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Sample records for accumbens caudate putamen

  1. Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.

    PubMed

    Li, Juan; Zhang, Lei; Chen, Zhenzhong; Xie, Minjuan; Huang, Lu; Xue, Jinhua; Liu, Yutong; Liu, Nuyun; Guo, Fukun; Zheng, Yi; Kong, Jiming; Zhang, Lin; Zhang, Lu

    2015-03-01

    Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.

  2. Nitric oxide synthase and NADPH-diaphorase after acute hypobaric hypoxia in the rat caudate putamen.

    PubMed

    Encinas, Juan Manuel; Fernández, Ana Patricia; Salas, Eduardo; Castro-Blanco, Susana; Muñoz, Priscila; Rodrigo, José; Serrano, Julia

    2004-03-01

    Changes in the production system of nitric oxide (NO), a multifunctional biological messenger known to participate in blood-flow regulation, neuromodulation, and neuroprotection or neurotoxicity, were investigated in the caudate putamen of adult rats submitted to hypobaric hypoxia. Employing immunohistochemistry, Western blotting, enzymatic assay, and NADPH-diaphorase staining, we demonstrate that neuronal nitric oxide synthase (nNOS) expression and constitutive nitric oxide synthase (cNOS) activity were transiently activated by 7 h of exposure to a simulated altitude of 8325 m (27,000 ft). In addition, endothelial nitric oxide synthase (eNOS) immunoreactivity and blood vessel NADPH-diaphorase staining peaked immediately after the hypoxic stimulus, whereas inducible nitric oxide synthase (iNOS) expression and activity remained unaltered. Nitrotyrosine formation, a marker of protein nitration, was evaluated by immunohistochemistry and Western blotting, and was found to increase parallel to nitric oxide synthesis. We conclude that the nitric oxide system undergoes significant transient alterations in the caudate putamen of adult rats submitted to acute hypobaric hypoxia.

  3. Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Subjects with Major Depressive Disorder

    PubMed Central

    Pizzagalli, Diego A.; Holmes, Avram J.; Dillon, Daniel G.; Goetz, Elena L.; Birk, Jeffrey L.; Bogdan, Ryan; Dougherty, Darin D.; Iosifescu, Dan V.; Rauch, Scott L.; Fava, Maurizio

    2009-01-01

    Objective Major depressive disorder (MDD) is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional magnetic resonance imaging (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that MDD participants would show reduced reward-related responses in basal ganglia structures. Method A monetary incentive delay task was presented to 30 unmedicated MDD subjects and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. Results Relative to comparison subjects, MDD participants showed significantly weaker responses to gains in the left nucleus accumbens and bilateral caudate. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in MDD emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although MDD subjects showed reduced activation to reward cues in a small sector of the left posterior putamen. Among MDD subjects, anhedonic symptoms and depression severity were associated with reduced bilateral caudate volume. Conclusions These results indicate that basal ganglia dysfunction in MDD may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in MDD is related to caudate volume. PMID:19411368

  4. Cellular localization of proenkephalin mRNA in rat brain: gene expression in the caudate-putamen and cerebellar cortex.

    PubMed Central

    Shivers, B D; Harlan, R E; Romano, G J; Howells, R D; Pfaff, D W

    1986-01-01

    The cellular locations of proenkephalin mRNA have been determined for the caudate-putamen and cerebellar cortex of the rat brain by in situ hybridization. In the caudate-putamen, more than half of the neurons express the proenkephalin gene. Morphologically, they are medium-sized cells that may represent projection neurons. In the cerebellar cortex, proenkephalin mRNA is present in a subpopulation of neurons in the granule layer that appear to be Golgi cells--i.e., inhibitory interneurons. The presence of [Met]enkephalin, a pentapeptide derived from proenkephalin, in these two brain areas is consistent with a synthetic role for this mRNA and implicates proenkephalin gene expression in the control of motor function. Images PMID:3461484

  5. Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

    PubMed

    Tobón, Krishna E; Catuzzi, Jennifer E; Cote, Samantha R; Sonaike, Adenike; Kuzhikandathil, Eldo V

    2015-07-01

    The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady-state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within 30 min when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated with the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within 5 min of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggest a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals. PMID:25900179

  6. Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice

    PubMed Central

    Tobón, Krishna E.; Catuzzi, Jennifer E.; Cote, Samantha R.; Sonaike, Adenike; Kuzhikandathil, Eldo V.

    2015-01-01

    The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression has been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within thirty minutes when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated to the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within five minutes of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggests a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals. PMID:25900179

  7. Dopamine Release in the Nonhuman Primate Caudate and Putamen Depends upon Site of Stimulation in the Subthalamic Nucleus

    PubMed Central

    Min, Hoon-Ki; Ross, Erika K.; Jo, Hang Joon; Cho, Shinho; Settell, Megan L.; Jeong, Ju Ho; Duffy, Penelope S.; Chang, Su-Youne; Bennet, Kevin E.; Blaha, Charles D.

    2016-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for medically refractory Parkinson's disease. Although DBS has recognized clinical utility, its biologic mechanisms are not fully understood, and whether dopamine release is a potential factor in those mechanisms is in dispute. We tested the hypothesis that STN DBS-evoked dopamine release depends on the precise location of the stimulation site in the STN and the site of recording in the caudate and putamen. We conducted DBS with miniature, scaled-to-animal size, multicontact electrodes and used functional magnetic resonance imaging to identify the best dopamine recording site in the brains of nonhuman primates (rhesus macaques), which are highly representative of human brain anatomy and circuitry. Real-time stimulation-evoked dopamine release was monitored using in vivo fast-scan cyclic voltammetry. This study demonstrates that STN DBS-evoked dopamine release can be reduced or increased by redirecting STN stimulation to a slightly different site. SIGNIFICANCE STATEMENT Electrical stimulation of deep structures of the brain, or deep brain stimulation (DBS), is used to modulate pathological brain activity. However, technological limitations and incomplete understanding of the therapeutic mechanisms of DBS prevent personalization of this therapy and may contribute to less-than-optimal outcomes. We have demonstrated that DBS coincides with changes in dopamine neurotransmitter release in the basal ganglia. Here we mapped relationships between DBS and changes in neurochemical activity. Importantly, this study shows that DBS-evoked dopamine release can be reduced or increased by refocusing the DBS on a slightly different stimulation site. PMID:27251623

  8. Ifenprodil attenuates the acquisition and expression of methamphetamine-induced behavioral sensitization and activation of Ras-ERK1/2 cascade in the caudate putamen.

    PubMed

    Li, Lu; Qiao, Chuchu; Chen, Gang; Qian, Hongyan; Hou, Ying; Li, Tao; Liu, Xinshe

    2016-10-29

    Chronic discontinuous use of many psychomotor stimulants leads to behavioral sensitization and, owing to it shares common mechanisms with relapse, most researchers use its animal model to explore the neurobiological mechanisms of addiction. Recent studies have proved that N-methyl-d-aspartate receptors (NMDARs) are implicated in psychomotor stimulant-induced behavioral sensitization. However, the function of GluN2B-containing NMDARs and their potential downstream cascade(s) in the acquisition and expression of behavioral sensitization to methamphetamine (METH) have not been explored. In this study, 2.5, 5, and 10mg/kg ifenprodil, the specific inhibitor of GluN2B, was used to explore the function of these receptors in distinct phases of behavioral sensitization to METH in mice. Then, using western blot, Ras, pERK1/2/ERK1/2, and ΔFosB levels in the prefrontal cortex (PFc), nucleus accumbens (NAc), and caudate putamen (CPu) were detected. Behavioral results showed that low-dose ifenprodil attenuated the acquisition and expression of behavioral sensitization to METH significantly. Western blot analysis revealed that pre-injection of low-dose ifenprodil in the acquisition markedly attenuated METH-induced ascent of Ras, pERK1/2/ERK1/2, and ΔFosB protein levels in the CPu. However, pre-treatment in the expression only affected the alterations of Ras and pERK1/2/ERK1/2 levels in the CPu. Moreover, chronic METH administration increased pERK1/2/ERK1/2 level in the NAc. In conclusion, GluN2B-containing NMDARs contribute to both the acquisition and expression of behavioral sensitization to METH in mice. Furthermore, the acquisition phase might be mediated by the Ras-ERK1/2-ΔFosB cascade in the CPu while the expression phase may be regulated by the Ras-ERK1/2 cascade in the CPu. PMID:27544406

  9. Classical conditioning of tone-signaled bradycardia modifies 2-deoxyglucose uptake patterns in cortex, thalamus, habenula, caudate-putamen and hippocampal formation.

    PubMed

    Gonzalez-Lima, F; Scheich, H

    1986-01-22

    The 2-[14C]deoxyglucose (2-DG) autoradiographic method was used to map metabolic activity in all telencephalic and diencephalic structures of the rat brain during and after classical conditioning. A trial was made of a 4-5 KHz frequency modulated tone (CS) paired with midbrain reticular stimulation (US). The unconditioned response was a rapid bradycardia elicited by the US. Alert rats were injected with 2-DG, placed in a sound-proof chamber, and subjected during 90 min to a given treatment: (1) the CS before conditioning, (2) the US alone, (3) the paired CS-US (acquisition), (4) the CS after conditioning (extinction), (5) the US prior to the CS (sensitization), (6) the unpaired CS-US (pseudoconditioning), (7) the CS after pseudoconditioning and (8) no stimulation. The prefrontal cortex showed discrete regions with enhanced 2-DG uptake during conditioning and pseudoconditioning. A columnar organization was well-defined in the posterior parietal cortex of rats subjected to CS-US pairing. The medial thalamus was greatly activated in all groups subjected to reticular stimulation. The dorsomedial nucleus showed its largest activation during conditioning. The lateral habenula and a caudal portion of caudate-putamen showed an overall increase in 2-DG uptake during conditioning. The hippocampal formation showed a specific pattern of metabolic activation during conditioning and after conditioning. A laminar densitometric analysis showed that 2-DG uptake was concentrated in a central band along the sides of the hippocampal fissure which corresponded to the molecular layers. Only this neuropil band of greater metabolic activity showed the learning-related changes. In addition, the hippocampal formation was the only nonauditory structure in the forebrain which clearly responded to the acquired signal value of the tone CS after conditioning. These changes revealed by 2-DG provide a first demonstration of forebrain substrates with localized metabolic alterations related to

  10. Lesions and reversible inactivation of the dorsolateral caudate-putamen impair cocaine-primed reinstatement to cocaine-seeking in rats

    PubMed Central

    Gabriele, Amanda; See, Ronald E.

    2011-01-01

    Recent evidence suggests that cocaine addiction may involve progressive drug-induced neuroplasticity of the dorsal striatum. Here, we examined the effects of a) dorsolateral caudate putamen (dlCPu) lesions on cocaine self-administration, extinction of responding, and subsequent reinstatement to cocaine-seeking, and b) reversible inactivation of the dlCPu with GABA receptor agonists (baclofen and muscimol) immediately prior to reinstatement testing. Male, Sprague-Dawley rats self-administered cocaine (0.2 mg/50 μl infusion, i.v.) along an FR1 schedule in daily 2 hr sessions for 10 days, whereby lever presses resulted in cocaine infusions and presentation of a paired light-tone stimulus complex. After 14 days of abstinence, animals were returned to the self-administration chamber and lever responding was recorded, but had no programmed consequences (relapse test). Animals then underwent daily extinction, followed by reinstatement tests in the presence of the conditioned cues, after a cocaine priming injection (10 mg/kg), or cues + cocaine prime. Lesions of the dlCPu failed to affect responding during self-administration, extinction, relapse, or cued-induced reinstatement. However, lesioned animals showed reduced cocaine-seeking during cocaine-primed reinstatement as compared to sham controls. Furthermore, reversible inactivation of the dlCPu significantly impaired both cocaine-primed and cocaine-primed + cue-induced reinstatement. These results demonstrate the critical involvement of the dlCPu in cocaine-primed reinstatement, perhaps via chronic drug-induced changes in the interoceptive effects of cocaine that impact drug-seeking. PMID:21890120

  11. Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: the role of mu opioid receptor activation.

    PubMed

    Horner, Kristen A; Noble, Erika S; Gilbert, Yamiece E

    2010-06-01

    Amphetamines induce stereotypy, which correlates with patch-enhanced c-Fos expression the patch compartment of caudate putamen (CPu). Methamphetamine (METH) treatment also induces patch-enhanced expression of prodynorphin (PD), arc and zif/268 in the CPu. Whether patch-enhanced activation of any of these genes correlates with METH-induced stereotypy is unknown, and the factors that contribute to this pattern of expression are poorly understood. Activation of mu opioid receptors, which are expressed by the neurons of the patch compartment, may underlie METH-induced patch-enhanced gene expression and stereotypy. The current study examined whether striatal mu opioid receptor blockade altered METH-induced stereotypy and patch-enhanced gene expression, and if there was a correlation between the two responses. Animals were intrastriatally infused with the mu antagonist CTAP (10 microg/microl), treated with METH (7.5 mg/kg, s.c.), placed in activity chambers for 3h, and then sacrificed. CTAP pretreatment attenuated METH-induced increases in PD, arc and zif/268 mRNA expression and significantly reduced METH-induced stereotypy. Patch-enhanced PD and arc mRNA expression in the dorsolateral CPu correlated negatively with METH-induced stereotypy. These data indicate that mu opioid receptor activation contributes to METH-induced gene expression in the CPu and stereotypy, and that patch-enhanced PD and arc expression may be a homeostatic response to METH treatment.

  12. Paradoxical augmented relapse in alcohol-dependent rats during deep-brain stimulation in the nucleus accumbens

    PubMed Central

    Hadar, R; Vengeliene, V; Barroeta Hlusicke, E; Canals, S; Noori, H R; Wieske, F; Rummel, J; Harnack, D; Heinz, A; Spanagel, R; Winter, C

    2016-01-01

    Case reports indicate that deep-brain stimulation in the nucleus accumbens may be beneficial to alcohol-dependent patients. The lack of clinical trials and our limited knowledge of deep-brain stimulation call for translational experiments to validate these reports. To mimic the human situation, we used a chronic-continuous brain-stimulation paradigm targeting the nucleus accumbens and other brain sites in alcohol-dependent rats. To determine the network effects of deep-brain stimulation in alcohol-dependent rats, we combined electrical stimulation of the nucleus accumbens with functional magnetic resonance imaging (fMRI), and studied neurotransmitter levels in nucleus accumbens-stimulated versus sham-stimulated rats. Surprisingly, we report here that electrical stimulation of the nucleus accumbens led to augmented relapse behavior in alcohol-dependent rats. Our associated fMRI data revealed some activated areas, including the medial prefrontal cortex and caudate putamen. However, when we applied stimulation to these areas, relapse behavior was not affected, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain-stimulation-treated rats exhibited augmented alcohol-induced dopamine release compared with sham-stimulated animals. Our data suggest that deep-brain stimulation in the nucleus accumbens enhances alcohol-liking probably via augmented dopamine release and can thereby promote relapse. PMID:27327255

  13. Extended-access, but not limited-access, methamphetamine self-administration induces behavioral and nucleus accumbens dopamine response changes in rats

    PubMed Central

    Cozannet, Romain Le; Markou, Athina; Kuczenski, Ronald

    2013-01-01

    To better understand the neurobiology of methamphetamine (METH) dependence and the cognitive impairments induced by METH use, we compared the effects of extended (12 h) and limited (1 h) access to METH self-administration on locomotor activity and object place recognition, and on extracellular dopamine levels in the nucleus accumbens and caudate-putamen. Rats were trained to self-administer intravenous METH (0.05 mg/kg). One group had progressively extended access up to 12-h sessions. The other group had limited-access 1-h sessions. Microdialysis experiments were conducted during a 12-h and 1-h session, in which the effects of a single METH injection (self-administered, 0.05 mg/kg, i.v.) on extracellular dopamine levels were assessed in the nucleus accumbens and caudate-putamen compared with a drug-naive group. The day after the last 12-h session and the following day experimental groups were assessed for their locomotor activities and in a place recognition procedure, respectively. The microdialysis results revealed tolerance to the METH-induced increases in extracellular dopamine only in the nucleus accumbens, but not in the caudate-putamen in the extended-access group compared with the control and limited-access groups. These effects may be associated with the increased lever-pressing and drug-seeking observed during the first hour of drug exposure in the extended-access group. This increase in drug-seeking leads to higher METH intake and may result in more severe consequences in other structures responsible for the behavioral deficits (memory and locomotor activity) observed in the extended-access group, but not in the limited-access group. PMID:24112125

  14. Cage-induced stereotypic behaviour in laboratory mice covaries with nucleus accumbens FosB/ΔFosB expression.

    PubMed

    Phillips, Danielle; Choleris, Elena; Ervin, Kelsy S J; Fureix, Carole; Harper, Laura; Reynolds, Kathryn; Niel, Lee; Mason, Georgia J

    2016-03-15

    Stereotypic behaviour (SB) occurs in certain human disorders (e.g. autism), and animals treated with stimulants or raised in impoverished conditions, including laboratory mice in standard cages. Dysfunctional cortico-basal ganglia pathways have been implicated in these examples, but for cage-induced forms of SB, the relative roles of ventral versus dorsal striatum had not been fully ascertained. Here, we used immunohistochemical staining of FosB and ΔFosB to assess long-term activation within the nucleus accumbens and caudate-putamen of C57BL/6 mice. Housed in typical laboratory cages, these mice spontaneously developed different degrees of route-tracing, bar-mouthing and other forms of SB (spending 0% to over 50% of their active time budgets in this behaviour). The most highly stereotypic mice showed the most elevated FosB/ΔFosB activity in the nucleus accumbens. No such patterns occurred in the caudate-putamen. The cage-induced SB common in standard-housed mice thus involves elevated activity within the ventral striatum, suggesting an aetiology closer to compulsive gambling, eating and drug-seeking than to classic amphetamine stereotypies and other behaviours induced by motor loop over-activation.

