be driven by electrical stimulation of these two structures, preventing the proper execution of the ongoing instrumental task (mPFC) or stopping pellet intake (NAc). Long-term potentiation (LTP) evoked in these two cortical structures did not prevent the acquisition or retrieval process--namely, mPFC and/or NAc stimulation only prevented, or modified, the ongoing behavioral process. The dorsal hippocampus was not involved in either of these two behavioral processes. Thus, both ongoing observational learning and performance of an instrumental task require the active contribution of the mPFC and/or the NAc. PMID:22354947

  19. Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats.

    PubMed

    Pan, Bo; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-05-01

    The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling. PMID:26894264

  20. Dynamic fluctuations in dopamine efflux in the prefrontal cortex and nucleus accumbens during risk-based decision making.

    PubMed

    St Onge, Jennifer R; Ahn, Soyon; Phillips, Anthony G; Floresco, Stan B

    2012-11-21

    Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies. PMID:23175840

  1. Mu opioid receptor modulation in the nucleus accumbens lowers voluntary wheel running in rats bred for high running motivation.

    PubMed

    Ruegsegger, Gregory N; Toedebusch, Ryan G; Will, Matthew J; Booth, Frank W

    2015-10-01

    The exact role of opioid receptor signaling in mediating voluntary wheel running is unclear. To provide additional understanding, female rats selectively bred for motivation of low (LVR) versus high voluntary running (HVR) behaviors were used. Aims of this study were 1) to identify intrinsic differences in nucleus accumbens (NAc) mRNA expression of opioid-related transcripts and 2) to determine if nightly wheel running is differently influenced by bilateral NAc injections of either the mu-opioid receptor agonist D-Ala2, NMe-Phe4, Glyo5-enkephalin (DAMGO) (0.25, 2.5 μg/side), or its antagonist, naltrexone (5, 10, 20 μg/side). In Experiment 1, intrinsic expression of Oprm1 and Pdyn mRNAs were higher in HVR compared to LVR. Thus, the data imply that line differences in opioidergic mRNA in the NAc could partially contribute to differences in wheel running behavior. In Experiment 2, a significant decrease in running distance was present in HVR rats treated with 2.5 μg DAMGO, or with 10 μg and 20 μg naltrexone between hours 0-1 of the dark cycle. Neither DAMGO nor naltrexone had a significant effect on running distance in LVR rats. Taken together, the data suggest that the high nightly voluntary running distance expressed by HVR rats is mediated by increased endogenous mu-opioid receptor signaling in the NAc, that is disturbed by either agonism or antagonism. In summary, our findings on NAc opioidergic mRNA expression and mu-opioid receptor modulations suggest HVR rats, compared to LVR rats, express higher running levels mediated by an increase in motivation driven, in part, by elevated NAc opioidergic signaling. PMID:26044640

  2. Inhibition of Cdk5 in the nucleus accumbens enhances the locomotor-activating and incentive-motivational effects of cocaine.

    PubMed

    Taylor, Jane R; Lynch, Wendy J; Sanchez, Hayde; Olausson, Peter; Nestler, Eric J; Bibb, James A

    2007-03-01

    Neuronal adaptations in striatal dopamine signaling have been implicated in enhanced responses to addictive drugs. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine signaling and is a downstream target gene of the transcription factor DeltaFosB, which accumulates in striatal neurons after chronic cocaine exposure. Here we investigated the role of Cdk5 activity in the nucleus accumbens (NAc) on cocaine-induced locomotor sensitization, responding for reward-associated stimuli (conditioned reinforcement), and cocaine self-administration under a progressive ratio schedule. Repeated infusions of the Cdk5 inhibitor roscovitine into the NAc before cocaine injections augmented both the development and expression of cocaine sensitization without having any intrinsic stimulant actions of its own. Additionally, repeated intra-NAc infusions of roscovitine to saline-injected rats enhanced locomotor responses to a subsequent cocaine challenge. Similar effects were found after infusions of another Cdk5 inhibitor, olomoucine, but not its inactive congener, iso-olomoucine. Repeated inhibition of Cdk5 within the NAc also robustly enhanced the incentive-motivational effects of cocaine, similar to the effect of prior repeated cocaine exposure. The enhanced responding with conditioned reinforcement induced by cocaine persisted at least 2 weeks after the final roscovitine infusion. NAc infusions of olomoucine also produced acute and enduring increases in "breakpoints" achieved on a progressive ratio schedule for cocaine reinforcement. These results demonstrate profound and persistent effects of NAc Cdk5 inhibition on locomotor sensitization and incentive-motivational processes and provide direct evidence for a role for striatal Cdk5-induced alterations in the brain's long-term adaptations to cocaine. PMID:17360491

  3. BDNF–TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms

    PubMed Central

    Ren, Q; Ma, M; Yang, C; Zhang, J-C; Yao, W; Hashimoto, K

    2015-01-01

    Depression is a core symptom of methamphetamine (METH) withdrawal during the first several weeks of abstinence. However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF–TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3 mg kg−1 per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH-induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5 mg kg−1 per day for 14 days), but not TrkB agonist 7,8-dihydroxyflavone (10 mg kg−1 per day for 14 days). In vivo microdialysis showed that METH (1 mg kg−1)-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF–TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers. PMID:26506052

  4. Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats

    PubMed Central

    Fuchs, Rita A.; Ramirez, Donna R.; Bell, Guinevere H.

    2008-01-01

    Rationale The nucleus accumbens (NAC) is a functionally heterogeneous brain region with respect to its involvement in cocaine-seeking behavior triggered by drug-associated explicit conditioned stimuli, foot shock stress, or cocaine itself in the reinstatement animal model of drug relapse. However, it is not known whether the NAC or its subregions are critical for reinstatement of cocaine-seeking behavior produced by re-exposure to a previously cocaine-paired environmental context. Objectives The present study was designed to evaluate potentially unique contributions of the NAC core and shell to this behavior. Materials and methods Rats were trained to lever press for unsignaled cocaine infusions (0.15 mg/infusion, intravenous) in a distinct environmental context. Lever responding was then extinguished in a distinctly different environmental context (extinction context) during a minimum of seven daily training sessions. Subsequently, using a counterbalanced testing design, rats were re-exposed to the cocaine-paired context or the extinction context while cocaine seeking (i.e., responding on the previously cocaine-reinforced lever) was assessed. Before each test session, neural activity was inhibited selectively in the NAC core or shell using bilateral microinfusions of the γ-aminobutyric acid agonists, baclofen and muscimol (0/0 or 1.0/0.1 mM; 0.3 μl per hemisphere). Results Neural inactivation of the NAC shell or core attenuated responding in the cocaine context and, interestingly, increased responding in the extinction context. Control experiments indicated no effects on general activity or food-reinforced instrumental behavior. Conclusions These findings suggest that both subregions of the NAC may promote context-induced reinstatement by facilitating drug context-induced motivation for cocaine and context discrimination. PMID:18597075

  5. Changes in dopamine transporter binding in nucleus accumbens following chronic self-administration cocaine: heroin combinations.

    PubMed

    Pattison, Lindsey P; McIntosh, Scot; Sexton, Tammy; Childers, Steven R; Hemby, Scott E

    2014-10-01

    Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate of dopamine. The present studies were undertaken to determine whether chronic self-administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high- and low-affinity DAT binding sites. Saturation binding of the cocaine analog [(125) I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([(125) I]RTI-55) in rat NAc membranes resulted in binding curves that were best fit to two-site binding models, allowing calculation of dissociation constant (Kd ) and binding density (Bmax ) values corresponding to high- and low-affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high- and low- affinity binding sites in the NAc, with low-affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self-administration of cocaine and a cocaine:heroin combination increased the affinity of the low-affinity site for the cocaine congener RTI-55 compared to saline. These results indicate that the alterations observed following chronic speedball self-administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. PMID:24916769

  6. Assessment of individual differences in the rat nucleus accumbens transcriptome following taste-heroin extended access.

    PubMed

    Imperio, Caesar G; McFalls, Ashley J; Colechio, Elizabeth M; Masser, Dustin R; Vrana, Kent E; Grigson, Patricia S; Freeman, Willard M

    2016-05-01

    Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal responsibilities in favor of finding and using drugs. Only some recreational heroin users devolve into addiction but the basis of these individual differences is not known. We have shown in rats that avoidance of a heroin-paired taste cue reliably identifies individual animals with greater addiction-like behavior for heroin. Here rats received 5min access to a 0.15% saccharin solution followed by the opportunity to self-administer either saline or heroin for 6h. Large Suppressors of the heroin-paired taste cue displayed increased drug escalation, motivation for drug, and drug loading behavior compared with Small Suppressors. Little is known about the molecular mechanisms of these individual differences in addiction-like behavior. We examined the individual differences in mRNA expression in the nucleus accumbens (NAc) of rats that were behaviorally stratified by addiction-like behavior using next-generation sequencing. We hypothesized that based on the avoidance of the drug-paired cue there will be a unique mRNA profile in the NAc. Analysis of strand-specific whole genome RNA-Seq data revealed a number of genes differentially regulated in NAc based on the suppression of the natural saccharine reward. Large Suppressors exhibited a unique mRNA prolife compared to Saline controls and Small Suppressors. Genes related to immunity, neuronal activity, and behavior were differentially expressed among the 3 groups. In total, individual differences in avoidance of a heroin-paired taste cue are associated with addiction-like behavior along with differential NAc gene expression. PMID:26733446

  7. Reward and reinforcement activity in the nucleus accumbens during learning

    PubMed Central

    Gale, John T.; Shields, Donald C.; Ishizawa, Yumiko; Eskandar, Emad N.

    2014-01-01

    The nucleus accumbens core (NAcc) has been implicated in learning associations between sensory cues and profitable motor responses. However, the precise mechanisms that underlie these functions remain unclear. We recorded single-neuron activity from the NAcc of primates trained to perform a visual-motor associative learning task. During learning, we found two distinct classes of NAcc neurons. The first class demonstrated progressive increases in firing rates at the go-cue, feedback/tone and reward epochs of the task, as novel associations were learned. This suggests that these neurons may play a role in the exploitation of rewarding behaviors. In contrast, the second class exhibited attenuated firing rates, but only at the reward epoch of the task. These findings suggest that some NAcc neurons play a role in reward-based reinforcement during learning. PMID:24765069

  8. Nutrient-driven O-GlcNAc cycling - think globally but act locally.

    PubMed

    Harwood, Katryn R; Hanover, John A

    2014-05-01

    Proper cellular functioning requires that cellular machinery behave in a spatiotemporally regulated manner in response to global changes in nutrient availability. Mounting evidence suggests that one way this is achieved is through the establishment of physically defined gradients of O-GlcNAcylation (O-linked addition of N-acetylglucosamine to serine and threonine residues) and O-GlcNAc turnover. Because O-GlcNAcylation levels are dependent on the nutrient-responsive hexosamine signaling pathway, this modification is uniquely poised to inform upon the nutritive state of an organism. The enzymes responsible for O-GlcNAc addition and removal are encoded by a single pair of genes: both the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA, also known as MGEA5) genes are alternatively spliced, producing protein variants that are targeted to discrete cellular locations where they must selectively recognize hundreds of protein substrates. Recent reports suggest that in addition to their catalytic functions, OGT and OGA use their multifunctional domains to anchor O-GlcNAc cycling to discrete intracellular sites, thus allowing them to establish gradients of deacetylase, kinase and phosphatase signaling activities. The localized signaling gradients established by targeted O-GlcNAc cycling influence many important cellular processes, including lipid droplet remodeling, mitochondrial functioning, epigenetic control of gene expression and proteostasis. As such, the tethering of the enzymes of O-GlcNAc cycling appears to play a role in ensuring proper spatiotemporal responses to global alterations in nutrient supply. PMID:24762810

  9. The active site of O-GlcNAc transferase imposes constraints on substrate sequence

    PubMed Central

    Rafie, Karim; Blair, David E.; Borodkin, Vladimir S.; Albarbarawi, Osama; van Aalten, Daan M. F.

    2016-01-01

    O-GlcNAc transferase (OGT) glycosylates a diverse range of intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc), an essential and dynamic post-translational modification in metazoa. Although this enzyme modifies hundreds of proteins with O-GlcNAc, it is not understood how OGT achieves substrate specificity. In this study, we describe the application of a high-throughput OGT assay on a library of peptides. The sites of O-GlcNAc modification were mapped by ETD-mass spectrometry, and found to correlate with previously detected O-GlcNAc sites. Crystal structures of four acceptor peptides in complex with human OGT suggest that a combination of size and conformational restriction defines sequence specificity in the −3 to +2 subsites. This work reveals that while the N-terminal TPR repeats of hOGT may play a role in substrate recognition, the sequence restriction imposed by the peptide-binding site makes a significant contribution to O-GlcNAc site specificity. PMID:26237509

  10. Vimentin and desmin possess GlcNAc-binding lectin-like properties on cell surfaces.

    PubMed

    Ise, Hirohiko; Kobayashi, Satoshi; Goto, Mitsuaki; Sato, Takao; Kawakubo, Masatomo; Takahashi, Masafumi; Ikeda, Uichi; Akaike, Toshihiro

    2010-07-01

    Vimentin and desmin are intermediate filament proteins found in various mesenchymal and skeletal muscle cells, respectively. These proteins play an important role in the stabilization of the cytoplasmic architecture. Here, we found, using artificial biomimicking glycopolymers, that vimentin and desmin possess N-acetylglucosamine (GlcNAc)-binding lectin-like properties on the cell surfaces of various vimentin- and desmin-expressing cells such as cardiomyocytes and vascular smooth muscle cells. The rod II domain of these proteins was demonstrated to be localized to the cell surface and to directly bind to the artificial biomimicking GlcNAc-bearing polymer, by confocal laser microscopy and surface plasmon resonance analysis. These glycopolymers strongly interact with lectins and are useful tools for the analysis of lectin-carbohydrate interactions, since glycopolymers binding to lectins can induce the clustering of lectins due to multivalent glycoside ligand binding. Moreover, immunocytochemistry and pull-down assay with His-tagged vimentin-rod II domain protein showed that the vimentin-rod II domain interacts with O-GlcNAc proteins. These results suggest that O-GlcNAc proteins might be one candidate for physiological GlcNAc-bearing ligands with which vimentin and desmin interact. These findings demonstrate a novel function of vimentin and desmin that does not involve stabilization of the cytoplasmic architecture by which these proteins interact with physiological GlcNAc-bearing ligands such as O-GlcNAc proteins on the cell surface through their GlcNAc-binding lectin-like properties. PMID:20332081

  11. Muscarinic acetylcholine receptors in the nucleus accumbens core and shell contribute to cocaine priming-induced reinstatement of drug seeking

    PubMed Central

    Yee, Judy; Famous, Katie R.; Hopkins, Thomas J.; McMullen, Michael C.; Pierce, R. Christopher; Schmidt, Heath D.

    2011-01-01

    Muscarinic acetylcholine receptors in the nucleus accumbens play an important role in mediating the reinforcing effects of cocaine. However, there is a paucity of data regarding the role of accumbal muscarinic acetylcholine receptors in the reinstatement of cocaine-seeking behavior. The goal of these experiments was to assess the role of muscarinic acetylcholine receptors in the nucleus accumbens core and shell in cocaine and sucrose priming-induced reinstatement. Rats were initially trained to self-administer cocaine or sucrose on a fixed-ratio schedule of reinforcement. Lever-pressing behavior was then extinguished and followed by a subsequent reinstatement phase during which operant responding was induced by either a systemic injection of cocaine in cocaine-experienced rats or non-contingent delivery of sucrose pellets in subjects with a history of sucrose self-administration. Results indicated that systemic administration of the muscarinic acetylcholine receptor antagonist scopolamine (5.0 mg/kg, i.p.) dose-dependently attenuated cocaine, but not sucrose, reinstatement. Furthermore, administration of scopolamine (36.0 μg) directly into the nucleus accumbens shell or core attenuated cocaine-priming induced reinstatement. In contrast, infusion of scopolamine (36.0 μg) directly into the accumbens core, but not shell, attenuated sucrose reinstatement, which suggests that muscarinic acetylcholine receptors in these two subregions of the nucleus accumbens have differential roles in sucrose seeking. Taken together, these results indicate that cocaine-priming induced reinstatement is mediated, in part, by increased signaling through muscarinic acetylcholine receptors in the shell subregion of the nucleus accumbens. Muscarinic acetylcholine receptors in the core of the accumbens, in contrast, appear to play a more general (i.e. not cocaine specific) role in motivated behaviors. PMID:21034738

  12. The Novel Wheat Transcription Factor TaNAC47 Enhances Multiple Abiotic Stress Tolerances in Transgenic Plants

    PubMed Central

    Zhang, Lina; Zhang, Lichao; Xia, Chuan; Zhao, Guangyao; Jia, Jizeng; Kong, Xiuying

    2016-01-01

    NAC transcription factors play diverse roles in plant development and responses to abiotic stresses. However, the biological roles of NAC family members in wheat are not well understood. Here, we reported the isolation and functional characterization of a novel wheat TaNAC47 gene. TaNAC47 encoded protein, localizing in the nucleus, is able to bind to the ABRE cis-element and transactivate transcription in yeast, suggesting that it likely functions as a transcriptional activator. We also showed that TaNAC47 is differentially expressed in different tissues, and its expression was induced by the stress treatments of salt, cold, polyethylene glycol and exogenous abscisic acid. Furthermore, overexpression of TaNAC47 in Arabidopsis resulted in ABA hypersensitivity and enhancing tolerance of transgenic plants to drought, salt, and freezing stresses. Strikingly, overexpression of TaNAC47 was found to activate the expression of downstream genes and change several physiological indices that may enable transgenic plants to overcome unfavorable environments. Taken together, these results uncovered an important role of wheat TaNAC47 gene in response to ABA and abiotic stresses. PMID:26834757

  13. The effects of GABAA and NMDA receptors in the shell-accumbens on spatial memory of METH-treated rats.

    PubMed

    Heysieattalab, Soomaayeh; Naghdi, Nasser; Zarrindast, Mohammad-Reza; Haghparast, Abbas; Mehr, Shahram Ejtemaei; Khoshbouei, Habibeh

    2016-03-01

    Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment and deficits in hippocampal plasticity. Striatal dopamine system is one of the main targets of METH. The dopamine neurons in the striatum directly or indirectly regulate the GABA and glutamatergic signaling in this region and thus their outputs. This is consistent with previous reports showing modification of neuronal activity in the striatum modulates the expression of hippocampal LTP and hippocampal-dependent memory tasks such as Morris water maze (MWM). Therefore, reversing or preventing METH-induced synaptic modifications via pharmacological manipulations of the shell-nucleus accumbens (shell-NAc) may introduce a viable therapeutic target to attenuate the METH-induced memory deficits. This study is designed to investigate the role of intra-shell NAc manipulation of GABAA and NMDA receptors and their interaction with METH on memory performance in MWM task. Pharmacological manipulations were performed in rats received METH or saline. We found systemic saline plus intra-shell NAc infusions of muscimol dose-dependently impaired performance, while bicuculline had no effect. Surprisingly, the intra-NAc infusions of 0.005μg/rat muscimol that has no effect on memory performance (ineffective dose) prevented METH-induced memory impairment. In the contrary, the intra-NAc infusions of bicuculline (0.2μg/rat) increased METH-induced memory impairment. However, pre-training intra-NAc infusions of D-AP5 dose-dependently impaired performance, while NMDA had no effect in rats received systemic saline (control group). The intra-NAc infusions with an ineffective dose of NMDA (0.1μg/rat) increased METH-induced memory impairment. Furthermore, intra-NAc infusions of D-AP5 with an ineffective dose (0.1μg/rat) prevented METH-induced memory impairment. Our result is consistent with the interpretation that METH-mediated learning deficit

  14. Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity.

    PubMed

    Vazquez-DeRose, Jacqueline; Stauber, Gregory; Khroyan, Taline V; Xie, Xinmin Simon; Zaveri, Nurulain T; Toll, Lawrence

    2013-01-15

    Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0μM, 10μM, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction. PMID:23219985

  15. Orexin in Rostral Hotspot of Nucleus Accumbens Enhances Sucrose 'Liking' and Intake but Scopolamine in Caudal Shell Shifts 'Liking' Toward 'Disgust' and 'Fear'.

    PubMed

    Castro, Daniel C; Terry, Rachel A; Berridge, Kent C

    2016-07-01

    The nucleus accumbens (NAc) contains a hedonic hotspot in the rostral half of medial shell, where opioid agonist microinjections are known to enhance positive hedonic orofacial reactions to the taste of sucrose ('liking' reactions). Within NAc shell, orexin/hypocretin also has been reported to stimulate food intake and is implicated in reward, whereas blockade of muscarinic acetylcholine receptors by scopolamine suppresses intake and may have anti-reward effects. Here, we show that NAc microinjection of orexin-A in medial shell amplifies the hedonic impact of sucrose taste, but only within the same anatomically rostral site, identical to the opioid hotspot. By comparison, at all sites throughout medial shell, orexin microinjections stimulated 'wanting' to eat, as reflected by increases in intake of palatable sweet chocolates. At NAc shell sites outside the hotspot, orexin selectively enhanced 'wanting' to eat without enhancing sweetness 'liking' reactions. In contrast, microinjections of the antagonist scopolamine at all sites in NAc shell suppressed sucrose 'liking' reactions as well as suppressing intake of palatable food. Conversely, scopolamine increased aversive 'disgust' reactions elicited by bitter quinine at all NAc shell sites. Finally, scopolamine microinjections localized to the caudal half of medial shell additionally generated a fear-related anti-predator reaction of defensive treading and burying directed toward the corners of the transparent chamber. Together, these results confirm a rostral hotspot in NAc medial shell as a unique site for orexin induction of hedonic 'liking' enhancement, similar to opioid enhancement. They also reveal distinct roles for orexin and acetylcholine signals in NAc shell for hedonic reactions and motivated behaviors. PMID:26787120

  16. Behavioral and Structural Responses to Chronic Cocaine Require a Feed-Forward Loop Involving ΔFosB and CaMKII in the Nucleus Accumbens Shell

    PubMed Central

    Robison, Alfred J.; Vialou, Vincent; Mazei-Robison, Michelle; Feng, Jian; Kourrich, SaÏd; Collins, Miles; Wee, Sunmee; Koob, George; Turecki, Gustavo; Neve, Rachael; Thomas, Mark; Nestler, Eric J.

    2013-01-01

    The transcription factor ΔFosB and the brain-enriched protein kinase CaMKIIα (calcium/calmodulin-dependent protein kinase II) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, where the two proteins mediate sensitized drug responses. Although ΔFosB and CaMKIIα both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27, and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D1-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of ΔFosB are both CaMKII-dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB and CaMKII engage in a cell type- and brain region-specific positive feed-forward loop as a key mechanism for regulating the brain’s reward circuitry in response to chronic cocaine. PMID:23467346

  17. Oxytocin in the nucleus accumbens core reduces reinstatement of methamphetamine-seeking behaviour in rats.

    PubMed

    Baracz, Sarah J; Everett, Nicholas A; McGregor, Iain S; Cornish, Jennifer L

    2016-03-01

    The psychostimulant methamphetamine (METH) is an addictive illicit drug. Systemic administration of the neuropeptide oxytocin modulates METH-related reward and METH-seeking behaviour. Recent findings demonstrated a reduction in METH-induced reward by oxytocin administration into the nucleus accumbens (NAc) core. It is not known, however, if oxytocin acts in this region to reduce relapse to METH-seeking behaviour. Using the drug reinstatement paradigm in rats experienced at METH self-administration, we aimed to determine whether oxytocin pre-treatment within the NAc core would reduce relapse to METH use and if this could be reversed by the co-administration of the oxytocin receptor (OTR) antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT. Male Sprague-Dawley rats underwent surgery to implant an intravenous jugular vein catheter and bilateral microinjection cannulae in the NAc core. Rats were then trained to self-administer intravenous METH (0.1 mg/kg/infusion) by lever press during 2-hour fixed ratio 1 scheduled sessions for 20 days. Following extinction of lever press activity, the effect of microinjecting saline, oxytocin (0.5 pmol, 1.5 pmol, 4.5 pmol) or co-administration of oxytocin (1.5 pmol) and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT (1 nmol, 3 nmol) in the NAc core (500 nl/side) was examined on METH-primed (1 mg/kg, i.p.) reinstatement of drug-seeking behaviour. Our results showed oxytocin directly administered into the NAc core decreased METH-primed reinstatement in a dose-dependent manner. Co-administration of the selective OTR antagonist did not specifically reverse the inhibitory effects of oxytocin on METH priming, suggesting mediation by receptors other than the OTR. These findings highlight an important modulatory effect of oxytocin in the NAc core on relapse to METH seeking. PMID:25399704

  18. Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement.

    PubMed

    Hearing, Matthew C; Jedynak, Jakub; Ebner, Stephanie R; Ingebretson, Anna; Asp, Anders J; Fischer, Rachel A; Schmidt, Clare; Larson, Erin B; Thomas, Mark John

    2016-01-19

    Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type-specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10-14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies. PMID:26739562

  19. Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

    PubMed Central

    Hearing, Matthew C.; Jedynak, Jakub; Ebner, Stephanie R.; Ingebretson, Anna; Asp, Anders J.; Fischer, Rachel A.; Schmidt, Clare; Larson, Erin B.; Thomas, Mark John

    2016-01-01

    Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type–specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10–14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies. PMID:26739562

  20. The National Astronomy Consortium (NAC) - Overview

    NASA Astrophysics Data System (ADS)

    Sheth, Kartik; Mills, Elisabeth A. C.; Hooper, Eric; National Astronomy Consortium

    2015-01-01

    The National Astronomy Consortium (NAC; see https://sites.google.com/site/nraonac/) is a growing national partnership between majority and minority universities and institutions with the goal of increasing the numbers of under-represented minorities and students who might otherwise be overlooked by the traditional academic pipeline into STEM, or related, careers. The NAC model is based on the successful 'Posse Foundation' model for undergraduate success and incorporates all its major components: pre-training of cohorts to prepare them for the research experience, joint weekly cohort activities throughout the research summer, peer- and multiple mentoring, weekly discussion of various aspects of professional and career development, continued engagement of students in science after return to home institution and lifelong mentoring. The mentors also form a cohort, exchanging information and learning from each other. With its partner institutions, the NAC aims to build a complete pipeline from undergraduate through career for the next generation of scientists and engineers. Our annual goal is to create two to three cohorts of four to five students at each site (currently NRAO-Charlottesville, NRAO-Socorro and U. Wisconsin - Madison). Recruitment occurs in the fall semester with seminars and colloquia in partnership with faculty at the minority serving institutions and the GRAD-MAP program at the University of Maryland. In this talk we describe in detail all the components of the NAC and report on our progress. We are keen to interact and partner with new universities and institutions and encourage them to contact the NAC at nac4stem@googlegroups.com.

  1. Overexpression of a Novel NAC Domain-Containing Transcription Factor Gene (AaNAC1) Enhances the Content of Artemisinin and Increases Tolerance to Drought and Botrytis cinerea in Artemisia annua.

    PubMed

    Lv, Zongyou; Wang, Shu; Zhang, Fangyuan; Chen, Lingxian; Hao, Xiaolong; Pan, Qifang; Fu, Xueqing; Li, Ling; Sun, Xiaofen; Tang, Kexuan

    2016-09-01

    The NAC (NAM, ATAF and CUC) superfamily is one of the largest plant-specific transcription factor families. NAC transcription factors always play important roles in response to various abiotic stresses. A NAC transcription factor gene AaNAC1 containing a complete open reading frame (ORF) of 864 bp was cloned from Artemisia annua. The expression of AaNAC1 could be induced by dehydration, cold, salicylic acid (SA) and methyl jasmonate (MJ), suggesting that it might be a key regulator of stress signaling pathways in A. annua. AaNAC1 was shown to be localized to the nuclei by transforming tobacco leaf epidermal cells. When AaNAC1 was overexpressed in A. annua, the content of artemisinin and dihydroartemisinic acid was increased by 79% and 150%, respectively. The expression levels of artemisinin biosynthetic pathway genes, i.e. amorpha-4,11-diene synthase (ADS), artemisinic aldehyde Δ11(13) reductase (DBR2) and aldehyde dehydrogenase 1 (ALDH1), were increased. Dual luciferase (dual-LUC) assays showed that AaNAC1 could activate the transcription of ADS in vivo. The transgenic A. annua exhibited increased tolerance to drought and resistance to Botrytis cinerea. When AaNAC1 was overexpressed in Arabidopsis, the transgenic Arabidopsis were markedly more tolerant to drought. The transgenic Arabidopsis showed increased resistance to B. cinerea. These results indicate that AaNAC1 can potentially be used in transgenic breeding for improving the content of artemisinin and drought tolerance in A. annua. PMID:27388340

  2. New GlcNAc/GalNAc-specific lectin from the ascidian Didemnum ternatanum.

    PubMed

    Molchanova, Valentina; Chikalovets, Irina; Li, Wei; Kobelev, Stanislav; Kozyrevskaya, Svetlana; Bogdanovich, Raisa; Howard, Eric; Belogortseva, Natalia

    2005-05-25

    Previously we isolated GlcNAc-specific lectin (DTL) from the ascidian Didemnum ternatanum by affinity chromatography on cross-linked ovalbumin. Here we report the purification and characterization of new D-GlcNAc/D-GalNAc-specific lectin DTL-A from the same ascidian. This lectin was isolated from non-bound cross-linked ovalbumin fraction and further was purified by gel filtration on Sepharose CL-4B, affinity chromatography on GlcNAc-agarose and gel filtration on Superdex 200. SDS-polyacrylamide gel electrophoresis and gel filtration of purified lectin on Sepharose CL-4B indicates that it exists as large aggregates in the native state. Investigations of the carbohydrate specificity of DTL-A by enzyme-linked lectin assay suggest the multi-specificity of this lectin. DTL-A binds BSM, asialo-BSM as well as heparin and dextran sulfate. The binding of DTL-A to BSM was inhibited by monosaccharides D-GlcNAc and D-GalNAc, their alpha- but not beta-anomers. Among polysaccharides and glycoconjugates, DTL-A binding to BSM was effectively inhibited by BSM, asialo-BSM, pronase-treated BSM and synthetic alpha-D-GalNAc-PAA. Fetuin and asialofetuin showed a much lower inhibitory potency, heparin and dextran sulfate were noninhibitory. On the other hand, DTL-A binding to heparin was effectively inhibited by dextran sulfate, fucoidan, whereas BSM showed insignificantly inhibitory effect. DTL-A binding to heparin was not inhibited by D-GlcNAc and D-GalNAc. PMID:15784180

  3. Opposite Effects of mGluR1a and mGluR5 Activation on Nucleus Accumbens Medium Spiny Neuron Dendritic Spine Density.

    PubMed

    Gross, Kellie S; Brandner, Dieter D; Martinez, Luis A; Olive, M Foster; Meisel, Robert L; Mermelstein, Paul G

    2016-01-01

    The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capable of having distinct effects on cellular plasticity. We investigated the individual effects of mGluR1a or mGluR5 activation on dendritic spine density in medium spiny neurons in the nucleus accumbens (NAc), which has become relevant with the potential use of group I mGluR based therapeutics in the treatment of drug addiction. We found that systemic administration of mGluR subtype-specific positive allosteric modulators had opposite effects on dendritic spine densities. Specifically, mGluR5 positive modulation decreased dendritic spine densities in the NAc shell and core, but was without effect in the dorsal striatum, whereas increased spine densities in the NAc were observed with mGluR1a positive modulation. Additionally, direct activation of mGluR5 via CHPG administration into the NAc also decreased the density of dendritic spines. These data provide insight on the ability of group I mGluRs to induce structural plasticity in the NAc and demonstrate that the group I mGluRs are capable of producing not just distinct, but opposing, effects on dendritic spine density. PMID:27618534

  4. Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress

    PubMed Central

    Warren, Brandon L; Sial, Omar K.; Alcantara, Lyonna F.; Greenwood, Maria A.; Brewer, Jacob S.; Rozofsky, John P.; Parise, Eric M.; Bolaños-Guzmán, Carlos A.

    2014-01-01

    Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional or physical stress on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day [PD] 35) or adult (eight-week old) mice were exposed to emotional (ES) or physical stress (PS) using a vicarious social defeat paradigm. Twenty-four hours after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted ERK2, reduced transcription of ΔFosB, and had no effect on CREB mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent-exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice, and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc. PMID:24943326

  5. Prolonged Consumption of Sucrose in a Binge-Like Manner, Alters the Morphology of Medium Spiny Neurons in the Nucleus Accumbens Shell

    PubMed Central

    Klenowski, Paul M.; Shariff, Masroor R.; Belmer, Arnauld; Fogarty, Matthew J.; Mu, Erica W. H.; Bellingham, Mark C.; Bartlett, Selena E.

    2016-01-01

    The modern diet has become highly sweetened, resulting in unprecedented levels of sugar consumption, particularly among adolescents. While chronic long-term sugar intake is known to contribute to the development of metabolic disorders including obesity and type II diabetes, little is known regarding the direct consequences of long-term, binge-like sugar consumption on the brain. Because sugar can cause the release of dopamine in the nucleus accumbens (NAc) similarly to drugs of abuse, we investigated changes in the morphology of neurons in this brain region following short- (4 weeks) and long-term (12 weeks) binge-like sucrose consumption using an intermittent two-bottle choice paradigm. We used Golgi-Cox staining to impregnate medium spiny neurons (MSNs) from the NAc core and shell of short- and long-term sucrose consuming rats and compared these to age-matched water controls. We show that prolonged binge-like sucrose consumption significantly decreased the total dendritic length of NAc shell MSNs compared to age-matched control rats. We also found that the restructuring of these neurons resulted primarily from reduced distal dendritic complexity. Conversely, we observed increased spine densities at the distal branch orders of NAc shell MSNs from long-term sucrose consuming rats. Combined, these results highlight the neuronal effects of prolonged binge-like intake of sucrose on NAc shell MSN morphology. PMID:27047355

  6. Characterization of a novel wheat NAC transcription factor gene involved in defense response against stripe rust pathogen infection and abiotic stresses.

    PubMed

    Xia, Ning; Zhang, Gang; Liu, Xin-Ying; Deng, Lin; Cai, Gao-Lei; Zhang, Yi; Wang, Xiao-Jie; Zhao, Jie; Huang, Li-Li; Kang, Zhen-Sheng

    2010-12-01

    Proteins encoded by the NAC gene family constitute one of the largest plant-specific transcription factors, which have been identified to play many important roles in both abiotic and biotic stress adaptation, as well as in plant development regulation. In the current paper, a full-length cDNA sequence of a novel wheat NAC gene, designated as TaNAC4, was isolated using in silico cloning and the reverse transcription PCR (RT-PCR) methods. TaNAC4 sharing high homology with rice OsNAC4 gene was predicted to encode a protein of 308 amino acid residues, which contained a plant-specific NAC domain in the N-terminus. Transient expression analysis indicated that the deduced TaNAC4 protein was localized in the nucleus of onion epidemical cells. Yeast one-hybrid assay revealed that the C-terminal region of the TaNAC4 protein had transcriptional activity. The expression of TaNAC4 was largely higher in the wheat seedling roots, than that in leaves and stems. TaNAC4 transcript in wheat leaves was induced by the infection of strip rust pathogen, and also by exogenous applied methyl jasmonate (MeJA), ABA and ethylene. However, salicylic acid (SA) had no obvious effect on TaNAC4 expression. Environmental stimuli, including high salinity, wounding, and low-temperature also induced TaNAC4 expression. These results indicate that this novel TaNAC4 gene functions as a transcriptional activator involved in wheat response to biotic and abiotic stresses. PMID:20213512

  7. D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell.

    PubMed

    Kalyanasundar, B; Perez, Claudia I; Luna, Alvaro; Solorio, Jessica; Moreno, Mario G; Elias, David; Simon, Sidney A; Gutierrez, Ranier

    2015-07-01

    Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds. PMID:25972577

  8. D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell

    PubMed Central

    Kalyanasundar, B.; Perez, Claudia I.; Luna, Alvaro; Solorio, Jessica; Moreno, Mario G.; Elias, David; Simon, Sidney A.

    2015-01-01

    Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds. PMID:25972577

  9. Ethanol attenuation of long term depression in the nucleus accumbens can be overcome by activation of TRPV1 receptors

    PubMed Central

    Renteria, Rafael; Jeanes, Zachary M.; Morrisett, Richard A.

    2014-01-01

    Background Altered expression of synaptic plasticity within the nucleus accumbens (NAc) constitutes a critical neuroadaptive response to ethanol and other drugs of abuse. We have previously reported that NMDA receptor-dependent long-term depression (LTD) is markedly affected by chronic intermittent ethanol exposure in vivo; however, endocannabinoid (eCB)-dependent synaptic depression, despite being very well-documented in the dorsal striatum, is much less well understood in the NAc. Methods Whole cell patch clamp electrophysiology was used to investigate interactions between these different plasticity-induction systems. Excitatory postsynaptic currents (EPSCs) were measured in the NAc shell and NMDAR-LTD was induced by a pairing protocol (500 stimuli @ 1 Hz stimulation (LFS) paired with postsynaptic depolarization to −50 mV). AM251, a CB1 receptor antagonist, was used to determine whether this form of LTD is modulated by eCBs. To determine the effect of ethanol on a purely eCB-dependent response in the NAc, depolarization-induced suppression of excitation (DSE) was used in the presence of 40 mM ethanol. Finally, we determined whether the enhancement of eCB signaling with URB597, a fatty acid amide hydrolase inhibitor, and AM404, an anandamide reuptake inhibitor would also modulate LFS LTD in the presence of NMDA-receptor blockade or ethanol. Results In the presence of AM251, the LFS pairing protocol resulted in NMDA receptor-dependent long-term potentiation (LTP) that was blocked with either ethanol or DL-APV. We also found that DSE in the NAc shell was blocked by AM251 and suppressed by ethanol. Enhanced eCB signaling rescued NAc LTD expression in the presence of ethanol through a distinct mechanism requiring activation of TRPV1 receptors. Conclusion Ethanol modulation of synaptic plasticity in the NAc is dependent upon a complex interplay between NMDA receptors, eCBs and TRPV1 receptors. These findings demonstrate a novel form of TRPV1-dependent LTD in the NAc

  10. Influence of olfactory bulbectomy on maternal behavior and dopaminergic function in nucleus accumbens in mice.

    PubMed

    Sato, Atsushi; Nakagawasai, Osamu; Tan-No, Koichi; Onogi, Hiroshi; Niijima, Fukie; Tadano, Takeshi

    2010-12-20

    Olfactory bulbectomy (OBX) induces behavioral, physiological, and neurochemical alterations resembling clinical depression and is widely used as an animal model of depression. It has been reported that depression is a critical cause of child abuse and neglect and that maternal behavior involves dopaminergic neurons of the mesolimbic pathway. In a previous study we found that OBX mice show maternal behavior deficits which are improved by administration of apomorphine, a non-selective dopamine agonist. Therefore, in this study, we investigated the effect of l-3,4-dihydroxyphenylalanine (l-DOPA) on maternal behavior deficits to examine the influence of pre-synaptic dopaminergic function in OBX mice. Furthermore, we measured tyrosine hydroxylase (TH) levels using microphotometry and quantified dopamine D1- and D2-like receptors using autoradiography in the nucleus accumbens (NAc). As a result, 25mg/kg l-DOPA with 12.5mg/kg benserazide improved disrupted maternal behavior in OBX mice and there are no changes in TH levels or number of D1- and D2-like receptors between sham and OBX mothers. The behavioral data support the hypothesis that changed dopaminergic function may contribute to maternal behavior deficits in OBX mice. However, our findings concerning dopaminergic function suggest that the deficits in OBX mice are not simply due to changes in TH levels or dopamine receptor number in the NAc. PMID:20638419

  11. Dopamine and opioid systems interact within the nucleus accumbens to maintain monogamous pair bonds

    PubMed Central

    Resendez, Shanna L; Keyes, Piper C; Day, Jeremy J; Hambro, Caely; Austin, Curtis J; Maina, Francis K; Eidson, Lori N; Porter-Stransky, Kirsten A; Nevárez, Natalie; McLean, J William; Kuhnmuench, Morgan A; Murphy, Anne Z; Mathews, Tiffany A; Aragona, Brandon J

    2016-01-01

    Prairie vole breeder pairs form monogamous pair bonds, which are maintained through the expression of selective aggression toward novel conspecifics. Here, we utilize behavioral and anatomical techniques to extend the current understanding of neural mechanisms that mediate pair bond maintenance. For both sexes, we show that pair bonding up-regulates mRNA expression for genes encoding D1-like dopamine (DA) receptors and dynorphin as well as enhances stimulated DA release within the nucleus accumbens (NAc). We next show that D1-like receptor regulation of selective aggression is mediated through downstream activation of kappa-opioid receptors (KORs) and that activation of these receptors mediates social avoidance. Finally, we also identified sex-specific alterations in KOR binding density within the NAc shell of paired males and demonstrate that this alteration contributes to the neuroprotective effect of pair bonding against drug reward. Together, these findings suggest motivational and valence processing systems interact to mediate the maintenance of social bonds. DOI: http://dx.doi.org/10.7554/eLife.15325.001 PMID:27371827

  12. Role of GluR1 expression in nucleus accumbens neurons in cocaine sensitization and cocaine-seeking behavior.

    PubMed

    Bachtell, Ryan K; Choi, Kwang-Ho; Simmons, Diana L; Falcon, Edgardo; Monteggia, Lisa M; Neve, Rachael L; Self, David W

    2008-05-01

    Chronic cocaine use reduces glutamate levels in the nucleus accumbens (NAc), and is associated with experience-dependent changes in (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor membrane expression in NAc neurons. These changes accompany behavioral sensitization to cocaine and increased susceptibility to cocaine relapse. The functional relationship between neuroplasticity in AMPA receptors and the behavioral manifestation of cocaine addiction remains unclear. Thus, we examined the behavioral effects of up- and downregulating basal AMPA receptor function in the NAc core and shell using viral-mediated gene transfer of wild-type glutamate receptor 1 (wt-GluR1) or a dominant-negative pore-dead GluR1 (pd-GluR1), respectively. Transient increases in wt-GluR1 during or after cocaine treatments diminished the development of cocaine sensitization, while pd-GluR1 expression exacerbated cocaine sensitization. Parallel changes were found in D2, but not D1, receptor-mediated behavioral responses. As a correlate of the sensitization experiments, we overexpressed wt- or pd-GluR1 in the NAc core during cocaine self-administration, and tested the effects on subsequent drug-seeking behavior 3 weeks after overexpression declined. wt-GluR1 overexpression during self-administration had no effect on cocaine intake, but subsequently reduced cocaine seeking in extinction and cocaine-induced reinstatement, whereas pd-GluR1 facilitated cocaine-induced reinstatement. When overexpressed during reinstatement tests, wt-GluR1 directly attenuated cocaine- and D2 agonist-induced reinstatement, while pd-GluR1 enhanced reinstatement. In both experimental procedures, neither wt- nor pd-GluR1 expression affected cue-induced reinstatement. Together, these results suggest that degrading basal AMPA receptor function in NAc neurons is sufficient to facilitate relapse via sensitization in D2 receptor responses, whereas elevating basal AMPA receptor function

  13. MC4-R signaling within the nucleus accumbens shell, but not the lateral hypothalamus, modulates ethanol palatability in rats.