  15. The role of the left putamen in multilingual language production.

    PubMed

    Abutalebi, Jubin; Della Rosa, Pasquale Anthony; Gonzaga, Anna Kaarina Castro; Keim, Roland; Costa, Albert; Perani, Daniela

    2013-06-01

    Subcortical structures are a key component of bilingual language processing. For instance, there is now evidence that the head of the left caudate is involved in controlling languages in bilingual individuals. On the other hand, the left putamen is hypothesized to be involved in articulatory processes but little is known on its engagement in bilingual language processing. Here, our hypothesis was that the left putamen of multilinguals is engaged when producing words in the less proficient language. We investigated this issue with event-related functional Magnetic Resonance (er-fMRI) in a group of multilinguals (n = 14) and in monolinguals (n = 14) during a picture-naming task. Further, we hypothesized increased grey matter density in the left putamen as an effect of experience since multilinguals constantly face a major articulatory load (i.e., speaking multiple languages) during life. To test these hypotheses we measured structural differences between multilinguals and monolinguals using voxel-based morphometry (VBM). Our results indicate that multilinguals have increased activation in the left putamen for a non-native language, but only if they are not highly proficient in that language. In addition, we found increased grey matter density in the left putamen of multilinguals compared to monolinguals. These findings highlight that the multilingual brain handles a complex articulatory repertoire (i.e., dealing with multiple languages) by inducing structural plasticity in the left putamen.

  16. Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

    PubMed

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

    2011-01-01

    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.

  17. A selective involvement of putamen functional connectivity in youth with internet gaming disorder.

    PubMed

    Hong, Soon-Beom; Harrison, Ben J; Dandash, Orwa; Choi, Eun-Jung; Kim, Seong-Chan; Kim, Ho-Hyun; Shim, Do-Hyun; Kim, Chang-Dai; Kim, Jae-Won; Yi, Soon-Hyung

    2015-03-30

    Brain cortico-striatal circuits have consistently been implicated in the pathology of addiction related disorders. We applied a reliable seed-based analysis of the resting-state brain activity to comprehensively delineate the subdivisions of striatal functional connectivity implicated in internet gaming disorder. Among twelve right-handed male adolescents with internet gaming disorder and 11 right-handed and gender-matched healthy controls, we examined group differences in the functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen, as well as the association of these connectivity indices with behavioral measures of internet use. Adolescents with internet gaming disorder showed significantly reduced dorsal putamen functional connectivity with the posterior insula-parietal operculum. More time spent playing online games predicted significantly greater functional connectivity between the dorsal putamen and bilateral primary somatosensory cortices in adolescents with internet gaming disorder, and significantly lower functional connectivity between the dorsal putamen and bilateral sensorimotor cortices in healthy controls. The dorsal putamen functional connectivity was significantly and specifically different in adolescents with internet gaming disorder. The findings suggest a possible biomarker of internet gaming disorder.

  18. A selective involvement of putamen functional connectivity in youth with internet gaming disorder.

    PubMed

    Hong, Soon-Beom; Harrison, Ben J; Dandash, Orwa; Choi, Eun-Jung; Kim, Seong-Chan; Kim, Ho-Hyun; Shim, Do-Hyun; Kim, Chang-Dai; Kim, Jae-Won; Yi, Soon-Hyung

    2015-03-30

    Brain cortico-striatal circuits have consistently been implicated in the pathology of addiction related disorders. We applied a reliable seed-based analysis of the resting-state brain activity to comprehensively delineate the subdivisions of striatal functional connectivity implicated in internet gaming disorder. Among twelve right-handed male adolescents with internet gaming disorder and 11 right-handed and gender-matched healthy controls, we examined group differences in the functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen, as well as the association of these connectivity indices with behavioral measures of internet use. Adolescents with internet gaming disorder showed significantly reduced dorsal putamen functional connectivity with the posterior insula-parietal operculum. More time spent playing online games predicted significantly greater functional connectivity between the dorsal putamen and bilateral primary somatosensory cortices in adolescents with internet gaming disorder, and significantly lower functional connectivity between the dorsal putamen and bilateral sensorimotor cortices in healthy controls. The dorsal putamen functional connectivity was significantly and specifically different in adolescents with internet gaming disorder. The findings suggest a possible biomarker of internet gaming disorder. PMID:25553620

  19. Reacquisition of cocaine conditioned place preference and its inhibition by previous social interaction preferentially affect D1-medium spiny neurons in the accumbens corridor

    PubMed Central

    Prast, Janine M.; Schardl, Aurelia; Schwarzer, Christoph; Dechant, Georg; Saria, Alois; Zernig, Gerald

    2014-01-01

    We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric sulcus to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core. We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 h after reacquisition of CPP for cocaine after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders. PMID:25309368

  20. 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

  1. The Caudate Signals Bad Reputation during Trust Decisions

    PubMed Central

    Wardle, Margaret C.; Fitzgerald, Daniel A.; Angstadt, Michael; Sripada, Chandra S.; McCabe, Kevin; Luan Phan, K.

    2013-01-01

    The ability to initiate and sustain trust is critical to health and well-being. Willingness to trust is in part determined by the reputation of the putative trustee, gained via direct interactions or indirectly through word of mouth. Few studies have examined how the reputation of others is instantiated in the brain during trust decisions. Here we use an event-related functional MRI (fMRI) design to examine what neural signals correspond to experimentally manipulated reputations acquired in direct interactions during trust decisions. We hypothesized that the caudate (dorsal striatum) and putamen (ventral striatum) and amygdala would signal differential reputations during decision-making. Twenty-nine healthy adults underwent fMRI scanning while completing an iterated Trust Game as trusters with three fictive trustee partners who had different tendencies to reciprocate (i.e., likelihood of rewarding the truster), which were learned over multiple exchanges with real-time feedback. We show that the caudate (both left and right) signals reputation during trust decisions, such that caudate is more active to partners with two types of “bad” reputations, either indifferent partners (who reciprocate 50% of the time) or unfair partners (who reciprocate 25% of the time), than to those with “good” reputations (who reciprocate 75% of the time). Further, individual differences in caudate activity related to biases in trusting behavior in the most uncertain situation, i.e. when facing an indifferent partner. We also report on other areas that were activated by reputation at p < 0.05 whole brain corrected. Our findings suggest that the caudate is involved in signaling and integrating reputations gained through experience into trust decisions, demonstrating a neural basis for this key social process. PMID:23922638

  2. Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding.

    PubMed

    Wolf, S S; Jones, D W; Knable, M B; Gorey, J G; Lee, K S; Hyde, T M; Coppola, R; Weinberger, D R

    1996-08-30

    Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.

  3. Caudate clues to rewarding cues.

    PubMed

    Platt, Michael L

    2002-01-31

    Behavioral studies indicate that prior experience can influence discrimination of subsequent stimuli. The mechanisms responsible for highlighting a particular aspect of the stimulus, such as motion or color, as most relevant and thus deserving further scrutiny, however, remain poorly understood. In the current issue of Neuron, demonstrate that neurons in the caudate nucleus of the basal ganglia signal which dimension of a visual cue, either color or location, is associated with reward in an eye movement task. These findings raise the possibility that this structure participates in the reward-based control of visual attention.

  4. Dysfunctional putamen modulation during bimanual finger-to-thumb movement in patients with Parkinson's disease.

    PubMed

    Yan, Li-Rong; Wu, Yi-Bo; Zeng, Xiao-Hua; Gao, Li-Chen

    2015-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder affecting middle-aged and elderly people. PD can be viewed as "circuit disorder," indicating that large scale cortico-subcortical pathways were involved in its pathophysiology. The brain network in an experimental context is emerging as an important biomarker in disease diagnosis and prognosis prediction. This context-dependent network for PD and the underling functional mechanism remains unclear. In this paper, the brain network profiles in 11 PD patients without dementia were studied and compared with 12 healthy controls. The functional magnetic resonance imaging (fMRI) data were acquired when the subjects were performing a pseudorandomized unimanual or bimanual finger-to-thumb movement task. The activation was detected and the network profiles were analyzed by psychophysiological interaction (PPI) toolbox. For the controls and PD patients, the motor areas including the primary motor and premotor areas, supplementary motor area, the cerebellum and parts of the frontal, temporal and parietal gyrus were activated. The right putamen exhibited significant control > PD activation and weaker activity during the bimanual movement relative to the unimanual movement in the control group. The decreased putamen modulation on some nucleus in basal ganglia, such as putamen, thalamus and caudate, and some cortical areas, such as cingulate, parietal, angular, frontal, temporal and occipital gyrus was detected in the bimanual movement condition relative to the unimanual movement condition. Between-group PPI difference was detected in cingulate gyrus, angular gyrus and precuneus (control > PD) and inferior frontal gyrus (PD > control). The deficient putamen activation and its enhanced connectivity with the frontal gyrus could be a correlate of impaired basal ganglia inhibition and frontal gyrus compensation to maintain the task performance during the motor programs of PD patients. PMID:26483652

  5. Dysfunctional putamen modulation during bimanual finger-to-thumb movement in patients with Parkinson's disease

    PubMed Central

    Yan, Li-rong; Wu, Yi-bo; Zeng, Xiao-hua; Gao, Li-chen

    2015-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder affecting middle-aged and elderly people. PD can be viewed as “circuit disorder,” indicating that large scale cortico-subcortical pathways were involved in its pathophysiology. The brain network in an experimental context is emerging as an important biomarker in disease diagnosis and prognosis prediction. This context-dependent network for PD and the underling functional mechanism remains unclear. In this paper, the brain network profiles in 11 PD patients without dementia were studied and compared with 12 healthy controls. The functional magnetic resonance imaging (fMRI) data were acquired when the subjects were performing a pseudorandomized unimanual or bimanual finger-to-thumb movement task. The activation was detected and the network profiles were analyzed by psychophysiological interaction (PPI) toolbox. For the controls and PD patients, the motor areas including the primary motor and premotor areas, supplementary motor area, the cerebellum and parts of the frontal, temporal and parietal gyrus were activated. The right putamen exhibited significant control > PD activation and weaker activity during the bimanual movement relative to the unimanual movement in the control group. The decreased putamen modulation on some nucleus in basal ganglia, such as putamen, thalamus and caudate, and some cortical areas, such as cingulate, parietal, angular, frontal, temporal and occipital gyrus was detected in the bimanual movement condition relative to the unimanual movement condition. Between-group PPI difference was detected in cingulate gyrus, angular gyrus and precuneus (control > PD) and inferior frontal gyrus (PD > control). The deficient putamen activation and its enhanced connectivity with the frontal gyrus could be a correlate of impaired basal ganglia inhibition and frontal gyrus compensation to maintain the task performance during the motor programs of PD patients. PMID:26483652

  6. 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

  7. Putamen-midbrain functional connectivity is related to striatal dopamine transporter availability in patients with Lewy body diseases.

    PubMed

    Rieckmann, A; Gomperts, S N; Johnson, K A; Growdon, J H; Van Dijk, K R A

    2015-01-01

    Prior work has shown that functional connectivity between the midbrain and putamen is altered in patients with impairments in the dopamine system. This study examines whether individual differences in midbrain-striatal connectivity are proportional to the integrity of the dopamine system in patients with nigrostriatal dopamine loss (Parkinson's disease and dementia with Lewy bodies). We assessed functional connectivity of the putamen during resting state fMRI and dopamine transporter (DAT) availability in the striatum using 11C-Altropane PET in twenty patients. In line with the hypothesis that functional connectivity between the midbrain and the putamen reflects the integrity of the dopaminergic neurotransmitter system, putamen-midbrain functional connectivity was significantly correlated with striatal DAT availability even after stringent control for effects of head motion. DAT availability did not relate to functional connectivity between the caudate and thalamus/prefrontal areas. As such, resting state functional connectivity in the midbrain-striatal pathway may provide a useful indicator of underlying pathology in patients with nigrostriatal dopamine loss.

  8. Decreased caudate response to milkshake is associated with higher body mass index and greater impulsivity

    PubMed Central

    Babbs, R. Keith; Sun, Xue; Felsted, Jennifer; Chouinard-Decorte, Francois; Veldhuizen, Maria G.; Small, Dana

    2013-01-01

    Previous investigations consistently report a negative association between body mass index (BMI) and response in the caudate nucleus during the consumption of palatable and energy dense food. Since this response has also been linked to weight gain, we sought to replicate this finding and determine if the reduced response is associated with measures of impulsivity or food reward. Two studies were conducted in which fMRI was used to measure brain response to milkshake and a tasteless control solution. In study 1 (n = 25) we also assessed self-reported impulsivity, willingness to work for food, and subjective experiences of the pleasantness of milkshake taste and aroma. Replicating prior work, we report a negative association between BMI and brain response to milkshake vs. tasteless in the caudate nucleus. The opposite pattern was observed in the ventral putamen, with greater response observed in the 13 overweight compared to the 12 healthy weight subjects. Regression of brain response against impulsivity and food reward measures revealed one significant association: in the overweight but not healthy weight group self-reported impulsivity was negatively associated with caudate response to milkshake. In study 2 (n = 14), in addition to assessing brain response to milkshake and tasteless solutions subjects completed a go/no-go task outside the scanner. As predicted, we identified an inverse relationship between caudate response to milkshake vs. tasteless and failure to inhibit responses on the no go trials. We conclude that the inverse correlation between BMI and caudate response to milkshake is associated with impulsivity but not food reward. These findings suggest that response to milkshake in the dorsal striatum may be related to weight gain by promoting impulsive eating behavior. PMID:23562867

  9. Interpretive monitoring in the caudate nucleus

    PubMed Central

    Yanike, Marianna; Ferrera, Vincent P

    2014-01-01

    In a dynamic environment an organism has to constantly adjust ongoing behavior to adapt to a given context. This process requires continuous monitoring of ongoing behavior to provide its meaningful interpretation. The caudate nucleus is known to have a role in behavioral monitoring, but the nature of these signals during dynamic behavior is still unclear. We recorded neuronal activity in the caudate nucleus in monkeys during categorization behavior that changed rapidly across contexts. We found that neuronal activity maintained representation of the identity and context of a recently categorized stimulus, as well as interpreted the behavioral meaningfulness of the maintained trace. The accuracy of this cognitive monitoring signal was highest for behavior for which subjects were prone to make errors. Thus, the caudate nucleus provides interpretive monitoring of ongoing behavior, which is necessary for contextually specific decisions to adapt to rapidly changing conditions. DOI: http://dx.doi.org/10.7554/eLife.03727.001 PMID:25415238

  10. [Bilateral infarction of the caudate nuclei].

    PubMed

    Mrabet, A; Mrad-Ben Hammouda, I; Abroug, Z; Smiri, W; Haddad, A

    1994-01-01

    We report the case of a 57-year-old right-handed woman, with a history of hypertension, who, in February 1990, suddenly developed behavioral and cognitive abnormalities. Prior to the onset of her illness she had been normal. On examination, neuropsychological testing (Wechsler Mental Test, Wechsler Adult Intelligence Scale Revised, Knox Cube Test) elicited attention abnormalities, decreased recent memory, apathy, reduced spontaneity and initiative and left hemiparesia. CT scan showed small low density areas in the head of both caudate nuclei and right internal capsule, indicating infarction. Two years later, the deficit had partially resolved. Apathy persisted; psychometry showed an IQ of 57. Bilateral damage to the head of the caudate nuclei disrupt cortical-subcortical connections. The caudate nucleus is an essential component of basal ganglia-thalamo-cortical circuitry and its contribution to cognitive functions and behavior appears to be important. PMID:7801044

  11. Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer's disease.

    PubMed

    Ryan, Natalie S; Keihaninejad, Shiva; Shakespeare, Timothy J; Lehmann, Manja; Crutch, Sebastian J; Malone, Ian B; Thornton, John S; Mancini, Laura; Hyare, Harpreet; Yousry, Tarek; Ridgway, Gerard R; Zhang, Hui; Modat, Marc; Alexander, Daniel C; Rossor, Martin N; Ourselin, Sebastien; Fox, Nick C

    2013-05-01

    Amyloid imaging studies of presymptomatic familial Alzheimer's disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer's disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical

  12. Accumulation of iron in the putamen predicts its shrinkage in healthy older adults: A multi-occasion longitudinal study.

    PubMed

    Daugherty, Ana M; Raz, Naftali

    2016-03-01

    Accumulation of non-heme iron is believed to play a major role in neurodegeneration of the basal ganglia. In healthy aging, however, the temporal relationship between change in brain iron content and age-related volume loss is unclear. Here, we present the first long-term longitudinal multi-occasion investigation of changes in iron content and volume in the neostriatum in a sample of healthy middle-aged and older adults (N=32; ages 49-83years at baseline). Iron content, estimated via R2* relaxometry, increased in the putamen, but not the caudate nucleus. In the former, the rate of accumulation was coupled with change in volume. Moreover, greater baseline iron content predicted faster shrinkage and smaller volumes seven years later. Older age partially accounted for individual differences in neostriatal iron content and volume, but vascular risk did not. Thus, brain iron content may be a promising biomarker of impending decline in normal aging. PMID:26746579

  13. Accumulation of iron in the putamen predicts its shrinkage in healthy older adults: A multi-occasion longitudinal study.