    PubMed

    Lerma-Cabrera, Jose M; Carvajal, Francisca; Chotro, Gabriela; Gaztañaga, Mirari; Navarro, Montserrat; Thiele, Todd E; Cubero, Inmaculada

    2013-02-15

    The Melanocortin (MC) system is one of the crucial neuropeptidergic systems that modulate energy balance. The roles of endogenous MC and MC-4 receptor (MC4-R) signaling within the hypothalamus in the control of homeostatic aspects of feeding are well established. Additional evidence points to a key role for the central MC system in ethanol consumption. Recently, we have shown that nucleus accumbens (NAc), but not lateral hypothalamic (LH), infusion of a selective MC4-R agonist decreases ethanol consumption. Given that MC signaling might contribute to non-homeostatic aspects of feeding within limbic circuits, we assessed here whether MC4-R signaling within the NAc and the lateral hypothalamus (LH) alters normal ingestive hedonic and/or aversive responses to ethanol in rats as measured by a taste reactivity test. Adult male Sprague-Dawley rats were given NAc- or LH- bilateral infusion of the selective MC4-R agonist cyclo (NH-CH(2)-CH(2)-CO-His-D-Phe-Arg-Trp-Glu)-NH(2) (0, 0.75 or 1.5μg/0.5μl/site) and following 30 min, the animals received 1 ml of ethanol solution (6% w/v) intraoral for 1 minute and aversive and hedonic behaviors were recorded. We found that NAc-, but not LH-administration, of a selective MC4-R agonist decreased total duration of hedonic reactions and significantly increased aversive reactions relative to saline-infused animals which support the hypothesis that MC signaling within the NAc may contribute to ethanol consumption by modulating non-homeostatic aspects (palatability) of intake. PMID:23146409

  14. AMPA receptor upregulation in the nucleus accumbens shell of cocaine-sensitized rats depends upon S-nitrosylation of stargazin

    PubMed Central

    Milovanovic, Mike; Park, Diana J.; West, Anthony R.; Snyder, Solomon H.; Wolf, Marina E.

    2014-01-01

    Behavioral sensitization to cocaine is associated with increased AMPA receptor (AMPAR) surface expression in the nucleus accumbens (NAc). This upregulation is withdrawal-dependent, as it is not detected on withdrawal day (WD) 1, but is observed on WD7–21. Its underlying mechanisms have not been clearly established. Nitric oxide (NO) regulates AMPAR trafficking in the brain by S-nitrosylation of the AMPAR auxiliary subunit, stargazin, leading to increased AMPAR surface expression. Our goal was to determine if stargazin S-nitrosylation contributes to AMPAR upregulation during sensitization. First, we measured stargazin S-nitrosylation in NAc core and shell subregions on WD14 after 8 daily injections of saline or 15mg/kg cocaine. Stargazin S-nitrosylation was markedly increased in NAc shell but not core. To determine if this is associated with AMPAR upregulation, rats received 8 cocaine or saline injections followed by twice-daily treatments with vehicle or the nitric oxide synthase inhibitor L-NAME (50mg/kg) on WD1–6, the time when AMPAR upregulation is developing in cocaine-exposed rats. Cocaine/vehicle rats showed elevated stargazin and GluA1 surface expression on WD7 compared to saline/vehicle rats; the GluA1 increase was more robust in core, while stargazin increased more robustly in shell. These effects of cocaine were attenuated in shell but not core when cocaine injections were followed by L-NAME treatment on WD1–6. Together, these results indicate that elevated S-nitrosylation of stargazin contributes to AMPAR upregulation during sensitization selectively in the NAc shell. It is possible that AMPAR upregulation in core involves a different TARP, γ4, which also upregulates in the NAc of sensitized rats. PMID:24035918

  15. 75 FR 54221 - RTCA NextGen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-03

    ... Federal Aviation Administration RTCA NextGen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of RTCA NextGen Advisory Committee (NAC). SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA NextGen Advisory Committee (NAC). DATES:...

  16. Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats

    PubMed Central

    Diepenbroek, Charlene; van der Plasse, Geoffrey; Eggels, Leslie; Rijnsburger, Merel; Feenstra, Matthijs G. P.; Kalsbeek, Andries; Denys, Damiaan; Fliers, Eric; Serlie, Mireille J.; la Fleur, Susanne E.

    2013-01-01

    Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective therapy for obsessive compulsive disorder (OCD) and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc) influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of 1 h. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA) using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity- dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients. PMID:24339800

  17. Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats.

    PubMed

    Das, Sujan C; Yamamoto, Bryan K; Hristov, Alexandar M; Sari, Youssef

    2015-10-01

    Alteration of glutamatergic-neurotransmission is a hallmark of alcohol dependence. We have previously reported that chronic ethanol-drinking downregulated glutamate transporter 1 (GLT-1) in nucleus accumbens (NAc) in male P rats in a manner that was reversed by ceftriaxone treatment. However, the effect of ceftriaxone on extracellular glutamate concentrations in NAc after chronic ethanol-drinking has not yet been studied. In the present study, male P rats were treated with ceftriaxone (100 mg/kg/day, i.p.) for five consecutive days following five-weeks of free choice ethanol (15% and 30%) drinking. In vivo microdialysis was performed to measure the extracellular glutamate concentrations in NAc and the effect of blockade of GLT-1 with dihydrokainic acid (DHK) on extracellular glutamate in NAc of ceftriaxone-treated rats was determined. Ceftriaxone treatment attenuated ethanol intake as well as ethanol preference. Extracellular glutamate was significantly higher in NAc after five-weeks of ethanol drinking in saline-treated compared to water control rats. Ceftriaxone treatment blocked the increase extracellular glutamate produced by ethanol intake. Blockade of GLT-1 by DHK reversed the effects of ceftriaxone on glutamate and implicated the role of GLT-1 in the normalization of extracellular glutamate by ceftriaxone. In addition, GLT-1 protein was decreased in ethanol exposed animals and ceftriaxone treatment reversed this deficit. Ceftriaxone treatment also increased glutamine synthetase activity in NAc but not in PFC as compared to ethanol drinking saline-treated rats. Our present study demonstrates that ceftriaxone treatment prevents ethanol drinking in part through normalization of extracellular glutamate concentrations in NAc of male P rats via GLT-1. PMID:26002627

  18. mGluR5 activation in the nucleus accumbens is not essential for sexual behavior or cross-sensitization of amphetamine responses by sexual experience.

    PubMed

    Pitchers, K K; Di Sebastiano, A R; Coolen, L M

    2016-08-01

    Natural rewards and psychostimulants cause similar neural plasticity in the nucleus accumbens (NAc). In addition, sexual experience in male rats causes increased locomotor activity and conditioned place preference (CPP) induced by d-Amphetamine (amph). The latter is dependent on a period of abstinence from sexual reward. In this study, the role of mGluR5 activation in the NAc for expression of mating and the cross-sensitizing effects of sexual experience was tested. First, intra-NAc infusions of mGluR5 antagonists MPEP (1 or 10 μg/μL) or MTEP (1 μg/μL) 15 min prior to mating during 4 daily sessions had no effect on male rat sexual behavior. Subsequently, these sexually experienced males were tested for amph-induced locomotor activity and CPP after one week of abstinence from sexual reward. In addition, sexually naïve males that received MPEP, MTEP or vehicle infusions prior to 4 daily handling sessions were included. Cross-sensitization of locomotion or CPP was not prevented by NAc mGluR5 antagonism during acquisition of sexual experience. Instead, sexually naive animals that received NAc mGluR5 antagonists without mating demonstrated sensitized amph-induced locomotor responses and enhanced CPP on par with sexually experienced males. Finally, we showed that sexual experience caused prolonged down-regulation of mGluR5 protein in the NAc, dependent on abstinence from sexual behavior. Together, these findings suggest that mGluR5 activation in the NAc is not essential for the expression of mating, but that experience-induced reduction in mGluR5 protein may contribute to the cross-sensitization of amph responses by sexual experience and abstinence. PMID:26946431

  19. Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats.

    PubMed

    Diepenbroek, Charlene; van der Plasse, Geoffrey; Eggels, Leslie; Rijnsburger, Merel; Feenstra, Matthijs G P; Kalsbeek, Andries; Denys, Damiaan; Fliers, Eric; Serlie, Mireille J; la Fleur, Susanne E

    2013-01-01

    Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective therapy for obsessive compulsive disorder (OCD) and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc) influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of 1 h. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA) using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity- dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients. PMID:24339800

  20. Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell.

    PubMed

    Rada, P; Avena, N M; Hoebel, B G

    2005-01-01

    Most drugs of abuse increase dopamine (DA) in the nucleus accumbens (NAc), and do so every time as a pharmacological response. Palatable food also releases accumbens-shell DA, but in naïve rats the effect can wane during a long meal and disappears with repetition. Under select dietary circumstances, sugar can have effects similar to a drug of abuse. Rats show signs of DA sensitization and opioid dependence when given intermittent access to sucrose, such as alterations in DA and mu-opioid receptors, cross-sensitization with amphetamine and alcohol, and behavioral and neurochemical signs of naloxone-precipitated withdrawal. The present experiment asks whether sucrose-dependent rats release DA each time they binge. We also predict that acetylcholine (ACh), which rises as the end of a meal, will be delayed in rats with intermittent access to sucrose. To create dependency, the experimental group (Daily Intermittent Sucrose) was maintained on a diet of 12-h food deprivation that extended 4 h into the dark, followed by 12-h access to a 10% sucrose solution and chow, daily, for 21 days. As the main result, these rats gradually increased their sucrose intake from 37 to 112 ml per day (from 13 to 20 ml in the first hour of access), and repeatedly increased extracellular DA to 130% of baseline as measured in the NAc shell by microdialysis during the first hour of sucrose access on day 1, day 2 and day 21. Three control groups failed to show a significant increase in extracellular DA on day 21: Sucrose only for 1 h on days 1 and 21 (Sucrose Twice), ad libitum access to sucrose and chow (Daily Ad libitum Sucrose), and intermittent chow instead of sucrose (Daily Intermittent Chow). Acetylcholine measured at the same time as DA, increased significantly toward the end and after each test meal in all groups. In the Daily Intermittent Sucrose group, the highest ACh levels (133%) occurred during the first sample after the sucrose meal ended. In summary, sucrose-dependent animals

  1. Frequency Dependent Effects of Ethanol on Dopamine Release in the Nucleus Accumbens

    PubMed Central

    Yorgason, Jordan T.; Ferris, Mark J.; Steffensen, Scott C.; Jones, Sara R.

    2014-01-01

    Background Ethanol is known to have excitatory effects on dopamine (DA) release, with moderate to high doses (0.5–2.5 g/kg) of acute ethanol enhancing DA neuron firing rates in the ventral tegmental area (VTA) and DA levels in the nucleus accumbens (NAc). Ethanol has also been shown to reduce DA activity, with moderate doses (1–2 g/kg) attenuating electrically evoked release, and higher doses (5 g/kg) decreasing NAc DA levels, demonstrating a biphasic effect of ethanol on DA release. The purpose of the current study was to evaluate ethanol’s inhibitory effects on NAc DA terminal release under low- and high-frequency stimulation conditions. Methods Using fast-scan cyclic voltammetry in NAc slices from C57BL/6J mice, we examined ethanol’s (40–160 mM) effects on DA release under several different stimulation parameters, varying frequency (5–125 Hz), number of pulses (1–10), and stimulation intensity (50–350 µA). Additionally, calcium concentrations were manipulated under high-frequency stimulation conditions (20 Hz, 10 pulses, 350 µA) in order to determine if ethanol’s effects were dependent upon calcium concentration, and by extension, the amount of DA release. Results Acute ethanol (40–160 mM) inhibited DA release to a greater extent under high-frequency, multiple-pulse stimulation conditions, with increased sensitivity at 5 and 10 pulses and frequencies of 20 Hz or higher. High-frequency, multiple-pulse stimulations also resulted in greater DA release compared to single-pulse release, which was controlled by reducing stimulation intensity. Under reduced DA conditions, high-frequency stimulations still showed increased ethanol sensitivity. Reducing calcium levels also decreased DA release at high-frequency stimulations, but did not affect ethanol sensitivity. Conclusions Ethanol appears to inhibit DA release at NAc terminals under high-frequency stimulation conditions that are similar to release events observed during phasic burst firing in

  2. Arabidopsis ROCK1 transports UDP-GlcNAc/UDP-GalNAc and regulates ER protein quality control and cytokinin activity

    PubMed Central

    Niemann, Michael C. E.; Bartrina, Isabel; Ashikov, Angel; Weber, Henriette; Spíchal, Lukáš; Strnad, Miroslav; Strasser, Richard; Bakker, Hans; Schmülling, Thomas; Werner, Tomáš

    2015-01-01

    The formation of glycoconjugates depends on nucleotide sugars, which serve as donor substrates for glycosyltransferases in the lumen of Golgi vesicles and the endoplasmic reticulum (ER). Import of nucleotide sugars from the cytosol is an important prerequisite for these reactions and is mediated by nucleotide sugar transporters. Here, we report the identification of REPRESSOR OF CYTOKININ DEFICIENCY 1 (ROCK1, At5g65000) as an ER-localized facilitator of UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc) transport in Arabidopsis thaliana. Mutant alleles of ROCK1 suppress phenotypes inferred by a reduced concentration of the plant hormone cytokinin. This suppression is caused by the loss of activity of cytokinin-degrading enzymes, cytokinin oxidases/dehydrogenases (CKXs). Cytokinin plays an essential role in regulating shoot apical meristem (SAM) activity and shoot architecture. We show that rock1 enhances SAM activity and organ formation rate, demonstrating an important role of ROCK1 in regulating the cytokinin signal in the meristematic cells through modulating activity of CKX proteins. Intriguingly, genetic and molecular analysis indicated that N-glycosylation of CKX1 was not affected by the lack of ROCK1-mediated supply of UDP-GlcNAc. In contrast, we show that CKX1 stability is regulated in a proteasome-dependent manner and that ROCK1 regulates the CKX1 level. The increased unfolded protein response in rock1 plants and suppression of phenotypes caused by the defective brassinosteroid receptor bri1-9 strongly suggest that the ROCK1 activity is an important part of the ER quality control system, which determines the fate of aberrant proteins in the secretory pathway. PMID:25535363

  3. Characterization of a novel Medicago sativa NAC transcription factor gene involved in response to drought stress.

    PubMed

    Wang, Yong Xin

    2013-11-01

    Relying on the regulation of transcription factors, plants resist to various abiotic and biotic stresses. NAC (NAM, ATAF1/2, CUC2) are one of the largest families of plant-specific transcription factors and known to play important roles in plant development and response to environmental stresses. A new NAC gene was cloned on the basis of 503 bp EST fragment from the SSH cDNA library of Medicago sativa. It was 1,115 bp including an 816 bp ORF and encodes 271 amino acids. A highly conserved region is located from the 7th amino acid to the 315th amino acid in its N-terminal domain. The NAC protein is subcellularly localized in the nucleus of onion epidemical cells and possible functions as a transcription factor. The relative quantitative real-time RT-PCR was performed at different stress time. The results revealed that the transcription expression of NAC gene could be induced by drought, high salinity and ABA. The transgenic Arabidopsis with NAC gene has the drought tolerance better than the wild-type. PMID:24057250

  4. Evaluation of in vitro storage characteristics of cold stored platelet concentrates with N acetylcysteine (NAC).

    PubMed

    Handigund, Mallikarjun; Bae, Tae Won; Lee, Jaehyeon; Cho, Yong Gon

    2016-02-01

    Platelets play a vital role in hemostasis and thrombosis, and their demand and usage has multiplied many folds over the years. However, due to the short life span and storage constraints on platelets, it is allowed to store them for up to 7 days at room temperature (RT); thus, there is a need for an alternative storage strategy for extension of shelf life. Current investigation involves the addition of 50 mM N acetylcysteine (NAC) in refrigerated concentrates. Investigation results revealed that addition of NAC to refrigerated concentrates prevented platelet activation and reduced the sialidase activity upon rewarming as well as on prolonged storage. Refrigerated concentrates with 50 mM NAC expressed a 23.91 ± 6.23% of CD62P (P-Selectin) and 22.33 ± 3.42% of phosphotidylserine (PS), whereas RT-stored platelets showed a 46.87 ± 5.23% of CD62P and 25.9 ± 6.48% of phosphotidylserine (PS) after 5 days of storage. Further, key metabolic parameters such as glucose and lactate accumulation indicated reduced metabolic activity. Taken together, investigation and observations indicate that addition of NAC potentially protects refrigerated concentrates by preventing platelet activation, stabilizing sialidase activity, and further reducing the metabolic activity. Hence, we believe that NAC can be a good candidate for an additive solution to retain platelet characteristics during cold storage and may pave the way for extension of storage shelf life. PMID:26847865

  5. Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making.

    PubMed

    Zalocusky, Kelly A; Ramakrishnan, Charu; Lerner, Talia N; Davidson, Thomas J; Knutson, Brian; Deisseroth, Karl

    2016-03-31

    A marked bias towards risk aversion has been observed in nearly every species tested. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives. It is not known how neural activity underlies such important shifts in decision-making--either as a stable trait across individuals or at the level of variability within individuals. Here we describe a model of risk-preference in rats, in which stable individual differences, trial-by-trial choices, and responses to pharmacological agents all parallel human behaviour. By combining new genetic targeting strategies with optical recording of neural activity during behaviour in this model, we identify relevant temporally specific signals from a genetically and anatomically defined population of neurons. This activity occurred within dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens (NAc), signalled unfavourable outcomes from the recent past at a time appropriate for influencing subsequent decisions, and also predicted subsequent choices made. Having uncovered this naturally occurring neural correlate of risk selection, we then mimicked the temporally specific signal with optogenetic control during decision-making and demonstrated its causal effect in driving risk-preference. Specifically, risk-preferring rats could be instantaneously converted to risk-averse rats with precisely timed phasic stimulation of NAc D2R cells. These findings suggest that individual differences in risk-preference, as well as real-time risky decision-making, can be largely explained by the encoding in D2R-expressing NAc cells of prior unfavourable outcomes during decision-making. PMID:27007845

  6. Opposing Role for Egr3 in Nucleus Accumbens Cell Subtypes in Cocaine Action

    PubMed Central

    Chandra, Ramesh; Francis, T. Chase; Konkalmatt, Prasad; Amgalan, Ariunzaya; Gancarz, Amy M.; Dietz, David M.

    2015-01-01

    An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine D1 versus D2 receptors, is implicated in the behavioral responses to psychostimulants. To provide further insight into the molecular mechanisms occurring in MSN subtypes by cocaine, we examined the transcription factor early growth response 3 (Egr3). We evaluated Egr3 because it is a target of critical cocaine-mediated signaling pathways and because Egr3-binding sites are found on promoters of key cocaine-associated molecules. We first used a RiboTag approach to obtain ribosome-associated transcriptomes from each MSN subtype and found that repeated cocaine administration induced Egr3 ribosome-associated mRNA in NAc D1-MSNs while reducing Egr3 in D2-MSNs. Using Cre-inducible adeno-associated viruses combined with D1-Cre and D2-Cre mouse lines, we observed that Egr3 overexpression in D1-MSNs enhances rewarding and locomotor responses to cocaine, whereas overexpression in D2-MSNs blunts these behaviors. miRNA knock-down of Egr3 in MSN subtypes produced opposite behavioral responses from those observed with overexpression. Finally, we found that repeated cocaine administration altered Egr3 binding to promoters of genes that are important for cocaine-mediated cellular and behavioral plasticity. Genes with increased Egr3 binding to promoters, Camk2α, CREB, FosB, Nr4a2, and Sirt1, displayed increased mRNA in D1-MSNs and, in some cases, a reduction in D2-MSNs. Histone and the DNA methylation enzymes G9a and Dnmt3a displayed reduced Egr3 binding to their promoters and reduced mRNA in D1-MSNs. Our study provides novel insight into an opposing role of Egr3 in select NAc MSN subtypes in cocaine action. PMID:25995477

  7. Regulation of nucleus accumbens transcript levels in mice by early-life social stress and cocaine.

    PubMed

    Lo Iacono, Luisa; Valzania, Alessandro; Visco-Comandini, Federica; Viscomi, Maria Teresa; Felsani, Armando; Puglisi-Allegra, Stefano; Carola, Valeria

    2016-04-01

    Much interest has been piqued regarding the quality of one's environment at early ages in modulating the susceptibility to drug addiction in adulthood. However, the molecular mechanisms that are engaged during early trauma and mediate the risk for drug addiction are poorly understood. In rodents, exposure to early-life stress alters the rewarding effects of cocaine, amphetamine, and morphine in adulthood. Recently, we demonstrated that the exposure of juvenile mice to social threat (Social Stress, S-S) promoted cocaine-seeking behavior and relapse of cocaine-seeking after periods of withdrawal, compared with unhandled controls (UN) and with juvenile mice that experienced only daily isolation in a novel environment (no social stress, NS-S). Interestingly, while the exposure to NS-S slightly increased cocaine-seeking behavior compared with UN, the same was not sufficient to promote cocaine reinstatement. In this study, we examined the long-term transcriptional changes that are induced by S-S compared to NS-S and linked the increased susceptibility of S-S mice to cocaine reinstatement. To this end, we performed genome-wide RNA sequencing analysis in the nucleus accumbens (NAC), which revealed that 89 transcripts were differentially expressed between S-S and NS-S mice. By Gene Ontology classification, these hits were enriched in genes that mediate cell proliferation, neuronal differentiation, and neuron/forebrain development. Eleven of these genes have been reported to be involved in substance use disorders, and the remaining genes are novel candidates in this area. We characterized 4 candidates with regard to their significant neurobiological relevance (ZIC1, ZIC2, FABP7, and PRDM12) and measured their expression in the NAC by immunohistochemistry. These findings provide insights into novel molecular mechanisms in NAC that might be associated with the risk of relapse in cocaine-dependent individuals. PMID:26706499

  8. Nucleus accumbens cocaine-amphetamine regulated transcript mediates food intake during novelty conflict.

    PubMed

    Burghardt, P R; Krolewski, D M; Dykhuis, K E; Ching, J; Pinawin, A M; Britton, S L; Koch, L G; Watson, S J; Akil, H

    2016-05-01

    Obesity is a persistent and pervasive problem, particularly in industrialized nations. It has come to be appreciated that the metabolic health of an individual can influence brain function and subsequent behavioral patterns. To examine the relationship between metabolic phenotype and central systems that regulate behavior, we tested rats with divergent metabolic phenotypes (Low Capacity Runner: LCR vs. High Capacity Runner: HCR) for behavioral responses to the conflict between hunger and environmental novelty using the novelty suppressed feeding (NSF) paradigm. Additionally, we measured expression of mRNA, for peptides involved in energy management, in response to fasting. Following a 24-h fast, LCR rats showed lower latencies to begin eating in a novel environment compared to HCR rats. A 48-h fast equilibrated the latency to begin eating in the novel environment. A 24-h fast differentially affected expression of cocaine-amphetamine regulated transcript (CART) mRNA in the nucleus accumbens (NAc), where 24-h of fasting reduced CART mRNA in LCR rats. Bilateral microinjections of CART 55-102 peptide into the NAc increased the latency to begin eating in the NSF paradigm following a 24-h fast in LCR rats. These results indicate that metabolic phenotype influences how animals cope with the conflict between hunger and novelty, and that these differences are at least partially mediated by CART signaling in the NAc. For individuals with poor metabolic health who have to navigate food-rich and stressful environments, changes in central systems that mediate conflicting drives may feed into the rates of obesity and exacerbate the difficulty individuals have in maintaining weight loss. PMID:26926827

  9. Differential neuronal changes in medial prefrontal cortex, basolateral amygdala and nucleus accumbens after postweaning social isolation.

    PubMed

    Wang, Yu-Chun; Ho, Ue-Cheung; Ko, Meng-Ching; Liao, Chun-Chieh; Lee, Li-Jen

    2012-04-01

    The mesocorticolimbic system contains dopamine (DA)-producing neurons in the ventral tegmental area (VTA) and their projection targets, including the medial prefrontal cortex (mPFC), amygdala (AMY) and nucleus accumbens (NAc). Disruption of this system might attribute to mental illnesses. In the present study, we adopted the postweaning social isolation paradigm to model neuropsychiatric disorders and studied the functional and structural changes of the mesocorticolimbic system. After 8-9 weeks of isolation, rats exhibited hyperlocomotor activity and impaired sensorimotor gating compared to group-reared controls. However, the number of tyrosine hydroxylase-positive VTA neurons and the volume of VTA were not affected. Comparing with group-reared controls, the DA levels in the isolation-reared were not altered in the VTA, mPFC and NAc but decreased in the AMY. In the structural aspect, dendritic features of layer II/III pyramidal mPFC neurons; pyramidal neurons in the basolateral nucleus of amygdala (BLA) and medium spiny neurons in the core region of the NAc (NAcc) were examined. Interestingly, the neuronal changes were region-specific. The mPFC neurons had reduced dendritic complexity, spine density and elongated terminal branches. The BLA neurons had extensive dendritic arbors with short branches but unchanged spine density. The NAcc neurons had reduced total dendritic length but the segment length and spine density remained the same. Together, the results demonstrated the structural and functional changes in the mesocorticolimbic DA system of socially isolated rats. These changes may account for the behavioral impairments in these rats and attribute to the susceptibility to mental disorders related to schizophrenia and depression. PMID:22002740

  10. mGluR5 stimulates gliotransmission in the nucleus accumbens

    PubMed Central

    D'Ascenzo, Marcello; Fellin, Tommaso; Terunuma, Miho; Revilla-Sanchez, Raquel; Meaney, David F.; Auberson, Yves P.; Moss, Stephen J.; Haydon, Philip G.

    2007-01-01

    Although metabotropic glutamate receptor 5 (mGluR5) is essential for cocaine self-administration and drug-seeking behavior, there is limited knowledge of the cellular actions of this receptor in the nucleus accumbens (NAc). Although mGluR5 has the potential to regulate neurons directly, recent studies have shown the importance of mGluR5 in regulating Ca2+ signaling in astrocytes and, as a consequence, the Ca2+-dependent release of excitatory transmitters from these glia. In this study, we demonstrate that activation of mGluR5 induces Ca2+ oscillations in NAc astrocytes with the correlated appearance of NMDA receptor-dependent slow inward currents detected in medium spiny neurons (MSNs). Photolysis of caged Ca2+ loaded specifically into astrocytes evoked slow inward currents demonstrating that Ca2+ elevations in astrocytes are responsible for these excitatory events. Pharmacological evaluation of these glial-evoked NMDA currents shows that they are mediated by NR2B-containing NMDA receptors, whereas synaptic NMDA receptors rely on NR2A-containing receptors. Stimulation of glutamatergic afferents activates mGluR5-dependent astrocytic Ca2+ oscillations and gliotransmission that is sustained for minutes beyond the initial stimulus. Because gliotransmission is mediated by NMDA receptors, depolarized membrane potentials exhibited during up-states augment excitation provided by gliotransmission, which drives bursts of MSN action potentials. Because the predominant mGluR5-dependent action of glutamatergic afferents is to cause the sustained activation of astrocytes, which in turn excite MSNs through extrasynaptic NMDA receptors, our results raise the potential for gliotransmission being involved in prolonged mGluR5-dependent adaptation in the NAc. PMID:17259307

  11. Cue-evoked dopamine release in the nucleus accumbens shell tracks reinforcer magnitude during intracranial self-stimulation

    PubMed Central

    Beyene, Manna; Carelli, Regina M.; Wightman, R. Mark

    2010-01-01

    The mesolimbic dopamine system is critically involved in modulating reward-seeking behavior and is transiently activated upon presentation of reward-predictive cues. It has previously been shown, using fast-scan cyclic voltammetry in behaving rats, that cues predicting a variety of reinforcers including food/water, cocaine or intracranial self-stimulation (ICSS) elicit time-locked transient fluctuations in dopamine concentration in the nucleus accumbens (NAc) shell. These dopamine transients have been found to correlate with reward-related learning and are believed to promote reward-seeking behavior. Here, we investigated the effects of varying reinforcer magnitude (intracranial stimulation parameters) on cue-evoked dopamine release in the NAc shell in rats performing ICSS. We found that the amplitude of cue-evoked dopamine is adaptable, tracks reinforcer magnitude and is significantly correlated with ICSS seeking behavior. Specifically, the concentration of cue-associated dopamine transients increased significantly with increasing reinforcer magnitude, while, at the same time, the latency to lever press decreased with reinforcer magnitude. These data support the proposed role of NAc dopamine in the facilitation of reward-seeking and provide unique insight into factors influencing the plasticity of dopaminergic signaling during behavior. PMID:20600644

  12. Cue-evoked dopamine release in the nucleus accumbens shell tracks reinforcer magnitude during intracranial self-stimulation.

    PubMed

    Beyene, M; Carelli, R M; Wightman, R M

    2010-09-15

    The mesolimbic dopamine system is critically involved in modulating reward-seeking behavior and is transiently activated upon presentation of reward-predictive cues. It has previously been shown, using fast-scan cyclic voltammetry in behaving rats, that cues predicting a variety of reinforcers including food/water, cocaine or intracranial self-stimulation (ICSS) elicit time-locked transient fluctuations in dopamine concentration in the nucleus accumbens (NAc) shell. These dopamine transients have been found to correlate with reward-related learning and are believed to promote reward-seeking behavior. Here, we investigated the effects of varying reinforcer magnitude (intracranial stimulation parameters) on cue-evoked dopamine release in the NAc shell in rats performing ICSS. We found that the amplitude of cue-evoked dopamine is adaptable, tracks reinforcer magnitude and is significantly correlated with ICSS seeking behavior. Specifically, the concentration of cue-associated dopamine transients increased significantly with increasing reinforcer magnitude, while, at the same time, the latency to lever press decreased with reinforcer magnitude. These data support the proposed role of NAc dopamine in the facilitation of reward-seeking and provide unique insight into factors influencing the plasticity of dopaminergic signaling during behavior. PMID:20600644

  13. The ubiquitin ligase SEVEN IN ABSENTIA (SINA) ubiquitinates a defense-related NAC transcription factor and is involved in defense signaling.

    PubMed

    Miao, Min; Niu, Xiangli; Kud, Joanna; Du, Xinran; Avila, Julian; Devarenne, Timothy P; Kuhl, Joseph C; Liu, Yongsheng; Xiao, Fangming

    2016-07-01

    We recently identified a defense-related tomato (Solanum lycopersicum) NAC (NAM, ATAF1,2, CUC2) transcription factor, NAC1, that is subjected to ubiquitin-proteasome system-dependent degradation in plant cells. In this study, we identified a tomato ubiquitin ligase (termed SEVEN IN ABSENTIA3; SINA3) that ubiquitinates NAC1, promoting its degradation. We conducted coimmunoprecipitation and bimolecular fluorescence complementation to determine that SINA3 specifically interacts with the NAC1 transcription factor in the nucleus. Moreover, we found that SINA3 ubiquitinates NAC1 in vitro and promotes NAC1 degradation via polyubiquitination in vivo, indicating that SINA3 is a ubiquitin ligase that ubiquitinates NAC1, promoting its degradation. Our real-time PCR analysis indicated that, in contrast to our previous finding that NAC1 mRNA abundance increases upon Pseudomonas infection, the SINA3 mRNA abundance decreases in response to Pseudomonas infection. Moreover, using Agrobacterium-mediated transient expression, we found that overexpression of SINA3 interferes with the hypersensitive response cell death triggered by multiple plant resistance proteins. These results suggest that SINA3 ubiquitinates a defense-related NAC transcription factor for degradation and plays a negative role in defense signaling. PMID:26879496

  14. Differential Expression Analysis of a Subset of Drought-Responsive GmNAC Genes in Two Soybean Cultivars Differing in Drought Tolerance

    PubMed Central

    Thao, Nguyen Phuong; Thu, Nguyen Binh Anh; Hoang, Xuan Lan Thi; Van Ha, Chien; Tran, Lam-Son Phan

    2013-01-01

    The plant-specific NAC transcription factors play important roles in plant response to drought stress. Here, we have compared the expression levels of a subset of GmNAC genes in drought-tolerant DT51 and drought-sensitive MTD720 under both normal and drought stress conditions aimed at identifying correlation between GmNAC expression levels and drought tolerance degree, as well as potential GmNAC candidates for genetic engineering. The expression of 23 selected dehydration-responsive GmNACs was assessed in both stressed and unstressed root tissues of DT51 and MTD720 using real-time quantitative PCR. The results indicated that expression of GmNACs was genotype-dependent. Seven and 13 of 23 tested GmNACs showed higher expression levels in roots of DT51 in comparison with MTD720 under normal and drought stress conditions, respectively, whereas none of them displayed lower transcript levels under any conditions. This finding suggests that the higher drought tolerance of DT51 might be positively correlated with the higher induction of the GmNAC genes during water deficit. The drought-inducible GmNAC011 needs to be mentioned as its transcript accumulation was more than 76-fold higher in drought-stressed DT51 roots relative to MTD720 roots. Additionally, among the GmNAC genes examined, GmNAC085, 092, 095, 101 and 109 were not only drought-inducible but also more highly up-regulated in DT51 roots than in that of MTD720 under both treatment conditions. These data together suggest that GmNAC011, 085, 092, 095, 101 and 109 might be promising candidates for improvement of drought tolerance in soybean by biotechnological approaches. PMID:24322442

  15. Differential expression analysis of a subset of drought-responsive GmNAC genes in two soybean cultivars differing in drought tolerance.

    PubMed

    Thao, Nguyen Phuong; Thu, Nguyen Binh Anh; Hoang, Xuan Lan Thi; Van Ha, Chien; Tran, Lam-Son Phan

    2013-01-01

    The plant-specific NAC transcription factors play important roles in plant response to drought stress. Here, we have compared the expression levels of a subset of GmNAC genes in drought-tolerant DT51 and drought-sensitive MTD720 under both normal and drought stress conditions aimed at identifying correlation between GmNAC expression levels and drought tolerance degree, as well as potential GmNAC candidates for genetic engineering. The expression of 23 selected dehydration-responsive GmNACs was assessed in both stressed and unstressed root tissues of DT51 and MTD720 using real-time quantitative PCR. The results indicated that expression of GmNACs was genotype-dependent. Seven and 13 of 23 tested GmNACs showed higher expression levels in roots of DT51 in comparison with MTD720 under normal and drought stress conditions, respectively, whereas none of them displayed lower transcript levels under any conditions. This finding suggests that the higher drought tolerance of DT51 might be positively correlated with the higher induction of the GmNAC genes during water deficit. The drought-inducible GmNAC011 needs to be mentioned as its transcript accumulation was more than 76-fold higher in drought-stressed DT51 roots relative to MTD720 roots. Additionally, among the GmNAC genes examined, GmNAC085, 092, 095, 101 and 109 were not only drought-inducible but also more highly up-regulated in DT51 roots than in that of MTD720 under both treatment conditions. These data together suggest that GmNAC011, 085, 092, 095, 101 and 109 might be promising candidates for improvement of drought tolerance in soybean by biotechnological approaches. PMID:24322442

  16. Targeted disruption of cocaine-activated accumbens neurons prevents context-specific sensitization

    PubMed Central

    Koya, Eisuke; Golden, Sam A.; Harvey, Brandon K.; Guez, Danielle H.; Berkow, Alexander; Simmons, Danielle E.; Bossert, Jennifer M.; Nair, Sunila G.; Uejima, Jamie L.; Marin, Marcelo T.; Mitchell, Timothy; Farquhar, David; Ghosh, Sukhen; Mattson, Brandi J.; Hope, Bruce T.

    2009-01-01

    Learned associations between effects of abused drugs and the drug administration environment play important roles in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations between accumbens neuronal activity and responsivity to drugs and drug cues have been observed, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a novel method, termed ‘Daun02-inactivation method’, that selectively inactivates a minority of neurons activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool to study causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors. PMID:19620976

  17. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons.

    PubMed

    Beckley, Jacob T; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A; Ron, Dorit

    2016-01-20

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. Significance statement: Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  18. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons

    PubMed Central

    Beckley, Jacob T.; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A.

    2016-01-01

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. SIGNIFICANCE STATEMENT Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  19. Extracellular dopamine and its metabolites in the nucleus accumbens of Fisher and Lewis rats: Basal levels and cocaine-induced changes

    SciTech Connect

    Strecker, R.E.; Eberle, W.F.; Ashby, C.R. Jr.

    1995-11-01

    Rats of the Lewis (LEW) strain show a greater preference for drugs of abuse than do Fisher 344 (F344) rats. The in vivo microdialysis procedure was used to examine basal and cocaine-evoked extracellular (EC) levels of dopamine (DA), DOPAC, and HVA in the nucleus accumbens (NAc) of F344 and LEW rats. The basal EC levels of the DA metabolites DOPAC and HVA in the NAc were markedly lower in LEW than in F344 rats. Although the increase in ECDA after 3, 10 or 30 mg/kg, i/p. of cocaine was similar in both strains, LEW rats had a smaller peak DA elevation followed by a slower return to basal DA levels at the 30 mg/kg dose. The neurochemical differences observed may contribute to the strain differences in the behavioral response to cocaine. 20 refs., 3 figs.

  20. The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization.

    PubMed

    Todtenkopf, M S; Carreiras, T; Melloni, R H; Stellar, J R

    2002-04-01

    The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral

  1. General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

    PubMed

    Miner, Patricia; Shimonova, Lyudmila; Khaimov, Arthur; Borukhova, Yaffa; Ilyayeva, Ester; Ranaldi, Robert; Bodnar, Richard J

    2012-03-14

    Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist-opioid agonist and GABA antagonist-GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen

  2. Nucleus accumbens dopamine D2-receptor expressing neurons control behavioral flexibility in a place discrimination task in the IntelliCage.