    PubMed

    Daugherty, Ana M; Raz, Naftali

    2016-03-01

    Accumulation of non-heme iron is believed to play a major role in neurodegeneration of the basal ganglia. In healthy aging, however, the temporal relationship between change in brain iron content and age-related volume loss is unclear. Here, we present the first long-term longitudinal multi-occasion investigation of changes in iron content and volume in the neostriatum in a sample of healthy middle-aged and older adults (N=32; ages 49-83years at baseline). Iron content, estimated via R2* relaxometry, increased in the putamen, but not the caudate nucleus. In the former, the rate of accumulation was coupled with change in volume. Moreover, greater baseline iron content predicted faster shrinkage and smaller volumes seven years later. Older age partially accounted for individual differences in neostriatal iron content and volume, but vascular risk did not. Thus, brain iron content may be a promising biomarker of impending decline in normal aging.

  14. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen

    PubMed Central

    Weitemier, Adam; Inoue, Masato

    2015-01-01

    In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses. PMID:26110516

  15. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen.

    PubMed

    Yoshimi, Kenji; Kumada, Shiori; Weitemier, Adam; Jo, Takayuki; Inoue, Masato

    2015-01-01

    In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses.

  16. Subcortical intelligence: caudate volume predicts IQ in healthy adults.

    PubMed

    Grazioplene, Rachael G; G Ryman, Sephira; Gray, Jeremy R; Rustichini, Aldo; Jung, Rex E; DeYoung, Colin G

    2015-04-01

    This study examined the association between size of the caudate nuclei and intelligence. Based on the central role of the caudate in learning, as well as neuroimaging studies linking greater caudate volume to better attentional function, verbal ability, and dopamine receptor availability, we hypothesized the existence of a positive association between intelligence and caudate volume in three large independent samples of healthy adults (total N = 517). Regression of IQ onto bilateral caudate volume controlling for age, sex, and total brain volume indicated a significant positive correlation between caudate volume and intelligence, with a comparable magnitude of effect across each of the three samples. No other subcortical structures were independently associated with IQ, suggesting a specific biological link between caudate morphology and intelligence.

  17. Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease

    PubMed Central

    Keihaninejad, Shiva; Shakespeare, Timothy J.; Lehmann, Manja; Crutch, Sebastian J.; Malone, Ian B.; Thornton, John S.; Mancini, Laura; Hyare, Harpreet; Yousry, Tarek; Ridgway, Gerard R.; Zhang, Hui; Modat, Marc; Alexander, Daniel C.; Rossor, Martin N.; Ourselin, Sebastien; Fox, Nick C.

    2013-01-01

    Amyloid imaging studies of presymptomatic familial Alzheimer’s disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer’s disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the

  18. Release into the cerebral ventricles of substances with possible transmitter function in the caudate nucleus

    PubMed Central

    Portig, P. J.; Vogt, Marthe

    1969-01-01

    1. One caudate nucleus of the anaesthetized cat was superfused by perfusing the anterior horn of one lateral cerebral ventricle. The perfusates were examined for their content in acetylcholine (ACh), dopamine, homovanillic acid (HVA) and 5-hydroxytryptamine (5-HT), at rest and after a variety of stimuli. 2. When prostigmine was added to the perfusion fluid, ACh appeared in the effluent; its concentration tended to rise in the course of an experiment. Various afferent stimuli, all of which caused evoked responses recorded from the contra-lateral caudate nucleus, increased the ACh content of the effluent. Effective stimuli were noise and electrical stimulation of afferent nerves or of certain regions of the brain including the ipsi-lateral substantia nigra. 3. The dopamine content of the effluent was extremely low (of the order of 50 pg/min) at rest, but, on occasion, rose sharply when the substantia nigra was stimulated electrically with trains of pulses repeated once every 3 sec. The results were inconsistent. 4. Since dopamine in tissue is rapidly transformed enzymically into HVA, the appearance of this acid in the perfusate was examined. 5. At rest, HVA was found to appear in the effluent at a rate of 2-8 ng/min. Its concentration was rapidly depressed by increasing the depth of anaesthesia. 6. Stimulation of the substantia nigra for periods of 3 or 4 min caused an increment in the HVA content of the effluent lasting 1 hr or more. It was frequently seen when two points of the substantia nigra were stimulated simultaneously, less regularly with only one stimulating electrode, and rarely if this was placed in the most caudal part of the substantia nigra. 7. These results strongly support the view that there is a dopaminergic nigro-striatal pathway. The following assumption would explain the erratic appearance of dopamine and the long duration of increments in HVA: many of the axons originating in the substantia nigra end either in the putamen or in parts of the

  19. Dopamine D4 Receptor Counteracts Morphine-Induced Changes in μ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

    PubMed Central

    Suárez-Boomgaard, Diana; Gago, Belén; Valderrama-Carvajal, Alejandra; Roales-Buján, Ruth; Van Craenenbroeck, Kathleen; Duchou, Jolien; Borroto-Escuela, Dasiel O.; Medina-Luque, José; de la Calle, Adelaida; Fuxe, Kjell; Rivera, Alicia

    2014-01-01

    The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine. PMID:24451133

  20. The adenosine A2A receptor agonist, CGS-21680, blocks excessive rearing, acquisition of wheel running, and increases nucleus accumbens CREB phosphorylation in chronically food-restricted rats.

    PubMed

    Cabeza de Vaca, Soledad; Kannan, Pavitra; Pan, Yan; Jiang, Nancy; Sun, Yanjie; Carr, Kenneth D

    2007-04-20

    Adenosine A(2A) receptors are preferentially expressed in rat striatum, where they are concentrated in dendritic spines of striatopallidal medium spiny neurons and exist in a heteromeric complex with D(2) dopamine (DA) receptors. Behavioral and biochemical studies indicate an antagonistic relationship between A(2A) and D(2) receptors. Previous studies have demonstrated that food-restricted (FR) rats display behavioral and striatal cellular hypersensitivity to D(1) and D(2) DA receptor stimulation. These alterations may underlie adaptive, as well as maladaptive, behaviors characteristic of the FR rat. The present study examined whether FR rats are hypersensitive to the A(2A) receptor agonist, CGS-21680. In Experiment 1, spontaneous horizontal motor activity did not differ between FR and ad libitum fed (AL) rats, while vertical activity was greater in the former. Intracerebroventricular (i.c.v.) administration of CGS-21680 (0.25 and 1.0 nmol) decreased both types of motor activity in FR rats, and returned vertical activity levels to those observed in AL rats. In Experiment 2, FR rats given access to a running wheel for a brief period outside of the home cage rapidly acquired wheel running while AL rats did not. Pretreatment with CGS-21680 (1.0 nmol) blocked the acquisition of wheel running. When administered to FR subjects that had previously acquired wheel running, CGS-21680 suppressed the behavior. In Experiment 3, CGS-21680 (1.0 nmol) activated both ERK 1/2 and CREB in caudate-putamen with no difference between feeding groups. However, in nucleus accumbens (NAc), CGS-21680 failed to activate ERK 1/2 and selectively activated CREB in FR rats. These results indicate that FR subjects are hypersensitive to several effects of an adenosine A(2A) agonist, and suggest the involvement of an upregulated A(2A) receptor-linked signaling pathway in NAc. Medications targeting the A(2A) receptor may have utility in the treatment of maladaptive behaviors associated with FR

  1. Accelerated Echo Planer J-resolved Spectroscopic Imaging of Putamen and Thalamus in Obstructive Sleep Apnea

    PubMed Central

    Sarma, Manoj K.; Macey, Paul M.; Nagarajan, Rajakumar; Aysola, Ravi; Harper, Ronald M.; Thomas, M. Albert

    2016-01-01

    Obstructive sleep apnea syndrome (OSAS) leads to neurocognitive and autonomic deficits that are partially mediated by thalamic and putamen pathology. We examined the underlying neurochemistry of those structures using compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (JRESI), and quantified values with prior knowledge fitting. Bilaterally increased thalamic mI/Cr, putamen Glx/Cr, and Glu/Cr, and bilaterally decreased thalamic and putamen tCho/Cr and GABA/Cr occurred in OSAS vs healthy subjects (p < 0.05). Increased right thalamic Glx/Cr, Glu/Cr, Gln/Cr, Asc/Cr, and decreased GPC/Cr and decreased left thalamic tNAA/Cr, NAA/Cr were detected. The right putamen showed increased mI/Cr and decreased tCho/Cr, and the left, decreased PE/Cr ratio. ROC curve analyses demonstrated 60–100% sensitivity and specificity for the metabolite ratios in differentiating OSAS vs. controls. Positive correlations were found between: left thalamus mI/Cr and baseline oxygen saturation (SaO2); right putamen tCho/Cr and apnea hypopnea index; right putamen GABA/Cr and baseline SaO2; left putamen PE/Cr and baseline SaO2; and left putamen NAA/Cr and SaO2 nadir (all p < 0.05). Negative correlations were found between left putamen PE/Cr and SaO2 nadir. These findings suggest underlying inflammation or glial activation, with greater alterations accompanying lower oxygen saturation. These metabolite levels may provide biomarkers for future neurochemical interventions by pharmacologic or other means. PMID:27596614

  2. Microstructural Abnormality in Left Nucleus Accumbens Predicts Dysfunctional Beliefs in Treatment-Resistant Obsessive-Compulsive Disorder

    PubMed Central

    Li, Zhongchun; Ji, Weidong; Li, Deqiang; Li, Xujuan; Feng, Wei

    2014-01-01

    Background The aim of this study was to determine whether dysfunctional beliefs might predict treatment-resistance and to examine the relationship between fractional anisotropy (FA) in diffusion tensor imaging (DTI) and cognitive biases for optimal treatment choice. Material/Methods We recruited 11 non-resistant obsessive-compulsive disorder (OCD) patients, 11 resistant OCD patients, and 11 healthy subjects. Results OCD patients had higher Obsessive Beliefs Questionnaire (OBQ-87) subscale scores than subjects in non-resistant and resistant groups. A significant difference was found between non-resistant and resistant OCD patients in R-Scale and I-Scale. A significant decrease in FA was found in left dorsal frontal gyrus and left inferior parietal lobule in the non-resistant group as compared to the control group. FA also decreased significantly in left anterior cingulate cortex, putamen, and nucleus accumbens in the resistant group as compared to the control group. There was a significant decrease in FA in nucleus accumbens in the resistant group as compared to the non-resistant group. Reduced FA in left nucleus accumbens was negatively associated with OBQ-87 factor R and I and the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Conclusions Abnormalities in cortical-striatal white matter networks may contribute to the dysfunctional beliefs in patients with treatment-resistant OCD, and the left nucleus accumbens may be an important and promising target for the treatment of OCD. PMID:25393961

  3. Responses of cells in the tail of the caudate nucleus during visual discrimination learning.

    PubMed

    Brown, V J; Desimone, R; Mishkin, M

    1995-09-01

    1. The tail of the caudate nucleus and adjacent ventral putamen (ventrocaudal neostriatum) are major projection sites of the extrastriate visual cortex. Visual information is then relayed, directly or indirectly, to a variety of structures with motor functions. To test for a role of the ventrocaudal neostriatum in stimulus-response association learning, or habit formation, neuronal responses were recorded while monkeys performed a visual discrimination task. Additional data were collected from cells in cortical area TF, which serve as a comparison and control for the caudate data. 2. Two monkeys were trained to perform an asymmetrically reinforced go-no go visual discrimination. The stimuli were complex colored patterns, randomly assigned to be either positive or negative. The monkey was rewarded with juice for releasing a bar when a positive stimulus was presented, whereas a negative stimulus signaled that no reward was available and that the monkey should withhold its response. Neuronal responses were recorded both while the monkey performed the task with previously learned stimuli and while it learned the task with new stimuli. In some cases, responses were recorded during reversal learning. 3. There was no evidence that cells in the ventrocaudal neostriatum were influenced by the reward contingencies of the task. Cells did not fire preferentially to the onset of either positive or negative stimuli; neither did cells fire in response to the reward itself or in association with the motor response of the monkey. Only visual responses were apparent. 4. The visual properties of cells in these structures resembled those of cells in some of the cortical areas projecting to them. Most cells responded selectively to different visual stimuli. The degree of stimulus selectivity was assessed with discriminant analysis and was found to be quantitatively similar to that of inferior temporal cells tested with similar stimuli. Likewise, like inferior temporal cells, many cells

  4. Functionally distinct contributions of the anterior and posterior putamen during sublexical and lexical reading

    PubMed Central

    Oberhuber, Marion; Parker Jones, ‘Ōiwi; Hope, Thomas M. H.; Prejawa, Susan; Seghier, Mohamed L.; Green, David W.; Price, Cathy J.

    2013-01-01

    Previous studies have investigated orthographic-to-phonological mapping during reading by comparing brain activation for (1) reading words to object naming, or (2) reading pseudowords (e.g., “phume”) to words (e.g., “plume”). Here we combined both approaches to provide new insights into the underlying neural mechanisms. In fMRI data from 25 healthy adult readers, we first identified activation that was greater for reading words and pseudowords relative to picture and color naming. The most significant effect was observed in the left putamen, extending to both anterior and posterior borders. Second, consistent with previous studies, we show that both the anterior and posterior putamen are involved in articulating speech with greater activation during our overt speech production tasks (reading, repetition, object naming, and color naming) than silent one-back-matching on the same stimuli. Third, we compared putamen activation for words versus pseudowords during overt reading and auditory repetition. This revealed that the anterior putamen was most activated by reading pseudowords, whereas the posterior putamen was most activated by words irrespective of whether the task was reading words or auditory word repetition. The pseudoword effect in the anterior putamen is consistent with prior studies that associated this region with the initiation of novel sequences of movements. In contrast, the heightened word response in the posterior putamen is consistent with other studies that associated this region with “memory guided movement.” Our results illustrate how the functional dissociation between the anterior and posterior putamen supports sublexical and lexical processing during reading. PMID:24312042

  5. Microinjections of D-Ala2-Met5-enkephalinamide placed into nucleus accumbens suppress hypothalamically elicited hissing in the cat.

    PubMed

    Brutus, M; Zuabi, S; Siegel, A

    1989-04-01

    The effects of D-Ala2-Met5-enkephalinamide (DAME) upon the hissing component of hypothalamically elicited affective defense behavior in the cat were examined in this study. Microinjections of DAME placed into the nucleus accumbens significantly suppressed this response in a dose and time dependent manner. This dose dependent suppression of affective defense decreased toward baseline levels at 60 and 90 min following delivery of 1 and 10 micrograms/0.5 microliters of DAME, respectively. Similar injections placed into the caudate nucleus had no effects upon this response. Neither vehicle control nor naloxone placed into nucleus accumbens was found to significantly alter latencies for hissing. Naloxone injected into nucleus accumbens prior to administration of either a 1-microgram or a 10-micrograms dose of DAME blocked the suppressive effects of DAME that were observed when this drug was administered alone. These findings suggest that opioid receptors in the nucleus accumbens play an important role in the regulation of the hissing component of hypothalamically elicited affective defense behavior in the cat. PMID:2924870

  6. 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.

  7. 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

  8. Dynamic risk control by human nucleus accumbens

    PubMed Central

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

    2015-01-01

    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

  9. 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

  10. Brain putamen volume changes in newly-diagnosed patients with obstructive sleep apnea.

    PubMed

    Kumar, Rajesh; Farahvar, Salar; Ogren, Jennifer A; Macey, Paul M; Thompson, Paul M; Woo, Mary A; Yan-Go, Frisca L; Harper, Ronald M

    2014-01-01

    Obstructive sleep apnea (OSA) is accompanied by cognitive, motor, autonomic, learning, and affective abnormalities. The putamen serves several of these functions, especially motor and autonomic behaviors, but whether global and specific sub-regions of that structure are damaged is unclear. We assessed global and regional putamen volumes in 43 recently-diagnosed, treatment-naïve OSA (age, 46.4 ± 8.8 years; 31 male) and 61 control subjects (47.6 ± 8.8 years; 39 male) using high-resolution T1-weighted images collected with a 3.0-Tesla MRI scanner. Global putamen volumes were calculated, and group differences evaluated with independent samples t-tests, as well as with analysis of covariance (covariates; age, gender, and total intracranial volume). Regional differences between groups were visualized with 3D surface morphometry-based group ratio maps. OSA subjects showed significantly higher global putamen volumes, relative to controls. Regional analyses showed putamen areas with increased and decreased tissue volumes in OSA relative to control subjects, including increases in caudal, mid-dorsal, mid-ventral portions, and ventral regions, while areas with decreased volumes appeared in rostral, mid-dorsal, medial-caudal, and mid-ventral sites. Global putamen volumes were significantly higher in the OSA subjects, but local sites showed both higher and lower volumes. The appearance of localized volume alterations points to differential hypoxic or perfusion action on glia and other tissues within the structure, and may reflect a stage in progression of injury in these newly-diagnosed patients toward the overall volume loss found in patients with chronic OSA. The regional changes may underlie some of the specific deficits in motor, autonomic, and neuropsychologic functions in OSA.