    PubMed

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-07-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated group-housing experimental cage apparatus, in combination with a reversible neurotransmission blocking technique to examine the role of NAc D1- and D2-MSNs in the acquisition and reversal learning of a place discrimination task. We demonstrated that NAc D1- and D2-MSNs do not mediate the acquisition of the task, but that suppression of activity in D2-MSNs impairs reversal learning and increased perseverative errors. Additionally, global knockout of the dopamine D2L receptor isoform produced a similar behavioral phenotype to D2-MSN-blocked mice. These results suggest that D2L receptors and NAc D2-MSNs act to suppress the influence of previously correct behavioral strategies allowing transfer of behavioral control to new strategies. PMID:27317196

  3. Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement.

    PubMed

    Richard, Jocelyn M; Fields, Howard L

    2016-09-01

    Endogenous opioid signaling in ventral cortico-striatal-pallidal circuitry is implicated in elevated alcohol consumption and relapse to alcohol seeking. Mu-opioid receptor activation in the medial shell of the nucleus accumbens (NAc), a region implicated in multiple aspects of reward processing, elevates alcohol consumption while NAc opioid antagonists reduce it. However, the precise nature of the increases in alcohol consumption, and the effects of mu-opioid agonists on alcohol seeking and relapse are not clear. Here, we tested the effects of the mu-opioid agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) in rat NAc shell on lick microstructure in a free-drinking test, alcohol seeking during operant self-administration, extinction learning and expression, and cue-reinforced reinstatement of alcohol seeking. DAMGO enhanced the number, but not the size of drinking bouts. DAMGO also enhanced operant alcohol self-administration and cue-induced reinstatement, but did not affect extinction learning or elicit reinstatement in the absence of cues. Our results suggest that mu-opioid agonism in NAc shell elevates alcohol consumption, seeking and conditioned reinforcement primarily by enhancing the incentive motivational properties of alcohol and alcohol-paired cues, rather than by modulating palatability, satiety, or reinforcement. PMID:27089981

  4. Effect of nucleus accumbens shell 5-HT4 receptors on the impairment of ACPA-induced emotional memory consolidation in male Wistar rats.

    PubMed

    Khodayar, Ebrahim; Oryan, Shahrbanoo; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

    2016-02-01

    The present study investigates the effects of 5-HT4 receptors of the nucleus accumbens (NAc) shell on the impairment of emotional memory consolidation induced by cannabinoid CB1 receptor stimulation. The elevated plus maze test-retest paradigm was used to assess memory in adult male Wistar rats. Intra-NAc shell administration of ACPA (selective cannabinoid CB1 receptor agonist 0.006 µg/rat) and RS23597 (5-HT4 receptor antagonist 0.01 µg/rat), immediately after training, decreased emotional memory consolidation, suggesting a drug-induced amnesia, whereas post-training intra-NAc shell microinjections of RS67333 (5-HT4 receptor agonist 0.016 µg/rat) increased emotional memory consolidation. Interestingly, RS67333 exerted a dual effect on ACPA-induced behaviors, potentiating and restoring amnesia caused by the subthreshold and effective doses of ACPA, respectively. However, neither RS23597 nor AM251 (CB1 receptor antagonist 30, 60 and 120 ng/rat) affected emotional memory consolidation. Nonetheless, a subthreshold dose of AM251 (120 ng/rat) reversed the amnesia induced by ACPA (0.006 µg/rat) and RS23597 (0.01 µg/rat). None of the above doses altered the locomotor activity. In conclusion, our results suggest that the NAc-shell 5-HT4 receptors are involved in the modulation of ACPA-induced amnesia. PMID:26340366

  5. Orexin receptors within the nucleus accumbens shell mediate the stress but not drug priming-induced reinstatement of morphine conditioned place preference

    PubMed Central

    Qi, Keke; Wei, Chuguang; Li, Yonghui; Sui, Nan

    2013-01-01

    Orexins are found to participate in mediating stress-induced drug relapse. However, the neuroanatomical basis that orexin transmission modulates stress-induced drug seeking remains unknown. The nucleus accumbens shell (NAcSh), best known for its role in appetitive and negative motivation via dopamine receptors, is likely to be the potential important brain area where the orexin system mediates stress-induced drug relapse since the function of dopamine system in the NAcSh can be regulated by orexin transmission. In the present study, a morphine conditioned place preference (CPP) model was used to determine whether the two types of orexin receptors would be involved into footshock-induced and/or drug priming-induced CPP reinstatement differentially. The results showed that blockade of orexin-1 or orexin-2 receptor in the NAcSh significantly attenuated stress-induced morphine CPP reinstatement, but neither of the orexin antagonists had any effect on morphine priming-induced reinstatement. These findings indicate that the NAcSh is a brain area through which orexins participate in stress but not drug priming-induced relapse of opioid seeking. PMID:24133421

  6. Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events.

    PubMed

    Aragona, Brandon J; Cleaveland, Nathan A; Stuber, Garret D; Day, Jeremy J; Carelli, Regina M; Wightman, R Mark

    2008-08-27

    Preferential enhancement of dopamine transmission within the nucleus accumbens (NAc) shell is a fundamental aspect of the neural regulation of cocaine reward. Despite its importance, the nature of this effect is poorly understood. Here, we used fast-scan cyclic voltammetry to examine specific transmission processes underlying cocaine-evoked increases in dopamine transmission within the NAc core and shell. Initially, we examined altered terminal dopamine concentrations after global autoreceptor blockade. This was the first examination of autoreceptor regulation of naturally occurring phasic dopamine transmission and provided a novel characterization of specific components of dopamine neurotransmission. Comparison of increased dopamine signaling evoked by autoreceptor blockade and cocaine administration allowed robust resolution between increased frequency, concentration, and duration of phasic dopamine release events after cocaine delivery. Cocaine increased dopamine transmission by slowed uptake and increased concentration of dopamine released in the core and shell. However, an additional increase in the number phasic release events occurred only within the NAc shell, and this increase was eliminated by inactivation of midbrain dopaminergic neurons. This represents the first evidence that cocaine directly increases the frequency of dopamine release events and reveals that this is responsible for preferentially increased dopamine transmission within the NAc shell after cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration, and subregion differences were abolished when cocaine was administered in the absence of autoregulation. Together, these results demonstrate that cocaine administration results in a temporally and regionally specific increase in phasic dopamine release that is significantly regulated by dopamine autoreceptors. PMID:18753384

  7. Transplantation of human retinal pigment epithelial cells in the nucleus accumbens of cocaine self-administering rats provides protection from seeking.

    PubMed

    Venkiteswaran, Kala; Alexander, Danielle N; Puhl, Matthew D; Rao, Anand; Piquet, Amanda L; Nyland, Jennifer E; Subramanian, Megha P; Iyer, Puja; Boisvert, Matthew M; Handly, Erin; Subramanian, Thyagarajan; Grigson, Patricia Sue

    2016-05-01

    Chronic exposure to drugs and alcohol leads to damage to dopaminergic neurons and their projections in the 'reward pathway' that originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). This damage is thought to contribute to the signature symptom of addiction: chronic relapse. In this study we show that bilateral transplants of human retinal pigment epithelial cells (RPECs), a cell mediated dopaminergic and trophic neuromodulator, into the medial shell of the NAc, rescue rats with a history of high rates of cocaine self-administration from drug-seeking when returned, after 2 weeks of abstinence, to the drug-associated chamber under extinction conditions (i.e., with no drug available). Excellent survival was noted for the transplant of RPECs in the shell and/or the core of the NAc bilaterally in all rats that showed behavioral recovery from cocaine seeking. Design based unbiased stereology of tyrosine hydroxylase (TH) positive cell bodies in the VTA showed better preservation (p<0.035) in transplanted animals compared to control animals. This experiment shows that the RPEC graft provides beneficial effects to prevent drug seeking in drug addiction via its effects directly on the NAc and its neural network with the VTA. PMID:26562520

  8. Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

    PubMed Central

    Grotewold, Susan K.; Wall, Vanessa L.; Goodell, Dayton J.; Hayter, Cassandra

    2015-01-01

    Rationale Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation. Objectives The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT). Methods Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters. Results ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT. Conclusions Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates. PMID:24553577

  9. Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

    PubMed Central

    Ma, Yao-Ying; Henley, Sandy M.; Toll, Jeff; Jentsch, James D.; Evans, Christopher J.; Levine, Michael S.; Cepeda, Carlos

    2013-01-01

    To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction. PMID:24000958

  10. Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens.

    PubMed

    Chefer, V I; Shippenberg, T S

    2006-01-01

    Quantitative and conventional microdialysis were used to investigate the effects of constitutive deletion of the prodynorphin gene on basal dopamine (DA) dynamics in the nucleus accumbens (NAc) and the responsiveness of DA neurons to an acute cocaine challenge. Saline- and cocaine-evoked locomotor activity were also assessed. Quantitative microdialysis revealed that basal extracellular DA levels were decreased, while the DA extraction fraction, an indirect measure of DA uptake, was unchanged in dynorphin (DYN) knockout (KO) mice. The ability of cocaine to increase NAc DA levels was reduced in KO. Similarly, cocaine-evoked locomotor activity was decreased in KO. The selective kappa opioid receptor agonist U-69593 decreased NAc dialysate DA levels in wildtype mice and this effect was enhanced in KO. Administration of the selective kappa opioid receptor (KOPr) antagonist nor-binaltorphimine to KO mice attenuated the decrease in cocaine-induced DA levels. However, it was ineffective in altering the decreased locomotor response to cocaine. These studies demonstrate that constitutive deletion of prodynorphin is associated with a reduction of extracellular NAc DA levels and a decreased responsiveness to acute cocaine. Data regarding the effects of U-69593 and nor-binaltorphimine in KO suggest that the kappa opioid receptor is up-regulated as a consequence of prodynorphin gene deletion and that this adaptation underlies the decrease in basal DA dynamics and cocaine-evoked DA levels observed in DYN KO mice. These findings suggest that the phenotype of DYN KO mice is not solely due to loss of endogenous opioid peptide but also reflects developmental compensations that occur at the level of the opioid receptor. PMID:16420432

  11. Pain relief induces dopamine release in the rat nucleus accumbens during the early but not late phase of neuropathic pain.

    PubMed

    Kato, Takahiro; Ide, Soichiro; Minami, Masabumi

    2016-08-26

    Comorbidity of chronic pain and depression has long been recognized in the clinic, and preclinical studies have reported depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for chronic pain and depression. The neuronal pathway from the ventral tegmental area to the nucleus accumbens (NAc) is critical in the mesolimbic dopamine (DA) reward circuit, and dysfunction of this pathway has been implicated in depression. Although time-dependent development of depression-related behaviors has been reported in chronic pain animals, time-dependent functional changes in this pathway remain to be examined. To address this issue, we examined the effects of two types of rewards, pain relief by intrathecal injection of pregabalin (100μg in 10μL phosphate buffered saline) and 30% sucrose solution intake, on intra-NAc DA release in rats subjected to spinal nerve ligation (SNL). Specifically, the effects were investigated during the early (17-20days after ligation) and late (31-34days after ligation) phases of neuropathic pain. Pain relief increased the intra-NAc DA levels in the SNL rats during the early but not late phase of neuropathic pain. Intake of the sucrose solution increased the intra-NAc DA levels both in the SNL and sham animals during the early phase of neuropathic pain, while it induced DA release in the sham but not SNL animals during the late phase. These results suggest that dysfunction of the mesolimbic DA reward circuit develops in a time-dependent manner. Mesolimbic DA reward circuit dysfunction might be a common neuronal mechanism underlying chronic pain and depression, and a potential target for novel analgesic and antidepressant medications. PMID:27369326

  12. The monoamine stabilizer (-)-OSU6162 counteracts downregulated dopamine output in the nucleus accumbens of long-term drinking Wistar rats.

    PubMed

    Feltmann, Kristin; Fredriksson, Ida; Wirf, Malin; Schilström, Björn; Steensland, Pia

    2016-03-01

    We recently established that the monoamine stabilizer (-)-OSU6162 (OSU6162) decreased voluntary alcohol-mediated behaviors, including alcohol intake and cue/priming-induced reinstatement, in long-term drinking rats, while blunting alcohol-induced dopamine output in the nucleus accumbens (NAc) of alcohol-naïve rats. Therefore, we hypothesized that OSU6162 attenuates alcohol-mediated behaviors by blunting alcohol's rewarding effects. Here, we evaluated the effects of long-term drinking and OSU6162 treatment (30 mg/kg, sc) on basal and alcohol-induced (2.5 g/kg, ip) NAc dopamine outputs in Wistar rats after 10 months of intermittent access to 20% alcohol. The results showed that basal and alcohol-induced NAc dopamine outputs were significantly lower in long-term drinking rats, compared with alcohol-naïve rats. In the long-term drinking rats, OSU6162 slowly increased and maintained the dopamine output significantly elevated compared with baseline for at least 4 hours. Furthermore, OSU6162 pre-treatment did not blunt the alcohol-induced output in the long-term drinking rats, a finding that contrasted with our previous results in alcohol-naïve rats. Finally, OSU6162 did not induce conditioned place preference (CPP) in either long-term drinking or alcohol-naïve rats, indicating that OSU6162 has no reinforcing properties. To verify that the CPP results were not due to memory acquisition impairment, we demonstrated that OSU6162 did not affect novel object recognition. In conclusion, these results indicate that OSU6162 attenuates alcohol-mediated behaviors by counteracting NAc dopamine deficits in long-term drinking rats and that OSU6162 is not rewarding on its own. Together with OSU6162's beneficial side-effect profile, the present study merits evaluation of OSU6162's clinical efficacy to attenuate alcohol use in alcohol-dependent patients. PMID:26464265

  13. Changes in dopamine transporter binding in nucleus accumbens following chronic self-administration of cocaine:heroin combinations

    PubMed Central

    Pattison, Lindsey P.; McIntosh, Scot; Sexton, Tammy; Childers, Steven R.; Hemby, Scott E.

    2014-01-01

    Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate (Vmax) of dopamine. The present studies were undertaken to determine whether chronic self-administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high- and low-affinity DAT binding sites. Saturation binding of the cocaine analog [125I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([125I]RTI-55) in rat NAc membranes resulted in binding curves that were best fit to two-site binding models, allowing calculation of dissociation constant (Kd) and binding density (Bmax) values corresponding to high- and low-affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high- and low- affinity binding sites in the NAc, with low-affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self-administration of cocaine and a cocaine:heroin combination increased the affinity of the low-affinity site for the cocaine congener RTI-55 compared to saline. These results indicate that the alterations observed following chronic speedball self-administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. PMID:24916769

  14. Nucleus accumbens neuronal activity correlates to the animal’s behavioral response to acute and chronic methylphenidate

    PubMed Central

    Claussen, Catherine M; Chong, Samuel L; Dafny, Nachum

    2014-01-01

    Acute and chronic Methylphenidate (MPD) exposure was recorded simultaneously for the rat’s locomotor activity and the nucleus accumbens (NAc) neuronal activity. The evaluation of the neuronal events was based on the animal’s behavior response to chronic MPD administration: 1) Animals exhibiting behavioral sensitization 2) Animals exhibiting behavioral tolerance. The experiment lasted for 10 days with four groups of animals; saline, 0.6, 2.5, and 10.0mg/kg MPD. For the main behavioral findings, about half of the animals exhibited behavioral sensitization or behavioral tolerance to 0.6, 2.5, and/or 10 mg/kg MPD respectively. Three hundred and forty one NAc neuronal units were evaluated. Approximately 80% of NAc units responded to 0.6, 2.5, and 10.0 mg/kg MPD. When the neuronal activity was analyzed based on the animals behavioral response to chronic MPD exposure, significant differences were seen between the neuronal populations responses recorded from animals that expressed behavioral sensitization when compared to the NAc neuronal responses recorded from animals exhibiting behavioral tolerance. Three types of neurophysiological sensitization and neurophysiological tolerance can be recognized following chronic MPD administration to the neuronal populations. Collectively, these findings show that the same dose of chronic MPD can elicit either behavioral tolerance or behavioral sensitization. Differential statistical analysis were used to verify our hypothesis that the neuronal activity recorded from animals exhibiting behavioral sensitization will respond differently to MPD compared to those animals exhibiting behavioral tolerance. Thus, suggesting that it is essential to record the animals behavior concomitantly with neuronal recordings. PMID:24534179

  15. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1.

    PubMed

    Chandra, Ramesh; Lenz, Jeffrey D; Gancarz, Amy M; Chaudhury, Dipesh; Schroeder, Gabrielle L; Han, Ming-Hu; Cheer, Joseph F; Dietz, David M; Lobo, Mary Kay

    2013-01-01

    Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function. PMID:23745104

  16. Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

    PubMed

    Perrine, Shane A; Ghoddoussi, Farhad; Desai, Kirtan; Kohler, Robert J; Eapen, Ajay T; Lisieski, Michael J; Angoa-Perez, Mariana; Kuhn, Donald M; Bosse, Kelly E; Conti, Alana C; Bissig, David; Berkowitz, Bruce A

    2015-11-01

    A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence. PMID:26411897

  17. Dopamine receptor expression and distribution dynamically change in the rat nucleus accumbens after withdrawal from cocaine self-administration

    PubMed Central

    Conrad, Kelly L.; Ford, Kerstin; Marinelli, Michela; Wolf, Marina E.

    2010-01-01

    Dopamine receptors (DARs) in the nucleus accumbens (NAc) are critical for cocaine's actions but the nature of adaptations in DAR function after repeated cocaine exposure remains controversial. This may be due in part to the fact that different methods used in previous studies measured different DAR pools. In the present study, we used a protein crosslinking assay to make the first measurements of DAR surface expression in the NAc of cocaine-experienced rats. Intracellular and total receptor levels were also quantified. Rats self-administered saline or cocaine for ten days. The entire NAc, or core and shell subregions, were collected one or 45 days later, when rats are known to exhibit low and high levels of cue-induced drug seeking, respectively. We found increased cell surface D1 DARs in the NAc shell on the first day after discontinuing cocaine self-administration (designated withdrawal day 1, or WD1) but this normalized by WD45. Decreased intracellular and surface D2 DAR levels were observed in the cocaine group. In shell, both measures decreased on WD1 and WD45. In core, decreased D2 DAR surface expression was only observed on WD45. Similarly, WD45 but not WD1 was associated with increased D3 DAR surface expression in the core. Taking into account many other studies, we suggest that decreased D2 DAR and increased D3 DAR surface expression on WD45 may contribute to enhanced cocaine-seeking after prolonged withdrawal, although this is likely to be a modulatory effect, in light of the mediating effect previously demonstrated for AMPA-type glutamate receptors. PMID:20435100

  18. Role of Acetylcholine Transmission in Nucleus Accumbens and Ventral Tegmental Area in Heroin-Seeking Induced by Conditioned Cues

    PubMed Central

    Zhou, Wenhua; Liu, Huifen; Zhang, Fuqiang; Tang, Suien; Zhu, Huaqiang; Lai, Miaojun; Kalivas, Peter W.

    2007-01-01

    The involvement of cholinergic transmission in heroin self-administration and the reinstatement of heroin-seeking was examined in rats trained to nose-poke for intravenous heroin. Systemic treatment with physostigmine, an inhibitor of acetylcholinesterase, modestly reduced the acquisition and rate of heroin self-administration, and this suppression of heroin intake was reversed by pretreatment with scopolamine but not by mecamylamine. Following 10–14 days of self-administration, rats were left in the home environment for 14 days. Subsequently, rats were evaluated for extinction of nose-pokes during the first hour after being returned to the self-administration apparatus. One hr later a conditioned stimulus (house light, light in the nose-poke hole, sound of the infusion pump) was presented to initiate cue-induced reinstatement. Physostigmine produced a dose-dependent inhibition of cue-induced reinstatement, but only the dose of 0.5 mg/kg significantly decreased nose-poke responding in the extinction test. Chronic treatment with physostigmine (0.1 mg/kg) did not impair performance during acquisition of heroin self-administration. However, during a subsequent reinstatement test conducted in the absence of physostigmine pretreatment, heroin seeking was significantly below that of rats chronically pretreated with saline. To evaluate brain regions mediating the effects of systemic drug treatment on reinstatement, physostigmine was microinjected into the nucleus accumbens (NAc) or ventral tegmental area (VTA). Microinjection of physostigmine into the NAc prior to presenting conditioned cues inhibited the reinstatement of heroin-seeking, without affecting extinction responding. In contrast, microinjection of physostigmine into the VTA augmented the reinstatement induced by conditioned cues and extinction responding. Inactivation of either NAc or VTA by microinjecting tetrodotoxin blocked both extinction responding and cue-induced reinstatement. These data demonstrate

  19. Genome-Wide Survey and Expression Analysis of the Plant-Specific NAC Transcription Factor Family in Soybean During Development and Dehydration Stress

    PubMed Central

    Le, Dung Tien; Nishiyama, Rie; Watanabe, Yasuko; Mochida, Keiichi; Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo; Tran, Lam-Son Phan

    2011-01-01

    Plant-specific NAC transcription factors (TFs) play important roles in regulating diverse biological processes, including development, senescence, growth, cell division and responses to environmental stress stimuli. Within the soybean genome, we identified 152 full-length GmNAC TFs, including 11 membrane-bound members. In silico analysis of the GmNACs, together with their Arabidopsis and rice counterparts, revealed similar NAC architecture. Next, we explored the soybean Affymetrix array and Illumina transcriptome sequence data to analyse tissue-specific expression profiles of GmNAC genes. Phylogenetic analysis using stress-related NAC TFs from Arabidopsis and rice as seeding sequences identified 58 of the 152 GmNACs as putative stress-responsive genes, including eight previously reported dehydration-responsive GmNACs. We could design gene-specific primers for quantitative real-time PCR verification of 38 out of 50 newly predicted stress-related genes. Twenty-five and six GmNACs were found to be induced and repressed 2-fold or more, respectively, in soybean roots and/or shoots in response to dehydration. GmNAC085, whose amino acid sequence was 39%; identical to that of well-known SNAC1/ONAC2, was the most induced gene upon dehydration, showing 390-fold and 20-fold induction in shoots and roots, respectively. Our systematic analysis has identified excellent tissue-specific and/or dehydration-responsive candidate GmNAC genes for in-depth characterization and future development of improved drought-tolerant transgenic soybeans. PMID:21685489

  20. Global Expressions Landscape of NAC Transcription Factor Family and Their Responses to Abiotic Stresses in Citrullus lanatus

    PubMed Central

    Lv, Xiaolong; Lan, Shanrong; Guy, Kateta Malangisha; Yang, Jinghua; Zhang, Mingfang; Hu, Zhongyuan

    2016-01-01

    Watermelon (Citrullus lanatus) is one xerophyte that has relative higher tolerance to drought and salt stresses as well as more sensitivity to cold stress, compared with most model plants. These characteristics facilitate it a potential model crop for researches on salt, drought or cold tolerance. In this study, a genome-wide comprehensive analysis of the ClNAC transcription factor (TF) family was carried out for the first time, to investigate their transcriptional profiles and potential functions in response to these abiotic stresses. The expression profiling analysis reveals that several NAC TFs are highly responsive to abiotic stresses and development, for instance, subfamily IV NACs may play roles in maintaining water status under drought or salt conditions, as well as water and metabolites conduction and translocation toward fruit. In contrast, rapid and negative responses of most of the ClNACs to low-temperature adversity may be related to the sensitivity to cold stress. Crosstalks among these abiotic stresses and hormone (abscisic acid and jasmonic acid) pathways were also discussed based on the expression of ClNAC genes. Our results will provide useful insights for the functional mining of NAC family in watermelon, as well as into the mechanisms underlying abiotic tolerance in other cash crops. PMID:27491393

  1. Global Expressions Landscape of NAC Transcription Factor Family and Their Responses to Abiotic Stresses in Citrullus lanatus.

    PubMed

    Lv, Xiaolong; Lan, Shanrong; Guy, Kateta Malangisha; Yang, Jinghua; Zhang, Mingfang; Hu, Zhongyuan

    2016-01-01

    Watermelon (Citrullus lanatus) is one xerophyte that has relative higher tolerance to drought and salt stresses as well as more sensitivity to cold stress, compared with most model plants. These characteristics facilitate it a potential model crop for researches on salt, drought or cold tolerance. In this study, a genome-wide comprehensive analysis of the ClNAC transcription factor (TF) family was carried out for the first time, to investigate their transcriptional profiles and potential functions in response to these abiotic stresses. The expression profiling analysis reveals that several NAC TFs are highly responsive to abiotic stresses and development, for instance, subfamily IV NACs may play roles in maintaining water status under drought or salt conditions, as well as water and metabolites conduction and translocation toward fruit. In contrast, rapid and negative responses of most of the ClNACs to low-temperature adversity may be related to the sensitivity to cold stress. Crosstalks among these abiotic stresses and hormone (abscisic acid and jasmonic acid) pathways were also discussed based on the expression of ClNAC genes. Our results will provide useful insights for the functional mining of NAC family in watermelon, as well as into the mechanisms underlying abiotic tolerance in other cash crops. PMID:27491393

  2. Comparative Genomics of NAC Transcriptional Factors in Angiosperms: Implications for the Adaptation and Diversification of Flowering Plants.

    PubMed

    Pereira-Santana, Alejandro; Alcaraz, Luis David; Castaño, Enrique; Sanchez-Calderon, Lenin; Sanchez-Teyer, Felipe; Rodriguez-Zapata, Luis

    2015-01-01

    NAC proteins constitute one of the largest groups of plant-specific transcription factors and are known to play essential roles in various developmental processes. They are also important in plant responses to stresses such as drought, soil salinity, cold, and heat, which adversely affect growth. The current knowledge regarding the distribution of NAC proteins in plant lineages comes from relatively small samplings from the available data. In the present study, we broadened the number of plant species containing the NAC family origin and evolution to shed new light on the evolutionary history of this family in angiosperms. A comparative genome analysis was performed on 24 land plant species, and NAC ortholog groups were identified by means of bidirectional BLAST hits. Large NAC gene families are found in those species that have experienced more whole-genome duplication events, pointing to an expansion of the NAC family with divergent functions in flowering plants. A total of 3,187 NAC transcription factors that clustered into six major groups were used in the phylogenetic analysis. Many orthologous groups were found in the monocot and eudicot lineages, but only five orthologous groups were found between P. patens and each representative taxa of flowering plants. These groups were called basal orthologous groups and likely expanded into more recent taxa to cope with their environmental needs. This analysis on the angiosperm NAC family represents an effort to grasp the evolutionary and functional diversity within this gene family while providing a basis for further functional research on vascular plant gene families. PMID:26569117

  3. Comparative Genomics of NAC Transcriptional Factors in Angiosperms: Implications for the Adaptation and Diversification of Flowering Plants

    PubMed Central

    Pereira-Santana, Alejandro; Alcaraz, Luis David; Castaño, Enrique; Sanchez-Calderon, Lenin; Sanchez-Teyer, Felipe; Rodriguez-Zapata, Luis

    2015-01-01

    NAC proteins constitute one of the largest groups of plant-specific transcription factors and are known to play essential roles in various developmental processes. They are also important in plant responses to stresses such as drought, soil salinity, cold, and heat, which adversely affect growth. The current knowledge regarding the distribution of NAC proteins in plant lineages comes from relatively small samplings from the available data. In the present study, we broadened the number of plant species containing the NAC family origin and evolution to shed new light on the evolutionary history of this family in angiosperms. A comparative genome analysis was performed on 24 land plant species, and NAC ortholog groups were identified by means of bidirectional BLAST hits. Large NAC gene families are found in those species that have experienced more whole-genome duplication events, pointing to an expansion of the NAC family with divergent functions in flowering plants. A total of 3,187 NAC transcription factors that clustered into six major groups were used in the phylogenetic analysis. Many orthologous groups were found in the monocot and eudicot lineages, but only five orthologous groups were found between P. patens and each representative taxa of flowering plants. These groups were called basal orthologous groups and likely expanded into more recent taxa to cope with their environmental needs. This analysis on the angiosperm NAC family represents an effort to grasp the evolutionary and functional diversity within this gene family while providing a basis for further functional research on vascular plant gene families. PMID:26569117

  4. N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration.

    PubMed

    Winefield, Robert D; Heemskerk, Anthonius A M; Kaul, Swetha; Williams, Todd D; Caspers, Michael J; Prisinzano, Thomas E; McCance-Katz, Elinore F; Lunte, Craig E; Faiman, Morris D

    2015-03-25

    Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291>128) is easily separable from DETC-NAC (MIM: 263>100) on C18 RP media with a methanol gradient. The method's linear range is 0.5-500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250 mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95-105) is discussed. PMID:25720821

  5. Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates.

    PubMed

    Hemby, Scott E; Tang, Wenxue; Muly, Emil C; Kuhar, Michael J; Howell, Leonard; Mash, Deborah C

    2005-12-01

    Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical-NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 +/- 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser. PMID:16363995

  6. Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates

    PubMed Central

    Hemby, Scott E.; Tang, Wenxue; Muly, Emil C.; Kuhar, Michael J.; Howell, Leonard; Mash, Deborah C.

    2013-01-01

    Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical–NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (±)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 ± 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser. PMID:16363995

  7. The Bivalent Side of the Nucleus Accumbens

    PubMed Central

    Levita, Liat; Hare, Todd A.; Voss, Henning U.; Glover, Gary; Ballon, Douglas J.; Casey, B.J.

    2009-01-01

    An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both incentive reward processes and in adaptive responses to conditioned and unconditioned aversive stimuli. Yet, it has been argued that NAcc activation to aversive stimuli may be a consequence of the rewarding effects of their termination, i.e., relief. To address this question we used fMRI to delineate brain response to the onset and offset of unpleasant and pleasant auditory stimuli in the absence of learning or motor response. Increased NAcc activity was seen for the onset of both pleasant and unpleasant stimuli. Our results support the expanded bivalent view of NAcc function and call for expansion of current models of NAcc function that are solely focused on reward. PMID:18976715

  8. Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose.

    PubMed

    Avena, N M; Rada, P; Hoebel, B G

    2008-10-28

    The present study tested whether rats release more accumbens dopamine (DA) during a sugar binge when they are underweight vs. normal weight. Since acetylcholine (ACh) in the nucleus accumbens (NAc) normally increases as a meal progresses and satiety ensues, we also tested whether ACh release is altered when an animal has lost weight. Rats were maintained on daily 8-h access to chow, with 10% sucrose solution available for the first 2 h. Microdialysis performed on day 21, at normal body weight, revealed an increase in extracellular DA to 122% of baseline in response to drinking sucrose. Extracellular ACh peaked at the end of the meal. Next, the rats were food and sucrose restricted so that by day 28 they were at 85% body weight. When retested, these animals released significantly more DA when drinking sucrose (179%), but ACh release failed to rise. A control group was tested in the same manner but given sugar only on days 1, 21 and 28. At normal body weight, control animals showed a non-significant rise in DA when drinking sucrose on day 21. On day 28, at 85% body weight, the controls showed a small increase (124%) in DA release; however, this was significantly lower than the 179% observed in the underweight rats with daily sugar access. These findings suggest that when an animal binges on sugar and then loses weight, the binge releases significantly more DA and less ACh than when animals are at a normal body weight. PMID:18790017

  9. UNDERWEIGHT RATS HAVE ENHANCED DOPAMINE RELEASE AND BLUNTED ACETYLCHOLINE RESPONSE IN THE NUCLEUS ACCUMBENS WHILE BINGEING ON SUCROSE

    PubMed Central

    AVENA, N. M.; RADA, P.; HOEBEL, B. G.

    2015-01-01

    The present study tested whether rats release more accumbens dopamine (DA) during a sugar binge when they are underweight vs. normal weight. Since acetylcholine (ACh) in the nucleus accumbens (NAc) normally increases as a meal progresses and satiety ensues, we also tested whether ACh release is altered when an animal has lost weight. Rats were maintained on daily 8-h access to chow, with 10% sucrose solution available for the first 2 h. Microdialysis performed on day 21, at normal body weight, revealed an increase in extracellular DA to 122% of baseline in response to drinking sucrose. Extracellular ACh peaked at the end of the meal. Next, the rats were food and sucrose restricted so that by day 28 they were at 85% body weight. When retested, these animals released significantly more DA when drinking sucrose (179%), but ACh release failed to rise. A control group was tested in the same manner but given sugar only on days 1, 21 and 28. At normal body weight, control animals showed a non-significant rise in DA when drinking sucrose on day 21. On day 28, at 85% body weight, the controls showed a small increase (124%) in DA release; however, this was significantly lower than the 179% observed in the underweight rats with daily sugar access. These findings suggest that when an animal binges on sugar and then loses weight, the binge releases significantly more DA and less ACh than when animals are at a normal body weight. PMID:18790017

  10. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex

    PubMed Central

    Ikemoto, Satoshi

    2007-01-01

    Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that: (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive, and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization. PMID:17574681

  11. Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine

    PubMed Central

    Wakabayashi, Ken T.; Kiyatkin, Eugene A.

    2015-01-01

    The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6–8 s; ~50 μM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 μM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells. PMID:25729349

  12. Inhibition of actin polymerization in the NAc shell inhibits morphine-induced CPP by disrupting its reconsolidation

    PubMed Central

    Li, Gongying; Wang, Yanmei; Yan, Min; Xu, Yunshuai; Song, Xiuli; Li, Qingqing; Zhang, Jinxiang; Ma, Hongxia; Wu, Yili

    2015-01-01

    Drug-associated contextual cues contribute to drug craving and relapse after abstinence, which is a major challenge to drug addiction treatment. Previous studies showed that disrupting memory reconsolidation impairs drug reward memory. However, the underlying mechanisms remain elusive. Although actin polymerization is involved in memory formation, its role in the reconsolidation of drug reward memory is unknown. In addition, the specific brain areas responsible for drug memory have not been fully identified. In the present study, we found that inhibiting actin polymerization in the nucleus accumbens (NAc) shell, but not the NAc core, abolishes morphine-induced conditioned place preference (CPP) by disrupting its reconsolidation in rats. Moreover, this effect persists for more than 2 weeks by a single injection of the actin polymerization inhibitor, which is not reversed by a morphine-priming injection. Furthermore, the application of actin polymerization inhibitor outside the reconsolidation window has no effect on morphine-associated contextual memory. Taken together, our findings first demonstrate that inhibiting actin polymerization erases morphine-induced CPP by disrupting its reconsolidation. Our study suggests that inhibition of actin polymerization during drug memory reconsolidation may be a potential approach to prevent drug relapse. PMID:26538334

  13. A thalamic input to the nucleus accumbens mediates opiate dependence.

    PubMed

    Zhu, Yingjie; Wienecke, Carl F R; Nachtrab, Gregory; Chen, Xiaoke

    2016-02-11

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction. PMID:26840481

  14. Conserved miR164-targeted NAC genes negatively regulate drought resistance in rice

    PubMed Central

    Xie, Kabin; Xiong, Lizhong

    2014-01-01

    MicroRNAs constitute a large group of endogenous small RNAs of ~22 nt that emerge as vital regulators, mainly by targeting mRNAs for post-transcriptional repression. Previous studies have revealed that the miR164 family in Arabidopsis is comprised of three members which guide the cleavage of the mRNAs of five NAC genes to modulate developmental processes. However, the functions of the miR164-targeted NAC genes in crops are poorly deciphered. In this study, the conserved features of six miR164-targeted NAC genes (OMTN1–OMTN6) in rice are described, and evidence is provided that four of them confer a negative regulatory role in drought resistance. OMTN proteins have the characteristics of typical NAC transcriptional factors. The miR164 recognition sites of the OMTN genes are highly conserved in rice germplasms. Deletion of the recognition sites impaired the transactivation activity, indicating that the conserved recognition sites play a crucial role in maintaining the function of the OMTN proteins. The OMTN genes were responsive to abiotic stresses, and showed diverse spatio-temporal expression patterns in rice. Overexpression of OMTN2, OMTN3, OMTN4, and OMTN6 in rice led to negative effects on drought resistance at the reproductive stage. The expression of numerous genes related to stress response, development, and metabolism was altered in OMTN2-, OMTN3-, OMTN4-, and OMTN6-overexpressing plants. Most of the up-regulated genes in the OMTN-overexpressing plants were down-regulated by drought stress. The results suggest that the conserved miR164-targeted NAC genes may be negative regulators of drought tolerance in rice, in addition to their reported roles in development. PMID:24604734

  15. Characterizing N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) binding for lead poisoning treatment.

    PubMed

    Chen, Weiqing; Ercal, Nuran; Huynh, Tien; Volkov, Anatoliy; Chusuei, Charles C

    2012-04-01

    Using antioxidants is an important means of treating lead poisoning. Prior in vivo studies showed marked differences between various chelator antioxidants in their ability to decrease both blood Pb(II) levels and oxidative stress resulting from lead poisoning. The comparative abilities of NAC and NACA to Pb(II) were studied in vitro, for the first time, to examine the role of the -OH/-NH(2) functional group in antioxidant binding behavior. To assay the antioxidant-divalent metal interaction, the antioxidants were probed as solid surfaces, adsorbing Pb(II) onto them. Surface characterization was carried out using X-ray photoelectron spectroscopy (XPS) analysis to quantify Pb(II) in the resulting adducts. XPS of the Pb 4f orbitals showed that more Pb(II) was chemically bound to NACA than NAC. In addition, the antioxidant surfaces probed via point-of-zero charge (PZC) measurements of NAC and NACA were obtained to gain further insight into the Pb-NAC and Pb-NACA binding, showing that Coulombic interactions played a partial role in facilitating complex formation. The data correlated well with solution analysis of metal-ligand complexation. UV-vis spectroscopy was used to probe complexation behavior. NACA was found to have the higher binding affinity as shown by free Pb(II) available in the solution after complexation from HPLC data. Electrospray ionization mass spectrometry (ESI-MS) was applied to delineate the structures of Pb-antioxidant complexes. Experimental results were further supported by density functional theory (DFT) calculations of supermolecular interaction energies (E(inter)) showing a greater interaction of Pb(II) with NACA than NAC. PMID:22284448

  16. Exposure to morphine-associated cues increases mu opioid receptor mRNA expression in the nucleus accumbens of Wistar Kyoto rats.

    PubMed

    Dennis, Torry S; Beck, Kevin D; Cominski, Tara P; Bobzean, Samara A M; Kuzhikandathil, Eldo V; Servatius, Richard J; Perrotti, Linda I

    2016-10-15

    The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability as it exhibits pronounced behavioral inhibition, passive avoidance, exaggerated startle response, enhanced HPA-axis activation, and active avoidance that is resistant to extinction. Accumulating evidence suggests that WKY rats respond differently to rewarding stimuli when compared to outbred strains of rat. Conditioned responding to drug-associated cues is linked with alterations in the activation of mu opioid receptors (MOR) and kappa opioid receptors (KOR) in the nucleus accumbens (NAc). Furthermore, alterations in KOR expression/activation in the NAc of WKY rats are implicated in the regulation of some of the components that make up the unique behavioral phenotype of this strain. The purpose of this study was to extend upon previous work from our laboratory by investigating conditioned morphine reward in adult male WKY and SD rats, and to examine levels of KOR mRNA and MOR mRNA in the NAc at baseline and after acquisition of morphine CPP. Our results demonstrate that SD rats displayed morphine-induced CPP to each of the six doses of morphine tested (0.5, 1.25, 2.5, 5, 7.5, or 10mg/kg). Interestingly, WKY rats demonstrated CPP for only the 1.25, 2.5, and 5mg/kg doses, yet no preference at the lowest (0.5mg/kg) or highest (7.5 and 10mg/kg) doses. qPCR analysis of MOR and KOR in the NAc revealed no strain differences in basal levels of MOR, but higher levels of KOR in WKY rats compared to those of SD rats. Interestingly, after completion of the CPP task, WKY rats had overall higher levels of NAc MOR mRNA compared to SD rats; the initial basal differences in NAc KOR levels persisted without change due to CPP in either strain. These results demonstrate that the WKY rat exhibits a unique pattern of behavioral responding to morphine and implicates differences in NAc KOR signaling as a potential source of aversion to higher doses of morphine. Additionally, the CPP-induced upregulation of

  17. Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice.

    PubMed

    Chefer, Vladimir I; Kieffer, Brigitte L; Shippenberg, Toni S

    2003-10-01

    Conventional and no net flux microdialysis were used to quantify basal and morphine-induced extracellular dopamine (DA) levels and the basal extraction fraction, which provides an estimate of the rate of DA uptake, in the nucleus accumbens (NAc) of wild-type mice and those with a constitutive deletion of mu (MOR)- or delta (DOR)-opioid receptors. Locomotor activity was assessed in these same animals. No difference between genotypes in basal dialysate DA levels was seen. No net flux studies revealed significant decreases in the DA extraction fraction in both MOR- and DOR-knockout mice, indicating decreased basal DA uptake in both genotypes. Extracellular DA, however, was unchanged. Because extracellular neurotransmitter levels are determined by the dynamics of both release and uptake, these findings provide suggestive evidence that basal DA release is decreased in mutant mice. Systemic administration of morphine significantly increased locomotor activity and dialysate DA levels in wild-type mice. MOR-knockout mice failed to exhibit a behavioural response to morphine. The ability of morphine to increase DA levels, however, was reduced but not prevented. No alteration in the effects of morphine was observed in DOR-knockout mice. These data provide genetic evidence for the existence of tonically active MOR and DOR systems that modulate basal DA neurotransmission in the NAc. Furthermore, they demonstrate that in contrast to the locomotor-activating effects of morphine, a small component of morphine-evoked DA release occurs independently of MOR activation. PMID:14622224

  18. Quantitative no-net-flux microdialysis permits detection of increases and decreases in dopamine uptake in mouse nucleus accumbens.

    PubMed

    Chefer, Vladimir I; Zapata, Agustin; Shippenberg, Toni S; Bungay, Peter M

    2006-09-15

    A number of investigators are using the quantitative no-net-flux microdialysis technique to monitor basal neurotransmitter dynamics in discrete brain regions of behaving animals. The predictive validity of the probe extraction fraction (Ed) for quantifying decreases in the rate of dopamine (DA) clearance from the extracellular space is well documented. It was recently suggested, however, that Ed may be insensitive to increases in DA clearance. Here we report that the Ed for DA in the nucleus accumbens (NAc) of the behaving mouse is increased following pharmacological inactivation of kappa-opioid receptors, a treatment previously shown to augment DA uptake. The Ed obtained in control mice and those that received the long-acting kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), satisfied the requirement that the mean values of each were lower than the mean value in vitro for the same probes immersed in well-stirred artificial cerebrospinal fluid. The Ed was increased in the NAc of nor-BNI-treated mice as compared to saline-treated control animals. The corresponding increase in the DA uptake rate was quantified by using the Ed values to calculate a change in the apparent clearance rate constant. Nor-BNI treatment did not alter the apparent extracellular dopamine concentration represented by the point of no-net-flux indicating that the rates of DA uptake and release were both increased. PMID:16466808

  19. Individual differences in nucleus accumbens dopamine receptors predict development of addiction-like behavior: a computational approach.

    PubMed

    Piray, Payam; Keramati, Mohammad Mahdi; Dezfouli, Amir; Lucas, Caro; Mokri, Azarakhsh

    2010-09-01

    Clinical and experimental observations show individual differences in the development of addiction. Increasing evidence supports the hypothesis that dopamine receptor availability in the nucleus accumbens (NAc) predisposes drug reinforcement. Here, modeling striatal-midbrain dopaminergic circuit, we propose a reinforcement learning model for addiction based on the actor-critic model of striatum. Modeling dopamine receptors in the NAc as modulators of learning rate for appetitive--but not aversive--stimuli in the critic--but not the actor--we define vulnerability to addiction as a relatively lower learning rate for the appetitive stimuli, compared to aversive stimuli, in the critic. We hypothesize that an imbalance in this learning parameter used by appetitive and aversive learning systems can result in addiction. We elucidate that the interaction between the degree of individual vulnerability and the duration of exposure to drug has two progressive consequences: deterioration of the imbalance and establishment of an abnormal habitual response in the actor. Using computational language, the proposed model describes how development of compulsive behavior can be a function of both degree of drug exposure and individual vulnerability. Moreover, the model describes how involvement of the dorsal striatum in addiction can be augmented progressively. The model also interprets other forms of addiction, such as obesity and pathological gambling, in a common mechanism with drug addiction. Finally, the model provides an answer for the question of why behavioral addictions are triggered in Parkinson's disease patients by D2 dopamine agonist treatments. PMID:20569176

  20. The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens.

    PubMed

    Ji, Xincai; Saha, Sucharita; Martin, Gilles E

    2015-01-01

    It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different information (e.g., spatial, emotional and cognitive). Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD) and long-term potentiation (LTP) and long-term potentiation (tLTP) and their regulation by alcohol. While we observed both tLTP and tLTD at amygadala and hippocampal synapses, we showed that cortical inputs only undergo tLTD. Functionally, we provide evidence that acute Ethyl Alcohol (EtOH) has little effects on higher order information coming from the PFCx, while severely impacting the ability of emotional and contextual information to induce long-lasting changes of synaptic strength. PMID:26257641

  1. ADOLESCENT INTERMITTENT ETHANOL EXPOSURE ENHANCES ETHANOL ACTIVATION OF THE NUCLEUS ACCUMBENS WHILE BLUNTING THE PREFRONTAL CORTEX RESPONSES IN ADULT RAT

    PubMed Central

    LIU, W.; CREWS, F. T.

    2016-01-01

    The brain continues to develop through adolescence when excessive alcohol consumption is prevalent in humans. We hypothesized that binge drinking doses of ethanol during adolescence will cause changes in brain ethanol responses that persist into adulthood. To test this hypothesis Wistar rats were treated with an adolescent intermittent ethanol (AIE; 5 g/kg, i.g. 2 days on–2 days off; P25–P54) model of underage drinking followed by 25 days of abstinence during maturation to young adulthood (P80). Using markers of neuronal activation c-Fos, EGR1, and phophorylated extracellar signal regulated kinase (pERK1/2), adult responses to a moderate and binge drinking ethanol challenge, e.g., 2 or 4 g/kg, were determined. Adult rats showed dose dependent increases in neuronal activation markers in multiple brain regions during ethanol challenge. Brain regional responses correlated are consistent with anatomical connections. AIE led to marked decreases in adult ethanol PFC (prefrontal cortex) and blunted responses in the amygdala. Binge drinking doses led to the nucleus accumbens (NAc) activation that correlated with the ventral tegmental area (VTA) activation. In contrast to other brain regions, AIE enhanced the adult NAc response to binge drinking doses. These studies suggest that adolescent alcohol exposure causes long-lasting changes in brain responses to alcohol that persist into adulthood. PMID:25727639

  2. Dopaminergic effects of histamine administration in the nucleus accumbens and the impact of H1-receptor blockade.

    PubMed

    Galosi, R; Lenard, L; Knoche, A; Haas, H; Huston, J P; Schwarting, R K

    2001-03-01

    The mesolimbic dopamine system is thought to play a critical role in reward-related processes. A number of studies have shown that lesion or inhibition of histaminergic neurons acting through H1 receptors can potentiate the effects of drug-induced reward (e.g., psychostimulants and opioids) and can enhance the reinforcing effects of electrical stimulation of the brain. Since dopamine transmission in the nucleus accumbens is thought to provide a crucial link in these histaminergic actions, we examined the effects of local histamine application (0.1, 1.0 and 10.0 micromol/l) on dopamine and its metabolites in the nucleus accumbens of anesthetized rats by means of unilateral reverse dialysis. To study the influence of H1 receptors, we also applied the H1-receptor antagonist pyrilamine (10.0 and 20.0 mg/kg, intraperitoneally) 20 min before histamine administration (1 mmol/l). Finally, pyrilamine (0.1, 1.0 and 10.0 micromol/l) was locally administered into the nucleus accumbens. The data show that histamine can enhance extracellular dopamine levels in the nucleus accumbens in a dose-dependent way. This increase was partially antagonized by prior peripheral administration of 10 mg/kg, and was completely blocked by 20 mg/kg, of pyrilamine. Finally, intra-accumbens administration of pyrilamine locally decreased dopamine and increased dihydroxyphenylacetic acid and homovanillic acid levels. These data are discussed with respect to the possible interactions between dopaminergic and histaminergic mechanisms in the mesolimbic system and their relation to mechanisms of reinforcement. PMID:11249972

  3. A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence

    PubMed Central

    Marchant, Nathan J.; Kaganovsky, Konstantin

    2015-01-01

    In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, where alcohol seeking that is suppressed with extinction training in a context (B) renews when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence due to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence is imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol preferring ‘P rats’ to self-administer 20% alcohol in context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment. PMID:25914922

  4. Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens

    PubMed Central

    Ebner, Stephanie R.; Roitman, Mitchell F.; Potter, David N.; Rachlin, Anna B.; Chartoff, Elena H.

    2010-01-01

    Rationale Kappa opioid receptors (KORs) have been implicated in depressive-like states associated with chronic administration of drugs of abuse and stress. Although KOR agonists decrease dopamine in the nucleus accumbens (NAc), KOR modulation of phasic dopamine release in the core and shell subregions of the NAc—which have distinct roles in reward processing—remains poorly understood. Objectives Studies were designed to examine whether the time course of effects of KOR activation on phasic dopamine release in the NAc core or shell are similar to effects on motivated behavior. Methods The effect of systemic administration of the KOR agonist salvinorin A (salvA)—at a dose (2.0 mg/kg) previously determined to have depressive-like effects—was measured on electrically evoked phasic dopamine release in the NAc core or shell of awake and behaving rats using fast scan cyclic voltammetry. In parallel, the effects of salvA on intracranial self-stimulation (ICSS) and sucrose-reinforced responding were assessed. For comparison, a threshold dose of salvA (0.25 mg/kg) was also tested. Results The active, but not threshold, dose of salvA significantly decreased phasic dopamine release without affecting dopamine reuptake in the NAc core and shell. SalvA increased ICSS thresholds and significantly lowered breakpoint on the progressive ratio schedule, indicating a decrease in motivation. The time course of the KOR-mediated decrease in dopamine in the core was qualitatively similar to the effects on motivated behavior. Conclusions These data suggest that the effects of KOR activation on motivation are due, in part, to inhibition of phasic dopamine signaling in the NAc core. PMID:20372879

  5. Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress.

    PubMed

    Warren, Brandon L; Sial, Omar K; Alcantara, Lyonna F; Greenwood, Maria A; Brewer, Jacob S; Rozofsky, John P; Parise, Eric M; Bolaños-Guzmán, Carlos A

    2014-01-01

    Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional stress (ES) or physical stress (PS) on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day 35) or adult (8-week-old) mice were exposed to ES or PS using a witness social defeat paradigm. Then, 24 h after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted extracellular signal-related kinase 2 (ERK2), reduced transcription of ΔFosB and had no effect on cAMP response element-binding protein (CREB) mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc. PMID:24943326

  6. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement.

    PubMed

    Wang, Lei; Lv, Zhigang; Hu, Zhaoyang; Sheng, Jian; Hui, Bin; Sun, Jie; Ma, Lan

    2010-03-01

    The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIalpha, but not CaMKIIbeta, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIalpha, but not CaMKIIbeta, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIalpha, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. PMID:20010550

  7. A Diverse Range of Bacterial and Eukaryotic Chitinases Hydrolyzes the LacNAc (Galβ1–4GlcNAc) and LacdiNAc (GalNAcβ1–4GlcNAc) Motifs Found on Vertebrate and Insect Cells*

    PubMed Central

    Frederiksen, Rikki F.; Yoshimura, Yayoi; Storgaard, Birgit G.; Paspaliari, Dafni K.; Petersen, Bent O.; Chen, Kowa; Larsen, Tanja; Duus, Jens Ø.; Ingmer, Hanne; Bovin, Nicolai V.; Westerlind, Ulrika; Blixt, Ola; Palcic, Monica M.; Leisner, Jørgen J.

    2015-01-01

    There is emerging evidence that chitinases have additional functions beyond degrading environmental chitin, such as involvement in innate and acquired immune responses, tissue remodeling, fibrosis, and serving as virulence factors of bacterial pathogens. We have recently shown that both the human chitotriosidase and a chitinase from Salmonella enterica serovar Typhimurium hydrolyze LacNAc from Galβ1–4GlcNAcβ-tetramethylrhodamine (LacNAc-TMR (Galβ1–4GlcNAcβ(CH2)8CONH(CH2)2NHCO-TMR)), a fluorescently labeled model substrate for glycans found in mammals. In this study we have examined the binding affinities of the Salmonella chitinase by carbohydrate microarray screening and found that it binds to a range of compounds, including five that contain LacNAc structures. We have further examined the hydrolytic specificity of this enzyme and chitinases from Sodalis glossinidius and Polysphondylium pallidum, which are phylogenetically related to the Salmonella chitinase, as well as unrelated chitinases from Listeria monocytogenes using the fluorescently labeled substrate analogs LacdiNAc-TMR (GalNAcβ1–4GlcNAcβ-TMR), LacNAc-TMR, and LacNAcβ1–6LacNAcβ-TMR. We found that all chitinases examined hydrolyzed LacdiNAc from the TMR aglycone to various degrees, whereas they were less active toward LacNAc-TMR conjugates. LacdiNAc is found in the mammalian glycome and is a common motif in invertebrate glycans. This substrate specificity was evident for chitinases of different phylogenetic origins. Three of the chitinases also hydrolyzed the β1–6 bond in LacNAcβ1–6LacNAcβ-TMR, an activity that is of potential importance in relation to mammalian glycans. The enzymatic affinities for these mammalian-like structures suggest additional functional roles of chitinases beyond chitin hydrolysis. PMID:25561735

  8. A diverse range of bacterial and eukaryotic chitinases hydrolyzes the LacNAc (Galβ1-4GlcNAc) and LacdiNAc (GalNAcβ1-4GlcNAc) motifs found on vertebrate and insect cells.

    PubMed

    Frederiksen, Rikki F; Yoshimura, Yayoi; Storgaard, Birgit G; Paspaliari, Dafni K; Petersen, Bent O; Chen, Kowa; Larsen, Tanja; Duus, Jens Ø; Ingmer, Hanne; Bovin, Nicolai V; Westerlind, Ulrika; Blixt, Ola; Palcic, Monica M; Leisner, Jørgen J

    2015-02-27

    There is emerging evidence that chitinases have additional functions beyond degrading environmental chitin, such as involvement in innate and acquired immune responses, tissue remodeling, fibrosis, and serving as virulence factors of bacterial pathogens. We have recently shown that both the human chitotriosidase and a chitinase from Salmonella enterica serovar Typhimurium hydrolyze LacNAc from Galβ1-4GlcNAcβ-tetramethylrhodamine (LacNAc-TMR (Galβ1-4GlcNAcβ(CH2)8CONH(CH2)2NHCO-TMR)), a fluorescently labeled model substrate for glycans found in mammals. In this study we have examined the binding affinities of the Salmonella chitinase by carbohydrate microarray screening and found that it binds to a range of compounds, including five that contain LacNAc structures. We have further examined the hydrolytic specificity of this enzyme and chitinases from Sodalis glossinidius and Polysphondylium pallidum, which are phylogenetically related to the Salmonella chitinase, as well as unrelated chitinases from Listeria monocytogenes using the fluorescently labeled substrate analogs LacdiNAc-TMR (GalNAcβ1-4GlcNAcβ-TMR), LacNAc-TMR, and LacNAcβ1-6LacNAcβ-TMR. We found that all chitinases examined hydrolyzed LacdiNAc from the TMR aglycone to various degrees, whereas they were less active toward LacNAc-TMR conjugates. LacdiNAc is found in the mammalian glycome and is a common motif in invertebrate glycans. This substrate specificity was evident for chitinases of different phylogenetic origins. Three of the chitinases also hydrolyzed the β1-6 bond in LacNAcβ1-6LacNAcβ-TMR, an activity that is of potential importance in relation to mammalian glycans. The enzymatic affinities for these mammalian-like structures suggest additional functional roles of chitinases beyond chitin hydrolysis. PMID:25561735

  9. Reversible Palmitoylation Regulates Surface Stability of AMPA Receptors in the Nucleus Accumbens in Response to Cocaine in vivo

    PubMed Central

    Van Dolah, Dustin K.; Mao, Li-Min; Shaffer, Christopher; Guo, Ming-Lei; Fibuch, Eugene E.; Chu, Xiang-Ping; Buch, Shilpa; Wang, John Q.

    2010-01-01

    Background Palmitoylation is emerging as one of the most important posttranslational modifications of excitatory synaptic proteins in mammalian brain cells. As a reversible and regulatable modification sensitive to changing synaptic inputs, palmitoylation of ionotropic glutamate receptors contributes to not only the modulation of normal receptor and synaptic activities, but also the pathogenesis of various neuropsychiatric disorders. Here, we report that palmitoylation of the AMPA receptor is regulated by the psychostimulant, cocaine, and such regulation is involved in cocaine action. Methods We tested palmitoylation and surface expression of AMPA receptors in striatal neurons and psychomotor behavior in responses to cocaine in rats. Results All four AMPA receptor subunits (GluA1-4 or GluR1-4) are palmitoylated in the nucleus accumbens (NAc) of adult rats. Among them, GluA1 and GluA3 are preferentially upregulated in their palmitoylation levels by a systemic injection of cocaine. The upregulated GluA1 and 3 palmitoylation is a transient and reversible event. Consequently, it increases the susceptibility of surface-expressed GluA1 and 3 to internalization trafficking, leading to a temporal loss of surface receptor expression. Blockade of the regulated GluA1/3 palmitoylation with a palmitoylation inhibitor in the local NAc reverses the loss of surface GluA1/3. The inhibition of palmitoylation also concurrently sustains behavioral responsivity to cocaine. Conclusions Our data identify a novel drug-palmitoylation coupling in the center of limbic reward circuits. Through palmitoylating selective AMPA receptor subunits, cocaine activity-dependently regulates trafficking and subcellular localization of the receptor in NAc neurons and dynamically controls psychomotor sensitivity to the psychoactive drug in vivo. PMID:21216391

  10. Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.

    PubMed

    Leite-Morris, Kimberly A; Kobrin, Kendra L; Guy, Marsha D; Young, Angela J; Heinrichs, Stephen C; Kaplan, Gary B

    2014-04-15

    Recurrent opiate use combined with environmental cues, in which the drug was administered, provokes cue-induced drug craving and conditioned drug reward. Drug abuse craving is frequently linked with stimuli from a prior drug-taking environment via classical conditioning and associative learning. We modeled the conditioned morphine reward process by using acquisition and extinction of conditioned place preference (CPP) in C57BL/6 mice. Mice were trained to associate a morphine injection with a drug context using a classical conditioning paradigm. In morphine conditioning (0, 0.25, 0.5, 1, 5, or 10 mg/kg) experimental mice acquired a morphine CPP dose response with 10mg/kg as most effective. During morphine CPP extinction experiments, mice were divided into three test groups: morphine CPP followed by extinction training, morphine CPP followed by sham extinction, and saline controls. Extinction of morphine CPP developed within one extinction experiment (4 days) that lasted over two more trials (another 8 days). However, the morphine CPP/sham extinction group retained a place preference that endured through all three extinction trials. Brains were harvested following CPP extinction and processed using Golgi-Cox impregnation. Changes in dendritic morphology and spine quantity were examined in the nucleus accumbens (NAc) Core and Shell neurons. In the NAcCore only, morphine CPP/extinguished mice produced less dendritic arborization, and a decrease in neuronal activity marker c-Fos compared to the morphine CPP/sham extinction group. Extinction of morphine CPP is associated with decreased structural complexity of dendrites in the NAcCore and may represent a substrate for learning induced structural plasticity relevant to addiction. PMID:24406724

  11. Differential effects of acute and chronic nicotine on dopamine output in the core and shell of the rat nucleus accumbens.

    PubMed

    Nisell, M; Marcus, M; Nomikos, G G; Svensson, T H

    1997-01-01

    Like several drugs of abuse, nicotine increase dopamine (DA) release in the nucleus accumbens (NAC). In the present study, the effects of acute and chronic nicotine on DA output in two subdivisions of the NAC, the core and the shell, which are largely associated with motor control and limbic functions, respectively, were examined by means of in vivo differential normal pulse voltammetry in anesthetized, pargyline-treated rats. In the first experiment, acute administration of nicotine (25, 50 and 100 micrograms/kg, cumulative doses; i.v.) was found to increase DA levels in the NACshell to 163% of baseline, whereas DA output in the NACcore was not significantly affected. In the second experiment, animals were pretreated with twelve daily injections of saline or nicotine (0.5 mg/kg, i.p.); about 24 hours after the last injection, the animals were challenged with nicotine (50 micrograms/kg and 100 micrograms/kg, cumulative doses; i.v.). Under these conditions, nicotine increased DA output in the NACshell in saline-pretreated animals to 248% and in nicotine-pretreated rats to 180%. Also, nicotine increased DA output in the NACcore in saline-pretreated animals to 185%, whereas no significant effect was observed in nicotine-pretreated rats. The results of the present experiments indicate (i) that acutely administered nicotine or nicotine challenge in chronically pretreated animals with either saline or nicotine consistently increases DA release to a greater extent in the NACshell than in the NACcore, and (ii) that chronic nicotine pretreatment reduces the stimulatory-action of nicotine on DA output in either the shell or the core subdivision of the NAC. PMID:9085189

  12. Novel role of ZmaNAC36 in co-expression of starch synthetic genes in maize endosperm.

    PubMed

    Zhang, Junjie; Chen, Jiang; Yi, Qiang; Hu, Yufeng; Liu, Hanmei; Liu, Yinghong; Huang, Yubi

    2014-02-01

    Starch is an essential commodity that is widely used as food, feed, fuel and in industry. However, its mechanism of synthesis is not fully understood, especially in terms of the expression and regulation of the starch synthetic genes. It was reported that the starch synthetic genes were co-expressed during maize endosperm development; however, the mechanism of the co-expression was not reported. In this paper, the ZmaNAC36 gene was amplified by homology-based cloning, and its expression vector was constructed for transient expression. The nuclear localization, transcriptional activation and target sites of the ZmaNAC36 protein were identified. The expression profile of ZmaNAC36 showed that it was strongly expressed in the maize endosperm and was co-expressed with most of the starch synthetic genes. Moreover, the expressions of many starch synthesis genes in the endosperm were upregulated when ZmaNAC36 was transiently overexpressed. All our results indicated that NAC36 might be a transcription factor and play a potential role in the co-expression of starch synthetic genes in the maize endosperm. PMID:24235061

  13. GalNAc-T4 putatively modulates the estrogen regulatory network through FOXA1 glycosylation in human breast cancer cells.

    PubMed

    Niang, Bachir; Jin, Liyuan; Chen, Xixi; Guo, Xiaohan; Zhang, Hongshuo; Wu, Qiong; Padhiar, Arshad Ahmed; Xiao, Min; Fang, Deyu; Zhang, Jianing

    2016-01-01

    GALNT4 belongs to a family of N-acetylgalactosaminyltransferases, which catalyze the transfer of GalNAc to Serine or Threonine residues in the initial step of mucin-type O-linked protein glycosylation. This glycosylation type is the most complex post-translational modification of proteins, playing important roles during cellular differentiation and in pathological disorders. Most of the breast cancer subtypes are estrogen receptor positive, and hence, the estrogen pathway represents a key regulatory network. We investigated the expression of GalNAc-T4 in a panel of mammary epithelial cell lines and found its expression is associated with the estrogen status of the cells. FOXA1, a key transcription factor, functions to promote estrogen responsive gene expression by acting as a cofactor to estrogen receptor alpha (ERα), but all the aspects of this regulatory mechanism are not fully explored. This study found that knockdown of GALNT4 expression in human breast cancer cells attenuated the protein expression of ERα, FOXA1, and Cyclin D1. Further, our immunoprecipitation assays depicted the possibility of FOXA1 to undergo O-GalNAc modifications with a decrease of GalNAc residues in the GALNT4 knockdown cells and also impairment in the FOXA1-ERα association. Rescuing GALNT4 expression could restore the interaction as well as the glycosylation of FOXA1. Together, these findings suggest a key role for GalNAc-T4 in the estrogen pathway through FOXA1 glycosylation. PMID:26541755

  14. New priorities and developments at NAC

    NASA Astrophysics Data System (ADS)

    Conradie, J. L.; Botha, A. H.; Celliers, P. J.; Cronje, P. M.; Delsink, J. L. G.; de Villiers, J. G.; du Plessis, H.; du Toit, J. S.; Fourie, D. T.; Hogan, M. E.; Jungwirth, H. N.; Kohler, I. H.; Müller, A.; Rohwer, P. F.; Smit, H. A.; Theron, P. J.; van Niekerk, M. J.

    2001-12-01

    The facilities at the National Accelerator Center (NAC) are utilized for proton and neutron therapy, the production of radioisotopes and for nuclear physics experiments. This implies an operating schedule with nine energy changes per week. Mainly due to this the reliability of beam delivery deteriorated to such an extent that we recently had to revert to a beam schedule with only four energy changes per week. This necessitated redefinition of the priorities for our proton therapy program. The request for higher proton beam currents at 66 MeV, for radioisotope production, stimulated the design of dedicated flat-top systems for both the light-ion injector cyclotron (SPC1) and the separated-sector cyclotron (SSC). We also investigated the feasibility of accelerating high-intensity proton beams (500 μA) in the SSC by using the high-intensity space-charge mode developed at PSI. The design of a vertical beamline and modifications to the existing beam transport system for the new high-intensity target station are in progress. Further developments include an additional septum magnet for the SSC extraction system and a new Local Area Network computer-control system for the RF systems. The progress with these projects will be presented and the status of the facilities discussed.

  15. Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

    PubMed Central

    Rose, Jamie H.; Karkhanis, Anushree N.; Steiniger-Brach, Björn; Jones, Sara R.

    2016-01-01

    The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs. PMID:27472317

  16. S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: a microdialysis study.

    PubMed

    Faiman, Morris D; Kaul, Swetha; Latif, Shaheen A; Williams, Todd D; Lunte, Craig E

    2013-12-01

    Disulfiram (DSF), used for the treatment of alcohol use disorders (AUDs) for over six decades, most recently has shown promise for treating cocaine dependence. Although DSF's mechanism of action in alcohol abuse is due to the inhibition of liver mitochondrial aldehyde dehydrogenase (ALDH2), its mechanism of action in the treatment of cocaine dependence is unknown. DSF is a pro-drug, forming a number of metabolites each with discrete pharmacological actions. One metabolite formed during DSF bioactivation is S-(N, N-diethylcarbamoyl) glutathione (carbamathione) (carb). We previously showed that carb affects glutamate binding. In the present studies, we employed microdialysis techniques to investigate the effect of carb administration on dopamine (DA), GABA, and glutamate (Glu) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two brain regions implicated in substance abuse dependence. The effect of DSF on DA, GABA, and Glu in the NAc also was determined. Both studies were carried out in male rats. Carb (20, 50, 200 mg/kg i v) in a dose-dependent manner increased DA, decreased GABA, and had a biphasic effect on Glu, first increasing and then decreasing Glu in both the NAc and mPFC. These changes all occurred concurrently. After carb administration, NAc and mPFC carb, as well as carb in plasma, were rapidly eliminated with a half-life for each approximately 4 min, while the changes in DA, GABA, and GLu in the NAc and mPFC persisted for approximately two hours. The maximal increase in carb (Cmax) in the NAc and mPFC after carb administration was dose-dependent, as was the area under the curve (AUC). DSF (200 mg/kg i p) also increased DA, decreased GABA, and had a biphasic effect on Glu in the NAc similar to that observed in the NAc after carb administration. When the cytochrome P450 inhibitor N-benzylimidazole (NBI) (20 mg/kg i p) was administered before DSF dosing, no carb could be detected in the NAc and plasma and also no changes in NAc DA, GABA

  17. Genome-wide identification and expression analysis of the CaNAC family members in chickpea during development, dehydration and ABA treatments.

    PubMed

    Ha, Chien Van; Esfahani, Maryam Nasr; Watanabe, Yasuko; Tran, Uyen Thi; Sulieman, Saad; Mochida, Keiichi; Nguyen, Dong Van; Tran, Lam-Son Phan

    2014-01-01

    The plant-specific NAC transcription factors (TFs) play important roles in regulation of diverse biological processes, including development, growth, cell division and responses to environmental stimuli. In this study, we identified the members of the NAC TF family of chickpea (Cicer arietinum) and assess their expression profiles during plant development and under dehydration and abscisic acid (ABA) treatments in a systematic manner. Seventy-one CaNAC genes were detected from the chickpea genome, including 8 membrane-bound members of which many might be involved in dehydration responses as judged from published literature. Phylogenetic analysis of the chickpea and well-known stress-related Arabidopsis and rice NACs enabled us to predict several putative stress-related CaNACs. By exploring available transcriptome data, we provided a comprehensive expression atlas of CaNACs in various tissues at different developmental stages. With the highest interest in dehydration responses, we examined the expression of the predicted stress-related and membrane-bound CaNACs in roots and leaves of chickpea seedlings, subjected to well-watered (control), dehydration and ABA treatments, using real-time quantitative PCR (RT-qPCR). Nine-teen of the 23 CaNACs examined were found to be dehydration-responsive in chickpea roots and/or leaves in either ABA-dependent or -independent pathway. Our results have provided a solid foundation for selection of promising tissue-specific and/or dehydration-responsive CaNAC candidates for detailed in planta functional analyses, leading to development of transgenic chickpea varieties with improved productivity under drought. PMID:25479253

  18. Phosphorylation of a NAC Transcription Factor by a Calcium/Calmodulin-Dependent Protein Kinase Regulates Abscisic Acid-Induced Antioxidant Defense in Maize.

    PubMed

    Zhu, Yuan; Yan, Jingwei; Liu, Weijuan; Liu, Lei; Sheng, Yu; Sun, Yue; Li, Yanyun; Scheller, Henrik Vibe; Jiang, Mingyi; Hou, Xilin; Ni, Lan; Zhang, Aying

    2016-07-01

    Calcium/calmodulin-dependent protein kinase (CCaMK) has been shown to play an important role in abscisic acid (ABA)-induced antioxidant defense and enhance the tolerance of plants to drought stress. However, its downstream molecular events are poorly understood. Here, we identify a NAC transcription factor, ZmNAC84, in maize (Zea mays), which physically interacts with ZmCCaMK in vitro and in vivo. ZmNAC84 displays a partially overlapping expression pattern with ZmCCaMK after ABA treatment, and H2O2 is required for ABA-induced ZmNAC84 expression. Functional analysis reveals that ZmNAC84 is essential for ABA-induced antioxidant defense in a ZmCCaMK-dependent manner. Furthermore, ZmCCaMK directly phosphorylates Ser-113 of ZmNAC84 in vitro, and Ser-113 is essential for the ABA-induced stimulation of antioxidant defense by ZmCCaMK. Moreover, overexpression of ZmNAC84 in tobacco (Nicotiana tabacum) can improve drought tolerance and alleviate drought-induced oxidative damage of transgenic plants. These results define a mechanism for ZmCCaMK function in ABA-induced antioxidant defense, where ABA-produced H2O2 first induces expression of ZmCCaMK and ZmNAC84 and activates ZmCCaMK. Subsequently, the activated ZmCCaMK phosphorylates ZmNAC84 at Ser-113, thereby inducing antioxidant defense by activating downstream genes. PMID:27208250

  19. Phosphorylation of a NAC Transcription Factor by a Calcium/Calmodulin-Dependent Protein Kinase Regulates Abscisic Acid-Induced Antioxidant Defense in Maize1[OPEN

    PubMed Central

    Zhu, Yuan; Yan, Jingwei; Liu, Weijuan; Liu, Lei; Sheng, Yu; Sun, Yue; Li, Yanyun; Hou, Xilin; Ni, Lan

    2016-01-01

    Calcium/calmodulin-dependent protein kinase (CCaMK) has been shown to play an important role in abscisic acid (ABA)-induced antioxidant defense and enhance the tolerance of plants to drought stress. However, its downstream molecular events are poorly understood. Here, we identify a NAC transcription factor, ZmNAC84, in maize (Zea mays), which physically interacts with ZmCCaMK in vitro and in vivo. ZmNAC84 displays a partially overlapping expression pattern with ZmCCaMK after ABA treatment, and H2O2 is required for ABA-induced ZmNAC84 expression. Functional analysis reveals that ZmNAC84 is essential for ABA-induced antioxidant defense in a ZmCCaMK-dependent manner. Furthermore, ZmCCaMK directly phosphorylates Ser-113 of ZmNAC84 in vitro, and Ser-113 is essential for the ABA-induced stimulation of antioxidant defense by ZmCCaMK. Moreover, overexpression of ZmNAC84 in tobacco (Nicotiana tabacum) can improve drought tolerance and alleviate drought-induced oxidative damage of transgenic plants. These results define a mechanism for ZmCCaMK function in ABA-induced antioxidant defense, where ABA-produced H2O2 first induces expression of ZmCCaMK and ZmNAC84 and activates ZmCCaMK. Subsequently, the activated ZmCCaMK phosphorylates ZmNAC84 at Ser-113, thereby inducing antioxidant defense by activating downstream genes. PMID:27208250

  20. Genome-Wide Identification and Expression Analysis of the CaNAC Family Members in Chickpea during Development, Dehydration and ABA Treatments

    PubMed Central

    Ha, Chien Van; Nasr Esfahani, Maryam; Watanabe, Yasuko; Tran, Uyen Thi; Sulieman, Saad; Mochida, Keiichi; Van Nguyen, Dong; Tran, Lam-Son Phan

    2014-01-01

    The plant-specific NAC transcription factors (TFs) play important roles in regulation of diverse biological processes, including development, growth, cell division and responses to environmental stimuli. In this study, we identified the members of the NAC TF family of chickpea (Cicer arietinum) and assess their expression profiles during plant development and under dehydration and abscisic acid (ABA) treatments in a systematic manner. Seventy-one CaNAC genes were detected from the chickpea genome, including 8 membrane-bound members of which many might be involved in dehydration responses as judged from published literature. Phylogenetic analysis of the chickpea and well-known stress-related Arabidopsis and rice NACs enabled us to predict several putative stress-related CaNACs. By exploring available transcriptome data, we provided a comprehensive expression atlas of CaNACs in various tissues at different developmental stages. With the highest interest in dehydration responses, we examined the expression of the predicted stress-related and membrane-bound CaNACs in roots and leaves of chickpea seedlings, subjected to well-watered (control), dehydration and ABA treatments, using real-time quantitative PCR (RT-qPCR). Nine-teen of the 23 CaNACs examined were found to be dehydration-responsive in chickpea roots and/or leaves in either ABA-dependent or -independent pathway. Our results have provided a solid foundation for selection of promising tissue-specific and/or dehydration-responsive CaNAC candidates for detailed in planta functional analyses, leading to development of transgenic chickpea varieties with improved productivity under drought. PMID:25479253

  1. Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats

    PubMed Central

    Swerdlow, Neal R.; Powell, Susan B.; Breier, Michelle R.; Hines, Samantha R.; Light, Gregory A.

    2013-01-01

    Background After neonatal ventral hippocampal lesions (NVHLs), adult rats exhibit evidence of neural processing deficits relevant to schizophrenia, including reduced prepulse inhibition (PPI) of acoustic startle and impaired sensory processing. In intact rats, the regulation of PPI by the ventral hippocampus (VH) is mediated via interactions with medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked responses and expression of 7 schizophrenia-related genes in mPFC and NAC, in adult rats after sham- or real NVHLs. Methods Male inbred Buffalo (BUF) rat pups (d7; n=36) received either vehicle or ibotenic acid infusion into the VH. PPI and auditory-evoked dentate gyrus local field potentials (LFPs) were measured on d56 and d66, respectively. Brains were processed for RT-PCR measures of mPFC and NAC Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Results NVHL rats exhibited significant deficits in PPI (p=0.005) and LFPs (p<0.015) proportional to lesion size. Sham vs. NVHL rats did not differ in gene expression levels in mPFC or NAC. As we previously reported, multiple gene expression levels were highly correlated within- (mean r's≈0.5), but not across-brain regions (mean r's≈0). However, for three genes – Comt, Slc1a2 and Ncam1 – after NVHLs, expression levels became significantly correlated, or “coupled,” across the mPFC and NAC (p's < 0.03, 0.002 and 0.05, respectively), and the degree of “coupling” increased with VH lesion size. Conclusions After NVHLs that disrupt PPI and auditory processing, specific gene expression levels suggest an abnormal functional coupling of the mPFC and NAC. This model of VH-mPFC-NAC network dysfunction after NVHLs may have implications for understanding the neural basis for PPI- and related sensory processing deficits in schizophrenia patients. PMID:23810830

  2. Ultrastructural localization of tyrosine hydroxylase in tree shrew nucleus accumbens core and shell

    PubMed Central

    McCollum, Lesley A.; Roberts, Rosalinda C.

    2014-01-01

    Many behavioral, physiological, and anatomical studies utilize animal models to investigate human striatal pathologies. Although commonly used, rodent striatum may not present the optimal animal model for certain studies due to a lesser morphological complexity than that of non-human primates, which are increasingly restricted in research. As an alternative, the tree shrew could provide a beneficial animal model for studies of the striatum. The gross morphology of the tree shrew striatum resembles that of primates, with separation of the caudate and putamen by the internal capsule. The neurochemical anatomy of the ventral striatum, specifically the nucleus accumbens, has never been examined. This major region of the limbic system plays a role in normal physiological functioning and is also an area of interest for human striatal disorders. The current study uses immunohistochemistry of calbindin and tyrosine hydroxylase (TH) to determine the ultrastructural organization of the nucleus accumbens core and shell of the tree shrew (Tupaia glis belangeri). Stereology was used to quantify the ultrastructural localization of TH, which displays weaker immunoreactivity in the core and denser immunoreactivity in the shell. In both regions, synapses with TH-immunoreactive axon terminals were primarily symmetric and showed no preference for targeting dendrites versus dendritic spines. The results were compared to previous ultrastructural studies of TH and dopamine in rat and monkey nucleus accumbens. Tree shrew and monkey show no preference for the postsynaptic target in the shell, in contrast to rats which show a preference for synapsing with dendrites. Tree shrews have a ratio of asymmetric to symmetric synapses formed by TH-immunoreactive terminals that is intermediate between rats and monkey. The findings from this study support the tree shrew as an alternative model for studies of human striatal pathologies. PMID:24769226

  3. Microinjection of recombinant O-GlcNAc transferase potentiates Xenopus oocytes M-phase entry

    SciTech Connect

    Dehennaut, Vanessa; Hanoulle, Xavier; Bodart, Jean-Francois; Vilain, Jean-Pierre; Michalski, Jean-Claude; Landrieu, Isabelle; Lippens, Guy; Lefebvre, Tony

    2008-05-02

    In order to understand the importance of the cytosolic and nuclear-specific O-linked N-acetylglucosaminylation (O-GlcNAc) on cell cycle regulation, we recently reported that inhibition of O-GlcNAc transferase (OGT) delayed or blocked Xenopus laevis oocyte germinal vesicle breakdown (GVBD). Here, we show that increased levels of the long OGT isoform (ncOGT) accelerate X. laevis oocyte GVBD. A N-terminally truncated isoform (sOGT) with a similar in vitro catalytic activity towards a synthetic CKII-derived peptide had no effect, illustrating the important role played by the N-terminal tetratrico-peptide repeats. ncOGT microinjection in the oocytes increases both the speed and extent of O-GlcNAc addition, leads to a quicker activation of the MPF and MAPK pathways and finally results in a faster GVBD. Microinjection of anti-OGT antibodies leads to a delay of the GVBD kinetics. Our results hence demonstrate that OGT is a key molecule for the timely progression of the cell cycle.

  4. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells.

    PubMed

    Li, Pengying; Wu, Meilin; Wang, Jing; Sui, Yilun; Liu, Shanlin; Shi, Dongyun

    2016-08-01

    Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS) and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity. The over-elimination of ROS by NAC resulted in the inhibition of Akt pathway. Our results suggest that ROS is involved in the regulation of cancer telomerase activity through Akt pathway. The different intracellular redox homeostasis and antioxidant system in normal cells and tumor cells may be the cause of the opposite effect on telomerase activity in response to NAC treatment. Our results provide a theoretical base of using antioxidants selectively inhibit cancer telomerase activity. Findings of the present study may provide insights into novel approaches for cancer treatment. PMID:26771767

  5. Glucokinase expression is regulated by glucose through O-GlcNAc glycosylation.

    PubMed

    Baldini, Steffi F; Steenackers, Agata; Olivier-Van Stichelen, Stéphanie; Mir, Anne-Marie; Mortuaire, Marlène; Lefebvre, Tony; Guinez, Céline

    2016-09-16

    Blood glucose fluctuates with the fasting-feeding cycle. One of the liver's functions is to maintain blood glucose concentrations within a physiological range. Glucokinase (GCK) or hexokinase IV, is the main enzyme that regulates the flux and the use of glucose in the liver leading to a compensation of hyperglycemia. In hepatocytes, GCK catalyzes the phosphorylation of glucose into glucose-6-phosphate. This critical enzymatic reaction is determinant for the metabolism of glucose in the liver which includes glycogen synthesis, glycolysis, lipogenesis and gluconeogenesis. In liver, simultaneous increase of glucose and insulin enhances GCK activity and gene expression, changes its subcellular location and interaction with regulatory proteins. The post-translational O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) acts as a glucose-sensitive modification and is believed to take part in hepatic glucose sensing by modifying key regulatory proteins. Therefore, we aimed to determine whether GCK is modified by O-GlcNAcylation in the liver of mice and investigated the role that this modification plays in regulating GCK protein expression. We demonstrated that endogenous GCK expression correlated with O-GlcNAc levels in the pathophysiological model ob/ob mice. More specifically, in response to the pharmacological inhibition of O-GlcNAcase (OGA) contents of GCK increased. Using the GlcNAc specific lectin succinylated-WGA and click chemistry labeling approaches, we demonstrated that GCK is modified by O-GlcNAcylation. Further, we demonstrated that siRNA-mediated Ogt knock-down not only decreases O-GlcNAc content but also GCK protein level. Altogether, our in vivo and in vitro results demonstrate that GCK expression is regulated by nutrient-sensing O-GlcNAc cycling in liver. PMID:27520373

  6. Outdoor Play and Play Equipment.

    ERIC Educational Resources Information Center

    Naylor, Heather

    1985-01-01

    Discusses aspects of the play environment and its effect on children's play behavior. Indoor and outdoor play spaces are considered along with factors affecting the use of outdoor environments for play. Children's preferences for different outdoor play environments and for various play structures are explored. Guides for choosing play equipment…

  7. Activation of mGluR7s inhibits cocaine-induced reinstatement of drug-seeking behavior by a nucleus accumbens glutamate-mGluR2/3 mechanism in rats.