  11. Response properties of neurons in the cat's putamen during auditory discrimination.

    PubMed

    Zhao, Zhenling; Sato, Yu; Qin, Ling

    2015-10-01

    The striatum integrates diverse convergent input and plays a critical role in the goal-directed behaviors. To date, the auditory functions of striatum are less studied. Recently, it was demonstrated that auditory cortico-striatal projections influence behavioral performance during a frequency discrimination task. To reveal the functions of striatal neurons in auditory discrimination, we recorded the single-unit spike activities in the putamen (dorsal striatum) of free-moving cats while performing a Go/No-go task to discriminate the sounds with different modulation rates (12.5 Hz vs. 50 Hz) or envelopes (damped vs. ramped). We found that the putamen neurons can be broadly divided into four groups according to their contributions to sound discrimination. First, 40% of neurons showed vigorous responses synchronized to the sound envelope, and could precisely discriminate different sounds. Second, 18% of neurons showed a high preference of ramped to damped sounds, but no preference for modulation rate. They could only discriminate the change of sound envelope. Third, 27% of neurons rapidly adapted to the sound stimuli, had no ability of sound discrimination. Fourth, 15% of neurons discriminated the sounds dependent on the reward-prediction. Comparing to passively listening condition, the activities of putamen neurons were significantly enhanced by the engagement of the auditory tasks, but not modulated by the cat's behavioral choice. The coexistence of multiple types of neurons suggests that the putamen is involved in the transformation from auditory representation to stimulus-reward association.

  12. 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.

  13. Automatic brain caudate nuclei segmentation and classification in diagnostic of Attention-Deficit/Hyperactivity Disorder.

    PubMed

    Igual, Laura; Soliva, Joan Carles; Escalera, Sergio; Gimeno, Roger; Vilarroya, Oscar; Radeva, Petia

    2012-12-01

    We present a fully automatic diagnostic imaging test for Attention-Deficit/Hyperactivity Disorder diagnosis assistance based on previously found evidences of caudate nucleus volumetric abnormalities. The proposed method consists of different steps: a new automatic method for external and internal segmentation of caudate based on Machine Learning methodologies; the definition of a set of new volume relation features, 3D Dissociated Dipoles, used for caudate representation and classification. We separately validate the contributions using real data from a pediatric population and show precise internal caudate segmentation and discrimination power of the diagnostic test, showing significant performance improvements in comparison to other state-of-the-art methods.

  14. Activity in the caudate nucleus of monkey during spatial sequencing.

    PubMed

    Kermadi, I; Joseph, J P

    1995-09-01

    1. There are indications that the execution of behavioral sequences involves the basal ganglia. In this study we examined the role of the caudate nucleus in the construction, storage, and execution of spatial plans. 2. Two monkeys (Macaca mulatta) were trained to perform sequences of saccades and arm movements. The animals had to remember the order of illumination, variable from one sequence to another, of three fixed spatial targets. After a delay, they had to visually orient toward, and press each target in the same order. Six different sequences were executed on the basis of the order of illumination of the targets. Single cell activity was recorded from the four caudate nuclei of the two monkeys. 3. Neural activity was analyzed in each sequence during 10 different periods: the instruction period in which the targets were illuminated, the three orientation periods toward the different targets, the three postsaccadic periods, and the three periods of target pressing. Statistical comparisons were made to detect differences between the different sequences with respect to activity in each period (sequence specificity). 4. A total of 2,100 neurons were studied, of which 387 were task related. The task-related cells were found in both the head and the body of the caudate nucleus. 5. During central fixation, anticipatory activity (n = 81) preceded onset of specific events. Four groups were considered: 1) neurons (n = 46) anticipating offset of the central fixation point, 2) neurons (n = 7) anticipating the illumination of any target, regardless of its spatial position or order of presentation (rank), 3) neurons (n = 17) anticipating the illumination of the first target, regardless of its spatial position, and 4) neurons (n = 11) anticipating the illumination of a given target, regardless of its rank. 6. Phasic visual responses to target onset were observed in 48 cells. The cells responded primarily to the contralateral and upper targets. In a majority (n = 35), visual

  15. Structural plasticity of the left caudate in bimodal bilinguals.

    PubMed

    Zou, Lijuan; Ding, Guosheng; Abutalebi, Jubin; Shu, Hua; Peng, Danling

    2012-10-01

    Bilinguals need an effective neural mechanism to select and control their languages for successful communication. Recent evidence indicates that the left caudate nucleus (LCN) is a critical part of this mechanism. Here we show that bimodal bilinguals, who use spoken and sign languages, have greater grey matter volume (GMV) in the head of the LCN as compared to monolinguals. We also found higher functional activation of this region in bimodal bilinguals when they switched between sign language and spoken language compared to when they did not switch languages. Furthermore, GMV was positively correlated with the magnitude of the switching effect in the head of the LCN. These findings indicate that for bimodal bilinguals, the LCN is shaped by bilingualism both anatomically and functionally.

  16. Insular and caudate lesions release abnormal yawning in stroke patients.

    PubMed

    Krestel, Heinz; Weisstanner, Christian; Hess, Christian W; Bassetti, Claudio L; Nirkko, Arto; Wiest, Roland

    2015-03-01

    Abnormal yawning is an underappreciated phenomenon in patients with ischemic stroke. We aimed at identifying frequently affected core regions in the supratentorial brain of stroke patients with abnormal yawning and contributing to the anatomical network concept of yawning control. Ten patients with acute anterior circulation stroke and ≥3 yawns/15 min without obvious cause were analyzed. The NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), symptom onset, period with abnormal yawning, blood oxygen saturation, glucose, body temperature, blood pressure, heart rate, and modified Rankin scale (mRS) were assessed for all patients. MRI lesion maps were segmented on diffusion-weighted images, spatially normalized, and the extent of overlap between the different stroke patterns was determined. Correlations between the period with abnormal yawning and the apparent diffusion coefficient (ADC) in the overlapping regions, total stroke volume, NIHSS and mRS were performed. Periods in which patients presented with episodes of abnormal yawning lasted on average for 58 h. Average GCS, NIHSS, and mRS scores were 12.6, 11.6, and 3.5, respectively. Clinical parameters were within normal limits. Ischemic brain lesions overlapped in nine out of ten patients: in seven patients in the insula and in seven in the caudate nucleus. The decrease of the ADC within the lesions correlated with the period with abnormal yawing (r = -0.76, Bonferroni-corrected p = 0.02). The stroke lesion intensity of the common overlapping regions in the insula and the caudate nucleus correlates with the period with abnormal yawning. The insula might be the long sought-after brain region for serotonin-mediated yawning.

  17. High-Frequency Deep Brain Stimulation of the Putamen Improves Bradykinesia in Parkinson’s Disease

    PubMed Central

    Montgomery, Erwin B.; Huang, He; Walker, Harrison C.; Guthrie, Barton L.; Watts, Ray L.

    2014-01-01

    Deep brain stimulation is effective for a wide range of neurological disorders; however, its mechanisms of action remain unclear. With respect to Parkinson’s disease, the existence of multiple effective targets suggests that putamen stimulation also may be effective and raises questions as to the mechanisms of action. Are there as many mechanisms of action as there are effective targets or some single or small set of mechanisms common to all effective targets? During the course of routine surgery of the globus pallidus interna in patients with Parkinson’s disease, the deep brain stimulation lead was placed in the putamen en route to the globus pallidus interna. Recordings of hand opening and closing during high-frequency and no stimulation were made. Speed of the movements, based on the amplitude and frequency of the repetitive hand movements as well as the decay in amplitude, were studied. Hand speed in 6 subjects was statistically significantly faster during active deep brain stimulation than the no-stimulation condition. There were no statistically significant differences in decay in the amplitude of hand movements. High-frequency deep brain stimulation of the putamen improves bradykinesia in a hand-opening and -closing task in patients with Parkinson’s disease. Consequently, high-frequency deep brain stimulation of virtually every structure in the basal ganglia-thalamic-cortical system improves bradykinesia. These observations, together with microelectrode recordings reported in the literature, argue that deep brain stimulation effects may be system specific and not structure specific. PMID:21714010

  18. Evidence for a caudate role in aphasia from FDG positron emission tomography

    SciTech Connect

    Metter, E.J.; Riege, W.H.; Hanson, W.R.; Phelps, M.; Kuhl, D.E.

    1982-01-01

    In a recent study correlations between language function and regional glucose metabolism from FDG positron computed tomography were examined. Caudate metabolism correlated with PICA speaking and comprehension factors, as well as BDAE mean writing and reading scores. To identify the language function implicated with caudate metabolism in these eleven patients, twenty subtests making up these two PICA factors and mean BDAE scores were correlated to caudate metabolism. Also a principle components analysis on the twenty subtests identified three factors, only one of which correlated with caudate metabolism. Evidence was found that the caudate has a functional relationship to recognition or motor planning of simple and overlearned materials. This involved simple syntax, low levels of abstraction, identification or sequencing of phonetic and semantic material. This role appeared related to but independent of Broca and frontal lobe function, and may involve the focusing of cortical functions, by allowing two or more regions to interact together.

  19. 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

  20. Caudate Nucleus in Retrieval of Trace Eyeblink Conditioning after Consolidation

    PubMed Central

    Flores, Luke C.; Disterhoft, John F.

    2013-01-01

    Trace eyeblink conditioning (EBC) is an associative learning task in which a stimulus-free trace period separates the presentation of a behaviorally neutral conditioned stimulus (CS, whisker stimulation) from a behaviorally salient unconditioned stimulus (US, airpuff to the eye). Repeated pairings of the CS with the US results in the emergence of the conditioned response (CR, eyeblink following CS presentation and preceding US presentation). The goal of these experiments was to determine whether the caudate nucleus (CN) plays a role in retrieval of previously acquired trace EBC after memory consolidation. Lesions of the CN were made one month after initial trace EBC. CN lesioned rabbits performed fewer adaptive CRs and more short-latency non-adaptive responses than sham lesioned controls. They were not able to improve their CR performance after consolidation as were controls. Single unit recordings taken from separate cohorts of rabbits demonstrated that neurons in the CN were still responsive to the CS and US one month after initial trace EBC, particularly in the medial and ventral CN on trials when a CR occurred. The proportion of rate increasing neurons was higher in trace conditioned than in pseudo conditioned rabbits. Neurons in regions destroyed in the behavioral experiment demonstrated prolonged firing during the trace period, which might underlie the results from the behavioral experiment. These data demonstrate that the CN plays an important role in retrieval of a previously learned associative task after memory consolidation has occurred. PMID:23407942

  1. Shape of Caudate Nucleus and Its Cognitive Correlates in Neuroleptic-Naive Schizotypal Personality Disorder

    PubMed Central

    Levitt, James J.; Westin, Carl-Fredrik; Nestor, Paul G.; Estepar, Raul S.J.; Dickey, Chandlee C.; Voglmaier, Martina M.; Seidman, Larry J.; Kikinis, Ron; Jolesz, Ferenc A.; McCarley, Robert W.; Shenton, Martha E.

    2009-01-01

    Background We measured the shape of the head of the caudate nucleus with a new approach based on magnetic resonance imaging (MRI) in schizotypal personality disorder (SPD) subjects in whom we previously reported decreased caudate nucleus volume. We believe MRI shape analysis complements traditional MRI volume measurements. Methods Magnetic resonance imaging scans were used to measure the shape of the caudate nucleus in 15 right-handed male subjects with SPD, who had no prior neuroleptic exposure, and in 14 matched normal comparison subjects. With MRI processing tools, we measured the head of the caudate nucleus using a shape index, which measured how much a given shape deviates from a sphere. Results In relation to comparison subjects, neuroleptic never-medicated SPD subjects had significantly higher (more “edgy”) head of the caudate shape index scores, lateralized to the right side. Additionally, for SPD subjects, higher right and left head of the caudate SI scores correlated significantly with poorer neuropsychological performance on tasks of visuospatial memory and auditory/verbal working memory, respectively. Conclusions These data confirm the value of measuring shape, as well as volume, of brain regions of interest and support the association of intrinsic pathology in the caudate nucleus, unrelated to neuroleptic medication, with cognitive abnormalities in the schizophrenia spectrum. PMID:14732598

  2. The contribution of the putamen to sensory aspects of pain: insights from structural connectivity and brain lesions

    PubMed Central

    Starr, Christopher J.; Sawaki, Lumy; Wittenberg, George F.; Burdette, Jonathan H.; Oshiro, Yoshitetsu; Quevedo, Alexandre S.; McHaffie, John G.

    2011-01-01

    Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex. PMID:21616963

  3. In vivo stereological assessment of caudate volume in man: Effect of normal aging

    SciTech Connect

    Krishnan, K.R.; Husain, M.M.; McDonald, W.M.; Doraiswamy, P.M.; Figiel, G.S.; Boyko, O.B.; Ellinwood, E.H.; Nemeroff, C.B. )

    1990-01-01

    Using intermediate weighted magnetic resonance imaging (MRI) and a systematic sampling stereological method in 39 normal volunteers aged 24-79 years old, we demonstrated a marked age-associated decline in caudate nuclei volume. The mean absolute volume of the caudate nuclei in this study was almost identical to that reported in a previous autopsy study and further confirms the validity of this stereological technique for use with MR images. This technique will provide a method for measuring the caudate and other nuclei in vivo, from brain images and, as such, a research tool to correlate age-associated changes in cognitive, sensory and motor function with caudate nucleus volume and other brain regions.

  4. Dopamine evoked inhibition of single cells of the feline putamen and basolateral amygdala.

    PubMed

    Ben-Ari, Y; Kelly, J S

    1976-03-01

    1. In cats under pentobarbitone or halothane anaesthesia, neurones of the putamen and basolateral amygdala were inhibited with a similar time course by iontophoretic applications of dopamine and gamma-aminobutyric acid (GABA), ejected with relatively short (20 sec) low intensity (less than 40 nA) pulses of positive current from five and seven barrelled extracellular micropipettes. The use of a stereotaxically positioned guide tube, sealed to the skull with dental cement, made it possible to obtain stable recording conditions and to correlate the stereotaxic position of the cells with the position of the micro-electrode tracks determined histologically by the post-mortem reconstruction of serial sections. 2. Since in cats anaesthetized with pentobarbitone none of the cells were found to be spontaneously active, the relative potency of dopamine and GABA were compared on glutamate excited cells. Approximately 2-5 times more current was required to release sufficient dopamine to cause just submaximal inhibition, equal in magnitude and duration to that evoked by GABA. 3. In nitrous oxide/halothane anaesthetized cats, approximately one quarter of the cells were spontaneously active. Relative potency studies showed that for dopamine, currents 2-0 and 1-6 times larger than those used for GABA were required to inhibit glutamate excited and spontaneously active cells respectively. 4. When the depth distribution of the cells was compared with the sensitivity of the cells to dopamine and GABA, the most sensitive cells were found to lie within the putamen and the basolateral amygdala. 5. On more than one third of the cells tested, iontophoretic application of the neuroleptic, alpha-flupenthixol of more than 3 or 4 min in duration, greatly reduced or abolished the inhibition of the cells by dopamine without impairing their sensitivity to GABA. 6. In four cats, large I.V. injections of alpha-flupenthixol (10 mg/kg) and the more potent neuroleptic pimozide (1 mg/kg) had no

  5. Differential recruitment of the sensorimotor putamen and frontoparietal cortex during motor chunking in humans

    PubMed Central

    Wymbs, Nicholas F.; Bassett, Danielle S.; Mucha, Peter J.; Porter, Mason A.; Grafton, Scott T.

    2012-01-01

    Motor chunking facilitates movement production by combining motor elements into integrated units of behavior. Previous research suggests that chunking involves two processes: concatenation, aimed at the formation of motor-motor associations between elements or sets of elements; and segmentation, aimed at the parsing of multiple contiguous elements into shorter action sets. We used fMRI to measure the trial-wise recruitment of brain regions associated with these chunking processes as healthy subjects performed a cued sequence production task. A novel dynamic network analysis identified chunking structure for a set of motor sequences acquired during fMRI and collected on three days of training. Activity in the bilateral sensorimotor putamen positively correlated with chunk concatenation, whereas a left hemisphere frontoparietal network was correlated with chunk segmentation. Across subjects, there was an aggregate increase in chunk strength (concatenation) with training, suggesting that subcortical circuits play a direct role in the creation of fluid transitions across chunks. PMID:22681696

  6. SIMULATING CONVECTION-ENHANCED DELIVERY IN THE PUTAMEN USING PROBABILISTIC TRACTOGRAPHY

    PubMed Central

    Tromp, Do P.M.; Adluru, Nagesh; Alexander, Andrew L.; Emborg, Marina E.

    2016-01-01

    The treatment of brain diseases is complicated by the presence of the blood-brain barrier. This barrier limits the crossing of therapeutic molecules from the blood vessels into the brain. Today, direct intracerebral infusion applying convection-enhanced delivery (CED) is proposed to circumvent this problem and enhance the area of distribution of infusate beyond the parameters of diffusion. Several factors affect the efficacy, predictability and replicability of CED, such as the catheter model, infusion rate and site of infusion. We set out to investigate if probabilistic tractography can be used to model the infusion flow and predict the intracerebral movement of molecules. In this study we describe a modeling and analysis framework based upon probabilistic tractography. This framework was used to compare probabilistic tractography modeling and actual CED infusion measurements in the putamen of non-human primates, as this gray matter structure is proposed as a target for CED treatment of Parkinson’s disease.