    PubMed

    Li, Xia; Li, Jie; Gardner, Eliot L; Xi, Zheng-Xiong

    2010-09-01

    The metabotropic glutamate receptor 7 (mGluR7) has been reported to be involved in cocaine and alcohol self-administration. However, the role of mGluR7 in relapse to drug seeking is unknown. Using a rat relapse model, we found that systemic administration of AMN082, a selective mGluR7 allosteric agonist, dose-dependently inhibits cocaine-induced reinstatement of drug-seeking behavior. Intracranial microinjections of AMN082 into the nucleus accumbens (NAc) or ventral pallidum, but not the dorsal striatum, also inhibited cocaine-primed reinstatement, an effect that was blocked by local co-administration of MMPIP, a selective mGluR7 antagonist. In vivo microdialysis demonstrated that cocaine priming significantly increased extracellular dopamine in the NAc, ventral pallidum and dorsal striatum, while increasing extracellular glutamate in the NAc only. AMN082 alone failed to alter extracellular dopamine, but produced a slow-onset long-lasting increase in extracellular glutamate in the NAc only. Pre-treatment with AMN082 dose-dependently blocked both cocaine-enhanced NAc glutamate and cocaine-induced reinstatement, an effect that was blocked by MMPIP or LY341497 (a selective mGluR2/3 antagonist). These data suggest that mGluR7 activation inhibits cocaine-induced reinstatement of drug-seeking behavior by a glutamate-mGluR2/3 mechanism in the NAc. The present findings support the potential use of mGluR7 agonists for the treatment of cocaine addiction. PMID:20534005

  8. The effect of Gly-Gln [ß-endorphin30-31] on morphine-evoked serotonin and GABA efflux in the nucleus accumbens of conscious rats.

    PubMed

    Basaran, Nesrin F; Buyukuysal, R Levent; Sertac Yilmaz, M; Aydin, Sami; Cavun, Sinan; Millington, William R

    2016-08-01

    Glycyl-L-glutamine (Gly-Gln; β-endorphin30-31) is an endogenous dipeptide synthesized through the post-translational processing of β-endorphin1-31. Central Gly-Gln administration inhibits the rewarding properties of morphine and attenuates morphine tolerance, dependence and withdrawal although it does not interfere with morphine analgesia. In an earlier study, we found that Gly-Gln inhibits morphine-induced dopamine efflux in the nucleus accumbens (NAc), consistent with its ability to inhibit morphine reward. To further investigate the mechanism responsible for its central effects we tested whether i.c.v. Gly-Gln administration influences the rise in extracellular serotonin and GABA concentrations evoked by morphine in the NAc. Conscious rats were treated with Gly-Gln (100nmol/5μl) or saline i.c.v. followed, 2min later, by morphine (2.5mg/kg) or saline i.p. and extracellular serotonin and GABA concentrations were analyzed by microdialysis and HPLC. Morphine administration increased extracellular serotonin and GABA concentrations significantly within 20min, as shown previously. Unexpectedly, Gly-Gln also increased extracellular serotonin concentrations significantly in control animals. Combined treatment with Gly-Gln+morphine also elevated extracellular serotonin concentrations although the magnitude of the response did not differ significantly from the effect of Gly-Gln or morphine, given alone suggesting that Gly-Gln suppressed morphine induced serotonin efflux. Gly-Gln abolished the morphine-induced rise in extracellular GABA concentrations but had no effect on extracellular GABA when given alone to otherwise untreated animals. These data show that Gly-Gln stimulates NAc serotonin efflux and, together with earlier studies, support the hypothesis that Gly-Gln inhibits the rewarding effects of morphine by modulating morphine induced dopamine, GABA and serotonin efflux in the NAc. PMID:26861257

  9. Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens.

    PubMed

    Garcia-Keller, C; Martinez, S A; Esparza, M A; Bollati, F; Kalivas, P W; Cancela, L M

    2013-03-01

    Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine. PMID:23360446

  10. mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior

    PubMed Central

    Sinclair, Courtney M.; Cleva, Richard M.; Hood, Lauren E.; Olive, M. Foster; Gass, Justin T.

    2012-01-01

    Pharmacological blockade of the type 5 metabotropic glutamate receptor (mGluR5) attenuates cue-induced reinstatement of ethanol-seeking behavior, yet the brain regions involved in these effects are not yet known. The purpose of the present study was to determine if local blockade of mGluR5 receptors in the basolateral amygdala (BLA) and/or the nucleus accumbens (NAc), two brain regions known to be involved in stimulus-reward associations, attenuates the reinstatement of ethanol-seeking behavior induced by ethanol-paired cues. As a control for possible non-specific effects, the effects of mGluR5 blockade in these regions on cue-induced reinstatement of sucrose-seeking were also assessed. Male Wistar rats were implanted with bilateral microinjection cannulae aimed at the BLA or NAc. Following recovery, animals were trained to self-administer ethanol (10% w/v) or 45 mg sucrose pellets on an FR1 schedule of reinforcement in 30 min daily sessions using a sucrose fading procedure. Following stabilization of responding, animals underwent extinction training. Next, animals received infusions of vehicle or the selective mGluR5 antagonist MTEP (3 μg/μl) into the BLA or NAc prior to cue-induced reinstatement testing sessions. mGluR5 blockade eliminated cue-induced reinstatement of alcohol-but not sucrose-seeking behavior. Results from this study indicate that mGluR5 receptors in the BLA and NAc mediate cue-induced reinstatement of ethanol-seeking behavior, and provide two potential neuroanatomical sites of action where systemically administered mGluR5 antagonists attenuate cue-induced reinstatement. These data are consistent with previous findings that cue-induced reinstatement of ethanol-seeking increases neuronal activity and glutamatergic transmission in these two regions. PMID:22296815

  11. Expression of alpha-GalNAc glycoproteins by breast cancers.

    PubMed Central

    Brooks, S. A.; Leathem, A. J.

    1995-01-01

    The expression of complex carbohydrates recognised by Helix pomatia lectin (HPA, nominal monosaccharide binding specificity alpha-GalNAc) has been shown to predict unfavourable prognosis in breast and other cancers. It has been suggested that the prognostic significance of HPA binding may be through recognition of either Tn epitope (alpha-GalNAc-O-serine/threonine) or blood group A antigen (terminal alpha-1-->3GalNAc attached to the basic H-antigen, Fuc-alpha-1-->2-Gal-beta-1-->4(or 3) GlcNAc-->R). In this study, the expression of glycoproteins terminating in alpha-GalNAc residues was investigated immunohistochemically using HPA and two monoclonal antibodies--BRIC 66 (anti-alpha-GalNAc) and BRIC 111 (anti-Tn). In paraffin sections, 74/87 (85%) of breast cancers expressed HPA-binding ligands, while 28/87 (32%) were positive for BRIC 66 binding and 25/87 (29%) expressed Tn. Distribution of staining patterns were distinctive and different with the three markers. BRIC 66, BRIC 111 and HPA binding to glycoproteins derived from breast cancer homogenates and to blood group A and Tn positive glycoproteins in Western blots confirmed the immunohistochemistry data. The results suggest that the prognostic significance of HPA binding in breast cancer is unlikely to be simply through recognition of blood group A antigen or Tn epitope on cancer cells. Breast cancers may express a complex profile of related but distinct glycans sharing similar terminal immunodominant sugar GalNAc, which may be implicated in aggressive biological behaviour. Images Figure 1 Figure 2 PMID:7537516

  12. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    PubMed Central

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

  13. pGlcNAc Nanofiber Treatment of Cutaneous Wounds Stimulate Increased Tensile Strength and Reduced Scarring via Activation of Akt1

    PubMed Central

    Lindner, Haley Buff; Felmly, Lloyd McPherson; Demcheva, Marina; Seth, Arun; Norris, Russell; Bradshaw, Amy D.; Vournakis, John; Muise-Helmericks, Robin C.

    2015-01-01

    Treatment of cutaneous wounds with poly-N-acetyl-glucosamine containing nanofibers (pGlcNAc), a novel polysaccharide material derived from a marine diatom, results in increased wound closure, antibacterial activities and innate immune responses. We have shown that Akt1 plays a central role in the regulation of these activities. Here, we show that pGlcNAc treatment of cutaneous wounds results in a smaller scar that has increased tensile strength and elasticity. pGlcNAc treated wounds exhibit decreased collagen content, increased collagen organization and decreased myofibroblast content. A fibrin gel assay was used to assess the regulation of fibroblast alignment in vitro. In this assay, fibrin lattice is formed with two pins that provide focal points upon which the gel can exert force as the cells align from pole to pole. pGlcNAc stimulation of embedded fibroblasts results in cellular alignment as compared to untreated controls, by a process that is Akt1 dependent. We show that Akt1 is required in vivo for the pGlcNAc-induced increased tensile strength and elasticity. Taken together, our findings suggest that pGlcNAc nanofibers stimulate an Akt1 dependent pathway that results in the proper alignment of fibroblasts, decreased scarring, and increased tensile strength during cutaneous wound healing. PMID:25955155

  14. pGlcNAc Nanofiber Treatment of Cutaneous Wounds Stimulate Increased Tensile Strength and Reduced Scarring via Activation of Akt1.

    PubMed

    Lindner, Haley Buff; Felmly, Lloyd McPherson; Demcheva, Marina; Seth, Arun; Norris, Russell; Bradshaw, Amy D; Vournakis, John; Muise-Helmericks, Robin C

    2015-01-01

    Treatment of cutaneous wounds with poly-N-acetyl-glucosamine containing nanofibers (pGlcNAc), a novel polysaccharide material derived from a marine diatom, results in increased wound closure, antibacterial activities and innate immune responses. We have shown that Akt1 plays a central role in the regulation of these activities. Here, we show that pGlcNAc treatment of cutaneous wounds results in a smaller scar that has increased tensile strength and elasticity. pGlcNAc treated wounds exhibit decreased collagen content, increased collagen organization and decreased myofibroblast content. A fibrin gel assay was used to assess the regulation of fibroblast alignment in vitro. In this assay, fibrin lattice is formed with two pins that provide focal points upon which the gel can exert force as the cells align from pole to pole. pGlcNAc stimulation of embedded fibroblasts results in cellular alignment as compared to untreated controls, by a process that is Akt1 dependent. We show that Akt1 is required in vivo for the pGlcNAc-induced increased tensile strength and elasticity. Taken together, our findings suggest that pGlcNAc nanofibers stimulate an Akt1 dependent pathway that results in the proper alignment of fibroblasts, decreased scarring, and increased tensile strength during cutaneous wound healing. PMID:25955155

  15. New Play.

    ERIC Educational Resources Information Center

    Lersten, Kenneth C.

    There have been many theories and hypotheses about play, one of which is the equation of play with "transcendence." Play may have the ingredients to allow us to transcend and, for a moment, remythologize life. There have been recent authors who have given play the status of theology, indicating that play contains elements also found in religion.…

  16. Playful Gaming.

    ERIC Educational Resources Information Center

    Makedon, Alexander

    A philosophical analysis of play and games is undertaken in this paper. Playful gaming, which is shown to be a synthesis of play and games, is utilized as a category for undertaking the examination of play and games. The significance of playful gaming to education is demonstrated through analyses of Plato's, Dewey's, Sartre's, and Marcuse's…

  17. Biofuel Potential of Plants Transformed Genetically with NAC Family Genes.

    PubMed

    Singh, Sadhana; Grover, Atul; Nasim, M

    2016-01-01

    NAC genes contribute to enhance survivability of plants under conditions of environmental stress and in secondary growth of the plants, thereby building biomass. Thus, genetic transformation of plants using NAC genes provides a possibility to tailor biofuel plants. Over-expression studies have indicated that NAC family genes can provide tolerance to various biotic and abiotic stresses, either by physiological or biochemical changes at the cellular level, or by affecting visible morphological and anatomical changes, for example, by development of lateral roots in a number of plants. Over-expression of these genes also work as triggers for development of secondary cell walls. In our laboratory, we have observed a NAC gene from Lepidium latifolium contributing to both enhanced biomass as well as cold stress tolerance of model plants tobacco. Thus, we have reviewed all the developments of genetic engineering using NAC genes which could enhance the traits required for biofuel plants, either by enhancing the stress tolerance or by enhancing the biomass of the plants. PMID:26858739

  18. Biofuel Potential of Plants Transformed Genetically with NAC Family Genes

    PubMed Central

    Singh, Sadhana; Grover, Atul; Nasim, M.

    2016-01-01

    NAC genes contribute to enhance survivability of plants under conditions of environmental stress and in secondary growth of the plants, thereby building biomass. Thus, genetic transformation of plants using NAC genes provides a possibility to tailor biofuel plants. Over-expression studies have indicated that NAC family genes can provide tolerance to various biotic and abiotic stresses, either by physiological or biochemical changes at the cellular level, or by affecting visible morphological and anatomical changes, for example, by development of lateral roots in a number of plants. Over-expression of these genes also work as triggers for development of secondary cell walls. In our laboratory, we have observed a NAC gene from Lepidium latifolium contributing to both enhanced biomass as well as cold stress tolerance of model plants tobacco. Thus, we have reviewed all the developments of genetic engineering using NAC genes which could enhance the traits required for biofuel plants, either by enhancing the stress tolerance or by enhancing the biomass of the plants. PMID:26858739

  19. Integrative proteomic analysis of the nucleus accumbens in rhesus monkeys following cocaine self-administration.

    PubMed

    Tannu, N S; Howell, L L; Hemby, S E

    2010-02-01

    The reinforcing effects and long-term consequences of cocaine self-administration have been associated with brain regions of the mesolimbic dopamine pathway, namely the nucleus accumbens (NAc). Studies of cocaine-induced biochemical adaptations in rodent models have advanced our knowledge; however, unbiased detailed assessments of intracellular alterations in the primate brain are scarce, yet essential, to develop a comprehensive understanding of cocaine addiction. To this end, two-dimensional difference in gel electrophoresis (2D-DIGE) was used to compare changes in cytosolic protein abundance in the NAc between rhesus monkeys self-administering cocaine and controls. Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser-desorption ionization time-of-flight time-of-flight (MALDI-TOF-TOF). In total, 1098 spots were subjected to statistical analysis with 22 spots found to be differentially abundant of which 18 proteins were positively identified by mass spectrometry. In addition, approximately 1000 protein spots were constitutively expressed of which 21 proteins were positively identified by mass spectrometry. Increased levels of proteins in the cocaine-exposed monkeys include glial fibrillary acidic protein, syntaxin-binding protein 3, protein kinase C isoform, adenylate kinase isoenzyme 5 and mitochondrial-related proteins, whereas decreased levels of proteins included beta-soluble N-ethylmaleimide-sensitive factor attachment protein and neural and non-neural enolase. Using a complimentary proteomics approach, the differential expression of phosphorylated proteins in the cytosolic fraction of these subjects was examined. Two-dimensional gel electrophoresis (2DGE) was followed by gel staining with Pro-Q Diamond phosphoprotein gel stain, enabling differentiation of approximately 150 phosphoprotein spots between the groups. Following excision and

  20. Role of protein kinase C epsilon (PKCε) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell

    PubMed Central

    Gass, Justin T.; Olive, M. Foster

    2009-01-01

    Rationale The type 5 metabotropic glutamate receptor (mGluR5) and the epsilon isoform of protein kinase C (PKCε) regulate ethanol intake, and we have previously demonstrated that mGluR5 receptor antagonism reduces ethanol consumption via a PKCε-dependent mechanism. Objectives We explored the neuroanatomical substrates of the regulation of ethanol reinforcement by this mGluR5-PKCε signaling pathway by infusing selective inhibitors of these proteins into the shell or core region of the nucleus accumbens (NAc). Methods Male Wistar rats were trained to self-administer ethanol intravenously and received intra-NAc infusions of vehicle or the selective mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) alone and in combination with a PKCε translocation inhibitor (εV1-2) or a scrambled control peptide (sεV1-2). The effects of intra-NAc MTEP on food-reinforced responding and open-field locomotor activity were also determined. Results MTEP (1 μg/μl) had no effect on ethanol or food reinforcement or locomotor activity when infused into the NAc core. MTEP (3 μg/μl) reduced ethanol reinforcement when infused into the NAc shell but not the core, and this effect was reversed by εV1-2 (1 μg/μl) but not sεV1-2 (1 μg/μl). In both regions, this concentration of MTEP did not alter food-reinforced responding or locomotor activity, and infusion of εV1-2 alone did not alter ethanol reinforcement. MTEP (10 μg/μl) reduced locomotor activity when infused into the shell, and therefore this concentration was not further tested on responding for ethanol or food. Conclusions Blockade of mGluR5 receptors in the NAc shell reduces ethanol reinforcement via a PKCε-dependent mechanism. PMID:19225761

  1. Chronic Methamphetamine Self-Administration Dysregulates Oxytocin Plasma Levels and Oxytocin Receptor Fibre Density in the Nucleus Accumbens Core and Subthalamic Nucleus of the Rat.

    PubMed

    Baracz, S J; Parker, L M; Suraev, A S; Everett, N A; Goodchild, A K; McGregor, I S; Cornish, J L

    2016-04-01

    The neuropeptide oxytocin attenuates reward and abuse for the psychostimulant methamphetamine (METH). Recent findings have implicated the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in oxytocin modulation of acute METH reward and relapse to METH-seeking behaviour. Surprisingly, the oxytocin receptor (OTR) is only modestly involved in both regions in oxytocin attenuation of METH-primed reinstatement. Coupled with the limited investigation of the role of the OTR in psychostimulant-induced behaviours, we primarily investigated whether there are cellular changes to the OTR in the NAc core and STh, as well as changes to oxytocin plasma levels, after chronic METH i.v. self-administration (IVSA) and after extinction of drug-taking. An additional aim was to examine whether changes to central corticotrophin-releasing factor (CRF) and plasma corticosterone levels were also apparent because of the interaction of oxytocin with stress-regulatory mechanisms. Male Sprague-Dawley rats were trained to lever press for i.v. METH (0.1 mg/kg/infusion) under a fixed-ratio 1 schedule or received yoked saline infusions during 2-h sessions for 20 days. An additional cohort of rats underwent behavioural extinction for 15 days after METH IVSA. Subsequent to the last day of IVSA or extinction, blood plasma was collected for enzyme immunoassay, and immunofluorescence was conducted on NAc core and STh coronal sections. Rats that self-administered METH had higher oxytocin plasma levels, and decreased OTR-immunoreactive (-IR) fibres in the NAc core than yoked controls. In animals that self-administered METH and underwent extinction, oxytocin plasma levels remained elevated, OTR-IR fibre density increased in the STh, and a trend towards normalisation of OTR-IR fibre density was evident in the NAc core. CRF-IR fibre density in both brain regions and corticosterone plasma levels did not change across treatment groups. These findings demonstrate that oxytocin systems, both centrally

  2. Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.

    PubMed

    Bull, Cecilia; Freitas, Kelen C C; Zou, Shiping; Poland, Ryan S; Syed, Wahab A; Urban, Daniel J; Minter, Sabrina C; Shelton, Keith L; Hauser, Kurt F; Negus, S Stevens; Knapp, Pamela E; Bowers, M Scott

    2014-11-01

    Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with

  3. Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

    PubMed Central

    Bull, Cecilia; Freitas, Kelen CC; Zou, Shiping; Poland, Ryan S; Syed, Wahab A; Urban, Daniel J; Minter, Sabrina C; Shelton, Keith L; Hauser, Kurt F; Negus, S Stevens; Knapp, Pamela E; Bowers, M Scott

    2014-01-01

    Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with

  4. Shielding analysis of the NAC-MPC storage system

    SciTech Connect

    Napolitano, D.G.; Romano, N.J.; Hertel, N.E.

    1997-12-01

    This paper presents the shielding analyses of the NAC-MPC dry cask storage system. The NAC-MPC dry cask storage system consists of a transportable storage canister, a transfer cask, and a vertical concrete storage cask. The NAC-MPC is designed to accommodate 36 {open_quotes}Yankee Class{close_quotes} fuel assemblies with a maximum burnup of 36,000 MWd/tonne U burnup and 8 yr cooling time. The shielding analysis is performed with the SCALE 4.3 code package which includes SAS2H for source term generation and SAS4A, a modification of SAS4, for shielding evaluations. SAS4 utilizes a one-dimensional XSDRNPM adjoint calculation of the cask to generate biasing parameters for a three-dimensional MORSE-SGC Monte Carlo model of the cask geometry.

  5. Uncertainty Analysis of LROC NAC Derived Elevation Models

    NASA Astrophysics Data System (ADS)

    Burns, K.; Yates, D. G.; Speyerer, E.; Robinson, M. S.

    2012-12-01

    One of the primary objectives of the Lunar Reconnaissance Orbiter Camera (LROC) [1] is to gather stereo observations with the Narrow Angle Camera (NAC) to generate digital elevation models (DEMs). From an altitude of 50 km, the NAC acquires images with a pixel scale of 0.5 meters, and a dual NAC observation covers approximately 5 km cross-track by 25 km down-track. This low altitude was common from September 2009 to December 2011. Images acquired during the commissioning phase and those acquired from the fixed orbit (after 11 December 2011) have pixel scales that range from 0.35 meters at the south pole to 2 meters at the north pole. Alimetric observations obtained by the Lunar Orbiter Laser Altimeter (LOLA) provide measurements of ±0.1 m between the spacecraft and the surface [2]. However, uncertainties in the spacecraft positioning can result in offsets (±20m) between altimeter tracks over many orbits. The LROC team is currently developing a tool to automatically register alimetric observations to NAC DEMs [3]. Using a generalized pattern search (GPS) algorithm, the new automatic registration adjusts the spacecraft position and pointing information during times when NAC images, as well as LOLA measurements, of the same region are acquired to provide an absolute reference frame for the DEM. This information is then imported into SOCET SET to aide in creating controlled NAC DEMs. For every DEM, a figure of merit (FOM) map is generated using SOCET SET software. This is a valuable tool for determining the relative accuracy of a specific pixel in a DEM. Each pixel in a FOM map is given a value to determine its "quality" by determining if the specific pixel was shadowed, saturated, suspicious, interpolated/extrapolated, or successfully correlated. The overall quality of a NAC DEM is a function of both the absolute and relative accuracies. LOLA altimetry provides the most accurate absolute geodetic reference frame with which the NAC DEMs can be compared. Offsets

  6. Genome-wide analysis, expression dynamics and varietal comparison of NAC gene family at various developmental stages in Morus notabilis.

    PubMed

    Baranwal, Vinay Kumar; Khurana, Paramjit

    2016-06-01

    NAC genes are important transcription factors and forms a large family in plants. They have shown to play an important role in growth and development and have also been shown to involve in regulation of stress-responsive genes. In the present study, a repertoire of NAC genes in recently published mulberry genome has been identified which consists of a total of 79 members. Structural analysis revealed that most of the NAC genes in mulberry contain two introns. The proteins encoded by them show a wide range of isoelectric points suggestive of their varied roles in varying microcellular environment. Phylogenetic and conserved motif analysis elucidate the presence of 15 sub-groups of these genes along with two novel sub-groups having distinct conserved motifs which are not present in Arabidopsis. Gene ontology term enrichment analysis and cis-element identification from their putative 1 K upstream regulatory region indicates their possible role in important biological processes like organ formation, meristem establishment, senescence, and various biotic and abiotic stresses. Expression analysis across various developmental stages led to identification of their preferential expression in diverse tissues. Taken together, this work provides a solid background information related to structure, function, expression and evolution of NAC gene family in mulberry. PMID:26942603

  7. Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis

    PubMed Central

    Chen, Sheng-Chia; Huang, Chi-Hung; Lai, Shu-Jung; Yang, Chia Shin; Hsiao, Tzu-Hung; Lin, Ching-Heng; Fu, Pin-Kuei; Ko, Tzu-Ping; Chen, Yeh

    2016-01-01

    The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme. PMID:26980148

  8. Overexpression of the Eggplant (Solanum melongena) NAC Family Transcription Factor SmNAC Suppresses Resistance to Bacterial Wilt

    PubMed Central

    Na, Chen; Shuanghua, Wu; Jinglong, Fu; Bihao, Cao; Jianjun, Lei; Changming, Chen; Jin, Jiang

    2016-01-01

    Bacterial wilt (BW) is a serious disease that affects eggplant (Solanum melongena) production. Although resistance to this disease has been reported, the underlying mechanism is unknown. In this study, we identified a NAC family transcription factor (SmNAC) from eggplant and characterized its expression, its localization at the tissue and subcellular levels, and its role in BW resistance. To this end, transgenic eggplant lines were generated in which the expression of SmNAC was constitutively up regulated or suppressed using RNAi. The results indicated that overexpression of SmNAC decreases resistance to BW. Moreover, SmNAC overexpression resulted in the reduced accumulation of the plant immune signaling molecule salicylic acid (SA) and reduced expression of ICS1 (a gene that encode isochorismate synthase 1, which is involved in SA biosynthesis). We propose that reduced SA content results in increased bacterial wilt susceptibility in the transgenic lines. Our results provide important new insights into the regulatory mechanisms of bacterial wilt resistance in eggplant. PMID:27528282

  9. Overexpression of the Eggplant (Solanum melongena) NAC Family Transcription Factor SmNAC Suppresses Resistance to Bacterial Wilt.

    PubMed

    Na, Chen; Shuanghua, Wu; Jinglong, Fu; Bihao, Cao; Jianjun, Lei; Changming, Chen; Jin, Jiang

    2016-01-01

    Bacterial wilt (BW) is a serious disease that affects eggplant (Solanum melongena) production. Although resistance to this disease has been reported, the underlying mechanism is unknown. In this study, we identified a NAC family transcription factor (SmNAC) from eggplant and characterized its expression, its localization at the tissue and subcellular levels, and its role in BW resistance. To this end, transgenic eggplant lines were generated in which the expression of SmNAC was constitutively up regulated or suppressed using RNAi. The results indicated that overexpression of SmNAC decreases resistance to BW. Moreover, SmNAC overexpression resulted in the reduced accumulation of the plant immune signaling molecule salicylic acid (SA) and reduced expression of ICS1 (a gene that encode isochorismate synthase 1, which is involved in SA biosynthesis). We propose that reduced SA content results in increased bacterial wilt susceptibility in the transgenic lines. Our results provide important new insights into the regulatory mechanisms of bacterial wilt resistance in eggplant. PMID:27528282

  10. Neuropeptide Y response to alcohol is altered in nucleus accumbens of mice selectively bred for drinking to intoxication.

    PubMed

    Barkley-Levenson, Amanda M; Ryabinin, Andrey E; Crabbe, John C

    2016-04-01

    The High Drinking in the Dark (HDID) mice have been selectively bred for drinking to intoxicating blood alcohol levels and represent a genetic model of risk for binge-like drinking. Presently, little is known about the specific genetic factors that promote excessive intake in these mice. Previous studies have identified neuropeptide Y (NPY) as a potential target for modulating alcohol intake. NPY expression differs in some rodent lines that have been selected for high and low alcohol drinking phenotypes, as well as inbred mouse strains that differ in alcohol preference. Alcohol drinking and alcohol withdrawal also produce differential effects on NPY expression in the brain. Here, we assessed brain NPY protein levels in HDID mice of two replicates of selection and control heterogeneous stock (HS) mice at baseline (water drinking) and after binge-like alcohol drinking to determine whether selection is associated with differences in NPY expression and its sensitivity to alcohol. NPY levels did not differ between HDID and HS mice in any brain region in the water-drinking animals. HS mice showed a reduction in NPY levels in the nucleus accumbens (NAc) - especially in the shell - in ethanol-drinking animals vs. water-drinking controls. However, HDID mice showed a blunted NPY response to alcohol in the NAc core and shell compared to HS mice. These findings suggest that the NPY response to alcohol has been altered by selection for drinking to intoxication in a region-specific manner. Thus, the NPY system may represent a potential target for altering binge-like alcohol drinking in these mice. PMID:26779672

  11. TaNAC1 acts as a negative regulator of stripe rust resistance in wheat, enhances susceptibility to Pseudomonas syringae, and promotes lateral root development in transgenic Arabidopsis thaliana

    PubMed Central

    Wang, Fengtao; Lin, Ruiming; Feng, Jing; Chen, Wanquan; Qiu, Dewen; Xu, Shichang

    2015-01-01

    Plant-specific NAC transcription factors (TFs) constitute a large family and play important roles in regulating plant developmental processes and responses to environmental stresses, but only some of them have been investigated for effects on disease reaction in cereal crops. Virus-induced gene silencing (VIGS) is an effective strategy for rapid functional analysis of genes in plant tissues. In this study, TaNAC1, encoding a new member of the NAC1 subgroup, was cloned from bread wheat and characterized. It is a TF localized in the cell nucleus, and contains an activation domain in its C-terminal. TaNAC1 was strongly expressed in wheat roots and was involved in responses to infection by the obligate pathogen Puccinia striiformis f. sp. tritici and defense-related hormone treatments such as salicylic acid (SA), methyl jasmonate, and ethylene. Knockdown of TaNAC1 with barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) enhanced stripe rust resistance. TaNAC1-overexpression in Arabidopsis thaliana plants gave enhanced susceptibility, attenuated systemic-acquired resistance to Pseudomonas syringae DC3000, and promoted lateral root development. Jasmonic acid-signaling pathway genes PDF1.2 and ORA59 were constitutively expressed in transgenic plants. TaNAC1 overexpression suppressed the expression levels of resistance-related genes PR1 and PR2 involved in SA signaling and AtWRKY70, which functions as a connection node between the JA- and SA-signaling pathways. Collectively, TaNAC1 is a novel NAC member of the NAC1 subgroup, negatively regulates plant disease resistance, and may modulate plant JA- and SA-signaling defense cascades. PMID:25774162

  12. Cell cycle-dependent alteration in NAC1 nuclear body dynamics and morphology

    NASA Astrophysics Data System (ADS)

    Wu, Pei-Hsun; Hung, Shen-Hsiu; Ren, Tina; Shih, Ie-Ming; Tseng, Yiider

    2011-02-01

    NAC1, a BTB/POZ family member, has been suggested to participate in maintaining the stemness of embryonic stem cells and has been implicated in the pathogenesis of human cancer. In ovarian cancer, NAC1 upregulation is associated with disease aggressiveness and with the development of chemoresistance. Like other BTB/POZ proteins, NAC1 forms discrete nuclear bodies in non-dividing cells. To investigate the biological role of NAC1 nuclear bodies, we characterized the expression dynamics of NAC1 nuclear bodies during different phases of the cell cycle. Fluorescence recovery after photobleaching assays revealed that NAC1 was rapidly exchanged between the nucleoplasm and NAC1 nuclear bodies in interphase cells. The number of NAC1 bodies significantly increased and their size decreased in the S phase as compared to the G0/G1 and G2 phases. NAC1 nuclear bodies disappeared and NAC1 became diffuse during mitosis. NAC1 nuclear bodies reappeared immediately after completion of mitosis. These results indicate that a cell cycle-dependent regulatory mechanism controls NAC1 body formation in the nucleus and suggest that NAC1 body dynamics are associated with mitosis or cytokinesis.

  13. 75 FR 56654 - RTCA NextGen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-16

    ... Notice in the Federal Register on September 3, 2010 (75-FR-54221), concerning a Notice to advise the... the Federal Register Notice on September 3, 2010, (75-FR-54221) is revised to read as follows: Opening... Federal Aviation Administration RTCA NextGen Advisory Committee (NAC) AGENCY: Federal...

  14. Oxidation pathway and exacerbations in COPD: the role of NAC.

    PubMed

    Matera, Maria Gabriella; Calzetta, Luigino; Cazzola, Mario

    2016-01-01

    Oxidative stress is an important trait in the pathogenesis of chronic obstructive pulmonary disease (COPD). Consequently, targeting oxidative stress is likely to be beneficial as a treatment in COPD. Glutathione (GSH) is an intracellular antioxidant that protects against a variety of different antioxidant species. The increase of lung GSH in COPD is an attempt to counter excess oxidant production but it is inadequate during exacerbations due to the excessive production of ROS. N-acetyl-l-cysteine (NAC) acts as a precursor for the substrate cysteine in synthesis of GSH and also as a mucolytic and anti-inflammatory agent. NAC prevents COPD exacerbations at high dosage (≥1200 mg daily), while a regular treatment with 600 mg daily is enough in chronic bronchitis. Nonetheless, we must still establish whether the level of bronchial obstruction may influence its effects, the effect of high-dose NAC in Caucasian patients with COPD, and the role of NAC in the escalation and de-escalation of therapy in COPD. PMID:26567752

  15. Adult Play.

    ERIC Educational Resources Information Center

    Charles, John M.

    In its broadest context, play can be interpreted as any pleasurable use of discretionary time. Playfulness is an intrinsic feature of being human, and should be viewed in the light of a total lifestyle, not as an occurrence in an isolated time of life. Adult play appears to be an indefinable and controversial concept. A holistic approach should be…

  16. Wanna Play?

    ERIC Educational Resources Information Center

    Chenfeld, Mimi Brodsky

    2006-01-01

    In this article, the author talks about the importance of play in the lives of children and describes how games and imaginative play contribute to the development of children. From her decades-old collection of countless incidents demonstrating children's love for self-directed, informal, imaginative play, the author shares three incidents that…

  17. City Play.

    ERIC Educational Resources Information Center

    Dargan, Amanda; Zeitlin, Steve

    2000-01-01

    Today, fewer city blocks preserve the confidence of lifestyle and urban geography that sustain traditional games and outdoor play. Large groups of children choosing sides and organizing Red Rover games are no longer commonplace. Teachers must encourage free play; urban planners must build cities that are safe play havens. (MLH)

  18. Active stimulation site of nucleus accumbens deep brain stimulation in obsessive-compulsive disorder is localized in the ventral internal capsule.

    PubMed

    van den Munckhof, Pepijn; Bosch, D Andries; Mantione, Mariska H M; Figee, Martijn; Denys, Damiaan A J P; Schuurman, P Richard

    2013-01-01

    Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder characterized by persistent thoughts and repetitive ritualistic behaviours. Despite optimal cognitive-behavioral and pharmacological therapy, approximately 10 % of patients remain treatment-resistant. Deep brain stimulation (DBS) is being investigated as experimental therapy for treatment-refractory OCD. In the current study, we determined the relationship between anatomical location of active electrode contacts and clinical outcome in 16 OCD patients undergoing bilateral nucleus accumbens (NAc) DBS. We found that most patients actually do not receive active stimulation in the NAc but in the more laterally, anteriorly and dorsally located ventral part of the anterior limb of the internal capsule, ventral ALIC (vALIC). Our nine patients receiving bilateral vALIC DBS improved on average 73 % on their Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, whereas the six patients with their centers of stimulation located otherwise improved on average only 42 %. We therefore propose bilateral vALIC as a promising new DBS target for patients with treatment-refractory OCD. Future studies employing a direct vALIC targeting approach in larger patient numbers are needed to test whether this proposal holds true. PMID:23652657

  19. Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens

    NASA Technical Reports Server (NTRS)

    During, Matthew J.; Acworth, Ian N.; Wurtman, Richard J.

    1988-01-01

    Intracerebral dialysis was used to monitor extracellular fluid from rat striatum and nucleus accumbens following the intraperitoneal administration of tyrosine. Dopamine concentrations in dialysates from both the striatum and the nucleus accumbens increased significantly in response to the tyrosine. The magnitude of the tyrosine effect was greater in the nucleus accumbens than in the striatum. Hence, mesolimbic dopaminergic neurons may be especially responsive to precursor availability.

  20. Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens

    PubMed Central

    Abrahao, Karina Possa; Oliveira Goeldner, Francine; Souza-Formigoni, Maria Lucia Oliveira

    2014-01-01

    In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor

  1. Relief memory consolidation requires protein synthesis within the nucleus accumbens.

    PubMed

    Bruning, Johann E A; Breitfeld, Tino; Kahl, Evelyn; Bergado-Acosta, Jorge R; Fendt, Markus

    2016-06-01

    Relief learning refers to the association of a stimulus with the relief from an aversive event. The thus-learned relief stimulus then can induce, e.g., an attenuation of the startle response or approach behavior, indicating positive valence. Previous studies revealed that the nucleus accumbens is essential for the acquisition and retrieval of relief memory. Here, we ask whether the nucleus accumbens is also the brain site for consolidation of relief memory into a long-term form. In rats, we blocked local protein synthesis within the nucleus accumbens by local infusions of anisomycin at different time points during a relief conditioning experiment. Accumbal anisomycin injections immediately after the relief conditioning session, but not 4 h later, prevented the consolidation into long-term relief memory. The retention of already consolidated relief memory was not affected by anisomycin injections. This identifies a time window and site for relief memory consolidation. These findings should complement our understanding of the full range of effects of adverse experiences, including cases of their distortion in humans such as post-traumatic stress disorder and/or phobias. PMID:26792192

  2. Left nucleus accumbens atrophy in deficit schizophrenia: A preliminary study.

    PubMed

    De Rossi, Pietro; Dacquino, Claudia; Piras, Fabrizio; Caltagirone, Carlo; Spalletta, Gianfranco

    2016-08-30

    A question that remains to be answered is whether schizophrenia can be characterized by a single etiopathophysiology or whether separate sub-syndromes should be differentiated to define specific mechanisms for each sub-type. Individuals affected by the deficit subtype of schizophrenia (DSZ) display avolitional/amotivational features that respond poorly to conventional treatments. Characterizing DSZ from a neuroanatomical point of view may help clarify this issue and develop new treatment strategies. To determine if DSZ is associated with structural alterations in specific deep grey matter structures linked to its key clinical features, 22 DSZ patients, 22 non-deficit schizophrenia (NDSZ) patients and 22 healthy controls (HC) were recruited for a case-control cross-sectional study. High-resolution magnetic resonance imaging was performed in all subjects and volumes of deep grey matter structures were measured using FreeSurfer. DSZ patients displayed smaller left accumbens volumes compared to both NDSZ patients and HC. Moreover, age and duration of illness were significantly associated with lower volume of the left accumbens in DSZ but not in NDSZ. Findings indicate that DSZ is associated with lower volume of the nucleus accumbens in the dominant hemisphere. This is consistent with the psychopathological features and functional impairments present in DSZ and thus indicates a potential mechanism. PMID:27322868

  3. Recognition of Chewing Behavior from Electroencephalogram Recorded in the Rat's Nucleus Accumbens.

    PubMed

    Shao, Xiaozhuo; Zhang, Hengyi; Zheng, Xiaoxiang

    2005-01-01

    Nucleus accumbens is used to be considered as the interface to motor nerve system. In this paper, our object is to study the relationship between the electro-activity of neurons in nucleus accumbens and the rat-behavior. We recorded neurons action potentials with multichannel microelectrodes, which were chronically implanted in a rat's nucleus accumbens, during rats-chewing behavior. Through digital signal processing, we found significant features associated with the chewing activity and we could recognize the chewing behavior easily from the electroencephalogram with these features. This study suggests that neurons action potentials in a nucleus accumbens are activated by specific animal actions. PMID:17282644

  4. Repeated cocaine administration decreases calcineurin (PP2B) but enhances DARPP-32 modulation of sodium currents in rat nucleus accumbens neurons.

    PubMed

    Hu, Xiu-Ti; Ford, Kerstin; White, Francis J

    2005-05-01

    Our previous studies have demonstrated that repeated cocaine (COC) administration reduces voltage-sensitive sodium and calcium currents (I(Na) or VSSCs and I(Ca) or VSCCs, respectively) in medium spiny nucleus accumbens (NAc) neurons of rats. The present findings further indicate that chronic COC-induced I(Na) reduction in NAc neurons is regulated by decreased dephosphorylation and enhanced phosphorylation of Na(+) channels. Whole-cell voltage-clamp recordings revealed that dephosphorylation of Na(+) channels by calcineurin (CaN) enhanced I(Na), while inhibition of protein phosphatase 1 (PP1) by phosphorylated dopamine- and cAMP-regulated phosphoprotein (M(r)=32 kDa) (DARPP-32) at the site of threonine 34 (p-Thr.34-DARPP-32) suppressed I(Na), in freshly dissociated NAc neurons of saline-pretreated rats. However, the effects of CaN on enhancing I(Na) were significantly attenuated, and the action of p-Thr.34-DARPP-32 to decrease I(Na) was mimicked, although not potentiated, by repeated COC pretreatment. Dephosphorylation of Na(+) channels by PP1 also enhanced I(Na), but this effect of PP1 on I(Na) was not apparently affected by repeated COC administration. Western blot analysis indicates that the protein levels of CaN and DARPP-32 were significantly decreased and increased, respectively, while the PP1 levels were unchanged, in the COC-withdrawn NAc as compared to saline-pretreated controls. Combined with previous findings, our results indicate that both CaN and PP1 modulate the increase in I(Na) via enhancing dephosphorylation, while p-Thr.34-DARPP-32 reduces I(Na) by inhibiting PP1-induced dephosphorylation, thereby stabilizing the phosphorylation state, of Na(+) channels in NAc neurons. They also suggest that chronic COC-induced I(Na) reduction may be attributed to a reduction in Ca(2+) signaling, which disrupts the physiological balance of phosphorylation and dephosphorylation of Na(+) channels. PMID:15726118

  5. Functional regulation of PI3K-associated signaling in the accumbens by binge alcohol drinking in male but not female mice.

    PubMed

    Cozzoli, Debra K; Kaufman, Moriah N; Nipper, Michelle A; Hashimoto, Joel G; Wiren, Kristine M; Finn, Deborah A

    2016-06-01

    It is well established that binge alcohol consumption produces alterations in Group 1 metabotropic glutamate receptors (mGlus) and related signaling cascades in the nucleus accumbens (NAC) of adult male mice, but female and adolescent mice have not been examined. Thus, the first set of studies determined whether repeated binge alcohol consumption produced similar alterations in protein and mRNA levels of Group 1 mGlu-associated signaling molecules in the NAC of male and female adult and adolescent mice. The adult (9 weeks) and adolescent (4 weeks) C57BL/6J mice were exposed to 7 binge alcohol sessions every 3rd day while controls drank water. Repeated binge alcohol consumption produced sexually divergent changes in protein levels and mRNA expression for Group 1 mGlus and downstream signaling molecules in the NAC, but there was no effect of age. Binge alcohol intake decreased mGlu5 levels in females, whereas it decreased indices of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), 4E-binding protein 1, and p70 ribosomal protein S6 kinase in males. Expression of genes encoding mGlu1, mGlu5, the NR2A subunit of the NMDA receptor, and Homer2 were all decreased by binge alcohol consumption in males, while females were relatively resistant (only phosphoinositide-dependent protein kinase 1 was decreased). The functional implication of these differences was investigated in a separate study by inhibiting mTOR in the NAC (via infusions of rapamycin) before binge drinking sessions. Rapamycin (50 and 100 ng/side) significantly decreased binge alcohol consumption in males, while consumption in females was unaffected. Altogether these results highlight that mTOR signaling in the NAC was necessary to maintain binge alcohol consumption only in male mice and that binge drinking recruits sexually divergent signaling cascades downstream of PI3K and presumably, Group 1 mGlus. Importantly, these findings emphasize that sex should be considered in the development

  6. UDP-GlcNAc transport across the golgi membrane: Electroneutral exchange for dianionic UMP

    SciTech Connect

    Waldman, B.C.; Rudnick, G. )

    1990-01-09

    The authors have examined the coupling and charge stoichiometry for UDP-GlcNAc transport into Golgi-enriched vesicles from rat liver. In the absence of added energy sources, these Golgi vesicles concentrate UDP-GlcNAc at least 20-fold, presumably by exchange with endogenous nucleotides. Under the conditions used, extravesicular degradation of UDP-GlcNAc has been eliminated, and less than 15% of the internalized radioactivity becomes associated with endogenous macromolecules. Of the remaining intravesicular label, 85% remains unmetabolized UDP-({sup 3}H)GlcNAc, and approximately 15% is hydrolyzed to ({sup 3}H)GlcNAc-1-phosphate. Efflux of accumulated UDP-({sup 3}H)GlcNAc is induced by addition of nonradioactive UDP-GlcNAc, UMP, UDP, or UDP-galactose to the external medium. Permeabilization of Golgi vesicles causes a rapid and nearly complete loss of internal UDP-({sup 3}H)GlcNAc, indicating that the results reflect transport and binding. Moreover, transport of UDP-({sup 3}H)GlcNAc into these Golgi vesicles was stimulated up to 5-fold by mechanically preloading vesicles with either UDP-GlcNAc or UMP. The response of UMP/UMP exchange and UMP/UDP-GlcNAc exchange to alterations in intravesicular and extravesicular pH suggests that UDP-GlcNAc enters the Golgi apparatus in electroneutral exchange with the dianionic form of UMP.

  7. 77 FR 54648 - Seventh Meeting: RTCA NextGen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-05

    ... Federal Aviation Administration Seventh Meeting: RTCA NextGen Advisory Committee (NAC) AGENCY: Federal...Gen Advisory Committee (NAC). SUMMARY: The FAA is issuing this notice to advise the public of the seventh meeting of the RTCA NextGen Advisory Committee (NAC). DATES: The meeting will be held October...

  8. 76 FR 3931 - Second Meeting RTCA NextGen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-21

    ... Federal Aviation Administration Second Meeting RTCA NextGen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: RTCA NextGen Advisory Committee (NAC). SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA NextGen Advisory Committee (NAC). DATES:...

  9. 76 FR 22162 - Third Meeting RTCA NextGen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-20

    ... Federal Aviation Administration Third Meeting RTCA NextGen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: RTCA NextGen Advisory Committee (NAC). SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA NextGen Advisory Committee (NAC). DATES:...

  10. 76 FR 54526 - Fourth Meeting RTCA NextGen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-01

    ... Federal Aviation Administration Fourth Meeting RTCA NextGen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: RTCA NextGen Advisory Committee (NAC). SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA NextGen Advisory Committee (NAC). DATES:...

  11. Isolation and Expression of NAC Genes during Persimmon Fruit Postharvest Astringency Removal

    PubMed Central

    Min, Ting; Wang, Miao-Miao; Wang, Hongxun; Liu, Xiaofen; Fang, Fang; Grierson, Donald; Yin, Xue-Ren; Chen, Kun-Song

    2015-01-01

    NAC genes have been characterized in numerous plants, where they are involved in responses to biotic and abiotic stress, including low oxygen stress. High concentration of CO2 is one of the most effective treatments to remove astringency of persimmon fruit owing to the action of the accumulated anoxia metabolite acetaldehyde. In model plants, NAC genes have been identified as being responsive to low oxygen. However, the possible relationship between NAC transcription factors and persimmon astringency removal remains unexplored. In the present research, treatment with a high concentration of CO2 (95%) effectively removed astringency of “Mopan” persimmon fruit by causing decreases in soluble tannin. Acetaldehyde content increased in response to CO2 treatment concomitantly with astringency removal. Using RNA-seq and Rapid amplification of cDNA ends (RACE), six DkNAC genes were isolated and studied. Transcriptional analysis indicated DkNAC genes responded differentially to CO2 treatment; DkNAC1, DkNAC3, DkNAC5 and DkNAC6 were transiently up-regulated, DkNAC2 was abundantly expressed 3 days after treatment, while the DkNAC4 was suppressed during astringency removal. It is proposed that DkNAC1/3/5/6 could be important candidates as regulators of persimmon astringency removal and the roles of other member are also discussed. PMID:25599529

  12. Characterization and expression profile of CaNAC2 pepper gene

    PubMed Central

    Guo, Wei-Li; Wang, Shu-Bin; Chen, Ru-Gang; Chen, Bi-Hua; Du, Xiao-Hua; Yin, Yan-Xu; Gong, Zhen-Hui; Zhang, Yu-Yuan

    2015-01-01

    The plant-specific NAC (NAM, ATAF, and CUC) transcription factors have diverse role in development and stress regulation. A new transcript encoding NAC protein, homologous to nam-like protein 4 from Petunia was identified from an ABA-regulated subtractive cDNA library of Capsicum annuum seedling. Here, this homolog (named CaNAC2) from C. annuum was characterized and investigated its role in abiotic stress tolerance. Our results indicated that a plant-specific and conserved NAC domain was located in the N-terminus domain of CaNAC2 which was predicted to encode a polypeptide of 410 amino acids. Phylogenetic analysis showed that CaNAC2 belonged to the NAC2 subgroup of the orthologous group 4d. The protein CaNAC2 was subcellularly localized in the nucleus and it had transcriptional activity in yeast cell. CaNAC2 was expressed mainly in seed and root. The transcription expression of CaNAC2 was strongly induced by cold, salt and ABA treatment and inhibited by osmotic stress and SA treatment. Silence of CaNAC2 in virus-induced gene silenced pepper seedlings resulted in the increased susceptibility to cold stress and delayed the salt-induced leaf chlorophyll degradation. These results indicated that this novel CaNAC2 gene might be involved in pepper response to abiotic stress tolerance. PMID:26442068

  13. Characterization and expression profile of CaNAC2 pepper gene.

    PubMed

    Guo, Wei-Li; Wang, Shu-Bin; Chen, Ru-Gang; Chen, Bi-Hua; Du, Xiao-Hua; Yin, Yan-Xu; Gong, Zhen-Hui; Zhang, Yu-Yuan

    2015-01-01

    The plant-specific NAC (NAM, ATAF, and CUC) transcription factors have diverse role in development and stress regulation. A new transcript encoding NAC protein, homologous to nam-like protein 4 from Petunia was identified from an ABA-regulated subtractive cDNA library of Capsicum annuum seedling. Here, this homolog (named CaNAC2) from C. annuum was characterized and investigated its role in abiotic stress tolerance. Our results indicated that a plant-specific and conserved NAC domain was located in the N-terminus domain of CaNAC2 which was predicted to encode a polypeptide of 410 amino acids. Phylogenetic analysis showed that CaNAC2 belonged to the NAC2 subgroup of the orthologous group 4d. The protein CaNAC2 was subcellularly localized in the nucleus and it had transcriptional activity in yeast cell. CaNAC2 was expressed mainly in seed and root. The transcription expression of CaNAC2 was strongly induced by cold, salt and ABA treatment and inhibited by osmotic stress and SA treatment. Silence of CaNAC2 in virus-induced gene silenced pepper seedlings resulted in the increased susceptibility to cold stress and delayed the salt-induced leaf chlorophyll degradation. These results indicated that this novel CaNAC2 gene might be involved in pepper response to abiotic stress tolerance. PMID:26442068

  14. Isolation and expression of NAC genes during persimmon fruit postharvest astringency removal.

    PubMed

    Min, Ting; Wang, Miao-Miao; Wang, Hongxun; Liu, Xiaofen; Fang, Fang; Grierson, Donald; Yin, Xue-Ren; Chen, Kun-Song

    2015-01-01

    NAC genes have been characterized in numerous plants, where they are involved in responses to biotic and abiotic stress, including low oxygen stress. High concentration of CO2 is one of the most effective treatments to remove astringency of persimmon fruit owing to the action of the accumulated anoxia metabolite acetaldehyde. In model plants, NAC genes have been identified as being responsive to low oxygen. However, the possible relationship between NAC transcription factors and persimmon astringency removal remains unexplored. In the present research, treatment with a high concentration of CO2 (95%) effectively removed astringency of "Mopan" persimmon fruit by causing decreases in soluble tannin. Acetaldehyde content increased in response to CO2 treatment concomitantly with astringency removal. Using RNA-seq and Rapid amplification of cDNA ends (RACE), six DkNAC genes were isolated and studied. Transcriptional analysis indicated DkNAC genes responded differentially to CO2 treatment; DkNAC1, DkNAC3, DkNAC5 and DkNAC6 were transiently up-regulated, DkNAC2 was abundantly expressed 3 days after treatment, while the DkNAC4 was suppressed during astringency removal. It is proposed that DkNAC1/3/5/6 could be important candidates as regulators of persimmon astringency removal and the roles of other member are also discussed. PMID:25599529

  15. Attenuation of cue-induced heroin-seeking behavior by cannabinoid CB1 antagonist infusions into the nucleus accumbens core and prefrontal cortex, but not basolateral amygdala.

    PubMed

    Alvarez-Jaimes, Lily; Polis, Ilham; Parsons, Loren H

    2008-09-01

    As with other drugs of abuse, heroin use is characterized by a high incidence of relapse following detoxification that can be triggered by exposure to conditioned stimuli previously associated with drug availability. Recent findings suggest that cannabinoid CB(1) receptors modulate the motivational properties of heroin-conditioned stimuli that induce relapse behavior. However, the neural substrates through which CB(1) receptors modulate cue-induced heroin seeking have not been elucidated. In this study, we evaluated alterations in cue-induced reinstatement of heroin-seeking behavior produced by infusions of the CB(1) receptor antagonist SR 141716A (0, 0.3 and 3 microg per side) delivered into the prefrontal cortex (PFC), nucleus accumbens (NAC), and basolateral amygdala (BLA) of rats. Results show that following extinction of operant behavior the presentation of a discriminative stimulus conditioned to heroin availability reinstated nonreinforced lever pressing to levels comparable to preextinction levels. Intra-PFC SR 141716A dose-dependently reduced cue-induced reinstatement of heroin seeking, with a significant reduction following the 3 microg per side dose. In the NAC, both SR 141716A doses induced a significant reduction in cue-induced reinstatement, with the highest dose completely blocking the effect of the cue. In contrast, intra-BLA SR 141716A did not alter cue-induced reinstatement of responding while systemic administration of this antagonist (3 mg/kg, i.p.) significantly blocked cue-induced reinstatement in all three-placement groups (BLA, PFC, and NAC). These findings provide new insights into the neural mechanisms through which CB(1) receptors modulate the motivational properties of heroin-associated cues inducing relapse. PMID:18059440

  16. Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects

    PubMed Central

    Kim, Y; McGee, S; Czeczor, J K; Walker, A J; Kale, R P; Kouzani, A Z; Walder, K; Berk, M; Tye, S J

    2016-01-01

    Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg−1) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation. PMID:27327257

  17. Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects.

    PubMed

    Kim, Y; McGee, S; Czeczor, J K; Walker, A J; Kale, R P; Kouzani, A Z; Walder, K; Berk, M; Tye, S J

    2016-01-01

    Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg(-1)) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation. PMID:27327257

  18. Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin.

    PubMed

    Suyama, Julie A; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A; Lazenka, Matthew F; Negus, S Stevens; Banks, Matthew L

    2016-01-01

    Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = -0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs. PMID:26645638

  19. Intra-accumbens shell injections of SR48692 enhanced cocaine self-administration intake in rats exposed to an environmentally-elicited reinstatement paradigm.

    PubMed

    Ramos-Ortolaza, Dinah L; Negrón, Alejandro; Cruz, Daryana; Falcón, Edgardo; Iturbe, Mari Carmen; Cajigas, Mariela Hernández; Maldonado-Vlaar, Carmen S

    2009-07-14

    Neurotensin (NT) is a neuropeptide involved in cocaine reward, and in learning and memory processes related to drug use within the mesolimbic dopamine (DA) system. Studies have demonstrated that NT receptor antagonists have potential as pharmacotherapeutical tools for cocaine abuse. Therefore, it is important to understand the molecular profile of NT within mesolimbic neurons and the behavioral effects of NT receptor inhibitors on environmentally-elicited cocaine seeking behavior. To address this issue, male Sprague Dawley rats were trained to self-administer cocaine and to discriminate between environmental cues signaling cocaine vs. saline availability. Then, following extinction, these cues were used to induce reinstatement of cocaine seeking behavior. A differential expression profile was observed throughout the experiment. Particularly, a significant increase of NT levels was observed within the nucleus accumbens (NAc) shell subregion during the acquisition phase of training. To further examine the implications of this increase, separate groups of animals received intra NAc shell injections of one of three doses (25, 50, 100 nM) of the NT1 receptor antagonist SR48692 after reaching stable self-administration. Animals were injected prior to placement in the operant conditioning chambers for four consecutive sessions. An increase in lever pressing was observed following antagonist treatment, whereas no major changes in locomotor activity were observed. We propose that the observed increase in lever pressing may be a compensatory response to a decrease in reinforcement, possibly due to decreased DA release, as previous studies show that chronic SR48692 decreases basal DA release in the NAc shell. PMID:19442653

  20. Serine versus threonine glycosylation with α-O-GalNAc: unexpected selectivity in their molecular recognition with lectins.

    PubMed

    Madariaga, David; Martínez-Sáez, Nuria; Somovilla, Víctor J; García-García, Laura; Berbis, M Álvaro; Valero-Gónzalez, Jessika; Martín-Santamaría, Sonsoles; Hurtado-Guerrero, Ramon; Asensio, Juan L; Jiménez-Barbero, Jesús; Avenoza, Alberto; Busto, Jesús H; Corzana, Francisco; Peregrina, Jesús M

    2014-09-22

    The molecular recognition of several glycopeptides bearing Tn antigen (α-O-GalNAc-Ser or α-O-GalNAc-Thr) in their structure by three lectins with affinity for this determinant has been analysed. The work yields remarkable results in terms of epitope recognition, showing that the underlying amino acid of Tn (serine or threonine) plays a key role in the molecular recognition. In fact, while Soybean agglutinin and Vicia villosa agglutinin lectins prefer Tn-threonine, Helix pomatia agglutinin shows a higher affinity for the glycopeptides carrying Tn-serine. The different conformational behaviour of the two Tn biological entities, the residues of the studied glycopeptides in the close proximity to the Tn antigen and the topology of the binding site of the lectins are at the origin of these differences. PMID:25111627

  1. α-NAC-Specific Autoreactive CD8+ T Cells in Atopic Dermatitis Are of an Effector Memory Type and Secrete IL-4 and IFN-γ.

    PubMed

    Roesner, Lennart M; Heratizadeh, Annice; Wieschowski, Susanne; Mittermann, Irene; Valenta, Rudolf; Eiz-Vesper, Britta; Hennig, Christian; Hansen, Gesine; Falk, Christine S; Werfel, Thomas

    2016-04-15

    Autoreactivity may play a critical role in the chronification of atopic dermatitis (AD). Several studies showed that AD patients produce IgE Abs specific for autoantigens, and we described Th as well as CD8(+) T cells specific for the autoallergen Hom s 2, the α-chain of the nascent polypeptide-associated complex (α-NAC). This study aimed to investigate the frequency and inflammatory phenotype of autoallergen-specific CD8(+) T cells. CD8(+) T cell immunodominant epitopes of α-NAC were mapped by applying prediction softwares, and binding affinity was confirmed by stabilization of empty MHC complexes. MHC class I tetramers were assembled and binding cells were analyzed directly ex vivo by flow cytometry and in terms of single-cell assessment by ChipCytometry. We report significantly elevated numbers of α-NAC-specific peripheral T cells in sensitized patients compared with nonatopic controls. These cells secrete IL-4 and IFN-γ, and surface markers revealed significantly elevated frequencies of circulating terminally differentiated α-NAC-specific CD8(+) T cells in patients with AD compared with nonatopic donors. The observed phenotype of α-NAC-specific CD8(+) T cells indicates a role in the pathogenesis of AD. PMID:26962231

  2. Pretend play.

    PubMed

    Weisberg, Deena Skolnick

    2015-01-01

    Pretend play is a form of playful behavior that involves nonliteral action. Although on the surface this activity appears to be merely for fun, recent research has discovered that children's pretend play has connections to important cognitive and social skills, such as symbolic thinking, theory of mind, and counterfactual reasoning. The current article first defines pretend play and then reviews the arguments and evidence for these three connections. Pretend play has a nonliteral correspondence to reality, hence pretending may provide children with practice with navigating symbolic relationships, which may strengthen their language skills. Pretend play and theory of mind reasoning share a focus on others' mental states in order to correctly interpret their behavior, hence pretending and theory of mind may be mutually supportive in development. Pretend play and counterfactual reasoning both involve representing nonreal states of affairs, hence pretending may facilitate children's counterfactual abilities. These connections make pretend play an important phenomenon in cognitive science: Studying children's pretend play can provide insight into these other abilities and their developmental trajectories, and thereby into human cognitive architecture and its development. PMID:26263228

  3. Barley plants over-expressing the NAC transcription factor gene HvNAC005 show stunting and delay in development combined with early senescence

    PubMed Central

    Christiansen, Michael W.; Matthewman, Colette; Podzimska-Sroka, Dagmara; O’Shea, Charlotte; Lindemose, Søren; Møllegaard, Niels Erik; Holme, Inger B.; Hebelstrup, Kim; Skriver, Karen; Gregersen, Per L.

    2016-01-01

    The plant-specific NAC transcription factors have attracted particular attention because of their involvement in stress responses, senescence, and nutrient remobilization. The HvNAC005 gene of barley encodes a protein belonging to subgroup NAC-a6 of the NAC family. This study shows that HvNAC005 is associated with developmental senescence. It was significantly up-regulated following ABA treatment, supported by ABA-responsive elements in its promoter, but it was not up-regulated during dark-induced senescence. The C-termini of proteins closely related to HvNAC005 showed overall high divergence but also contained conserved short motifs. A serine- and leucine-containing central motif was essential for transcriptional activity of the HvNAC005 C-terminus in yeast. Over-expression of HvNAC005 in barley resulted in a strong phenotype with delayed development combined with precocious senescence. The over-expressing plants showed up-regulation of genes involved with secondary metabolism, hormone metabolism, stress, signalling, development, and transport. Up-regulation of senescence markers and hormone metabolism and signalling genes supports a role of HvNAC005 in the cross field of different hormone and signalling pathways. Binding of HvNAC005 to promoter sequences of putative target genes containing the T[G/A]CGT core motif was shown by direct protein–DNA interactions of HvNAC005 with promoters for two of the up-regulated genes. In conclusion, HvNAC005 was shown to be a strong positive regulator of senescence and so is an obvious target for the fine-tuning of gene expression in future attempts to improve nutrient remobilization related to the senescence process in barley. PMID:27436280

  4. Molecular cloning and characterization of a membrane associated NAC family gene, SiNAC from foxtail millet [Setaria italica (L.) P. Beauv].

    PubMed

    Puranik, Swati; Bahadur, Ranjit Prasad; Srivastava, Prem S; Prasad, Manoj

    2011-10-01

    The plant-specific NAC (NAM, ATAF, and CUC) transcription factors have diverse role in development and stress regulation. A transcript encoding NAC protein, termed SiNAC was identified from a salt stress subtractive cDNA library of S. italica seedling (Puranik et al., J Plant Physiol 168:280-287, 2011). This single/low copy gene containing four exons and four introns within the genomic-sequence encoded a protein of 462 amino acids. Structural analysis revealed that highly divergent C terminus contains a transmembrane domain. The NAC domain consisted of a twisted antiparallel beta-sheet packing against N terminal alpha helix on one side and a shorter helix on the other side. The domain was predicted to homodimerize and control DNA-binding specificity. The physicochemical features of the SiNAC homodimer interface justified the dimeric form of the predicted model. A 1539 bp fragment upstream to the start codon of SiNAC gene was cloned and in silico analysis revealed several putative cis-acting regulatory elements within the promoter sequence. Transactivation analysis indicated that SiNAC activated expression of reporter gene and the activation domain lied at the C terminal. The SiNAC:GFP was detected in the nucleus and cytoplasm while SiNAC ΔC(1-158):GFP was nuclear localized in onion epidermal cells. SiNAC transcripts mostly accumulated in young spikes and were strongly induced by dehydration, salinity, ethephon, and methyl jasmonate. These results suggest that SiNAC encodes a membrane associated NAC-domain protein that may function as a transcriptional activator in response to stress and developmental regulation in plants. PMID:21312005

  5. Activities and expression pattern of the carbohydrate sulfotransferase GlcNAc6ST-3 (I-GlcNAc6ST): functional implications.

    PubMed

    Lee, Jin Kyu; Bistrup, Annette; van Zante, Annemieke; Rosen, Steven D

    2003-04-01

    In recent years, a family of five GlcNAc-6-O-sulfotransferases, called the GlcNAc6STs, has been molecularly cloned. One of these, GlcNAc6ST-2 (originally named HEC-GlcNAc6ST or LSST), shows a very restricted expression at the mRNA level in high endothelial cells (HECs) of lymph nodes high endothelial venules (HEVs). This enzyme has been shown to be involved in elaborating the 6-sulfo sLex structure on a set of mucin-like acceptors within HECs, thus providing a critical recognition determinant for L-selectin during the process of lymphocyte homing to lymph nodes. Limited information has been available about the closely related sulfotransferase known as GlcNAc6ST-3 (I-GlcNAc6ST). Here, employing transfection experiments with a series of glycoprotein acceptors, we report that this sulfotransferase has a marked preference for sulfating O-linked sugars of mucin-type acceptors, whereas other sulfotransferases in the family (GlcNAc6ST-1, GlcNAc6ST-2) and a Gal-6-O-sulfotransferase exhibit strong activity on both mucin-type acceptors and glycoproteins with predominantly N-linked chains. PCR analysis of cDNAs derived from a panel of tissues and purified cell populations confirms the strong expression of GlcNAc6ST-3 in gut-associated tissues and extends the expression to include lymphocytes. In contrast to GlcNAc6ST-2, GlcNAc6ST-3 transcripts are present minimally, if at all, in HECs; moreover, this enzyme is not able to generate the 6-sulfo sLex epitope in transfected cells. These latter findings argue that GlcNAc6ST-3 is not involved in generating HEV-expressed ligands for L-selectin. PMID:12626414

  6. Synthesis of 1,2-cis-homoiminosugars derived from GlcNAc and GalNAc exploiting a β-amino alcohol skeletal rearrangement.

    PubMed

    Blériot, Yves; Auberger, Nicolas; Jagadeesh, Yerri; Gauthier, Charles; Prencipe, Giuseppe; Tran, Anh Tuan; Marrot, Jérôme; Désiré, Jérôme; Yamamoto, Arisa; Kato, Atsushi; Sollogoub, Matthieu

    2014-11-01

    The synthesis of 1,2-cis-homoiminosugars bearing an NHAc group at the C-2 position is described. The key step to prepare these α-D-GlcNAc and α-D-GalNAc mimics utilizes a β-amino alcohol skeletal rearrangement applied to an azepane precursor. This strategy also allows access to naturally occurring α-HGJ and α-HNJ. The α-D-GlcNAc-configured iminosugar was coupled to a glucoside acceptor to yield a novel pseudodisaccharide. Preliminary glycosidase inhibition evaluation indicates that the α-D-GalNAc-configured homoiminosugar is a potent and selective α-N-acetylgalactosaminidase inhibitor. PMID:25330411

  7. Shadow Play

    ERIC Educational Resources Information Center

    Trundle, Kathy Cabe; Hilson, Margilee P.

    2012-01-01

    A bunny rabbit playfully hops across the wall. Then hands realign and fingers shift to make a hawk soar toward the ceiling. Most children have enjoyed the delightful experience of playing with shadow puppets. The authors build on this natural curiosity to help students link shadows to complex astronomical concepts such as seasons. The…

  8. NAC-1 cask dose rate calculations for LWR spent fuel

    SciTech Connect

    CARLSON, A.B.

    1999-02-24

    A Nuclear Assurance Corporation nuclear fuel transport cask, NAC-1, is being considered as a transport and storage option for spent nuclear fuel located in the B-Cell of the 324 Building. The loaded casks will be shipped to the 200 East Area Interim Storage Area for dry interim storage. Several calculations were performed to assess the photon and neutron dose rates. This report describes the analytical methods, models, and results of this investigation.

  9. NAC gets OK for waste canister, looks for buyers

    SciTech Connect

    Newman, P.

    1994-10-13

    The Nuclear Regulatory Commission has given design approval to the first dual-purpose waste cansiter suitable for storing and transporting irradiated nuclear fuel. The cask could be commercially available by January 1995. NRC issued a transportation certificate for the canister, which was developed by Atlanta-based NAC Services Inc., a subsidiary of NAC Holding Inc. That certificate, which says the cask is a suitable vessel for transporting radioactive wastes by rail and truck, is the first credential of a two-part licensing process the design must acquire. Testing of the cask has been extensive, including drop tests and pin-puncture tests. Roughly 19 feet long and eight feet in diameter, the cask is designed to hold 26 pressurized water reactor fuel assemblies. NAC officials say the cask design will soon be adapted to accomodate larger boiling water reactor fuel assemblies. Utilities will need some convincing that the dual-purpose $1.5 million cask is worth the money, particularly since companies currently have no use for the cask`s transportation capabilities.

  10. O-GlcNAc profiling: from proteins to proteomes

    PubMed Central

    2014-01-01

    O-linked β-D-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) onto serine and threonine residues of proteins is an important post-translational modification (PTM), which is involved in many crucial biological processes including transcription, translation, proteasomal degradation, and signal transduction. Aberrant protein O-GlcNAcylation is directly linked to the pathological progression of chronic diseases including diabetes, cancer, and neurodegenerative disorders. Identification, site mapping, and quantification of O-GlcNAc proteins are a prerequisite to decipher their functions. In this review, we mainly focus on technological developments regarding O-GlcNAc protein profiling. Specifically, on one hand, we show how these techniques are being used for the comprehensive characterization of certain targeted proteins in which biologists are most interested. On the other hand, we present several newly developed approaches for O-GlcNAcomic profiling as well as how they provide us with a systems perspective to crosstalk amongst different PTMs and complicated biological events. Promising technical trends are also highlighted to evoke more efforts by diverse laboratories, which would further expand our understanding of the physiological and pathological roles of protein O-GlcNAcylation in chronic diseases. PMID:24593906

  11. Characterization of a folate-induced hypermotility response after bilateral injection into the rat nucleus accumbens

    SciTech Connect

    Stephens, R.L. Jr.

    1986-01-01

    The objective of these studies was to pharmacologically characterize the mechanism responsible for a folate-induced stimulation of locomotor activity in rats after bilateral injection into the nucleus accumbens region of the brain. Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) produced this hypermotility response after intra-accumbens injection, while other reduced folic acid derivatives dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Studies were designed to determine the role of catecholamines in the nucleus accumbens in the folate-induced hypermotility response. The findings suggest that the folate-induced response is dependent on intact neuronal dopamine stores, and is mediated by stimulation of dopamine receptors of the nucleus accumbens. However the folates do not appear to enhance dopaminergic neutransmission. Thus, FA and FTHF were inefficient at 1 mM concentrations in stimulating /sup 3/H-dopamine release from /sup 3/H-dopamine preloaded nucleus accumbens slices or dopamine from endogenous stores. Pteroic acid, the chemical precursor of folic acid which lacks the glutamate moiety, was ineffective in producing a stimulation of locomotor activity after intra-accumbens injection. Since glutamate is an excitatory amino acid (EAA), compounds characterized as EAA receptor antagonists were utilized to determine if the folate-induced hypermotility response is mediated by activation of EAA receptors in the nucleus accumbens. These results suggest that activation of quisqualate receptors of the nucleus accumbens may mediate the folate-induced hypermotility response.

  12. The Rose (Rosa hybrida) NAC Transcription Factor 3 Gene, RhNAC3, Involved in ABA Signaling Pathway Both in Rose and Arabidopsis

    PubMed Central

    Lü, Peitao; Liu, Jitao; Gao, Junping; Zhang, Changqing

    2014-01-01

    Plant transcription factors involved in stress responses are generally classified by their involvement in either the abscisic acid (ABA)-dependent or the ABA-independent regulatory pathways. A stress-associated NAC gene from rose (Rosa hybrida), RhNAC3, was previously found to increase dehydration tolerance in both rose and Arabidopsis. However, the regulatory mechanism involved in RhNAC3 action is still not fully understood. In this study, we isolated and analyzed the upstream regulatory sequence of RhNAC3 and found many stress-related cis-elements to be present in the promoter, with five ABA-responsive element (ABRE) motifs being of particular interest. Characterization of Arabidopsis thaliana plants transformed with the putative RhNAC3 promoter sequence fused to the β-glucuronidase (GUS) reporter gene revealed that RhNAC3 is expressed at high basal levels in leaf guard cells and in vascular tissues. Moreover, the ABRE motifs in the RhNAC3 promoter were observed to have a cumulative effect on the transcriptional activity of this gene both in the presence and absence of exogenous ABA. Overexpression of RhNAC3 in A. thaliana resulted in ABA hypersensitivity during seed germination and promoted leaf closure after ABA or drought treatments. Additionally, the expression of 11 ABA-responsive genes was induced to a greater degree by dehydration in the transgenic plants overexpressing RhNAC3 than control lines transformed with the vector alone. Further analysis revealed that all these genes contain NAC binding cis-elements in their promoter regions, and RhNAC3 was found to partially bind to these putative NAC recognition sites. We further found that of 219 A. thaliana genes previously shown by microarray analysis to be regulated by heterologous overexpression RhNAC3, 85 are responsive to ABA. In rose, the expression of genes downstream of the ABA-signaling pathways was also repressed in RhNAC3-silenced petals. Taken together, we propose that the rose RhNAC3 protein

  13. Stimulated dopamine overflow and alpha-synuclein expression in the nucleus accumbens core distinguish rats bred for differential ethanol preference.

    PubMed

    Pelkonen, Anssi; Hiltunen, Mikko; Kiianmaa, Kalervo; Yavich, Leonid

    2010-08-01

    The key neurochemical systems and structures involved in the predisposition to substance abuse and preference to ethanol (EtOH) are not known in detail but clearly dopamine (DA) is an important modulator of addiction. Recent data indicate that alpha-synuclein (alpha-syn), a pre-synaptic protein, plays a role in regulation of DA release from the pre-synaptic terminals in striatum and the expression of this protein is different after drug abuse or following abstinence. In the present work, we analysed stimulated DA overflow in the dorsal and ventral striatum in EtOH naïve alko alchohol (AA) and alko non-alchohol (ANA) rats selected for more than 100 generations for their differential EtOH preference. In the same structures, we studied the expression of alpha-syn using western blotting. AA rats, in comparison with ANA rats, showed a marked reduction of stimulated peak DA overflow and higher levels of alpha-syn in the nucleus accumbens core. In the same structure, DA re-uptake was increased in AA rats in comparison with ANA rats. The effects of EtOH at low (0.1 g/kg) and higher (3 mg/kg) doses on DA overflow measured in the nucleus accumbens shell were similar in both lines. These results indicate that high expression of alpha-syn may contribute to the reduced DA overflow and the possible activation of re-uptake in the nucleus accumbens core of AA rats in comparison with ANA rats. PMID:20533994

  14. Activity Based High-Throughput Screening for Novel O-GlcNAc Transferase Substrates Using a Dynamic Peptide Microarray.

    PubMed

    Shi, Jie; Sharif, Suhela; Ruijtenbeek, Rob; Pieters, Roland J

    2016-01-01

    O-GlcNAcylation is a reversible and dynamic protein post-translational modification in mammalian cells. The O-GlcNAc cycle is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation plays important role in many vital cellular events including transcription, cell cycle regulation, stress response and protein degradation, and altered O-GlcNAcylation has long been implicated in cancer, diabetes and neurodegenerative diseases. Recently, numerous approaches have been developed to identify OGT substrates and study their function, but there is still a strong demand for highly efficient techniques. Here we demonstrated the utility of the peptide microarray approach to discover novel OGT substrates and study its specificity. Interestingly, the protein RBL-2, which is a key regulator of entry into cell division and may function as a tumor suppressor, was identified as a substrate for three isoforms of OGT. Using peptide Ala scanning, we found Ser 420 is one possible O-GlcNAc site in RBL-2. Moreover, substitution of Ser 420, on its own, inhibited OGT activity, raising the possibility of mechanism-based development for selective OGT inhibitors. This approach will prove useful for both discovery of novel OGT substrates and studying OGT specificity. PMID:26960196

  15. Activity Based High-Throughput Screening for Novel O-GlcNAc Transferase Substrates Using a Dynamic Peptide Microarray

    PubMed Central

    Shi, Jie; Sharif, Suhela; Ruijtenbeek, Rob; Pieters, Roland J.

    2016-01-01

    O-GlcNAcylation is a reversible and dynamic protein post-translational modification in mammalian cells. The O-GlcNAc cycle is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation plays important role in many vital cellular events including transcription, cell cycle regulation, stress response and protein degradation, and altered O-GlcNAcylation has long been implicated in cancer, diabetes and neurodegenerative diseases. Recently, numerous approaches have been developed to identify OGT substrates and study their function, but there is still a strong demand for highly efficient techniques. Here we demonstrated the utility of the peptide microarray approach to discover novel OGT substrates and study its specificity. Interestingly, the protein RBL-2, which is a key regulator of entry into cell division and may function as a tumor suppressor, was identified as a substrate for three isoforms of OGT. Using peptide Ala scanning, we found Ser 420 is one possible O-GlcNAc site in RBL-2. Moreover, substitution of Ser 420, on its own, inhibited OGT activity, raising the possibility of mechanism-based development for selective OGT inhibitors. This approach will prove useful for both discovery of novel OGT substrates and studying OGT specificity. PMID:26960196

  16. Ectopic expression of a GlcNAc 6-O-sulfotransferase, GlcNAc6ST-2, in colonic mucinous adenocarcinoma.

    PubMed

    Seko, Akira; Nagata, Koji; Yonezawa, Suguru; Yamashita, Katsuko

    2002-06-01

    The content of sulfated glycans having 6-O-sulfated GlcNAc residues alters in the course of colonic carcinogenesis. We previously characterized two GlcNAc 6-O-sulfotransferases (SulTs), SulT-a and -b, expressed in colonic normal tissues and adenocarcinomas [Seko et al. (2000) Glycobiology, 10, 919-929]. Levels of the enzymatic activities of SulT-a in normal colonic mucosa are higher than those in colonic adenocarcinomas, and the enzymatic activities of SulT-b are detected only in mucinous adenocarcinomas. To determine which GlcNAc 6-O-SulTs cloned so far correspond to SulT-a and -b, we expressed seven enzymes of a Gal/GalNAc/GlcNAc 6-O-SulT family in COS-7 cells and examined their substrate specificities in comparison with those of SulT-a and -b. GlcNAc6ST-2 (HEC-GlcNAc6ST, LSST, or GST-3) can recognize GlcNAcbeta1-->3GalNAcalpha1-O-pNP as a good acceptor as well as other O-linked- and N-linked-type oligosaccharides, and its substrate specificity was similar to that of SulT-b. GlcNAc6ST-3(I-GlcNAc6ST or GST-4alpha) preferred Galbeta1-->3(GlcNAcbeta1-->6)GalNAcalpha1-O-pNP as an acceptor to the other oligosaccharides examined, and its specificity was similar to that of SulT-a. To confirm these correspondences, we further performed quantitative analyses of transcripts for GlcNAc6ST-2 and -3 genes by competitive RT-PCR. As a result, GlcNAc6ST-2 gene was expressed in almost all the mucinous adenocarcinomas examined and hardly expressed in normal colonic mucosa and nonmucinous adenocarcinoma. Expression levels of transcript for GlcNAc6ST-3 in normal mucosa were significantly higher than those in adenocarcinomas. From these results, it was indicated that GlcNAc6ST-2 corresponds to mucinous adenocarcinoma-specific SulT-b and that expression of GlcNAc6ST-3 is down-regulated in colonic adenocarcinomas. PMID:12107080

  17. Oxidative damage due to copper ion and hydrogen peroxide induces GlcNAc-specific cleavage of an Asn-linked oligosaccharide.