  7. Athetoid cerebral palsy with cysts in the putamen after hypoxic-ischaemic encephalopathy.

    PubMed Central

    Rutherford, M A; Pennock, J M; Murdoch-Eaton, D M; Cowan, F M; Dubowitz, L M

    1992-01-01

    Three cases of athetoid cerebral palsy after hypoxic-ischaemic encephalopathy (HIE) are reported. All three neonates had haemorrhagic lesions in the basal ganglia and thalami on magnetic resonance imaging (MRI). Prior cranial ultrasound had detected the lesions in only two cases. In all three children athetoid movements began within the first year of life. Follow up MRI scans showed bilateral symmetrical cystic lesions in the posterior putamen. Although haemorrhagic lesions within the basal ganglia are a common MRI finding in neonates with HIE, few of these babies develop athetoid cerebral palsy. We believe this to be the first report of discrete cystic lesions found in the basal ganglia of children with athetoid cerebral palsy. Images Figure 1 Figure 2 Figure 3 PMID:1519987

  8. Levodopa-induced dyskinesias are associated with transient down-regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: reduced synthesis or increased catabolism?

    PubMed

    Sancesario, Giuseppe; Morrone, Luigi Antonio; D'Angelo, Vincenza; Castelli, Valentina; Ferrazzoli, Davide; Sica, Francesco; Martorana, Alessandro; Sorge, Roberto; Cavaliere, Federica; Bernardi, Giorgio; Giorgi, Mauro

    2014-12-01

    Second messenger cAMP and cGMP represent a key step in the action of dopamine that modulates directly or indirectly their synthesis. We aimed to verify whether levodopa-induced dyskinesias are associated with changes of the time course of levodopa/dopamine stimulated cAMP and cGMP levels, and/or with changes of their catabolism by phosphodiesterase activity in rats with experimental hemiparkinsonism. Microdialysis and tissue homogenates of the striatal tissues demonstrated that extracellular and intracellular cAMP/cGMP levels were lower in dyskinetic animals during the increasing phase of dyskinesias compared to eukinetic animals, but cAMP/cGMP levels increased in dyskinetic animals during the phase of decreasing and extinction of dyskinesias. Dyskinesias and the abnormal lowering of striatal cGMP and cAMP after levodopa were prevented by pretreatment with the multipotent drug amantadine, outlining the inverse relationship of cAMP/cGMP to dyskinesias. Moreover, dyskinetic animals showed higher striatal hydrolyzing cGMP-phosphodiesterase but not hydrolyzing cAMP-phosphodiesterase activity, suggesting that low cGMP but not cAMP levels could be due to increased catabolism. However, expressions of isozyme phosphodiesterase-1B and -10A highly and specifically located in the basal ganglia were not changed after levodopa in dyskinetic and eukinetic animals: accordingly, selective inhibitors of phosphodiesterase-1B and -10A were ineffective on levodopa dyskinesias. Therefore, the isozyme(s) expressing higher cGMP-phosphodiesterase activity in the striatum of dyskinetic animal should be determined. These observations suggest that dopamine-mediated processes of synthesis and/or degradation of cAMP/cGMP could be acutely impaired in levodopa dyskinesias, opening new ways to understanding physiopathology and treatment.

  9. A novel mutation in the monocarboxylate transporter 8 gene in a boy with putamen lesions and low free T4 levels in cerebrospinal fluid.

    PubMed

    Kakinuma, Hiroaki; Itoh, Masatsune; Takahashi, Hiroaki

    2005-10-01

    We describe brain lesions in a patient with a monocarboxylate transporter 8 mutation. Imaging showed a high T2 lesion in the left putamen at age 3 and a right putamen lesion at age 6. Cerebrospinal fluid free thyroxine concentrations were low, with normal 3,3',5-triiodothyronine concentrations.

  10. Reduced number of caudate nucleus dopamine uptake sites in vascular dementia.

    PubMed

    Allard, P; Englund, E; Marcusson, J

    1999-01-01

    The dopamine (DA) uptake sites in the caudate nucleus were studied in patients with vascular dementia (VAD) and in a control group using the presynaptic DA uptake site marker [3H][2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane] as radioligand. There was a significant decrease in the number of DA uptake sites in the VAD group, while the binding affinity was unchanged. The present results indicate that in the patients investigated, the cerebrovascular disease process involves dopaminergic neuron terminals in the caudate nucleus. Our findings are discussed in relation to the reductions in number of DA uptake sites that have previously been revealed in Alzheimer's and Parkinson's diseases.

  11. [Subcortical infarcts (caudate nucleus) in a case of bilateral anterior cerebral artery occlusion].

    PubMed

    Halicka, D; Jankowicz, E; Drozdowski, W; Kochanowicz, J

    1999-01-01

    The authors describe a patient with bilateral anterior cerebral artery (ACA) occlusion. CT and MRI revealed bilateral encephalomalacia in the regions supplied by Heubner arteries and/or by perforating branches of ACA. The patient presented mainly with frontal symptomatology resulting from caudate nuclei lesion. Frontal symptomatology due to caudate impairment is discussed in the sense of frontal-subcortical circuits: lateral orbitofrontal and anterior cingulate ones. We emphasise a similarity of behavioural and cognitive disorders in early Huntington's disease and in frontal lobe lesion.

  12. Somatic mtDNA Mutation Spectra in the Aging Human Putamen

    PubMed Central

    Williams, Siôn L.; Mash, Deborah C.; Züchner, Stephan; Moraes, Carlos T.

    2013-01-01

    The accumulation of heteroplasmic mitochondrial DNA (mtDNA) deletions and single nucleotide variants (SNVs) is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. To address this, we have used next generation sequencing of mtDNA-enriched libraries (Mito-Seq) to investigate mtDNA mutation spectra of putamen from young and aged donors. Frequencies of the “common” deletion and other “major arc” deletions were significantly increased in the aged cohort with the fold increase in the frequency of the common deletion exceeding that of major arc deletions. SNVs also increased with age with the highest rate of accumulation in the non-coding control region which contains elements necessary for translation and replication. Examination of predicted amino acid changes revealed a skew towards pathogenic SNVs in the coding region driven by mutation bias. Levels of the pathogenic m.3243A>G tRNA mutation were also found to increase with age. Novel multimeric tandem duplications that resemble murine control region multimers and yeast ρ− mtDNAs, were identified in both young and aged specimens. Clonal ∼50 bp deletions in the control region were found at high frequencies in aged specimens. Our results reveal the complex manner in which the mitochondrial genome alters with age and provides a foundation for studies of other tissues and disease states. PMID:24339796

  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.

  14. Clinical outcomes of endoscopic ultrasound-guided ethanol injection for hepatocellular carcinoma in the caudate lobe

    PubMed Central

    Nakaji, So; Hirata, Nobuto; Mikata, Rintaro; Kobayashi, Masayoshi; Shiratori, Toshiyasu; Ogasawara, Sadahisa; Ooka, Yoshihiko; Tsuyuguchi, Toshio; Yamaguchi, Taketo; Yokosuka, Osamu

    2016-01-01

    Background and study aims: Accurately puncturing hepatocellular carcinomas (HCC) that arise from the caudate lobe is generally considered to be technically difficult. We conducted a retrospective study to evaluate the feasibility and safety (the therapeutic outcomes and adverse events) of endoscopic ultrasound (EUS)-guided ethanol injection as a novel treatment for HCC in the caudate lobe. Patients and methods: Twelve patients with early-stage HCC of the caudate lobe that were treated with EUS-guided ethanol injection at two tertiary referral centers were reviewed retrospectively. To evaluate the therapeutic effect of the treatment, a local control curve and an overall survival curve were constructed using the Kaplan–Meier method. Results: The mean follow-up duration was 31.0 months. The 1-year local control rate was 80.2 %, and recurrent lesions developed in 2 cases (after 3 and 9 months, respectively). The overall survival rate was 91.7 %, 75.0 %, and 53.3 % at 1, 2, and 3 years, respectively. Concerning procedure-related adverse events (AEs), 2 patients suffered episodes of fever lasting a few days; however, no serious AEs occurred. Conclusions: EUS-guided ethanol injection could be a useful treatment for early-stage HCC in the caudate lobe because of its simplicity and reduced invasiveness. PMID:27747288

  15. Memory Dysfunction in Caudate Infarction Caused by Heubner's Recurring Artery Occlusion

    ERIC Educational Resources Information Center

    Mizuta, Hideko; Motomura, Naoyasu

    2006-01-01

    We report five cases with caudate infarction due to Heubner's recurring artery occlusion, in which we conducted detailed memory examinations in terms of explicit memory and implicit memory. We performed the auditory verbal learning test as explicit memory tasks, and motor and cognitive procedural memory tasks, developed by Komori, as implicit…

  16. Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

    PubMed Central

    Nyberg, Lars; Karalija, Nina; Salami, Alireza; Andersson, Micael; Wåhlin, Anders; Kaboovand, Neda; Köhncke, Ylva; Axelsson, Jan; Rieckmann, Anna; Papenberg, Goran; Garrett, Douglas D.; Riklund, Katrine; Lövdén, Martin; Bäckman, Lars

    2016-01-01

    D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [11C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions. PMID:27339132

  17. Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory.

    PubMed

    Nyberg, Lars; Karalija, Nina; Salami, Alireza; Andersson, Micael; Wåhlin, Anders; Kaboovand, Neda; Köhncke, Ylva; Axelsson, Jan; Rieckmann, Anna; Papenberg, Goran; Garrett, Douglas D; Riklund, Katrine; Lövdén, Martin; Lindenberger, Ulman; Bäckman, Lars

    2016-07-12

    D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [(11)C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions. PMID:27339132

  18. 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

  19. 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

  20. Angiographic Evaluation of Feeding Arteries of Hepatocellular Carcinoma in the Caudate Lobe of the Liver

    SciTech Connect

    Miyayama, Shiro Yamashiro, Masashi; Hattori, Yuki; Orito, Nobuaki; Matsui, Ken; Tsuji, Kazunobu; Yoshida, Miki; Matsui, Osamu

    2011-12-15

    Purpose: To evaluate the origins of feeders of hepatocellular carcinoma (HCC) in the caudate lobe (S1). Materials and Methods: Eighty-eight HCCs (mean diameter 21.4 mm) were treated by chemoembolization. The tumor-feeding caudate artery was confirmed when a tumor stain was demonstrated on angiogram and iodized oil was accumulated into the HCC and S1 on computed tomography (CT). The origins were divided into R{sub 1} (right proximal), R{sub 2} (right distal), L{sub 1} (left proximal), L{sub 2} (left distal), A (anterior segmental), P (posterior segmental), M (middle hepatic or medial segmental), Ph (proper hepatic), Ch (common hepatic), and Ex (extrahepatic). The origins of feeders supplying HCCs in the Spiegel lobe (SP; n = 36), the paracaval portion (PC; n = 38), and the caudate process (CP; n = 14) were also analyzed. Results: One hundred sixteen feeders were identified: 11 (9.5%) arose from R{sub 1}; 21 (18.1%) arose from R{sub 2}; nine arose (0.9%) from L{sub 1}; 15 (12.9%) arose from L{sub 2}; 24 (20.7%) arose from A; 25 (21.6%) arose from P; seven (6.0%) arose from M; one (0.9%) arose from Ph; and three (2.6%) arose from Ex. HCCs in the SP and the PC were fed by feeders from both hepatic arteries (the ratios of right to left were 3:2 and 3:1, respectively), and HCCs in the CP were dominantly fed by feeders from the right hepatic artery. Conclusion: The caudate artery most frequently arises from the right hepatic artery, followed with almost equal frequency by the left hepatic, the anterior segmental, and the posterior segmental artery. The origins of the caudate arteries differ according to the subsegmental locations.

  1. Cortical thinning and caudate abnormalities in first episode psychosis and their association with clinical outcome.

    PubMed

    Scanlon, Cathy; Anderson-Schmidt, Heike; Kilmartin, Liam; McInerney, Shane; Kenney, Joanne; McFarland, John; Waldron, Mairead; Ambati, Srinath; Fullard, Anna; Logan, Sam; Hallahan, Brian; Barker, Gareth J; Elliott, Mark A; McCarthy, Peter; Cannon, Dara M; McDonald, Colm

    2014-10-01

    First episode psychosis (FEP) has been associated with structural brain changes, largely identified by volumetric analyses. Advances in neuroimaging processing have made it possible to measure geometric properties that may identify subtle structural changes not appreciated by a measure of volume alone. In this study we adopt complementary methods of assessing the structural integrity of grey matter in FEP patients and assess whether these relate to patient clinical and functional outcome at 3 year follow-up. 1.5 Tesla T1-weighted Magnetic Resonance (MR) images were acquired for 46 patients experiencing their first episode of psychosis and 46 healthy controls. Cerebral cortical thickness and local gyrification index (LGI) were investigated using FreeSurfer software. Volume and shape of the hippocampus, caudate and lateral ventricles were assessed using manual tracing and spherical harmonics applied for shape description. A cluster of cortical thinning was identified in FEP compared to controls; this was located in the right superior temporal gyrus, sulcus, extended into the middle temporal gyrus (lateral temporal cortex - LTC). Bilateral caudate volumes were significantly lower in FEP relative to controls and the right caudate also displayed regions of shape deflation in the FEP group. No significant structural abnormalities were identified in cortical LGI or hippocampal or lateral ventricle volume/shape. Neither LTC nor caudate abnormalities were related to change in symptom severity or global functioning 3 years later. LTC and caudate abnormalities are present at the first episode of psychosis but do not appear to directly affect clinical or functional outcome. PMID:25124520

  2. Resting-State Functional Connectivity of the Nucleus Accumbens in Auditory and Visual Hallucinations in Schizophrenia

    PubMed Central

    Rolland, Benjamin; Amad, Ali; Poulet, Emmanuel; Bordet, Régis; Vignaud, Alexandre; Bation, Rémy; Delmaire, Christine; Thomas, Pierre; Cottencin, Olivier; Jardri, Renaud

    2015-01-01

    Both auditory hallucinations (AH) and visual hallucinations may occur in schizophrenia. One of the main hypotheses underlying their occurrence involves the increased activity of the mesolimbic pathway, which links the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). However, the precise contribution of the mesolimbic pathway in hallucinations across various sensory modalities has not yet been explored. We compared the resting-state functional connectivity (rs-FC) of the NAcc among 16 schizophrenia patients with pure AH, 15 with both visuoauditory hallucinations (VAH), and 14 without hallucinations (NoH). A between-group comparison was performed using random-effects ANCOVA (rs-FC of the bilateral NAcc as the dependent variable, groups as the between-subjects factor, age and Positive and Negative Syndrome Scale scores as covariates; q(false discovery rate [FDR]) < .05). Compared to the NoH group, the AH group exhibited significantly enhanced NAcc rs-FC with the left temporal superior gyrus, the cingulate gyri, and the VTA, whereas the VAH group, compared to the AH group, exhibited significantly enhanced NAcc rs-FC with the bilateral insula, putamen, parahippocampal gyri, and VTA. The strength in rs-FC between the NAcc and the VTA appeared to be positively associated with the presence of hallucinations, but the NAcc FC patterns changed with the complexity of these experiences (ie, 0, 1, or 2 sensory modalities), rather than with severity. This might support the aberrant salience hypothesis of schizophrenia. Moreover, these findings suggest that future clinical and neurobiological studies of hallucinations should evaluate not only the global severity of symptoms but also their sensorial features. PMID:25053649

  3. Resting-state functional connectivity of the nucleus accumbens in auditory and visual hallucinations in schizophrenia.

    PubMed

    Rolland, Benjamin; Amad, Ali; Poulet, Emmanuel; Bordet, Régis; Vignaud, Alexandre; Bation, Rémy; Delmaire, Christine; Thomas, Pierre; Cottencin, Olivier; Jardri, Renaud

    2015-01-01

    Both auditory hallucinations (AH) and visual hallucinations may occur in schizophrenia. One of the main hypotheses underlying their occurrence involves the increased activity of the mesolimbic pathway, which links the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). However, the precise contribution of the mesolimbic pathway in hallucinations across various sensory modalities has not yet been explored. We compared the resting-state functional connectivity (rs-FC) of the NAcc among 16 schizophrenia patients with pure AH, 15 with both visuoauditory hallucinations (VAH), and 14 without hallucinations (NoH). A between-group comparison was performed using random-effects ANCOVA (rs-FC of the bilateral NAcc as the dependent variable, groups as the between-subjects factor, age and Positive and Negative Syndrome Scale scores as covariates; q(false discovery rate [FDR]) < .05). Compared to the NoH group, the AH group exhibited significantly enhanced NAcc rs-FC with the left temporal superior gyrus, the cingulate gyri, and the VTA, whereas the VAH group, compared to the AH group, exhibited significantly enhanced NAcc rs-FC with the bilateral insula, putamen, parahippocampal gyri, and VTA. The strength in rs-FC between the NAcc and the VTA appeared to be positively associated with the presence of hallucinations, but the NAcc FC patterns changed with the complexity of these experiences (ie, 0, 1, or 2 sensory modalities), rather than with severity. This might support the aberrant salience hypothesis of schizophrenia. Moreover, these findings suggest that future clinical and neurobiological studies of hallucinations should evaluate not only the global severity of symptoms but also their sensorial features.