    PubMed

    Eguchi, Hironobu; Ikeda, Yoshitaka; Koyota, Souichi; Honke, Koichi; Suzuki, Keiichiro; Gutteridge, John M C; Taniguchi, Naoyuki

    2002-03-01

    Cleavage of an asparagine-linked sugar chain by hydrogen peroxide (H2O2) and a copper salt was investigated. Incubation of a 2-aminopyridine (PA)-labeled biantennary sugar chain, GlcNAcbeta1-2Manalpha1-6(GlcNAcbeta1-2Manalpha1-3)Manbeta1-4GlcNAcbeta1-4GlcNAc-PA, with H2O2 and Cu2+ led to formation of four major degradation products. Reversed phase high performance liquid chromatographic analysis coupled with glycosidase digestion indicated that the sugar chain is not randomly degraded but specifically degraded at a GlcNAc residue. Treatment with either of H2O2 or copper alone did not cleave nor degrade the sugar chain to any extent. Electron spin resonance (ESR) spectra obtained using a spin trap reagent were consistent with the generation of OH* or an OH*-like radical by the H2O2/copper salt mixture. The addition of ascorbic acid enhanced this radical generation as well as the degradation of the sugar chain. It was also found that H2O2/Cu2+ destroys the N-acetyl group of the monosaccharide GlcNAc, as judged by a decrease in the ultraviolet absorption spectrum of this group. On the other hand, replacement of copper by Fe2+ caused no cleavage of the sugar chain, although comparable levels of the same radical species were generated. Furthermore, spectrophotometric analysis showed that a GlcNAc-containing sugar chain coordinates to copper but not to iron, and, thus, the coordination appears to play an essential role in the degradation of the sugar chain. These findings suggest that coordination of copper ions to GlcNAc residues localizes the generation of a radical, which cleaves the glycosidic linkage, possibly involving alteration of the N-acetyl group, thereby allowing the GlcNAc-specific cleavage. PMID:11872178

  18. Expression of Vitis amurensis NAC26 in Arabidopsis enhances drought tolerance by modulating jasmonic acid synthesis

    PubMed Central

    Fang, Linchuan; Su, Lingye; Sun, Xiaoming; Li, Xinbo; Sun, Mengxiang; Karungo, Sospeter Karanja; Fang, Shuang; Chu, Jinfang; Li, Shaohua; Xin, Haiping

    2016-01-01

    The growth and fruit quality of grapevines are widely affected by abnormal climatic conditions such as water deficits, but many of the precise mechanisms by which grapevines respond to drought stress are still largely unknown. Here, we report that VaNAC26, a member of the NAC transcription factor family, was upregulated dramatically during cold, drought and salinity treatments in Vitis amurensis, a cold and drought-hardy wild Vitis species. Heterologous overexpression of VaNAC26 enhanced drought and salt tolerance in transgenic Arabidopsis. Higher activities of antioxidant enzymes and lower concentrations of H2O2 and O2 − were found in VaNAC26-OE lines than in wild type plants under drought stress. These results indicated that scavenging by reactive oxygen species (ROS) was enhanced by VaNAC26 in transgenic lines. Microarray-based transcriptome analysis revealed that genes related to jasmonic acid (JA) synthesis and signaling were upregulated in VaNAC26-OE lines under both normal and drought conditions. VaNAC26 showed a specific binding ability on the NAC recognition sequence (NACRS) motif, which broadly exists in the promoter regions of upregulated genes in transgenic lines. Endogenous JA content significantly increased in the VaNAC26-OE lines 2 and 3. Our data suggest that VaNAC26 responds to abiotic stresses and may enhance drought tolerance by transcriptional regulation of JA synthesis in Arabidopsis. PMID:27162276

  19. Expression of Vitis amurensis NAC26 in Arabidopsis enhances drought tolerance by modulating jasmonic acid synthesis.

    PubMed

    Fang, Linchuan; Su, Lingye; Sun, Xiaoming; Li, Xinbo; Sun, Mengxiang; Karungo, Sospeter Karanja; Fang, Shuang; Chu, Jinfang; Li, Shaohua; Xin, Haiping

    2016-04-01

    The growth and fruit quality of grapevines are widely affected by abnormal climatic conditions such as water deficits, but many of the precise mechanisms by which grapevines respond to drought stress are still largely unknown. Here, we report that VaNAC26, a member of the NAC transcription factor family, was upregulated dramatically during cold, drought and salinity treatments in Vitis amurensis, a cold and drought-hardy wild Vitis species. Heterologous overexpression of VaNAC26 enhanced drought and salt tolerance in transgenic Arabidopsis. Higher activities of antioxidant enzymes and lower concentrations of H2O2 and O2 (-) were found in VaNAC26-OE lines than in wild type plants under drought stress. These results indicated that scavenging by reactive oxygen species (ROS) was enhanced by VaNAC26 in transgenic lines. Microarray-based transcriptome analysis revealed that genes related to jasmonic acid (JA) synthesis and signaling were upregulated in VaNAC26-OE lines under both normal and drought conditions. VaNAC26 showed a specific binding ability on the NAC recognition sequence (NACRS) motif, which broadly exists in the promoter regions of upregulated genes in transgenic lines. Endogenous JA content significantly increased in the VaNAC26-OE lines 2 and 3. Our data suggest that VaNAC26 responds to abiotic stresses and may enhance drought tolerance by transcriptional regulation of JA synthesis in Arabidopsis. PMID:27162276

  20. [Identification and analysis of the NAC transcription factor family in Triticum urartu].

    PubMed

    Jianhui, Ma; Doudou, Tong; Wenli, Zhang; Daijing, Zhang; Yun, Shao; Yun, Yang; Lina, Jiang

    2016-03-01

    NAC transcription factors are one of plant-specific gene families with diverse functions, and they regulate plant development, organ formation and stress responses. Currently, the researches about NAC transcription factors mainly focus on model plants, Arabidopsis and rice, whereas such studies are hardly reported in wheat and other plants. In this study, the full-length coding sequences (CDS) of NAC transcription factors from Triticum urartu (TuNAC) were identified through bioinformatic analysis. Their biological function, evolutionary relationship, gene duplication and chromosomal locations were further predicted and analyzed. The quantitative real-time PCR (qRT-PCR) assay was used to verify the expression pattern of abiotic-related TuNAC transcription factors. A total of 87 TuNAC transcription factors with full-length CDS were identified, which were divided into seven subgroups through phylogenetic analysis. Thirty-nine TuNAC transcription factors were located on seven chromosomes, and five pairs of TuNAC transcription factors were duplicated. The expression of four TuNAC transcription factors was consistently increased under diverse abiotic stress by qRT-PCR assay. Our study thus provides basis for further functional investigations of TuNAC transcription factors. PMID:27001478

  1. Overexpression of a Stress-Responsive NAC Transcription Factor Gene ONAC022 Improves Drought and Salt Tolerance in Rice.

    PubMed

    Hong, Yongbo; Zhang, Huijuan; Huang, Lei; Li, Dayong; Song, Fengming

    2016-01-01

    The NAC transcription factors play critical roles in regulating stress responses in plants. However, the functions for many of the NAC family members in rice are yet to be identified. In the present study, a novel stress-responsive rice NAC gene, ONAC022, was identified. Expression of ONAC022 was induced by drought, high salinity, and abscisic acid (ABA). The ONAC022 protein was found to bind specifically to a canonical NAC recognition cis-element sequence and showed transactivation activity at its C-terminus in yeast. The ONAC022 protein was localized to nucleus when transiently expressed in Nicotiana benthamiana. Three independent transgenic rice lines with overexpression of ONAC022 were generated and used to explore the function of ONAC022 in drought and salt stress tolerance. Under drought stress condition in greenhouse, soil-grown ONAC022-overexpressing (N22oe) transgenic rice plants showed an increased drought tolerance, leading to higher survival ratios and better growth than wild-type (WT) plants. When grown hydroponically in Hogland solution supplemented with 150 mM NaCl, the N22oe plants displayed an enhanced salt tolerance and accumulated less Na(+) in roots and shoots as compared to WT plants. Under drought stress condition, the N22oe plants exhibited decreased rates of water loss and transpiration, reduced percentage of open stomata and increased contents of proline and soluble sugars. However, the N22oe lines showed increased sensitivity to exogenous ABA at seed germination and seedling growth stages but contained higher level of endogenous ABA. Expression of some ABA biosynthetic genes (OsNCEDs and OsPSY), signaling and regulatory genes (OsPP2C02, OsPP2C49, OsPP2C68, OsbZIP23, OsAP37, OsDREB2a, and OsMYB2), and late stress-responsive genes (OsRAB21, OsLEA3, and OsP5CS1) was upregulated in N22oe plants. Our data demonstrate that ONAC022 functions as a stress-responsive NAC with transcriptional activator activity and plays a positive role in drought

  2. Clay Play

    ERIC Educational Resources Information Center

    Rogers, Liz; Steffan, Dana

    2009-01-01

    This article describes how to use clay as a potential material for young children to explore. As teachers, the authors find that their dialogue about the potential of clay as a learning medium raises many questions: (1) What makes clay so enticing? (2) Why are teachers noticing different play and conversation around the clay table as compared to…

  3. Playing Teacher.

    ERIC Educational Resources Information Center

    Gilbert, Juan E.

    The acceptance of animation technologies is increasing. Video games, such as Sony PlayStation (SONY, 2002), have become part of the culture for young people from kindergarten through undergraduate school. Animation technologies have been implemented into educational systems in the form of animated pedagogical agents (Johnson, 2000). The research…

  4. Game playing.

    PubMed

    Rosin, Christopher D

    2014-03-01

    Game playing has been a core domain of artificial intelligence research since the beginnings of the field. Game playing provides clearly defined arenas within which computational approaches can be readily compared to human expertise through head-to-head competition and other benchmarks. Game playing research has identified several simple core algorithms that provide successful foundations, with development focused on the challenges of defeating human experts in specific games. Key developments include minimax search in chess, machine learning from self-play in backgammon, and Monte Carlo tree search in Go. These approaches have generalized successfully to additional games. While computers have surpassed human expertise in a wide variety of games, open challenges remain and research focuses on identifying and developing new successful algorithmic foundations. WIREs Cogn Sci 2014, 5:193-205. doi: 10.1002/wcs.1278 CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. PMID:26304308

  5. Sweet Play

    ERIC Educational Resources Information Center

    Leung, Shuk-kwan S.; Lo, Jane-Jane

    2010-01-01

    This article features Sweet play math, a "math by the month" activity that involves decorating and making sugar cubes. Teachers may want to substitute straws, paper squares, alphabet blocks, or such commercially made manipulatives as Unifix[R] cubes for the real sweets. Given no allergy concerns, teachers and students alike would enjoy some sweet…

  6. Disrupted-in-schizophrenia-1 Gln31Leu polymorphism results in social anhedonia associated with monoaminergic imbalance and reduction of CREB and β-arrestin-1,2 in the nucleus accumbens in a mouse model of depression.

    PubMed

    Lipina, Tatiana V; Fletcher, Paul J; Lee, Frankie H; Wong, Albert H C; Roder, John C

    2013-02-01

    Disrupted-in-schizophrenia-1 (DISC1) is associated with mental disorders, including major depression. We previously showed that DISC1-Q31L mutant mice have depression-like behaviors and can therefore be used to study neurobiological mechanisms of depression and antidepressant (AD) medication action. First, we found reduced levels of dopamine, serotonin and norepinephrine in the nucleus accumbens (NAC) of DISC1-Q31L mutants. Next, we assessed social-conditioned place preference as a reward-dependent task and the capacity of distinct ADs to correct impaired social behavior in DISC1-Q31L mice. Bupropion, but not fluoxetine or desipramine, was able to correct deficient social facilitation, social reward, and social novelty in DISC1-Q31L mutants, whereas all three ADs were able to improve social motivation and behavioral despair in DISC1-Q31L mutants. Furthermore, we sought to correlate social anhedonia with molecular and cellular features including dendritic spine density, β-arrestin-1,2, and cAMP-response-element-binding protein (CREB) in the NAC as biomarkers related to depression and the DISC1 pathway. DISC1-Q31L mutants showed reduced levels of β-arrestin-1,2, CREB, and spine density in the NAC, further supporting the construct validity of the genetic model. Bupropion induced the greatest effect on CREB in DISC1-Q31L mutants, whereas all studied ADs corrected the reduced levels of β-arrestin-1,2 and modestly ameliorated deficient spine density in this brain region. Overall, we find neurobiological changes accompanying social anhedonia in the NAC of DISC1-Q31L mutant mice, consistent with a role for DISC1 in regulating social reward as an endophenotype of depression. PMID:23011268

  7. Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus.

    PubMed

    Zhang, Jianbo; Wang, Na; Chen, Bo; Wang, Yi'nan; He, Jing; Cai, Xintong; Zhang, Hongbo; Wei, Shuguang; Li, Shengbin

    2016-09-01

    Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse. Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction. However, the downstream signaling of CB1R is not fully elucidated. In the present study, we investigated the relationship between CB1R and the extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) signaling in the nucleus accumbens (NAc) and hippocampus in morphine-induced conditioned place preference (CPP), which is used to assess the morphine-induced reward memory. The protein level of CB1R, ERK, CREB, and BDNF were detected by western blotting. Additionally, a CB1R antagonist, AM251, was used to study whether blockade of CB1R altered the CPP and above-mentioned molecules. We found an increase of CB1R expression in the NAc and hippocampus of the mice following morphine CPP, but not those after repeated morphine in home cage without context exposure (NO-CPP). Both morphine CPP and NO-CPP induced an upregulation of ERK, CREB phosphorylation and BDNF expression. Furthermore, pretreatment with AM251 before morphine attenuated the CPP acquisition and CB1R expression as well as the activation of ERK-CREB-BDNF cascade. Collectively, these findings demonstrate that (1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. (2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP. PMID:27461790

  8. A Relationship between Reduced Nucleus Accumbens Shell and Enhanced Lateral Hypothalamic Orexin Neuronal Activation in Long-Term Fructose Bingeing Behavior

    PubMed Central

    Rorabaugh, Jacki M.; Stratford, Jennifer M.; Zahniser, Nancy R.

    2014-01-01

    Fructose accounts for 10% of daily calories in the American diet. Fructose, but not glucose, given intracerebroventricularly stimulates homeostatic feeding mechanisms within the hypothalamus; however, little is known about how fructose affects hedonic feeding centers. Repeated ingestion of sucrose, a disaccharide of fructose and glucose, increases neuronal activity in hedonic centers, the nucleus accumbens (NAc) shell and core, but not the hypothalamus. Rats given glucose in the intermittent access model (IAM) display signatures of hedonic feeding including bingeing and altered DA receptor (R) numbers within the NAc. Here we examined whether substituting fructose for glucose in this IAM produces bingeing behavior, alters DA Rs and activates hedonic and homeostatic feeding centers. Following long-term (21-day) exposure to the IAM, rats given 8–12% fructose solutions displayed fructose bingeing but unaltered DA D1R or D2R number. Fructose bingeing rats, as compared to chow bingeing controls, exhibited reduced NAc shell neuron activation, as determined by c-Fos-immunoreactivity (Fos-IR). This activation was negatively correlated with orexin (Orx) neuron activation in the lateral hypothalamus/perifornical area (LH/PeF), a brain region linking homeostatic to hedonic feeding centers. Following short-term (2-day) access to the IAM, rats exhibited bingeing but unchanged Fos-IR, suggesting only long-term fructose bingeing increases Orx release. In long-term fructose bingeing rats, pretreatment with the Ox1R antagonist SB-334867 (30 mg/kg; i.p.) equally reduced fructose bingeing and chow intake, resulting in a 50% reduction in calories. Similarly, in control rats, SB-334867 reduced chow/caloric intake by 60%. Thus, in the IAM, Ox1Rs appear to regulate feeding based on caloric content rather than palatability. Overall, our results, in combination with the literature, suggest individual monosaccharides activate distinct neuronal circuits to promote feeding behavior

  9. Investigating the dynamics of the brain response to music: A central role of the ventral striatum/nucleus accumbens.

    PubMed

    Mueller, Karsten; Fritz, Thomas; Mildner, Toralf; Richter, Maxi; Schulze, Katrin; Lepsien, Jöran; Schroeter, Matthias L; Möller, Harald E

    2015-08-01

    Ventral striatal activity has been previously shown to correspond well to reward value mediated by music. Here, we investigate the dynamic brain response to music and manipulated counterparts using functional magnetic resonance imaging (fMRI). Counterparts of musical excerpts were produced by either manipulating the consonance/dissonance of the musical fragments or playing them backwards (or both). Results show a greater involvement of the ventral striatum/nucleus accumbens both when contrasting listening to music that is perceived as pleasant and listening to a manipulated version perceived as unpleasant (backward dissonant), as well as in a parametric analysis for increasing pleasantness. Notably, both analyses yielded a ventral striatal response that was strongest during an early phase of stimulus presentation. A hippocampal response to the musical stimuli was also observed, and was largely mediated by processing differences between listening to forward and backward music. This hippocampal involvement was again strongest during the early response to the music. Auditory cortex activity was more strongly evoked by the original (pleasant) music compared to its manipulated counterparts, but did not display a similar decline of activation over time as subcortical activity. These findings rather suggest that the ventral striatal/nucleus accumbens response during music listening is strongest in the first seconds and then declines. PMID:25976924

  10. RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles

    PubMed Central

    Keebaugh, Alaine C.; Barrett, Catherine E.; LaPrairie, Jamie L.; Jenkins, Jasmine J.; Young, Larry J.

    2015-01-01

    Oxytocin modulates many aspects of social cognition and behaviors, including maternal nurturing, social recognition and bonding. Natural variation in oxytocin receptor (OXTR) density in the nucleus accumbens (NAcc) is associated with variation in alloparental behavior, and artificially enhancing OXTR expression in the NAcc enhances alloparental behavior and pair bonding in socially monogamous prairie voles. Furthermore, infusion of an OXTR antagonist into the nucleus accumbens (NAcc) inhibits alloparental behavior and partner preference formation. However, antagonists can promiscuously interact with other neuropeptide receptors. To directly examine the role of OXTR signaling in social bonding, we used RNA interference to selectively knockdown, but not eliminate, OXTR in the NAcc of female prairie voles and examined the impact on social behaviors. Using an adeno-associated viral vector expressing a short hairpin RNA (shRNA) targeting Oxtr mRNA, we reduced accumbal OXTR density in female prairie voles from juvenile age through adulthood. Females receiving the shRNA vector displayed a significant reduction in alloparental behavior and disrupted partner preference formation. These are the first direct demonstrations that OXTR plays a critical role in alloparental behavior and adult social attachment, and suggest that natural variation in OXTR expression in this region alone can create variation in social behavior. PMID:25874849

  11. Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation.

    PubMed

    Cohen, Michael X; Bour, Lo; Mantione, Mariska; Figee, Martijn; Vink, Matthijs; Tijssen, Marina A J; van Rootselaar, Anne-Fleur; van den Munckhof, Pepijn; Schuurman, P Richard; Denys, Damiaan

    2012-01-01

    The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep-brain-stimulation treatment for obsessive-compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate "top-down" (cortex → nucleus accumbens)- from "bottom-up" (nucleus accumbens → cortex)-directed synchronization (functional connectivity). "Top-down"-directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward-related processing and may be relevant to understanding the mechanisms of deep-brain stimulation and its beneficial effects on psychiatric conditions. PMID:21547982

  12. Cortical drive of low-frequency oscillations in the human nucleus accumbens during action selection

    PubMed Central

    Litvak, Vladimir; Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.

    2015-01-01

    The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181–190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection. PMID:25878159

  13. Discovery of O-GlcNAc-6-phosphate Modified Proteins in Large-scale Phosphoproteomics Data*

    PubMed Central

    Hahne, Hannes; Kuster, Bernhard

    2012-01-01

    Phosphorylated O-GlcNAc is a novel post-translational modification that has so far only been found on the neuronal protein AP180 from the rat (Graham et al., J. Proteome Res. 2011, 10, 2725–2733). Upon collision induced dissociation, the modification generates a highly mass deficient fragment ion (m/z 284.0530) that can be used as a reporter for the identification of phosphorylated O-GlcNAc. Using a publically available mouse brain phosphoproteome data set, we employed our recently developed Oscore software to re-evaluate high resolution/high accuracy tandem mass spectra and discovered the modification on 23 peptides corresponding to 11 mouse proteins. The systematic analysis of 220 candidate phosphoGlcNAc tandem mass spectra as well as a synthetic standard enabled the dissection of the major phosphoGlcNAc fragmentation pathways, suggesting that the modification is O-GlcNAc-6-phosphate. We find that the classical O-GlcNAc modification often exists on the same peptides indicating that O-GlcNAc-6-phosphate may biosynthetically arise in two steps involving the O-GlcNAc transferase and a currently unknown kinase. Many of the identified proteins are involved in synaptic transmission and for Ca2+/calmodulin kinase IV, the O-GlcNAc-6-phosphate modification was found in the vicinity of two autophosphorylation sites required for full activation of the kinase suggesting a potential regulatory role for O-GlcNAc-6-phosphate. By re-analyzing mass spectrometric data from human embryonic and induced pluripotent stem cells, our study also identified Zinc finger protein 462 (ZNF462) as the first human O-GlcNAc-6-phosphate modified protein. Collectively, the data suggests that O-GlcNAc-6-phosphate is a general post-translation modification of mammalian proteins with a variety of possible cellular functions. PMID:22826440

  14. Discovery of O-GlcNAc-modified Proteins in Published Large-scale Proteome Data*

    PubMed Central

    Hahne, Hannes; Gholami, Amin Moghaddas; Kuster, Bernhard

    2012-01-01

    The attachment of N-acetylglucosamine to serine or threonine residues (O-GlcNAc) is a post-translational modification on nuclear and cytoplasmic proteins with emerging roles in numerous cellular processes, such as signal transduction, transcription, and translation. It is further presumed that O-GlcNAc can exhibit a site-specific, dynamic and possibly functional interplay with phosphorylation. O-GlcNAc proteins are commonly identified by tandem mass spectrometry following some form of biochemical enrichment. In the present study, we assessed if, and to which extent, O-GlcNAc-modified proteins can be discovered from existing large-scale proteome data sets. To this end, we conceived a straightforward O-GlcNAc identification strategy based on our recently developed Oscore software that automatically analyzes tandem mass spectra for the presence and intensity of O-GlcNAc diagnostic fragment ions. Using the Oscore, we discovered hundreds of O-GlcNAc peptides not initially identified in these studies, and most of which have not been described before. Merely re-searching this data extended the number of known O-GlcNAc proteins by almost 100 suggesting that this modification exists even more widely than previously anticipated and the modification is often sufficiently abundant to be detected without enrichment. However, a comparison of O-GlcNAc and phospho-identifications from the very same data indicates that the O-GlcNAc modification is considerably less abundant than phosphorylation. The discovery of numerous doubly modified peptides (i.e. peptides with one or multiple O-GlcNAc or phosphate moieties), suggests that O-GlcNAc and phosphorylation are not necessarily mutually exclusive, but can occur simultaneously at adjacent sites. PMID:22661428

  15. Hsp70-GlcNAc-binding activity is released by stress, proteasome inhibition, and protein misfolding

    SciTech Connect

    Guinez, Celine; Mir, Anne-Marie; Leroy, Yves; Cacan, Rene; Michalski, Jean-Claude; Lefebvre, Tony . E-mail: tony.lefebvre@univ-lille1.fr

    2007-09-21

    Numerous recent works strengthen the idea that the nuclear and cytosolic-specific O-GlcNAc glycosylation protects cells against injuries. We have first investigated O-GlcNAc level and Hsp70-GlcNAc-binding activity (HGBA) behaviour after exposure of HeLa and HepG{sub 2} cells to a wide variety of stresses. O-GlcNAc and HGBA responses were different according to the stress and according to the cell. HGBA was released for almost all stresses, while O-GlcNAc level was modified either upwards or downwards, depending to the stress. Against all expectations, we demonstrated that energy charge did not significantly vary with stress whereas UDP-GlcNAc pools were more dramatically affected even if differences in UDP-GlcNAc contents were not correlated with O-GlcNAc variations suggesting that O-GlcNAc transferase is itself finely regulated during cell injury. Finally, HGBA could be triggered by proteasome inhibition and by L-azetidine-2-carboxylic acid (a proline analogue) incorporation demonstrating that protein misfolding is one of the key-activator of this Hsp70 property.

  16. Genome-Wide Analysis of the NAC Gene Family in Physic Nut (Jatropha curcas L.)

    PubMed Central

    Wu, Zhenying; Xu, Xueqin; Xiong, Wangdan; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Wu, Guojiang; Jiang, Huawu

    2015-01-01

    The NAC proteins (NAM, ATAF1/2 and CUC2) are plant-specific transcriptional regulators that have a conserved NAM domain in the N-terminus. They are involved in various biological processes, including both biotic and abiotic stress responses. In the present study, a total of 100 NAC genes (JcNAC) were identified in physic nut (Jatropha curcas L.). Based on phylogenetic analysis and gene structures, 83 JcNAC genes were classified as members of, or proposed to be diverged from, 39 previously predicted orthologous groups (OGs) of NAC sequences. Physic nut has a single intron-containing NAC gene subfamily that has been lost in many plants. The JcNAC genes are non-randomly distributed across the 11 linkage groups of the physic nut genome, and appear to be preferentially retained duplicates that arose from both ancient and recent duplication events. Digital gene expression analysis indicates that some of the JcNAC genes have tissue-specific expression profiles (e.g. in leaves, roots, stem cortex or seeds), and 29 genes differentially respond to abiotic stresses (drought, salinity, phosphorus deficiency and nitrogen deficiency). Our results will be helpful for further functional analysis of the NAC genes in physic nut. PMID:26125188

  17. Genome-Wide Analysis of the NAC Gene Family in Physic Nut (Jatropha curcas L.).

    PubMed

    Wu, Zhenying; Xu, Xueqin; Xiong, Wangdan; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Wu, Guojiang; Jiang, Huawu

    2015-01-01

    The NAC proteins (NAM, ATAF1/2 and CUC2) are plant-specific transcriptional regulators that have a conserved NAM domain in the N-terminus. They are involved in various biological processes, including both biotic and abiotic stress responses. In the present study, a total of 100 NAC genes (JcNAC) were identified in physic nut (Jatropha curcas L.). Based on phylogenetic analysis and gene structures, 83 JcNAC genes were classified as members of, or proposed to be diverged from, 39 previously predicted orthologous groups (OGs) of NAC sequences. Physic nut has a single intron-containing NAC gene subfamily that has been lost in many plants. The JcNAC genes are non-randomly distributed across the 11 linkage groups of the physic nut genome, and appear to be preferentially retained duplicates that arose from both ancient and recent duplication events. Digital gene expression analysis indicates that some of the JcNAC genes have tissue-specific expression profiles (e.g. in leaves, roots, stem cortex or seeds), and 29 genes differentially respond to abiotic stresses (drought, salinity, phosphorus deficiency and nitrogen deficiency). Our results will be helpful for further functional analysis of the NAC genes in physic nut. PMID:26125188

  18. Sensory Deviancy Detection Measured Directly Within the Human Nucleus Accumbens.

    PubMed

    Dürschmid, Stefan; Zaehle, Tino; Hinrichs, Hermann; Heinze, Hans-Jochen; Voges, Jürgen; Garrido, Marta I; Dolan, Raymond J; Knight, Robert T

    2016-03-01

    Rapid changes in the environment evoke a comparison between expectancy and actual outcome to inform optimal subsequent behavior. The nucleus accumbens (NAcc), a key interface between the hippocampus and neocortical regions, is a candidate region for mediating this comparison. Here, we report event-related potentials obtained from the NAcc using direct intracranial recordings in 5 human participants while they listened to trains of auditory stimuli differing in their degree of deviation from repetitive background stimuli. NAcc recordings revealed an early mismatch signal (50-220 ms) in response to all deviants. NAcc activity in this time window was also sensitive to the statistics of stimulus deviancy, with larger amplitudes as a function of the level of deviancy. Importantly, this NAcc mismatch signal also predicted generation of longer latency scalp potentials (300-400 ms). The results provide direct human evidence that the NAcc is a key component of a network engaged in encoding statistics of the sensory environmental. PMID:25576536

  19. Taste pathways that mediate accumbens dopamine release by sapid sucrose.

    PubMed

    Hajnal, Andras; Norgren, Ralph

    2005-03-16

    Although it has been associated with the release of dopamine in the forebrain, reward remains a conundrum in neuroscience. Sucrose is inherently rewarding and its sensory message reaches the brain via the gustatory system. In rodents, the central gustatory system bifurcates in the pontine parabrachial nuclei, one arm forming a standard thalamocortical axis, the other distributing widely in the limbic forebrain. We report here that lesions of the gustatory thalamus fail to affect dopamine overflow during sucrose licking (149+/-5% vs. 149+/-4% for controls). Similar damage to the parabrachial nuclei, which severs the limbic taste projection, substantially reduces dopamine release from the nucleus accumbens (121+/-4% vs. 168+/-9% for sham operated controls; p<0.02). This represents the first demonstration that the affective character of a sensory stimulus might separate from the thalamocortical system as early as the second central synapse. PMID:15763573

  20. Expression of GhNAC2 from G. herbaceum, improves root growth and imparts tolerance to drought in transgenic cotton and Arabidopsis

    PubMed Central

    Gunapati, Samatha; Naresh, Ram; Ranjan, Sanjay; Nigam, Deepti; Hans, Aradhana; Verma, Praveen C.; Gadre, Rekha; Pathre, Uday V.; Sane, Aniruddha P.; Sane, Vidhu A.

    2016-01-01

    NAC proteins are plant-specific transcription factors that play essential roles in regulating development and responses to abiotic and biotic stresses. We show that over-expression of the cotton GhNAC2 under the CaMV35S promoter increases root growth in both Arabidopsis and cotton under unstressed conditions. Transgenic Arabidopsis plants also show improved root growth in presence of mannitol and NaCl while transgenic cotton expressing GhNAC2 show reduced leaf abscission and wilting upon water stress compared to control plants. Transgenic Arabidopsis plants also have larger leaves, higher seed number and size under well watered conditions, reduced transpiration and higher relative leaf water content. Micro-array analysis of transgenic plants over-expressing GhNAC2 reveals activation of the ABA/JA pathways and a suppression of the ethylene pathway at several levels to reduce expression of ERF6/ERF1/WRKY33/ MPK3/MKK9/ACS6 and their targets. This probably suppresses the ethylene-mediated inhibition of organ expansion, leading to larger leaves, better root growth and higher yields under unstressed conditions. Suppression of the ethylene pathway and activation of the ABA/JA pathways also primes the plant for improved stress tolerance by reduction in transpiration, greater stomatal control and suppression of growth retarding factors. PMID:27113714

  1. Expression of GhNAC2 from G. herbaceum, improves root growth and imparts tolerance to drought in transgenic cotton and Arabidopsis.

    PubMed

    Gunapati, Samatha; Naresh, Ram; Ranjan, Sanjay; Nigam, Deepti; Hans, Aradhana; Verma, Praveen C; Gadre, Rekha; Pathre, Uday V; Sane, Aniruddha P; Sane, Vidhu A

    2016-01-01

    NAC proteins are plant-specific transcription factors that play essential roles in regulating development and responses to abiotic and biotic stresses. We show that over-expression of the cotton GhNAC2 under the CaMV35S promoter increases root growth in both Arabidopsis and cotton under unstressed conditions. Transgenic Arabidopsis plants also show improved root growth in presence of mannitol and NaCl while transgenic cotton expressing GhNAC2 show reduced leaf abscission and wilting upon water stress compared to control plants. Transgenic Arabidopsis plants also have larger leaves, higher seed number and size under well watered conditions, reduced transpiration and higher relative leaf water content. Micro-array analysis of transgenic plants over-expressing GhNAC2 reveals activation of the ABA/JA pathways and a suppression of the ethylene pathway at several levels to reduce expression of ERF6/ERF1/WRKY33/ MPK3/MKK9/ACS6 and their targets. This probably suppresses the ethylene-mediated inhibition of organ expansion, leading to larger leaves, better root growth and higher yields under unstressed conditions. Suppression of the ethylene pathway and activation of the ABA/JA pathways also primes the plant for improved stress tolerance by reduction in transpiration, greater stomatal control and suppression of growth retarding factors. PMID:27113714

  2. Pattern of long-term sensorimotor recovery following intrastriatal and--accumbens DA micrografts in a rat model of Parkinson's disease.

    PubMed

    Falkenstein, Gero; Rosenthal, Christoph; Reum, Torsten; Morgenstern, Rudolf; Döbrössy, Máté; Nikkhah, Guido

    2009-07-01

    The functional restorative capacity of fetal dopaminergic (DA) transplants is governed by a number of critical parameters including graft location, survival of DA neurons, and transplantation technique. In addition, there is an ongoing controversy whether "too much" or "too little" survival of DA neurons is responsible for the incomplete functional recovery observed in some transplanted Parkinson's disease (PD) patients. Here we investigated two implantation sites, the nucleus accumbens (NAc) and the caudate-putamen unit (CPU), and two different graft distributions within the CPU, i.e., two 0.75 microL deposits (CPU-2) versus six 0.25 microL deposits (CPU-6) in a rat model of PD. Grafts were derived from E14 rat ventral mesencephalon and the long-term functional outcome was evaluated with a wide range of complex-sensorimotor behavioral tests. The data show that forelimb stepping, balancing behavior, and skilled forelimb reaching behavior was more restored in CPU-6-grafted animals as compared to CPU-2 animals, although the number surviving dopaminergic neurons and dopamine release were similar in the two groups. Furthermore, a correlation analysis revealed a number of inverse relationships between the rate of DA neuron survival and sensorimotor performances, e.g., for skilled forelimb use. DA grafts placed into the NAc induced a partial recovery in drug-induced rotation tests but failed to restore any of the other sensorimotor behaviors tested. Taken together, these data have important implications both for a better understanding of the complex functional graft-host interactions as well as for the further optimization of clinical neural transplantation strategies in neurodegenerative diseases. PMID:19399892

  3. Administration of activated glial condition medium in the nucleus accumbens extended extinction and intensified reinstatement of methamphetamine-induced conditioned place preference.

    PubMed

    Arezoomandan, Reza; Moradi, Marzieh; Attarzadeh-Yazdi, Ghassem; Tomaz, Carlos; Haghparast, Abbas

    2016-07-01

    Methamphetamine (METH) is a psychostimulant drug with significant abuse potential and neurotoxic effects. A high percentage of users relapse to use after detoxification and no effective medication has been developed for treatment of METH addiction. Developing evidences indicated the role of glial cells in drugs abused related phenomena. However, little is known about the role of these cells in the maintenance and reinstatement of METH-seeking behaviors. Therefore, the current study was conducted to clarify the role of glial cells in the maintenance and reinstatement of METH-induced conditioned place preference (CPP) in rats. Astrocyte condition medium (ACM) and neuroglia conditioned medium (NCM) are liquid mediums prepared from primary astrocyte and neuroglia cells. These mediums seem to contain many factors that release by glia cells. CPP was induced by systemic administration of METH (1mg/kg for 5days, s.c.). Following the establishment of CPP, the rats were given daily bilateral injections (0.5μl/side) of either vehicle, ACM or NCM into the nucleus accumbens (NAc) and then were tested for the maintenance and reinstatement. Intra-NAc administration of ACM treated with METH, could extend the extinction period and also, intensified the magnitude of METH reinstatement. Furthermore, intra-accumbal administration of NCM treated with METH notably delayed the extinction period by four days and significantly increased the magnitude of CPP score in the reinstatement phase compared to the post-test phase. Collectively, these findings suggested that activation of glial cells may be involved in the maintenance and reinstatement of METH-seeking behaviors. It provides new evidence that glia cells might be considered as a potential target for the treatment of METH addiction. PMID:27346277

  4. Nucleus accumbens associated 1 is recruited within the promyelocytic leukemia nuclear body through SUMO modification

    PubMed Central

    Tatemichi, Yoshinori; Shibazaki, Masahiko; Yasuhira, Shinji; Kasai, Shuya; Tada, Hiroshi; Oikawa, Hiroki; Suzuki, Yuji; Takikawa, Yasuhiro; Masuda, Tomoyuki; Maesawa, Chihaya

    2015-01-01

    Nucleus accumbens associated 1 (NACC1) is a cancer-associated BTB/POZ (pox virus and zinc finger/bric-a-brac tramtrack broad complex) gene, and is involved in several cellular functions in neurons, cancer and stem cells. Some of the BTB/POZ proteins associated with cancer biology are SUMOylated, which appears to play an important role in transcription regulation. We show that NACC1 is SUMOylated on a phylogenetically conserved lysine (K167) out of three consensus SUMOylation motif sites. Amino acid substitution in the SIM sequence (SIM/M) within the BTB/POZ domain partially reduced K167 SUMOylation activity of NACC1. Overexpression of GFP-NACC1 fusion protein leads to formation of discrete nuclear foci similar to promyelocytic leukemia nuclear bodies (PML-NB), which colocalized with SUMO paralogues (SUMO1/2/3). Both NACC1 nuclear body formation and colocalization with SUMO paralogues were completely suppressed in the GFP-NACC1-SIM/M mutant, whereas they were partially maintained in the NACC1 K167R mutant. Confocal immunofluorescence analysis showed that endogenous and exogenous NACC1 proteins colocalized with endogenous PML protein. A pull-down assay revealed that the consensus motifs of the SUMO acceptor site at K167 and the SIM within the BTB/POZ domain were both necessary for efficient binding to PML protein. Our study demonstrates that NACC1 can be modified by SUMO paralogues, and cooperates with PML protein. PMID:25891951

  5. mTOR signalling in the nucleus accumbens shell is critical for augmented effect of TFF3 on behavioural response to cocaine

    PubMed Central

    Luo, Yi-Xiao; Han, Hua; Shao, Juan; Gao, Yuan; Yin, Xi; Zhu, Wei-Li; Han, Ying; Shi, Hai-Shui

    2016-01-01

    Neuropeptides play important roles in modulating the rewarding value of abused drugs. Trefoil factor 3 (TFF3) was recently reported to modulate withdrawal syndrome of morphine, but the effects of TFF3 on the cocaine-induced behavioral changes are still elusive. In the present study, cocaine-induced hyperlocomotion and conditioned place preference (CPP) rat paradigms were provided to investigate the role of TFF3 in the reward response to cocaine. High-performance liquid chromatography (HPLC) analysis was used to analyse the dopamine concentration. The results showed that systemic TFF3 administration (0.1 mg/kg i.p.) significantly augmented cocaine- induced hyperlocomotion and CPP formation, without any effects on locomotor activity and aversive or rewarding effects per se. TFF3 significantly augmented the increment of the dopamine concentration in the NAc and the activity of the mTOR signalling pathway induced by acute cocaine exposure (10 mg/kg, i.p.) in the NAc shell, but not the core. The Intra-NAc shell infusion of rapamycin blocked TFF3-induced hyperactivity in cocaine-treatment rats. These findings indicated that TFF3 could potentiate behavioural response to cocaine, which may be associated with regulating dopamine concentration. Furthermore, the findings indicated that mTOR signalling pathway in the NAc shell is important for TFF3-induced enhancement on the cocaine-induced behavioral changes. PMID:27282818

  6. mTOR signalling in the nucleus accumbens shell is critical for augmented effect of TFF3 on behavioural response to cocaine.

    PubMed

    Luo, Yi-Xiao; Han, Hua; Shao, Juan; Gao, Yuan; Yin, Xi; Zhu, Wei-Li; Han, Ying; Shi, Hai-Shui

    2016-01-01

    Neuropeptides play important roles in modulating the rewarding value of abused drugs. Trefoil factor 3 (TFF3) was recently reported to modulate withdrawal syndrome of morphine, but the effects of TFF3 on the cocaine-induced behavioral changes are still elusive. In the present study, cocaine-induced hyperlocomotion and conditioned place preference (CPP) rat paradigms were provided to investigate the role of TFF3 in the reward response to cocaine. High-performance liquid chromatography (HPLC) analysis was used to analyse the dopamine concentration. The results showed that systemic TFF3 administration (0.1 mg/kg i.p.) significantly augmented cocaine- induced hyperlocomotion and CPP formation, without any effects on locomotor activity and aversive or rewarding effects per se. TFF3 significantly augmented the increment of the dopamine concentration in the NAc and the activity of the mTOR signalling pathway induced by acute cocaine exposure (10 mg/kg, i.p.) in the NAc shell, but not the core. The Intra-NAc shell infusion of rapamycin blocked TFF3-induced hyperactivity in cocaine-treatment rats. These findings indicated that TFF3 could potentiate behavioural response to cocaine, which may be associated with regulating dopamine concentration. Furthermore, the findings indicated that mTOR signalling pathway in the NAc shell is important for TFF3-induced enhancement on the cocaine-induced behavioral changes. PMID:27282818

  7. Banana fruit NAC transcription factor MaNAC5 cooperates with MaWRKYs to enhance the expression of pathogenesis-related genes against Colletotrichum musae.

    PubMed

    Shan, Wei; Chen, Jian-Ye; Kuang, Jian-Fei; Lu, Wang-Jin

    2016-04-01

    Plants respond to pathogen attack by the modulation of a large set of genes, which are regulated by different types of transcription factor (TF). NAC (NAM/ATAF/CUC) and WRKY are plant-specific families of TFs, and have received much attention as transcriptional regulators in plant pathogen defence. However, the cooperation between NAC and WRKY TFs in the disease response remains largely unknown. Our previous study has revealed that two banana fruit WRKY TFs, MaWRKY1 and MaWRKY2, are involved in salicylic acid (SA)- and methyl jasmonate (MeJA)-induced resistance against Colletotrichum musae via binding to promoters of pathogenesis-related (PR) genes. Here, we found that MaNAC1, MaNAC2 and MaNAC5 were up-regulated after C. musae infection, and were also significantly enhanced by SA and MeJA treatment. Protein-protein interaction analysis showed that MaNAC5 physically interacted with MaWRKY1 and MaWRKY2. More importantly, dual-luciferase reporter (DLR) assay revealed that MaNAC5, MaWRKY1 and MaWRKY2 were transcriptional activators, and individually or cooperatively activated the transcriptional activities of MaPR1-1, MaPR2, MaPR10c and MaCHIL1 genes. Collectively, our results indicate that MaNAC5 cooperates with MaWRKY1 and MaWRKY2 to regulate the expression of a specific set of PR genes in the disease response, and to contribute at least partially to SA- and MeJA-induced pathogen resistance. PMID:26033522

  8. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.

    PubMed

    Gilman, Jodi M; Kuster, John K; Lee, Sang; Lee, Myung Joo; Kim, Byoung Woo; Makris, Nikos; van der Kouwe, Andre; Blood, Anne J; Breiter, Hans C

    2014-04-16

    Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization. PMID:24741043

  9. Cannabis Use Is Quantitatively Associated with Nucleus Accumbens and Amygdala Abnormalities in Young Adult Recreational Users

    PubMed Central

    Gilman, Jodi M.; Kuster, John K.; Lee, Sang; Lee, Myung Joo; Kim, Byoung Woo; Makris, Nikos; van der Kouwe, Andre; Blood, Anne J.

    2014-01-01

    Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization. PMID:24741043

  10. Experimental Studies of Interacting Electronic States in NaCs

    NASA Astrophysics Data System (ADS)

    Faust, Carl E.

    This dissertation describes methods and results of spectroscopic studies of the NaCs molecule. NaCs is of particular interest in many labs where experimental studies of ultra-cold molecules are being conducted. Data obtained in the present work will also be useful as benchmarks for various theoretical calculations. Our goals in studying this molecule were to map out high lying electronic states and to understand how these states interact with one another. Sodium and cesium metal were heated in a heat-pipe oven to form a vapor of NaCs molecules. These molecules were excited using narrow band, continuous wave (cw), tunable lasers. We employed the optical-optical double resonance (OODR) technique to obtain Doppler-free spectra of transitions to rotational and vibrational levels of high lying electronic states. One state of particular interest was the 12(0+) electronic state. Rovibrational level energies corresponding to this state were measured and used to generate a potential energy curve using computer programs to implement both the Rydberg-Klein-Rees (RKR) method and the inverted perturbation approach (IPA). By observing fluorescence from the 12(0+) state resolved as a function of wavelength, we determined that this state interacts with the nearby 11(0+) electronic state, which was previously mapped out by Ashman et al. A two-stage coupling model was devised to describe the resolved fluorescence originating from these two interacting states. The electronic states interact via spin-orbit coupling, while the individual rovibrational levels interact via a second mechanism, likely nonadiabatic coupling. This two-stage coupling between the levels of these states causes quantum interference between fluorescence pathways associated with different components of the wavefunctions describing these levels. This interference results in more complicated resolved fluorescence spectra. The model was used to fit parameters describing these interactions so that the resolved

  11. The Nitrate-Inducible NAC Transcription Factor TaNAC2-5A Controls Nitrate Response and Increases Wheat Yield1[OPEN

    PubMed Central

    He, Xue; Qu, Baoyuan; Li, Wenjing; Zhao, Xueqiang; Teng, Wan; Ma, Wenying; Ren, Yongzhe; Li, Bin; Li, Zhensheng; Tong, Yiping

    2015-01-01

    Nitrate is a major nitrogen resource for cereal crops; thus, understanding nitrate signaling in cereal crops is valuable for engineering crops with improved nitrogen use efficiency. Although several regulators have been identified in nitrate sensing and signaling in Arabidopsis (Arabidopsis thaliana), the equivalent information in cereals is missing. Here, we isolated a nitrate-inducible and cereal-specific NAM, ATAF, and CUC (NAC) transcription factor, TaNAC2-5A, from wheat (Triticum aestivum). A chromatin immunoprecipitation assay showed that TaNAC2-5A could directly bind to the promoter regions of the genes encoding nitrate transporter and glutamine synthetase. Overexpression of TaNAC2-5A in wheat enhanced root growth and nitrate influx rate and, hence, increased the root’s ability to acquire nitrogen. Furthermore, we found that TaNAC2-5A-overexpressing transgenic wheat lines had higher grain yield and higher nitrogen accumulation in aerial parts and allocated more nitrogen in grains in a field experiment. These results suggest that TaNAC2-5A is involved in nitrate signaling and show that it is an exciting gene resource for breeding crops with more efficient use of fertilizer. PMID:26371233

  12. Sweet potato NAC transcription factor, IbNAC1, upregulates sporamin gene expression by binding the SWRE motif against mechanical wounding and herbivore attack.

    PubMed

    Chen, Shi-Peng; Lin, I Winnie; Chen, Xuanyang; Huang, Yin-Hao; Chang, Shiao-Chi; Lo, Hui-Shan; Lu, Hseuh-Han; Yeh, Kai-Wun

    2016-05-01

    Sporamin is a tuberous storage protein with trypsin inhibitory activity in sweet potato (Ipomoea batatas Lam.), which accounts for 85% of the soluble protein in tubers. It is constitutively expressed in tuberous roots but is expressed in leaves only after wounding. Thus far, its wound-inducible signal transduction mechanisms remain unclear. In the present work, a 53-bp DNA region, sporamin wound-response cis-element (SWRE), was identified in the sporamin promoter and was determined to be responsible for the wounding response. Using yeast one-hybrid screening, a NAC domain protein, IbNAC1, that specifically bound to the 5'-TACAATATC-3' sequence in SWRE was isolated from a cDNA library from wounded leaves. IbNAC1 was constitutively expressed in root tissues and was induced earlier than sporamin following the wounding of leaves. Transgenic sweet potato plants overexpressing IbNAC1 had greatly increased sporamin expression, increased trypsin inhibitory activity, and elevated resistance against Spodoptera litura. We further demonstrated that IbNAC1 has multiple biological functions in the jasmonic acid (JA) response, including the inhibition of root formation, accumulation of anthocyanin, regulation of aging processes, reduction of abiotic tolerance, and overproduction of reactive oxygen species (ROS). Thus, IbNAC1 is a core transcription factor that reprograms the transcriptional response to wounding via the JA-mediated pathway in sweet potato. PMID:26996980

  13. 78 FR 5860 - Eighth Meeting: RTCA Next Gen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ... Federal Aviation Administration Eighth Meeting: RTCA Next Gen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), U.S. Department of Transportation (DOT). ACTION: Notice of RTCA NextGen... meeting of the RTCA NextGen Advisory Committee (NAC). DATES: The meeting will be held February 7,...

  14. 78 FR 54509 - Tenth Meeting: RTCA Next Gen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-04

    ... Federal Aviation Administration Tenth Meeting: RTCA Next Gen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), U.S. Department of Transportation (DOT). ACTION: Notice of RTCA NextGen... of the RTCA NextGen Advisory Committee (NAC). DATES: The meeting will be held September 19, 2013...

  15. 78 FR 28940 - Ninth Meeting: RTCA Next Gen Advisory Committee (NAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-16

    ... Federal Aviation Administration Ninth Meeting: RTCA Next Gen Advisory Committee (NAC) AGENCY: Federal Aviation Administration (FAA), U.S. Department of Transportation (DOT). ACTION: Notice of RTCA NextGen... of the RTCA NextGen Advisory Committee (NAC). DATES: The meeting will be held June 4, 2013 from...

  16. Probing polypeptide GalNAc-transferase isoform substrate specificities by in vitro analysis

    PubMed Central

    Kong, Yun; Joshi, Hiren J; Schjoldager, Katrine Ter-Borch Gram; Madsen, Thomas Daugbjerg; Gerken, Thomas A; Vester-Christensen, Malene B; Wandall, Hans H; Bennett, Eric Paul; Levery, Steven B; Vakhrushev, Sergey Y; Clausen, Henrik

    2015-01-01

    N-acetylgalactosaminyltransferase (GalNAc)-type (mucin-type) O-glycosylation is an abundant and highly diverse modification of proteins. This type of O-glycosylation is initiated in the Golgi by a large family of up to 20 homologous polypeptide GalNAc-T isoenzymes that transfer GalNAc to Ser, Thr and possibly Tyr residues. These GalNAc residues are then further elongated by a large set of glycosyltransferases to build a variety of complex O-glycan structures. What determines O-glycan site occupancy is still poorly understood, although it is clear that the substrate specificities of individual isoenzymes and the repertoire of GalNAc-Ts in cells are key parameters. The GalNAc-T isoenzymes are differentially expressed in cells and tissues in principle allowing cells to produce unique O-glycoproteomes dependent on the specific subset of isoforms present. In vitro analysis of acceptor peptide substrate specificities using recombinant expressed GalNAc-Ts has been the method of choice for probing activities of individual isoforms, but these studies have been hampered by biological validation of actual O-glycosylation sites in proteins and number of substrate testable. Here, we present a systematic analysis of the activity of 10 human GalNAc-T isoenzymes with 195 peptide substrates covering known O-glycosylation sites and provide a comprehensive dataset for evaluating isoform-specific contributions to the O-glycoproteome. PMID:25155433

  17. Structural, evolutionary and functional analysis of the NAC domain protein family in Eucalyptus.

    PubMed

    Hussey, Steven G; Saïdi, Mohammed N; Hefer, Charles A; Myburg, Alexander A; Grima-Pettenati, Jacqueline

    2015-06-01

    NAC domain transcription factors regulate many developmental processes and stress responses in plants and vary widely in number and family structure. We analysed the characteristics and evolution of the NAC gene family of Eucalyptus grandis, a fast-growing forest tree in the rosid order Myrtales. NAC domain genes identified in the E. grandis genome were subjected to amino acid sequence, phylogenetic and motif analyses. Transcript abundance in developing tissues and abiotic stress conditions in E. grandis and E. globulus was quantified using RNA-seq and reverse transcription quantitative PCR (RT-qPCR). One hundred and eighty-nine E. grandis NAC (EgrNAC) proteins, arranged into 22 subfamilies, are extensively duplicated in subfamilies associated with stress response. Most EgrNAC genes form tandem duplicate arrays that frequently carry signatures of purifying selection. Sixteen amino acid motifs were identified in EgrNAC proteins, eight of which are enriched in, or unique to, Eucalyptus. New candidates for the regulation of normal and tension wood development and cold responses were identified. This first description of a Myrtales NAC domain family reveals an unique history of tandem duplication in stress-related subfamilies that has likely contributed to the adaptation of eucalypts to the challenging Australian environment. Several new candidates for the regulation of stress, wood formation and tree-specific development are reported. PMID:25385212

  18. Two Brassica napus genes encoding NAC transcription factors are involved in response to high-salinity stress.

    PubMed

    Zhong, Hui; Guo, Qian-Qian; Chen, Liang; Ren, Feng; Wang, Qing-Qing; Zheng, Yong; Li, Xue-Bao

    2012-11-01

    The NAC protein family is one of the novel classes of plant-specific transcription factors. In this study, two genes (BnNAC2 and BnNAC5) encoding the putative NAC transcription factors were identified in Brassica napus. Sequence analysis revealed that the deduced BnNAC proteins contain conserved N-terminal region (NAC domain) and highly divergent C-terminal domain. Yeast transactivation analysis showed that BnNAC2 could activate reporter gene expression, suggesting that BnNAC2 functions as a transcriptional activator. Quantitative RT-PCR analysis revealed that BnNAC2 was preferentially expressed in flowers, whereas BnNAC5 mRNAs accumulated at the highest level in stems. Further experimental results indicated that the two genes are high-salinity-, drought- and abscisic acid (ABA)-induced. Overexpression of BnNAC2 and BnNAC5 genes in yeast (Schizosaccharomyces pombe) remarkably inhibited the growth rate of the host cells, and enhanced the cells sensitive to high-salinity and osmotic stresses. Complementation test indicated that BnNAC5 could recover the defects such as salt-hypersensitivity and accelerated-leaf senescence of vni2 T-DNA insertion mutant. Several stress-responsive genes including COR15A and RD29A were enhanced in the complemented plants. These results suggest that BnNAC5 may perform the similar function of VNI2 in response to high-salinity stress and regulation of leaf aging. Key message BnNAC2 and BnNAC5 are salt-, drought- and ABA-induced genes. Overexpression of BnNAC5 in Arabidopsis vni2 mutant recovered the mutant defects (salt-hypersensitivity and accelerated-leaf senescence) to the phenotype of wild type. PMID:22801866

  19. Characterization of Two UDP-Gal:GalNAc-Diphosphate-Lipid β1,3-Galactosyltransferases WbwC from Escherichia coli Serotypes O104 and O5

    PubMed Central

    Wang, Shuo; Czuchry, Diana; Liu, Bin; Vinnikova, Anna N.; Gao, Yin; Vlahakis, Jason Z.; Szarek, Walter A.; Wang, Lei

    2014-01-01

    Escherichia coli displays O antigens on the outer membrane that play an important role in bacterial interactions with the environment. The O antigens of enterohemorrhagic E. coli O104 and O5 contain a Galβ1-3GalNAc disaccharide at the reducing end of the repeating unit. Several other O antigens contain this disaccharide, which is identical to the mammalian O-glycan core 1 or the cancer-associated Thomsen-Friedenreich (TF) antigen. We identified the wbwC genes responsible for the synthesis of the disaccharide in E. coli serotypes O104 and O5. To functionally characterize WbwC, an acceptor substrate analog, GalNAcα-diphosphate-phenylundecyl, was synthesized. WbwC reaction products were isolated by high-pressure liquid chromatography and analyzed by mass spectrometry, nuclear magnetic resonance, galactosidase and O-glycanase digestion, and anti-TF antibody. The results clearly showed that the Galβ1-3GalNAcα linkage was synthesized, confirming WbwCECO104 and WbwCECO5 as UDP-Gal:GalNAcα-diphosphate-lipid β1,3-Gal-transferases. Sequence analysis revealed a conserved DxDD motif, and mutagenesis showed the importance of these Asp residues in catalysis. The purified enzymes require divalent cations (Mn2+) for activity and are specific for UDP-Gal and GalNAc-diphosphate lipid substrates. WbwC was inhibited by bis-imidazolium salts having aliphatic chains of 18 to 22 carbons. This work will help to elucidate mechanisms of polysaccharide synthesis in pathogenic bacteria and provide technology for vaccine synthesis. PMID:24957618

  20. Shielding analysis of the NAC-LWT cask with MTR fuel using SCALE

    SciTech Connect

    Napolitano, D.G.

    1995-12-31

    NAC International has used the SCALE Code Package extensively for transport and storage cask design. This includes the design of the NAC-STC dual purpose cask, the ENSA-DPT dual purpose cask as well as design modifications to the NAC-LWT cask. The NAC-LWT is a legal weight truck cask that was originally designed to transport one pressurized water reactor (PWR) fuel assembly or two boiling water reactor (BWR) fuel assemblies. Recently, this cask has been modified to transport up to 42 materials test reactor (MTR) fuel elements. This paper discusses the use of the SCALE package in performing a source term analysis of MTR fuel and shielding analysis of the NAC-LWT cask in support of a 10 CFR Part 71 license amendment for MTR fuel contents.

  1. The Utilities of Chemical Reactions and Molecular Tools for O-GlcNAc Proteomic Studies.

    PubMed

    Kim, Eun Ju

    2015-07-01

    The post-translational modification of nuclear and cytoplasmic proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) is involved in a wide variety of cellular processes and is associated with the pathological progression of chronic diseases. Considering its emerging biological significance, systematic identification, site mapping, and quantification of O-GlcNAc proteins are essential and have led to the development of several approaches for O-GlcNAc protein profiling. This minireview mainly focuses on the various useful chemical reactions and molecular tools with detailed reaction mechanisms widely adopted for O-GlcNAc protein/peptide enrichment and its quantification for comprehensive O-GlcNAc protein profiling. PMID:26096757

  2. O-GlcNAc regulates NEDD4-1 stability via caspase-mediated pathway.

    PubMed

    Jiang, Kuan; Bai, Bingyang; Ta, Yajie; Zhang, Tingling; Xiao, Zikang; Wang, Peng George; Zhang, Lianwen

    2016-03-18

    O-GlcNAc modification of cytosolic and nuclear proteins regulates essential cellular processes such as stress responses, transcription, translation, and protein degradation. Emerging evidence indicates O-GlcNAcylation has a dynamic interplay with ubiquitination in cellular regulation. Here, we report that O-GlcNAc indirectly targets a vital E3 ubiquitin ligase enzyme of NEDD4-1. The protein level of NEDD4-1 is accordingly decreased following an increase of overall O-GlcNAc level upon PUGNAc or glucosamine stimulation. O-GlcNAc transferase (OGT) knockdown, overexpression and mutation results confirm that the stability of NEDD4-1 is negatively regulated by cellular O-GlcNAc. Moreover, the NEDD4-1 degradation induced by PUGNAc or GlcN is significantly inhibited by the caspase inhibitor. Our study reveals a regulation mechanism of NEDD4-1 stability by O-GlcNAcylation. PMID:26876577

  3. Chemical tools to explore nutrient-driven O-GlcNAc cycling.

    PubMed

    Kim, Eun J; Bond, Michelle R; Love, Dona C; Hanover, John A

    2014-01-01

    Posttranslational modifications (PTM) including glycosylation, phosphorylation, acetylation, methylation and ubiquitination dynamically alter the proteome. The evolutionarily conserved enzymes O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase are responsible for the addition and removal, respectively, of the nutrient-sensitive PTM of protein serine and threonine residues with O-GlcNAc. Indeed, the O-GlcNAc modification acts at every step in the "central dogma" of molecular biology and alters signaling pathways leading to amplified or blunted biological responses. The cellular roles of OGT and the dynamic PTM O-GlcNAc have been clarified with recently developed chemical tools including high-throughput assays, structural and mechanistic studies and potent enzyme inhibitors. These evolving chemical tools complement genetic and biochemical approaches for exposing the underlying biological information conferred by O-GlcNAc cycling. PMID:25039763

  4. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review.

    PubMed

    Sadowska, A M; Manuel-Y-Keenoy, B; De Backer, W A

    2007-01-01

    In order to develop efficient therapeutic regimes for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) has been tested as a medication which can suppress various pathogenic processes in this disease. Besides its well-known and efficient mucolytic action, NAC meets these needs by virtue of its antioxidant and anti-inflammatory modes of action. NAC is a thiol compound which by providing sulfhydryl groups, can act both as a precursor of reduced glutathione and as a direct ROS scavenger, hence regulating the redox status in the cells. In this way it can interfere with several signaling pathways that play a role in regulating apoptosis, angiogenesis, cell growth and arrest and inflammatory response. Overall, the antioxidant effects of NAC are well documented in in vivo and in vitro studies. It successfully inhibits oxidative stress at both high and low concentrations, under acute (in vitro) and chronic administration (in vivo). With regard to its anti-inflammatory action, in contrast, the effects of NAC differ in vivo and in vitro and are highly dose-dependent. In the in vitro settings anti-inflammatory effects are seen at high but not at low concentrations. On the other hand, some long-term effectiveness is reported in several in vivo studies even at low dosages. Increasing the dose seems to improve NAC bioavailability and may also consolidate some of its effects. In this way, the effects that are observed in the clinical and in vivo studies do not always reflect the success of the in vitro experiments. Furthermore, the results obtained with healthy volunteers do not always provide incontrovertible proof of its usefulness in COPD especially when number of exacerbations and changes in lung function are chosen as the primary outcomes. Despite these considerations and in view of the present lack of effective therapies to inhibit disease progression in COPD, NAC and its derivatives, because of their multiple molecular modes of action, remain promising

  5. Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference.

    PubMed

    Chandrasekar, Vijay; Dreyer, Jean-Luc

    2011-05-01

    Molecular adaptations underlying drug seeking and relapse remain largely unknown. Studies highlight post-transcriptional modifications mediated by microRNAs (miRNAs) in addiction and other neurological disorders. We have previously shown that chronic cocaine suppresses miR-124 and let-7d and induces the expression of miR-181a in mesolimbic pathway. To further address the role and target gene regulation network of these miRNAs in vivo in cocaine addiction, we developed lentiviral vector (LV)-expressing miRNAs and their corresponding silencers for stable and regulatable miRNA expression. We tested in vivo miRNA gain and loss of function on cocaine-induced conditioned place preference (CPP) by localized LV-miRNA regulation in the nucleus accumbens (NAc). LV-miR-124 and let-7d expression in the NAc attenuates cocaine CPP, whereas LV-miR-181a enhances it. Silencing miRNAs by corresponding LV-miRNA silencers expressing perfect miRNA target sequences inversed this effect on cocaine CPP. Doxycycline treatment for switching off silencer expression abolished the observed behavioral changes. Behavioral changes mediated by LV-miRNA regulation resulted in dynamic alterations in transcription factors, receptors, and other effector genes involved in cocaine-induced plasticity. Our results describe a complex regulatory pathway mediated by miRNAs in cocaine-mediated neuronal adaptations. PMID:21307844

  6. Episodic sucrose intake during food restriction increases synaptic abundance of AMPA receptors in nucleus accumbens and augments intake of sucrose following restoration of ad libitum feeding.

    PubMed

    Peng, X-X; Lister, A; Rabinowitsch, A; Kolaric, R; Cabeza de Vaca, S; Ziff, E B; Carr, K D

    2015-06-01

    Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for 10 occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-h chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR

  7. UDP-GlcNAc2-epimerase regulates cell surface sialylation and ceramide-induced cell death in human malignant lymphoma.

    PubMed

    Suzuki, Osamu; Tasaki, Kazuhiro; Kusakabe, Takashi; Abe, Masafumi

    2008-09-01

    Stress signals induce ceramide (cer) through sphingomyelinase activation, and metabolites of cer such as sphingosine (Sph) and sphingosine-1-phoshate (S-1-P) play a significant role in many biological processes. This study aimed to elucidate the association between the alteration in cell surface sialylation and ceramide-induced cell death in the human Burkitt's lymphoma cell line, HBL-8. The highly sialylated 3G3 clone was less sensitive to C6-ceramide-induced cell death. On the other hand, the hyposialylated 3D2 clone was more sensitive to C6-ceramide-induced cell death. Neuraminidase treatment or knockdown by siRNA of uridine diphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc2-epimerase), which is a key enzyme of sialic acid biosynthesis, enhanced the amount of cell death induced by C6-ceramide in the highly sialylated 3G3 clone. Sialic acid metabolic complementation assays using several precursors of sialic acid showed that cell surface resialylation by N-acetyl-D-mannosamine (ManNAc) inhibited C6-ceramide-induced cell death. The amount of cell death by C6-ceramide was enhanced after pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002 in both clones. In addition, clone 3G3 was less sensitive to Sph than the 3D2 clone. In conclusion, in human malignant lymphoma, ceramide and its metabolite-induced cell death is regulated by the amount of sialic acid on the cell surface which in turn is regulated by mRNA expression of UDP-GlcNAc2-epimerase. PMID:18698493

  8. Nucleus accumbens dopaminergic neurotransmission switches its modulatory action in chronification of inflammatory hyperalgesia.

    PubMed

    Dias, Elayne Vieira; Sartori, César Renato; Marião, Paula Ramos; Vieira, André Schwambach; Camargo, Lilian Calili; Athie, Maria Carolina Pedro; Pagliusi, Marco Oreste; Tambeli, Claudia Herrera; Parada, Carlos Amilcar

    2015-10-01

    Dopaminergic neurotransmission in the nucleus accumbens, a central component of the mesolimbic system, has been associated with acute pain modulation. As there is a transition from acute to chronic pain ('chronification'), modulatory structures may be involved in chronic pain development. Thus, this study aimed to elucidate the role of nucleus accumbens dopaminergic neurotransmission in chronification of pain. We used a rat model in which daily subcutaneous injection of prostaglandin E2 in the hindpaw for 14 days induces a long-lasting state of nociceptor sensitization that lasts for at least 30 days following the end of the treatment. Our findings demonstrated that the increase of dopamine in the nucleus accumbens by local administration of GBR12909 (0.5 nmol/0.25 μL), a dopamine reuptake inhibitor, blocked prostaglandin E2 -induced acute hyperalgesia. This blockade was prevented by a dopamine D2 receptor antagonist (raclopride, 10 nmol/0.25 μL) but not changed by a D1 receptor antagonist (SCH23390, 0.5, 3 or 10 nmol/0.25 μL), both co-administered with GBR12909 in the nucleus accumbens. In contrast, the induction of persistent hyperalgesia was facilitated by continuous infusion of GBR12909 in the nucleus accumbens (0.021 nmol/0.5 μL/h) over 7 days of prostaglandin E2 treatment. The development of persistent hyperalgesia was impaired by SCH23390 (0.125 nmol/0.5 μL/h) and raclopride (0.416 nmol/0.5 μL/h), both administered continuously in the nucleus accumbens over 7 days. Taken together, our data suggest that the chronification of pain involves the plasticity of dopaminergic neurotransmission in the nucleus accumbens, which switches its modulatory role from antinociceptive to pronociceptive. PMID:26173870

  9. Role of nucleus accumbens shell neuronal ensembles in context-induced reinstatement of cocaine-seeking.

    PubMed

    Cruz, Fabio C; Babin, Klil R; Leao, Rodrigo M; Goldart, Evan M; Bossert, Jennifer M; Shaham, Yavin; Hope, Bruce T

    2014-05-28

    Environmental contexts previously associated with drug use provoke relapse to drug use in humans and reinstatement of drug seeking in animal models of drug relapse. We examined whether context-induced reinstatement of cocaine seeking is mediated by activation of context-selected nucleus accumbens neurons. We trained rats to self-administer cocaine in Context A and extinguished their lever-pressing in a distinct Context B. On test day, reexposure to the cocaine-associated Context A reinstated cocaine seeking and increased expression of the neural activity marker Fos in 3.3% of accumbens shell and 1.6% of accumbens core neurons. To assess a causal role for these activated neurons, we used the Daun02 inactivation procedure to selectively inactivate these neurons. We trained c-fos-lacZ transgenic rats to self-administer cocaine in Context A and extinguished their lever-pressing in Context B. On induction day, we exposed rats to either Context A or a novel Context C for 30 min and injected Daun02 or vehicle into accumbens shell or core 60 min later. On test day, 3 d after induction day, the ability of Context A to reinstate cocaine seeking and increase neuronal activity in accumbens shell was attenuated when Daun02 was previously injected after exposure to Context A. Daun02 injections after exposure to the novel Context C had no effect on context-induced reinstatement of cocaine seeking despite much greater numbers of Fos-expressing neurons induced by Context C. Daun02 injections in accumbens core had no effect. Our data suggest that context-induced reinstatement of cocaine seeking is mediated by activation of context-selected accumbens shell but not core neuronal ensembles. PMID:24872549

  10. Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca²⁺-permeable AMPA receptors during the incubation of cocaine craving.

    PubMed

    Ferrario, Carrie R; Loweth, Jessica A; Milovanovic, Mike; Ford, Kerstin A; Galiñanes, Gregorio L; Heng, Li-Jun; Tseng, Kuei Y; Wolf, Marina E

    2011-12-01

    Cue-induced cocaine seeking intensifies or incubates after withdrawal from extended access cocaine self-administration, a phenomenon termed incubation of cocaine craving. The expression of incubated craving is mediated by Ca²⁺-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). Thus, CP-AMPARs are a potential target for therapeutic intervention, making it important to understand mechanisms that govern their accumulation. Here we used subcellular fractionation and biotinylation of NAc tissue to examine the abundance and distribution of AMPAR subunits, and GluA1 phosphorylation, in the incubation model. We also studied two transmembrane AMPA receptor regulatory proteins (TARPs), γ-2 and γ-4. Our results, together with earlier findings, suggest that some of the new CP-AMPARs are synaptic. These are probably associated with γ-2, but they are loosely tethered to the PSD. Levels of GluA1 phosphorylated at serine 845 (pS845 GluA1) were significantly increased in biotinylated tissue and in an extrasynaptic membrane-enriched fraction. These results suggest that increased synaptic levels of CP-AMPARs may result in part from an increase in pS845 GluA1 in extrasynaptic membranes, given that S845 phosphorylation primes GluA1-containing AMPARs for synaptic insertion and extrasynaptic AMPARs supply the synapse. Some of the new extrasynaptic CP-AMPARs are likely associated with γ-4, rather than γ-2. The maintenance of CP-AMPARs in NAc synapses during withdrawal is accompanied by activation of CaMKII and ERK2 but not CaMKI. Overall, AMPAR plasticity in the incubation model shares some features with better described forms of synaptic plasticity, although the timing of the phenomenon and the persistence of related neuroadaptations are significantly different. PMID:21276808

  11. The Nucleus Accumbens: A Switchboard for Goal-Directed Behaviors

    PubMed Central

    O'Donnell, Patricio

    2009-01-01

    Reward intake optimization requires a balance between exploiting known sources of rewards and exploring for new sources. The prefrontal cortex (PFC) and associated basal ganglia circuits are likely candidates as neural structures responsible for such balance, while the hippocampus may be responsible for spatial/contextual information. Although studies have assessed interactions between hippocampus and PFC, and between hippocampus and the nucleus accumbens (NA), it is not known whether 3-way interactions among these structures vary under different behavioral conditions. Here, we investigated these interactions with multichannel recordings while rats explored an operant chamber and while they performed a learned lever-pressing task for reward in the same chamber shortly afterward. Neural firing and local field potentials in the NA core synchronized with hippocampal activity during spatial exploration, but during lever pressing they instead synchronized more strongly with the PFC. The latter is likely due to transient drive of NA neurons by bursting prefrontal activation, as in vivo intracellular recordings in anesthetized rats revealed that NA up states can transiently synchronize with spontaneous PFC activity and PFC stimulation with a bursting pattern reliably evoked up states in NA neurons. Thus, the ability to switch synchronization in a task-dependent manner indicates that the NA core can dynamically select its inputs to suit environmental demands, thereby contributing to decision-making, a function that was thought to primarily depend on the PFC. PMID:19352511

  12. Glutathione depletion and acute exercise increase O-GlcNAc protein modification in rat skeletal muscle.

    PubMed

    Peternelj, Tina Tinkara; Marsh, Susan A; Strobel, Natalie A; Matsumoto, Aya; Briskey, David; Dalbo, Vincent J; Tucker, Patrick S; Coombes, Jeff S

    2015-02-01

    Post-translational modification of intracellular proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) profoundly affects protein structure, function, and metabolism. Although many skeletal muscle proteins are O-GlcNAcylated, the modification has not been extensively studied in this tissue, especially in the context of exercise. This study investigated the effects of glutathione depletion and acute exercise on O-GlcNAc protein modification in rat skeletal muscle. Diethyl maleate (DEM) was used to deplete intracellular glutathione and rats were subjected to a treadmill run. White gastrocnemius and soleus muscles were analyzed for glutathione status, O-GlcNAc and O-GlcNAc transferase (OGT) protein levels, and mRNA expression of OGT, O-GlcNAcase and glutamine:fructose-6-phosphate amidotransferase. DEM and exercise both reduced intracellular glutathione and increased O-GlcNAc. DEM upregulated OGT protein expression. The effects of the interventions were significant 4 h after exercise (P < 0.05). The changes in the mRNA levels of O-GlcNAc enzymes were different in the two muscles, potentially resulting from different rates of oxidative stress and metabolic demands between the muscle types. These findings indicate that oxidative environment promotes O-GlcNAcylation in skeletal muscle and suggest an interrelationship between cellular redox state and O-GlcNAc protein modification. This could represent one mechanism underlying cellular adaptation to oxidative stress and health benefits of exercise. PMID:25416863

  13. Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

    PubMed Central

    Wells, Lance

    2016-01-01

    O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies. PMID:24524620

  14. An NAC transcription factor controls ethylene-regulated cell expansion in flower petals.

    PubMed

    Pei, Haixia; Ma, Nan; Tian, Ji; Luo, Jing; Chen, Jiwei; Li, Jing; Zheng, Yi; Chen, Xiang; Fei, Zhangjun; Gao, Junping

    2013-10-01

    Cell expansion is crucial for plant growth. It is well known that the phytohormone ethylene functions in plant development as a key modulator of cell expansion. However, the role of ethylene in the regulation of this process remains unclear. In this study, 2,189 ethylene-responsive transcripts were identified in rose (Rosa hybrida) petals using transcriptome sequencing and microarray analysis. Among these transcripts, an NAC (for no apical meristem [NAM], Arabidopsis transcription activation factor [ATAF], and cup-shaped cotyledon [CUC])-domain transcription factor gene, RhNAC100, was rapidly and dramatically induced by ethylene in the petals. Interestingly, accumulation of the RhNAC100 transcript was modulated by ethylene via microRNA164-dependent posttranscriptional regulation. Overexpression of RhNAC100 in Arabidopsis (Arabidopsis thaliana) substantially reduced the petal size by repressing petal cell expansion. By contrast, silencing of RhNAC100 in rose petals using virus-induced gene silencing significantly increased petal size and promoted cell expansion in the petal abaxial subepidermis (P < 0.05). Expression analysis showed that 22 out of the 29 cell expansion-related genes tested exhibited changes in expression in RhNAC100-silenced rose petals. Moreover, of those genes, one cellulose synthase and two aquaporin genes (Rosa hybrida Cellulose Synthase2 and R. hybrida Plasma Membrane Intrinsic Protein1;1/2;1) were identified as targets of RhNAC100. Our results suggest that ethylene regulates cell expansion by fine-tuning the microRNA164/RhNAC100 module and also provide new insights into the function of NAC transcription factors. PMID:23933991

  15. O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death.

    PubMed

    Ngoh, Gladys A; Hamid, Tariq; Prabhu, Sumanth D; Jones, Steven P

    2009-11-01

    We previously demonstrated that the O-linked beta-N-acetylglucosamine (O-GlcNAc) posttranslational modification confers cardioprotection at least partially through mitochondrial-dependent mechanisms, but it remained unclear if O-GlcNAc signaling interfered with other mechanisms of cell death. Because ischemia/hypoxia causes endoplasmic reticulum (ER) stress, we ascertained whether O-GlcNAc signaling could attenuate ER stress-induced cell death per se. Before induction of ER stress (with tunicamycin or brefeldin A), we adenovirally overexpressed O-GlcNAc transferase (AdOGT) or pharmacologically inhibited O-GlcNAcase [via O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate] to augment O-GlcNAc levels or adenovirally overexpressed O-GlcNAcase to reduce O-GlcNAc levels. AdOGT significantly (P < 0.05) attenuated the activation of the maladaptive arm of the unfolded protein response [according to C/EBP homologous protein (CHOP) activation] and cardiomyocyte death (reflected by percent propidium iodide positivity). Moreover, pharmacological inhibition of O-GlcNAcase significantly (P < 0.05) mitigated ER stress-induced CHOP activation and cardiac myocyte death. Interestingly, overexpression of GCA did not alter ER stress markers but exacerbated brefeldin A-induced cardiomyocyte death. We conclude that enhanced O-GlcNAc signaling represents a partially proadaptive response to reduce ER stress-induced cell death. These results provide new insights into a possible interaction between O-GlcNAc signaling and ER stress and may partially explain a mechanism of O-GlcNAc-mediated cardioprotection. PMID:19734355

  16. The Structure of MurNAc 6-Phosphate Hydrolase (MurQ) from Haemophilus influenzae with Bound Inhibitor

    PubMed Central

    Hadi, Timin; Hazra, Saugata; Tanner, Martin E.; Blanchard, John S.

    2014-01-01

    The breakdown and recycling of peptidoglycan, an essential polymeric cell structure, occurs in a number of bacterial species. A key enzyme in the recycling pathway of one of the components of the peptidoglycan layer, N-acetylmuramic acid (MurNAc), is MurNAc 6-phosphate hydrolase (MurQ). This enzyme catalyzes the cofactor-independent cleavage of a relatively non-labile ether bond and presents an interesting target for mechanistic studies. Open-chain product and substrate analogs were synthesized and tested as competitive inhibitors (Kis values of 1.1 +/− 0.3 mM and 0.23 +/− 0.02 mM, respectively) of the MurNAc 6P hydrolase from Escherichia coli (MurQ-EC). To identify the roles of active site residues important for catalysis, the substrate analog was co-crystallized with the MurNAc 6P hydrolase from Haemophilus influenzae (MurQ-HI) that was amenable to crystallographic studies. The co-crystal structure of MurQ-HI with the substrate analog showed that Glu89 was located in close proximity to both the carbon at the C2 position and the oxygen at the C3 position of the bound inhibitor, and that no other potential acid/base residue that could act as an active site acid/base was located in the vicinity. The conserved residues Glu120 and Lys239 were found within hydrogen-bonding distance of the C5 hydroxyl group and C6 phosphate group, suggesting that they play a role in substrate binding and ring-opening. Combining these results with previous biochemical data, a one base mechanism of action where Glu89 functions to both deprotonate at the C2 position and assist in the departure of the lactyl ether at the C3 position is proposed. This same residue would serve to deprotonate the incoming water and reprotonate the enolate in the second half of the catalytic cycle. PMID:24251551

  17. Wood reinforcement of poplar by rice NAC transcription factor.

    PubMed

    Sakamoto, Shingo; Takata, Naoki; Oshima, Yoshimi; Yoshida, Kouki; Taniguchi, Toru; Mitsuda, Nobutaka

    2016-01-01

    Lignocellulose, composed of cellulose, hemicellulose, and lignin, in the secondary cell wall constitutes wood and is the most abundant form of biomass on Earth. Enhancement of wood accumulation may be an effective strategy to increase biomass as well as wood strength, but currently only limited research has been undertaken. Here, we demonstrated that OsSWN1, the orthologue of the rice NAC Secondary-wall Thickening factor (NST) transcription factor, effectively enhanced secondary cell wall formation in the Arabidopsis inflorescence stem and poplar (Populus tremula×Populus tremuloides) stem when expressed by the Arabidopsis NST3 promoter. Interestingly, in transgenic Arabidopsis and poplar, ectopic secondary cell wall deposition in the pith area was observed in addition to densification of the secondary cell wall in fiber cells. The cell wall content or density of the stem increased on average by up to 38% and 39% in Arabidopsis and poplar, respectively, without causing growth inhibition. As a result, physical strength of the stem increased by up to 57% in poplar. Collectively, these data suggest that the reinforcement of wood by NST3pro:OsSWN1 is a promising strategy to enhance wood-biomass production in dicotyledonous plant species. PMID:26812961

  18. Wood reinforcement of poplar by rice NAC transcription factor

    PubMed Central

    Sakamoto, Shingo; Takata, Naoki; Oshima, Yoshimi; Yoshida, Kouki; Taniguchi, Toru; Mitsuda, Nobutaka

    2016-01-01

    Lignocellulose, composed of cellulose, hemicellulose, and lignin, in the secondary cell wall constitutes wood and is the most abundant form of biomass on Earth. Enhancement of wood accumulation may be an effective strategy to increase biomass as well as wood strength, but currently only limited research has been undertaken. Here, we demonstrated that OsSWN1, the orthologue of the rice NAC Secondary-wall Thickening factor (NST) transcription factor, effectively enhanced secondary cell wall formation in the Arabidopsis inflorescence stem and poplar (Populus tremula×Populus tremuloides) stem when expressed by the Arabidopsis NST3 promoter. Interestingly, in transgenic Arabidopsis and poplar, ectopic secondary cell wall deposition in the pith area was observed in addition to densification of the secondary cell wall in fiber cells. The cell wall content or density of the stem increased on average by up to 38% and 39% in Arabidopsis and poplar, respectively, without causing growth inhibition. As a result, physical strength of the stem increased by up to 57% in poplar. Collectively, these data suggest that the reinforcement of wood by NST3pro:OsSWN1 is a promising strategy to enhance wood-biomass production in dicotyledonous plant species. PMID:26812961

  19. Rheological properties of the product slurry of the Nitrate to Ammonia and Ceramic (NAC) process

    SciTech Connect

    Muguercia, I.; Yang, G.; Ebadian, M.A.; Lee, D.D.; Mattus, A.J.; Hunt, R.D.

    1995-03-01

    The Nitrate to Ammonia and Ceramic (NAC) process is an innovative technology for immobilizing the liquid from Low Level radioactive Waste (LLW). An experimental study was conducted to measure the rheological properties of the pipe flow of the NAC product slurry. Test results indicate that the NAC product slurry has a profound rheological behavior. At low solids concentration, the slurry exhibits a typical dilatant fluid (or shear thinning)fluid.