  4. Convection-enhanced delivery of MANF--volume of distribution analysis in porcine putamen and substantia nigra.

    PubMed

    Barua, N U; Bienemann, A S; Woolley, M; Wyatt, M J; Johnson, D; Lewis, O; Irving, C; Pritchard, G; Gill, S

    2015-10-15

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20kDa human protein which has both neuroprotective and neurorestorative activity on dopaminergic neurons and therefore may have application for the treatment of Parkinson's Disease. The aims of this study were to determine the translational potential of convection-enhanced delivery (CED) of MANF for the treatment of PD by studying its distribution in porcine putamen and substantia nigra and to correlate histological distribution with co-infused gadolinium-DTPA using real-time magnetic resonance imaging. We describe the distribution of MANF in porcine putamen and substantia nigra using an implantable CED catheter system using co-infused gadolinium-DTPA to allow real-time MRI tracking of infusate distribution. The distribution of gadolinium-DTPA on MRI correlated well with immunohistochemical analysis of MANF distribution. Volumetric analysis of MANF IHC staining indicated a volume of infusion (Vi) to volume of distribution (Vd) ratio of 3 in putamen and 2 in substantia nigra. This study confirms the translational potential of CED of MANF as a novel treatment strategy in PD and also supports the co-infusion of gadolinium as a proxy measure of MANF distribution in future clinical studies. Further study is required to determine the optimum infusion regime, flow rate and frequency of infusions in human trials.

  5. Control of nucleus accumbens activity with neurofeedback.

    PubMed

    Greer, Stephanie M; Trujillo, Andrew J; Glover, Gary H; Knutson, Brian

    2014-08-01

    The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be presented as "neurofeedback." In an fMRI-based neurofeedback experiment designed to elicit NAcc activity, we found that subjects could increase their own NAcc activity, and that display of neurofeedback significantly enhanced their ability to do so. Subjects were not as capable of decreasing their NAcc activity, however, and enhanced control did not persist after subsequent removal of neurofeedback. Further analyses suggested that individuals who recruited positive aroused affect were better able to increase NAcc activity in response to neurofeedback, and that NAcc neurofeedback also elicited functionally correlated activity in the medial prefrontal cortex. Together, these findings suggest that humans can modulate their own NAcc activity and that fMRI-based neurofeedback may augment their efforts. The observed association between positive arousal and effective NAcc control further supports an anticipatory affect account of NAcc function.

  6. Control of nucleus accumbens activity with neurofeedback

    PubMed Central

    Greer, Stephanie M.; Trujillo, Andrew J.; Glover, Gary H.; Knutson, Brian

    2014-01-01

    The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be presented as “neurofeedback.” In an fMRI-based neurofeedback experiment designed to elicit NAcc activity, we found that subjects could increase their own NAcc activity, and that display of neurofeedback significantly enhanced their ability to do so. Subjects were not as capable of decreasing their NAcc activity, however, and enhanced control did not persist after subsequent removal of neurofeedback. Further analyses suggested that individuals who recruited positive arousal affect were better able to increase NAcc activity in response to neurofeedback, and that NAcc neurofeedback also elicited functionally correlated activity in the medial prefrontal cortex. Together, these findings suggest that humans can modulate their own NAcc activity and that fMRI-based neurofeedback may augment their efforts. The observed association between positive arousal and effective NAcc control further supports an anticipatory affect account of NAcc function. PMID:24705203

  7. Choice of approach for hepatectomy for hepatocellular carcinoma located in the caudate lobe: Isolated or combined lobectomy?

    PubMed Central

    Liu, Peng; Qiu, Bao-An; Bai, Gang; Bai, Hong-Wei; Xia, Nian-Xin; Yang, Ying-Xiang; Zhu, Jian-Yong; An, Yang; Hu, Bing

    2012-01-01

    AIM: To investigate the significance of the surgical approaches in the prognosis of hepatocellular carcinoma (HCC) located in the caudate lobe with a multivariate regression analysis using a Cox proportional hazard model. METHODS: Thirty-six patients with HCC underwent caudate lobectomy at a single tertiary referral center between January 1995 and June 2010. In this series, left-sided, right-sided and bilateral approaches were used. The outcomes of patients who underwent isolated caudate lobectomy or caudate lobectomy combined with an additional partial hepatectomy were compared. The survival curves of the isolated and combined resection groups were generated by the Kaplan-Meier method and compared by a log-rank test. RESULTS: Sixteen (44.4%) of 36 patients underwent isolated total or partial caudate lobectomy whereas 20 (55.6%) received a total or partial caudate lobectomy combined with an additional partial hepatectomy. The median diameter of the tumor was 6.7 cm (range, 2.1-15.8 cm). Patients who underwent an isolated caudate lobectomy had significantly longer operative time (240 min vs 170 min), longer length of hospital stay (18 d vs 13 d) and more blood loss (780 mL vs 270 mL) than patients who underwent a combined caudate lobectomy (P < 0.05). There were no perioperative deaths in both groups of patients. The complication rate was higher in the patients who underwent an isolated caudate lobectomy than in those who underwent combined caudate lobectomy (31.3% vs 10.0%, P < 0.05). The 1-, 3- and 5-year disease-free survival rates for the isolated caudate lobectomy and the combined caudate lobectomy groups were 54.5%, 6.5% and 0% and 85.8%, 37.6% and 0%, respectively (P < 0.05). The corresponding overall survival rates were 73.8%, 18.5% and 0% and 93.1%, 43.6% and 6.7% (P < 0.05). CONCLUSION: The caudate lobectomy combined with an additional partial hepatectomy is preferred because this approach is technically less demanding and offers an adequate surgical

  8. Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study.

    PubMed

    Papoiu, Alexandru D P; Kraft, Robert A; Coghill, Robert C; Yosipovitch, Gil

    2015-02-01

    Opioid receptors in the central nervous system are important modulators of itch transmission. In this study, we examined the effect of mixed-action opioid butorphanol on histamine itch, cowhage itch, and heat pain in healthy volunteers. Using functional MRI, we investigated significant changes in cerebral perfusion to identify the critical brain centers mediating the antipruritic effect of butorphanol. Butorphanol suppressed the itch induced experimentally with histamine, reduced the intensity of cowhage itch by approximately 35%, and did not affect heat pain sensitivity. In comparison with the placebo, butorphanol produced a bilateral deactivation of claustrum, insula, and putamen, areas activated during itch processing. Analysis of cerebral perfusion patterns of brain processing of itch versus itch inhibition under the effect of the drug revealed that the reduction in cowhage itch by butorphanol was correlated with changes in cerebral perfusion in the midbrain, thalamus, S1, insula, and cerebellum. The suppression of histamine itch by butorphanol was paralleled by the activation of nucleus accumbens and septal nuclei, structures expressing high levels of kappa opioid receptors. In conclusion, important relays of the mesolimbic circuit were involved in the inhibition of itch by butorphanol and could represent potential targets for the development of antipruritic therapy. PMID:25211175

  9. Reduction of Caudate Nucleus Volumes in Neuroleptic-Naïve Female Subjects with Schizotypal Personality Disorder

    PubMed Central

    Koo, Min-Seong; Levitt, James J.; McCarley, Robert W.; Seidman, Larry J.; Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Voglmaier, Martina M.; Zamani, Payman; Long, Katherine R.; Kim, Sunnie S.; Shenton, Martha E.

    2009-01-01

    Background The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. Methods Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-naïve women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. Results We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. Conclusions These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology. PMID:16460694

  10. The visual corticostriatal loop through the tail of the caudate: circuitry and function

    PubMed Central

    Seger, Carol A.

    2013-01-01

    Although high level visual cortex projects to a specific region of the striatum, the tail of the caudate, and participates in corticostriatal loops, the function of this visual corticostriatal system is not well understood. This article first reviews what is known about the anatomy of the visual corticostriatal loop across mammals, including rodents, cats, monkeys, and humans. Like other corticostriatal systems, the visual corticostriatal system includes both closed loop components (recurrent projections that return to the originating cortical location) and open loop components (projections that terminate in other neural regions). The article then reviews what previous empirical research has shown about the function of the tail of the caudate. The article finally addresses the possible functions of the closed and open loop connections of the visual loop in the context of theories and computational models of corticostriatal function. PMID:24367300

  11. Treating and Downstaging Hepatocellular Carcinoma in the Caudate Lobe with Yttrium-90 Radioembolization

    SciTech Connect

    Ibrahim, Saad M.; Kulik, Laura; Baker, Talia; Ryu, Robert K.; Mulcahy, Mary F.; Abecassis, Michael; Salem, Riad; Lewandowski, Robert J.

    2012-10-15

    Purpose: This study was designed to determine the technical feasibility, safety, efficacy, and potential to downstage patients to within transplantation criteria when treating patients with hepatocellular carcinoma (HCC) of the caudate lobe using Y90 radioembolization. Methods: During a 4-year period, 8 of 291 patients treated with radioembolization for unresectable HCC had disease involving the caudate lobe. All patients were followed for treatment-related clinical/biochemical toxicities, serum tumor marker response, and treatment response. Imaging response was assessed with the World Health Organization (WHO) and European Association for the Study of the Liver (EASL) classification schemes. Pathologic response was reported as percent necrosis at explantation. Results: Caudate lobe radioembolization was successfully performed in all eight patients. All patients presented with both cirrhosis and portal hypertension. Half were United Network for Organ Sharing (UNOS) stage T3 (n = 4, 50%). Fatigue was reported in half of the patients (n = 4, 50%). One (13%) grade 3/4 bilirubin toxicity was reported. One patient (13%) showed complete tumor response by WHO criteria, and three patients (38%) showed complete response using EASL guidelines. Serum AFP decreased by more than 50% in most patients (n = 6, 75%). Four patients (50%) were UNOS downstaged from T3 to T2, three of who underwent transplantation. One specimen showed histopathologic evidence of 100% complete necrosis, and two specimens demonstrated greater than 50% necrosis. Conclusions: Radioembolization with yttrium-90 appears to be a feasible, safe, and effective treatment option for patients with unresectable caudate lobe HCC. It has the potential to downstage patients to transplantation.

  12. Ultrastructural Changes of Caudate Nucleus in Mice Chronically Treated with Manganese.

    PubMed

    Villalobos, Virginia; Hernández-Fonseca, Juan Pablo; Bonilla, Ernesto; Medina-Leendertz, Shirley; Mora, Marylu; Mosquera, Jesús

    2015-01-01

    Manganese (Mn) is able to cross the blood-brain barrier and induces functional and structural alterations during the intoxication by this metal. Therefore, the effects of chronic administration of Mn in the caudate nucleus of mice were evaluated by electron microscopy. Male albino mice were injected intraperitoneally with MnCl2 (5 mg/kg/d) 5 d per week during 9 weeks. The control group received only 0.9% of NaCl solution. The caudate nuclei were extracted and subsequently processed to be observed on a conventional transmission electron microscope at 2, 4, 6, and 9 weeks after treatment. A high percentage of vacuolated and swollen mitochondria were found throughout all the analyzed periods. Myelin disarrangement and ultrastructural alterations related to edema were observed increased in Mn-treated mice at week 9. Granular degeneration of myelin at week 9 accompanied with deposition of electron dense granules in the neuropil was also observed. Edema in neuropil and glial cells was detected from week 2 to week 9 accompanied by swollen mitochondria. Neuronal bodies, synaptic terminals, and perivascular cells were found swollen. Decreased electron density in postsynaptic areas and decreased and dispersed synaptic vesicles in presynaptic areas were noted in Mn-treated animals. Some neurons from Mn-treated mice showed cisternae dilation of the Golgi apparatus. These results suggest that Mn-treatment produces structural alterations in the caudate nucleus that could be responsible for some of the neurotoxic effects of this metal.

  13. Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates.

    PubMed

    Yin, Dali; Valles, Francisco E; Fiandaca, Massimo S; Bringas, John; Gimenez, Francisco; Berger, Mitchel S; Forsayeth, John; Bankiewicz, Krystof S

    2011-01-01

    Optimal results in the direct brain delivery of brain therapeutics such as growth factors or viral vector into primate brain depend on reproducible distribution throughout the target region. In the present study, we retrospectively analyzed MRI of 25 convection-enhanced delivery (CED) infusions with MRI contrast into the putamen of non-human primates (NHP). Infused volume (V(i)) was compared to total volume of distribution (V(d)) versus V(d) within the target putamen. Excellent distribution of contrast agent within the putamen was obtained in eight cases that were used to define an optimal target volume or "green" zone. Partial or poor distribution with leakage into adjacent anatomical structures was noted in 17 cases, defining "blue" and "red" zones, respectively. Quantitative containment (99±1%) of infused gadoteridol within the putamen was obtained when the cannula was placed in the green zone, 87±3% in the blue zone and 49±0.05% in the red zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for putaminal infusions in NHP and human putamen. We conclude that cannula placement and definition of optimal (green zone) stereotactic coordinates have important implications in ensuring effective delivery of therapeutics into the putamen utilizing routine stereotactic MRI localization procedures and should be considered when local therapies such as gene transfer or protein administration are being translated into clinical therapy.

  14. Parkinson's disease: decreased density of /sup 3/H-imipramine and /sup 3/H-paroxetine binding sites in putamen

    SciTech Connect

    Raisman, R.; Cash, R.; Agid, Y.

    1986-04-01

    The density of high-affinity /sup 3/H-imipramine and /sup 3/H-paroxetine binding sites (two serotonin-uptake blockers) was decreased in the putamen of parkinsonian patients. The correlation between serotonin levels and the number of /sup 3/H-imipramine and /sup 3/H-paroxetine binding sites suggests that they are located on serotoninergic nerve terminals and could be used to study serotoninergic innervation in the human brain. Since imipramine and paroxetine are powerful antidepressants, these results furthermore suggest that decreased serotoninergic transmission may be implicated in the pathophysiology of depression in Parkinson's disease.

  15. Caudate nucleus-dependent navigational strategies are associated with increased use of addictive drugs

    PubMed Central

    Bohbot, Veronique D; Balso, Daniel; Conrad, Kate; Konishi, Kyoko; Leyton, Marco

    2013-01-01

    This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4-on-8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal-dependent spatial navigational strategies and caudate nucleus-dependent stimulus-response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus-response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue-responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty-five young adults were tested on the 4/8VM and completed a time-line follow-back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition. © 2013 The Authors

  16. Functional properties of monkey caudate neurons. I. Activities related to saccadic eye movements.

    PubMed

    Hikosaka, O; Sakamoto, M; Usui, S

    1989-04-01

    1. We recorded single cell activities in the caudate nucleus of the monkeys trained to perform a series of visuomotor tasks. In the first part of this paper, we summarize the types and locations of neurons in the monkey caudate nucleus. In the second part, we report the characteristics of neurons related to saccadic eye movements. 2. Neurons were classified into two types in terms of spontaneous discharge pattern. A majority of the neurons (2,287/2,559, 89%) had very low-frequency discharges (mostly less than 1 Hz). The rest (n = 272) showed irregular-tonic discharges (3-8 Hz) with broad spikes. 3. Of 2,559 neurons tested, 867 showed spike activity related to some aspects of the tasks; 502 neurons showed discharges in response to environmental changes outside, not in relation to, the tasks. None of the neurons responsive in or outside the tasks belonged to the irregular-tonic type. 4. The task-related activities were classified as: Saccade-related, Visual, Auditory, Cognitive, Fixation-related, and Reward-related. The activities detected outside the tasks were classified into: Visual, Auditory, Movement-related, Reward-related, and Other. Few neurons had both task-related and task-unrelated activities. 5. The locations of recorded neurons were determined using a coordinate system based on the anterior and posterior commissures. Task-related neurons were clustered longitudinally in the central part of the caudate. Neurons responsive outside the tasks were more widely distributed; specifically, auditory neurons were in the medial part, whereas movement-related neurons were in the lateral part. The irregular-tonic neurons were dispersed all over the caudate. 6. The monkey was trained to fixate on a spot of light on the screen and, when the spot moved, to follow it by making a saccade. A visually guided saccade occurred when the spot moved to another location without a time gap (saccade task). A memory-guided saccade occurred when the spot first disappeared and after a

  17. Disruption of caudate working memory activation in chronic blast-related traumatic brain injury.

    PubMed

    Newsome, Mary R; Durgerian, Sally; Mourany, Lyla; Scheibel, Randall S; Lowe, Mark J; Beall, Erik B; Koenig, Katherine A; Parsons, Michael; Troyanskaya, Maya; Reece, Christine; Wilde, Elisabeth; Fischer, Barbara L; Jones, Stephen E; Agarwal, Rajan; Levin, Harvey S; Rao, Stephen M

    2015-01-01

    Mild to moderate traumatic brain injury (TBI) due to blast exposure is frequently diagnosed in veterans returning from the wars in Iraq and Afghanistan. However, it is unclear whether neural damage resulting from blast TBI differs from that found in TBI due to blunt-force trauma (e.g., falls and motor vehicle crashes). Little is also known about the effects of blast TBI on neural networks, particularly over the long term. Because impairment in working memory has been linked to blunt-force TBI, the present functional magnetic resonance imaging (fMRI) study sought to investigate whether brain activation in response to a working memory task would discriminate blunt-force from blast TBI. Twenty-five veterans (mean age = 29.8 years, standard deviation = 6.01 years, 1 female) who incurred TBI due to blast an average of 4.2 years prior to enrollment and 25 civilians (mean age = 27.4 years, standard deviation = 6.68 years, 4 females) with TBI due to blunt-force trauma performed the Sternberg Item Recognition Task while undergoing fMRI. The task involved encoding 1, 3, or 5 items in working memory. A group of 25 veterans (mean age = 29.9 years, standard deviation = 5.53 years, 0 females) and a group of 25 civilians (mean age = 27.3 years, standard deviation = 5.81 years, 0 females) without history of TBI underwent identical imaging procedures and served as controls. Results indicated that the civilian TBI group and both control groups demonstrated a monotonic relationship between working memory set size and activation in the right caudate during encoding, whereas the blast TBI group did not (p < 0.05, corrected for multiple comparisons using False Discovery Rate). Blast TBI was also associated with worse performance on the Sternberg Item Recognition Task relative to the other groups, although no other group differences were found on neuropsychological measures of episodic memory, inhibition, and general processing speed. These results could not be

  18. Disruption of caudate working memory activation in chronic blast-related traumatic brain injury

    PubMed Central

    Newsome, Mary R.; Durgerian, Sally; Mourany, Lyla; Scheibel, Randall S.; Lowe, Mark J.; Beall, Erik B.; Koenig, Katherine A.; Parsons, Michael; Troyanskaya, Maya; Reece, Christine; Wilde, Elisabeth; Fischer, Barbara L.; Jones, Stephen E.; Agarwal, Rajan; Levin, Harvey S.; Rao, Stephen M.

    2015-01-01

    Mild to moderate traumatic brain injury (TBI) due to blast exposure is frequently diagnosed in veterans returning from the wars in Iraq and Afghanistan. However, it is unclear whether neural damage resulting from blast TBI differs from that found in TBI due to blunt-force trauma (e.g., falls and motor vehicle crashes). Little is also known about the effects of blast TBI on neural networks, particularly over the long term. Because impairment in working memory has been linked to blunt-force TBI, the present functional magnetic resonance imaging (fMRI) study sought to investigate whether brain activation in response to a working memory task would discriminate blunt-force from blast TBI. Twenty-five veterans (mean age = 29.8 years, standard deviation = 6.01 years, 1 female) who incurred TBI due to blast an average of 4.2 years prior to enrollment and 25 civilians (mean age = 27.4 years, standard deviation = 6.68 years, 4 females) with TBI due to blunt-force trauma performed the Sternberg Item Recognition Task while undergoing fMRI. The task involved encoding 1, 3, or 5 items in working memory. A group of 25 veterans (mean age = 29.9 years, standard deviation = 5.53 years, 0 females) and a group of 25 civilians (mean age = 27.3 years, standard deviation = 5.81 years, 0 females) without history of TBI underwent identical imaging procedures and served as controls. Results indicated that the civilian TBI group and both control groups demonstrated a monotonic relationship between working memory set size and activation in the right caudate during encoding, whereas the blast TBI group did not (p < 0.05, corrected for multiple comparisons using False Discovery Rate). Blast TBI was also associated with worse performance on the Sternberg Item Recognition Task relative to the other groups, although no other group differences were found on neuropsychological measures of episodic memory, inhibition, and general processing speed. These results could not be

  19. CT-Guided Percutaneous Step-by-Step Radiofrequency Ablation for the Treatment of Carcinoma in the Caudate Lobe.

    PubMed

    Dong, Jun; Li, Wang; Zeng, Qi; Li, Sheng; Gong, Xiao; Shen, Lujun; Mao, Siyue; Dong, Annan; Wu, Peihong

    2015-09-01

    The location of the caudate lobe and its complex anatomy make caudate lobectomy and radiofrequency ablation (RFA) under ultrasound guidance technically challenging. The objective of the exploratory study was to introduce a novel modality of treatment of lesions in caudate lobe and discuss all details with our experiences to make this novel treatment modality repeatable and educational. The study enrolled 39 patients with liver caudate lobe tumor first diagnosed by computerized tomography (CT) or magnetic resonance imaging (MRI). After consultation of multi-disciplinary team, 7 patients with hepatic caudate lobe lesions were enrolled and accepted CT-guided percutaneous step-by-step RFA treatment. A total of 8 caudate lobe lesions of the 7 patients were treated by RFA in 6 cases and RFA combined with percutaneous ethanol injection (PEI) in 1 case. Median tumor diameter was 29 mm (range, 18-69 mm). A right approach was selected for 6 patients and a dorsal approach for 1 patient. Median operative time was 64 min (range, 59-102 min). Median blood loss was 10 mL (range, 8-16 mL) and mainly due to puncture injury. Median hospitalization time was 4 days (range, 2-5 days). All lesions were completely ablated (8/8; 100%) and no recurrence at the site of previous RFA was observed during median 8 months follow-up (range 3-11 months). No major or life-threatening complications or deaths occurred. In conclusion, percutaneous step-by-step RFA under CT guidance is a novel and effective minimally invasive therapy for hepatic caudate lobe lesions with well repeatability.

  20. The topographic order of inputs to nucleus accumbens in the rat.

    PubMed

    Phillipson, O T; Griffiths, A C

    1985-10-01

    Afferents to the nucleus accumbens have been studied with the retrograde transport of unconjugated wheatgerm agglutinin as detected by immunohistochemistry using the peroxidase-antiperoxidase method, in order to define precisely afferent topography from the cortex, thalamus, midbrain and amygdala. Cortical afferent topography was extremely precise. The largest number of cells was found following injections to the anterior accumbens. Anteromedial injections labelled a very large extent of the subiculum and part of the entorhinal cortex. Anterolateral injections produced less subicular and entorhinal label but also labelled the posterior perirhinal cortex. Posteromedial injections labelled only the ventral subiculum and a few cells in the adjacent medial entorhinal cortex. Posterolateral injections labelled few lateral entorhinal neurones but did label a long anteroposterior strip of perirhinal cortex. Prefrontal cortex label was found only after anterior accumbens injections. In the amygdala labelled neurones were found in cortical, central, lateral posterior, anteromedial and basolateral nuclei. Basolateral amygdala projected chiefly to the anteromedial accumbens and central nucleus to anterolateral accumbens. Only a weak amygdala label was found after posterior accumbens injections. In the ventral tegmental area, the midline interfascicular nucleus projected only to medial accumbens. The paranigral ventral tegmentum projected chiefly to the medial accumbens and the parabrachial area chiefly to the lateral accumbens. In the thalamus, heaviest label was found after anterior accumbens injections. Most cells were found in the paraventricular, reuniens and rhomboid nuclei and at posterior thalamic levels lying medial to the fasciculus retroflexus. There was only restricted topography found from thalamic sites. Retrograde label was also found in the ventral pallidum and lateral hypothalamus. Single small injection sites within accumbens received input from the whole

  1. Effects of cytotoxic nucleus accumbens lesions on instrumental conditioning in rats.

    PubMed

    de Borchgrave, R; Rawlins, J N P; Dickinson, A; Balleine, B W

    2002-05-01

    In two experiments the involvement of the nucleus accumbens in instrumental conditioning was investigated using rats as subjects. In experiment 1, extensive bilateral cytotoxic lesions of the nucleus accumbens mildly suppressed instrumental responding reinforced with food, but had no detectable effect on the sensitivity of the rats' performance either to outcome devaluation or to degradation of the instrumental contingency. In experiment 2, restricted accumbens lesions reliably attenuated the excitatory effect of systemically administered d-amphetamine on lever pressing for a conditioned reinforcer, and completely abolished Pavlovian-instrumental transfer. Taken together these results give a picture of the involvement of the rat nucleus accumbens in instrumental conditioning. They support the widely held theory that the nucleus accumbens mediates the excitatory effects of appetitively conditioned Pavlovian signals on instrumental performance and refute the hypothesis that the nucleus accumbens is part of the neural circuitry by which incentive value is attached to the representations of instrumental outcomes.

  2. 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

  3. 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

  4. 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.

  5. Higher Landing Accuracy in Expert Pilots is Associated with Lower Activity in the Caudate Nucleus

    PubMed Central

    Adamson, Maheen M.; Taylor, Joy L.; Heraldez, Daniel; Khorasani, Allen; Noda, Art; Hernandez, Beatriz; Yesavage, Jerome A.

    2014-01-01

    The most common lethal accidents in General Aviation are caused by improperly executed landing approaches in which a pilot descends below the minimum safe altitude without proper visual references. To understand how expertise might reduce such erroneous decision-making, we examined relevant neural processes in pilots performing a simulated landing approach inside a functional MRI scanner. Pilots (aged 20–66) were asked to “fly” a series of simulated “cockpit view” instrument landing scenarios in an MRI scanner. The scenarios were either high risk (heavy fog–legally unsafe to land) or low risk (medium fog–legally safe to land). Pilots with one of two levels of expertise participated: Moderate Expertise (Instrument Flight Rules pilots, n = 8) or High Expertise (Certified Instrument Flight Instructors or Air-Transport Pilots, n = 12). High Expertise pilots were more accurate than Moderate Expertise pilots in making a “land” versus “do not land” decision (CFII: d′ = 3.62±2.52; IFR: d′ = 0.98±1.04; p<.01). Brain activity in bilateral caudate nucleus was examined for main effects of expertise during a “land” versus “do not land” decision with the no-decision control condition modeled as baseline. In making landing decisions, High Expertise pilots showed lower activation in the bilateral caudate nucleus (0.97±0.80) compared to Moderate Expertise pilots (1.91±1.16) (p<.05). These findings provide evidence for increased “neural efficiency” in High Expertise pilots relative to Moderate Expertise pilots. During an instrument approach the pilot is engaged in detailed examination of flight instruments while monitoring certain visual references for making landing decisions. The caudate nucleus regulates saccade eye control of gaze, the brain area where the “expertise” effect was observed. These data provide evidence that performing “real world” aviation tasks in an fMRI provide objective data regarding the

  6. Oestradiol modulation of serotonin reuptake transporter and serotonin metabolism in the brain of monkeys.

    PubMed

    Sánchez, M G; Morissette, M; Di Paolo, T

    2013-06-01

    Serotonin (5-hydroxytryptamine; 5-HT) is an important brain neurotransmitter that is implicated in mental and neurodegenerative diseases and is modulated by ovarian hormones. Nevertheless, the effect of oestrogens on 5-HT neurotransmission in the primate caudate nucleus, putamen and nucleus accumbens, which are major components of the basal ganglia, and the anterior cerebral cortex, mainly the frontal and cingulate gyrus, is not well documented. The present study evaluated 5-HT reuptake transporter (SERT) and 5-HT metabolism in these brain regions in response to 1-month treatment with 17β-oestradiol in short-term (1 month) ovariectomised (OVX) monkeys (Macaca fascicularis). SERT-specific binding was measured by autoradiography using the radioligand [³H]citalopram. Biogenic amine concentrations were quantified by high-performance liquid chromatography. 17β-Oestradiol increased SERT in the superior frontal cortex and in the anterior cingulate cortex, in the nucleus accumbens, and in subregions of the caudate nucleus of OVX monkeys. 17β-Oestradiol left [³H]citalopram-specific binding unchanged in the putamen, as well as the dorsal and medial raphe nucleus. 17β-Oestradiol treatment decreased striatal concentrations of the precursor of 5-HT, 5-hydroxytryptophan, and increased 5-HT, dopamine and 3-methoxytyramine concentrations in the nucleus accumbens, caudate nucleus and putamen, whereas the concentrations of the metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid remained unchanged. No effect of 17β-oestradiol treatment was observed for biogenic amine concentrations in the cortical regions. A significant positive correlation was observed between [³H]citalopram-specific binding and 5-HT concentrations in the caudate nucleus, putamen and nucleus accumbens, suggesting their link. These results have translational value for women with low oestrogen, such as those in surgical menopause or perimenopause. PMID:23414342

  7. Abnormal resting-state functional connectivity of the left caudate nucleus in obsessive-compulsive disorder.

    PubMed

    Chen, Yunhui; Juhás, Michal; Greenshaw, Andrew J; Hu, Qiang; Meng, Xin; Cui, Hongsheng; Ding, Yongzhuo; Kang, Lu; Zhang, Yubo; Wang, Yuhua; Cui, Guangcheng; Li, Ping

    2016-06-01

    Altered brain activities in the cortico-striato-thalamocortical (CSTC) circuitry are implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, whether the underlying changes occur only within this circuitry or in large-scale networks is still not thoroughly understood. This study performed voxel-based functional connectivity analysis on resting-state functional magnetic resonance imaging (fMRI) data from thirty OCD patients and thirty healthy controls to investigate whole-brain intrinsic functional connectivity patterns in OCD. Relative to the healthy controls, OCD patients showed decreased functional connectivity within the CSTC circuitry but increased functional connectivity in other brain regions. Furthermore, decreased left caudate nucleus-thalamus connectivity within the CSTC circuitry was positively correlated with the illness duration of OCD. This study provides additional evidence that CSTC circuitry may play an essential role and alteration of large-scale brain networks may be involved in the pathophysiology of OCD. PMID:27143323

  8. Semantic memory retrieval circuit: role of pre-SMA, caudate, and thalamus.

    PubMed

    Hart, John; Maguire, Mandy J; Motes, Michael; Mudar, Raksha Anand; Chiang, Hsueh-Sheng; Womack, Kyle B; Kraut, Michael A

    2013-07-01

    We propose that pre-supplementary motor area (pre-SMA)-thalamic interactions govern processes fundamental to semantic retrieval of an integrated object memory. At the onset of semantic retrieval, pre-SMA initiates electrical interactions between multiple cortical regions associated with semantic memory subsystems encodings as indexed by an increase in theta-band EEG power. This starts between 100-150 ms after stimulus presentation and is sustained throughout the task. We posit that this activity represents initiation of the object memory search, which continues in searching for an object memory. When the correct memory is retrieved, there is a high beta-band EEG power increase, which reflects communication between pre-SMA and thalamus, designates the end of the search process and resultant in object retrieval from multiple semantic memory subsystems. This high beta signal is also detected in cortical regions. This circuit is modulated by the caudate nuclei to facilitate correct and suppress incorrect target memories.

  9. Trait positive affect is associated with hippocampal volume and change in caudate volume across adolescence.

    PubMed

    Dennison, Meg; Whittle, Sarah; Yücel, Murat; Byrne, Michelle L; Schwartz, Orli; Simmons, Julian G; Allen, Nicholas B

    2015-03-01

    Trait positive affect (PA) in childhood confers both risk and resilience to psychological and behavioral difficulties in adolescence, although explanations for this association are lacking. Neurodevelopment in key areas associated with positive affect is ongoing throughout adolescence, and is likely to be related to the increased incidence of disorders of positive affect during this period of development. The aim of this study was to prospectively explore the relationship between trait indices of PA and brain development in subcortical reward regions during early to mid-adolescence in a community sample of adolescents. A total of 89 (46 male, 43 female) adolescents participated in magnetic resonance imaging assessments during both early and mid-adolescence (mean age at baseline = 12.6 years, SD = 0.45; mean follow-up period = 3.78 years, SD = 0.21) and also completed self-report measures of trait positive and negative affect (at baseline). To examine the specificity of these effects, the relation between negative affect and brain development was also examined. The degree of volume reduction in the right caudate over time was predicted by PA. Independent of time, larger hippocampal volumes were associated with higher PA, and negative affect was associated with smaller left amygdala volume. The moderating effect of negative affect on the development of the left caudate varied as a function of lifetime psychiatric history. These findings suggest that early to mid-adolescence is an important period whereby neurodevelopmental processes may underlie key phenotypes conferring both risk and resilience for emotional and behavioral difficulties later in life. PMID:25231241

  10. Synchronized Drumming Enhances Activity in the Caudate and Facilitates Prosocial Commitment - If the Rhythm Comes Easily

    PubMed Central

    Kokal, Idil; Engel, Annerose; Kirschner, Sebastian; Keysers, Christian

    2011-01-01

    Why does chanting, drumming or dancing together make people feel united? Here we investigate the neural mechanisms underlying interpersonal synchrony and its subsequent effects on prosocial behavior among synchronized individuals. We hypothesized that areas of the brain associated with the processing of reward would be active when individuals experience synchrony during drumming, and that these reward signals would increase prosocial behavior toward this synchronous drum partner. 18 female non-musicians were scanned with functional magnetic resonance imaging while they drummed a rhythm, in alternating blocks, with two different experimenters: one drumming in-synchrony and the other out-of-synchrony relative to the participant. In the last scanning part, which served as the experimental manipulation for the following prosocial behavioral test, one of the experimenters drummed with one half of the participants in-synchrony and with the other out-of-synchrony. After scanning, this experimenter “accidentally” dropped eight pencils, and the number of pencils collected by the participants was used as a measure of prosocial commitment. Results revealed that participants who mastered the novel rhythm easily before scanning showed increased activity in the caudate during synchronous drumming. The same area also responded to monetary reward in a localizer task with the same participants. The activity in the caudate during experiencing synchronous drumming also predicted the number of pencils the participants later collected to help the synchronous experimenter of the manipulation run. In addition, participants collected more pencils to help the experimenter when she had drummed in-synchrony than out-of-synchrony during the manipulation run. By showing an overlap in activated areas during synchronized drumming and monetary reward, our findings suggest that interpersonal synchrony is related to the brain's reward system. PMID:22110623

  11. Abnormal Degree Centrality of Bilateral Putamen and Left Superior Frontal Gyrus in Schizophrenia with Auditory Hallucinations: A Resting-state Functional Magnetic Resonance Imaging Study

    PubMed Central

    Chen, Cheng; Wang, Hui-Ling; Wu, Shi-Hao; Huang, Huan; Zou, Ji-Lin; Chen, Jun; Jiang, Tian-Zi; Zhou, Yuan; Wang, Gao-Hua

    2015-01-01

    Background: Dysconnectivity hypothesis of schizophrenia has been increasingly emphasized. Recent researches showed that this dysconnectivity might be related to occurrence of auditory hallucination (AH). However, there is still no consistent conclusion. This study aimed to explore intrinsic dysconnectivity pattern of whole-brain functional networks at voxel level in schizophrenic with AH. Methods: Auditory hallucinated patients group (n = 42 APG), no hallucinated patients group (n = 42 NPG) and normal controls (n = 84 NCs) were analyzed by resting-state functional magnetic resonance imaging. The functional connectivity metrics index (degree centrality [DC]) across the entire brain networks was calculated and evaluated among three groups. Results: DC decreased in the bilateral putamen and increased in the left superior frontal gyrus in all the patients. However, in APG, the changes of DC were more obvious compared with NPG. Symptomology scores were negatively correlated with the DC of bilateral putamen in all patients. AH score of APG positively correlated with the DC in left superior frontal gyrus but negatively correlated with the DC in bilateral putamen. Conclusion: Our findings corroborated that schizophrenia was characterized by functional dysconnectivity, and the abnormal DC in bilateral putamen and left superior frontal gyrus might be crucial in the occurrence of AH. PMID:26612293

  12. Caudate asymmetry is related to attentional impulsivity and an objective measure of ADHD-like attentional problems in healthy adults.

    PubMed

    Dang, Linh C; Samanez-Larkin, Gregory R; Young, Jacob S; Cowan, Ronald L; Kessler, Robert M; Zald, David H

    2016-01-01

    Case-control studies comparing ADHD with typically developing individuals suggest that anatomical asymmetry of the caudate nucleus is a marker of attention deficit hyperactivity disorder (ADHD). However, there is no consensus on whether the asymmetry favors the right or left caudate nucleus in ADHD, or whether the asymmetry is increased or decreased in ADHD. The current study aimed to clarify this relationship by applying a dimensional approach to assessing ADHD symptoms that, instead of relying on clinical classification, utilizes the natural behavioral continuum of traits related to ADHD. Structural T1-weighted MRI was collected from 71 adults between 18 and 35 years and analyzed for caudate asymmetry. ADHD-like attentional symptoms were assessed with an objective measure of attentional problems, the ADHD score from the Test of Variables of Attention (TOVA). Impulsivity, a core feature in ADHD, was measured using the Barratt Impulsiveness Scale, a self-report measure that assesses attentional, non-planning, and motor features of impulsivity. We found that larger right relative to left caudate volumes correlated with both higher attentional impulsiveness and worse ADHD scores on the TOVA. Higher attentional impulsiveness also correlated with worse ADHD scores, establishing coherence between the objective measure and the self-report measure of attentional problems. These results suggest that a differential passage of information through frontal-striatal networks may produce instability leading to attentional problems. The findings also demonstrate the utility of a dimensional approach to understanding structural correlates of ADHD symptoms.

  13. Clinical correlations of grey matter reductions in the caudate nucleus of adults with attention deficit hyperactivity disorder

    PubMed Central

    Montes, Luis Guillermo Almeida; Ricardo-Garcell, Josefina; De La Torre, Lázaro Barajas; Alcántara, Hugo Prado; García, Reyna Beatriz Martínez; Fernández-Bouzas, Antonio; Acosta, David Ávila

    2010-01-01

    Background Magnetic resonance imaging (MRI) studies have shown decreased caudate volumes in individuals with attention deficit hyperactivity disorder (ADHD). However, most of these studies have been carried out in male children. Very little research has been done in adults, and the results obtained in children are difficult to extrapolate to adults. We sought to compare the volume of the caudate of adults with ADHD with that of healthy controls; we also compared these volumes between men and women. Methods We performed an MRI scan on 20 adults with ADHD (10 men and 10 women) aged 25–35 years and 20 healthy controls matched by age and sex. We used voxel-based morphometry with the DARTEL algorithm for image analyses. We used the specifically designed Friederichsen, Almeida, Serrano, Cortes Test (FASCT) to measure the severity of ADHD; both the self-reported (FASCT-SR) and the observer (FASCT-O) versions were used. Results The statistical parametric map showed a smaller region with low grey matter volume and a smaller concentration of grey matter in this region of the right caudate in ADHD patients than in health controls, both in the entire sample and within each sex. There was a significant correlation between the volume of this region of the caudate with the number of DSM IV-TR criteria, as well as with the total scores and most of the factors of the FASCT-SR and FASCT-O scales. A separate correlation analysis by sex gave similar results. Limitations The study design was cross-sectional. Conclusion The region of the right caudate with low grey matter volume was smaller in adults with ADHD in both sexes and was correlated with ADHD severity. PMID:20569650

  14. 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.

  15. Functional properties of monkey caudate neurons. III. Activities related to expectation of target and reward.

    PubMed

    Hikosaka, O; Sakamoto, M; Usui, S

    1989-04-01

    1. The present paper reports complex neural activities in the monkey caudate nucleus that precede and anticipate visual stimuli and reward in learned visuomotor paradigms. These activities were revealed typically in the delayed saccade task in which memory and anticipation were required. We classified these activities according to their relationships to the task. 2. Activity related to expectation of a cue (n = 46) preceded the presentation of a spot of light (target cue) that signified the future location of saccade target. When the target cue was delayed, the activity was prolonged accordingly. The same spot of light was preceded by no activity if it acted as a distracting stimulus. 3. The sustained activity (n = 80) was a tonic discharge starting after the target cue as if holding the spatial information. 4. The activity related to expectation of target (n = 109) preceded the appearance of the target whose location was cued previously. It started with or after a saccade to the cued target location and ended with the appearance of the target. The activity was greater when the target was expected to appear in the contralateral visual field. 5. The activity related to expectation of reward (n = 57) preceded a task-specific reward. It started with the appearance of the final target and ended with the reward. In most cases, the activity was nonselective for how the monkey obtained the reward, i.e., by visual fixation only, by a saccade, or by a hand movement. The activity was dependent partly on visual fixation. 6. A few neurons showed tonic activity selectively before lever release and are thus considered to be related to the preparation of hand movements. 7. The activity related to breaking fixation (n = 33) occurred phasically if the monkey broke fixation, aborting the trial. 8. Activity related to reward (n = 104) was a phasic discharge that occurred before or after a reward of water was delivered. The activity was not simply related to a specific movement

  16. Cocaine exposure alters dopaminergic modulation of prefronto-accumbens transmission.

    PubMed

    Wang, Xiusong; Liu, Lei; Adams, Wendy; Li, Shouxin; Zhang, Qian; Li, Bingjin; Wang, Min; Cui, Ranji

    2015-06-01

    In the nucleus accumbens (NAc), dopamine transmission modulates glutamatergic input from the prefrontal cortex (PFC). This neuromodulatory action of dopamine can be disrupted by repeated exposure to psychostimulants such as cocaine. However, it is unclear whether this modulation depends on the precise timing of transmission at the same medium spiny neurons (MSNs) and if so, then whether this timing related modulation is also influenced by cocaine experience. Here, combining cocaine self-administration and in vivo extracellular recordings in anesthetized rats, we show that dopamine efflux in the NAc evoked by electrically stimulating the ventral tegmental area (VTA) exerted timing-dependent regulation of the excitatory accumbens response to stimulation of the medial prefrontal cortex (mPFC), and also that this modulation was blunted following prolonged abstinence from cocaine self-administration. These data indicate that dopaminergic timing-dependent dysregulation of mPFC-NAc glutamatergic transmission is implicated in cocaine addiction and might contribute to vulnerability to drug relapse after prolonged abstinence.

  17. Caudate responses to reward anticipation associated with delay discounting behavior in healthy youth

    PubMed Central

    Benningfield, Margaret M.; Blackford, Jennifer U.; Ellsworth, Melissa E.; Samanez-Larkin, Gregory R.; Martin, Peter R.; Cowan, Ronald L.; Zald, David H.

    2014-01-01

    Background Choices requiring delay of gratification made during adolescence can have significant impact on life trajectory. Willingness to delay gratification can be measured using delay discounting tasks that require a choice between a smaller immediate reward and a larger delayed reward. Individual differences in the subjective value of delayed rewards are associated with risk for development of psychopathology including substance abuse. The neurobiological underpinnings related to these individual differences early in life are not fully understood. Using functional magnetic resonance imaging (fMRI), we tested the hypothesis that individual differences in delay discounting behavior in healthy youth are related to differences in responsiveness to potential reward. Method Nineteen 10 to 14 year-olds performed a monetary incentive delay task to assess neural sensitivity to potential reward and a questionnaire to measure discounting of future monetary rewards. Results Left ventromedial caudate activation during anticipation of potential reward was negatively correlated with delay discounting behavior. There were no regions where brain responses during notification of reward outcome were associated with discounting behavior. Conclusions Brain activation during anticipation of potential reward may serve as a marker for individual differences in ability or willingness to delay gratification in healthy youth. PMID:24309299

  18. Oxytocin in hypothalamic supraoptic nucleus is transferred to the caudate nucleus to influence pain modulation.

    PubMed

    Pan, Yang-Juan; Wang, Da-Xin; Yang, Jun; He, Xue-Ling; Xiao, Nai-Min; Ma, Rui-Qing; Wang, Chang-Hong; Lin, Bao-Cheng

    2016-08-01

    Oxytocin (OXT), which is synthesized and secreted in the hypothalamic supraoptic nucleus (SON), is the most important bioactive substance in SON regulating pain process. Our previous study has pointed that OXT in the caudate nucleus (CdN) plays a role in pain modulation. The communication was designed to investigate the source of OXT in the rat CdN during pain process using the methods of push-pull perfusion and radioimmunoassay. The results showed that (1) pain stimulation increased the OXT concentration in the CdN perfusion liquid; (2) SON cauterization inhibited the increase of OXT concentration in CdN perfusion liquid induced by the pain stimulation, which role in both sides of SON cauterization was stronger than that in one side of SON cauterization; and (3) SON microinjection of l-glutamate sodium, which excited the SON neurons, increased OXT concentration in the CdN perfusion liquid. The data suggested that OXT in the CdN was influenced by SON during pain process, i.e., OXT in the SON might be transferred to the CdN to influence pain modulation. PMID:27045802

  19. Feedback on Trait or Action Impacts on Caudate and Paracingulum Activity.

    PubMed

    Appelgren, Alva; Bengtsson, Sara L

    2015-01-01

    There is a general conception that positive associations to one's trait, e.g. 'I'm clever', are beneficial for cognitive performance. Scientific evidence shows that this is a simplification. In this functional magnetic resonance imaging (fMRI) study we used written trial-based trait feedback 'you are clever', or task feedback 'your choice was correct', on each correct response of a rule-switching task, to investigate how the character of positive self-associations influences performance outcome. Twenty participants took part in this crossover design study. We found that trait feedback was less beneficial for motivation and performance improvement, and resulting in enhanced neural activation on more difficult bivalent rule trials. This indicates that the task was treated as more complex in this condition. For example, 'you are clever' feedback led to enhanced activation in anterior caudate nucleus, an area known to process uncertainty. We further observed that activation in anterior paracingulate cortex was sensitive to whether self-reflection was imposed by external feedback or generated from internal processes, where the latter activation correlated positively with performance when following after task feedback. Our results illustrate how feedback can evoke self-reflections that either help or hinder motivation and performance, most likely by impacting on processes of uncertainty. The results support social psychological models stipulating that trait focus take resources away from task focus.

  20. Caudate nucleus reactivity predicts perceptual learning rate for visual feature conjunctions.

    PubMed

    Reavis, Eric A; Frank, Sebastian M; Tse, Peter U

    2015-04-15

    Useful information in the visual environment is often contained in specific conjunctions of visual features (e.g., color and shape). The ability to quickly and accurately process such conjunctions can be learned. However, the neural mechanisms responsible for such learning remain largely unknown. It has been suggested that some forms of visual learning might involve the dopaminergic neuromodulatory system (Roelfsema et al., 2010; Seitz and Watanabe, 2005), but this hypothesis has not yet been directly tested. Here we test the hypothesis that learning visual feature conjunctions involves the dopaminergic system, using functional neuroimaging, genetic assays, and behavioral testing techniques. We use a correlative approach to evaluate potential associations between individual differences in visual feature conjunction learning rate and individual differences in dopaminergic function as indexed by neuroimaging and genetic markers. We find a significant correlation between activity in the caudate nucleus (a component of the dopaminergic system connected to visual areas of the brain) and visual feature conjunction learning rate. Specifically, individuals who showed a larger difference in activity between positive and negative feedback on an unrelated cognitive task, indicative of a more reactive dopaminergic system, learned visual feature conjunctions more quickly than those who showed a smaller activity difference. This finding supports the hypothesis that the dopaminergic system is involved in visual learning, and suggests that visual feature conjunction learning could be closely related to associative learning. However, no significant, reliable correlations were found between feature conjunction learning and genotype or dopaminergic activity in any other regions of interest.

  1. Comparative studies on the vascular organization of carotid labyrinths of anurans and caudates.

    PubMed

    Kusakabe, T

    1990-04-01

    The three-dimensional structures of the carotid labyrinth in five species of anurans representing four families (Rana nigromaculata, Rana catesbeiana, Bufo japonicus, Hyla arborea, and Xenopus laevis), and three species of caudates representing three families (Cynops pyrrhogaster, Hynobius nebulosus, Ambystoma mexicanum) were compared using vascular corrosion castings and scanning electron microscopy (SEM). Anuran carotid labyrinths are spherical in shape and are classified into two groups according to the origin of the external and internal carotid arteries. One group, which included Rana, Hyla, and Bufo, is characterized by the presence of a vascular ring at the proximal end and some vascular routes at the distal end of the labyrinth. The external and internal carotid arteries originate from these structures. The other group, which includes only Xenopus, is characterized by the external carotid artery opening directly from the central chamber or the common carotid artery, and by the internal carotid artery originating from within the vascular maze. The vascular maze is most complex in Xenopus, less so in Rana and Bufo, and simplest in Hyla. The carotid labyrinths in Cynops and Hynobius are oblong in shape. The fundamental organization in salamanders is similar to that in anurans. The vascular maze, however, is much simpler than in Hyla. There is no specialized swelling in Ambystoma mexicanum. The present findings suggest that most amphibian carotid labyrinths have the appropriate architecture for controlling vascular tone.

  2. Activity of Caudate Nucleus Neurons in a Visual Fixation Paradigm in Behaving Cats

    PubMed Central

    Nagypál, Tamás; Gombkötő, Péter; Barkóczi, Balázs; Benedek, György; Nagy, Attila

    2015-01-01

    Beside its motor functions, the caudate nucleus (CN), the main input structure of the basal ganglia, is also sensitive to various sensory modalities. The goal of the present study was to investigate the effects of visual stimulation on the CN by using a behaving, head-restrained, eye movement-controlled feline model developed recently for this purpose. Extracellular multielectrode recordings were made from the CN of two cats in a visual fixation paradigm applying static and dynamic stimuli. The recorded neurons were classified in three groups according to their electrophysiological properties: phasically active (PAN), tonically active (TAN) and high-firing (HFN) neurons. The response characteristics were investigated according to this classification. The PAN and TAN neurons were sensitive primarily to static stimuli, while the HFN neurons responded primarily to changes in the visual environment i.e. to optic flow and the offset of the stimuli. The HFNs were the most sensitive to visual stimulation; their responses were stronger than those of the PANs and TANs. The majority of the recorded units were insensitive to the direction of the optic flow, regardless of group, but a small number of direction-sensitive neurons were also found. Our results demonstrate that both the static and the dynamic components of the visual information are represented in the CN. Furthermore, these results provide the first piece of evidence on optic flow processing in the CN, which, in more general terms, indicates the possible role of this structure in dynamic visual information processing. PMID:26544604

  3. Caudate nucleus and programming behaviour in cats: role of dopamine in switching motor patterns.

    PubMed

    Jaspers, R; Schwarz, M; Sontag, K H; Cools, A R

    1984-10-01

    Cats were trained to walk on a specially designed treadmill: the cats were able to collect food pellets by switching motor patterns with or without the help of exteroceptive stimuli inherent to the treadmill. To study the involvement of the caudate nucleus in switching motor patterns cats received intracaudate bilateral injections of haloperidol. In addition, in a final series of experiments, EMG recordings of two antagonistic muscles, together with recordings of characteristic changes in the length of one muscle, were made before and after the haloperidol treatment. Haloperidol treatment resulted in a decreased number of motor patterns which were not directed by exteroceptive stimuli (non-exteroceptively directed motor patterns). This haloperidol-induced effect was dose-dependently counteracted by the additional intracaudate injections of apomorphine which per se remained ineffective. Haloperidol neither altered the number of food collecting attempts nor reduced the number of exteroceptively directed motor patterns. Furthermore, haloperidol did not affect the capacity to switch to proprioceptively directed motor patterns. Finally, haloperidol did not produce abnormalities in EMG and length signals recorded from hindlimb muscles. It is concluded that haloperidol selectively reduced the animal's capacity to 'programme non-stimulus directed motor behaviour'. The data are discussed in view of their significance for therapy of patients with basal ganglia disorders, such as patients suffering from Parkinson's disease.

  4. 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

  5. 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

  6. 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

  7. One pair of hands is not like another: caudate BOLD response in dogs depends on signal source and canine temperament

    PubMed Central

    Cook, Peter F.; Spivak, Mark

    2014-01-01

    Having previously used functional MRI to map the response to a reward signal in the ventral caudate in awake unrestrained dogs, here we examined the importance of signal source to canine caudate activation. Hand signals representing either incipient reward or no reward were presented by a familiar human (each dog’s respective handler), an unfamiliar human, and via illustrated images of hands on a computer screen to 13 dogs undergoing voluntary fMRI. All dogs had received extensive training with the reward and no-reward signals from their handlers and with the computer images and had minimal exposure to the signals from strangers. All dogs showed differentially higher BOLD response in the ventral caudate to the reward versus no reward signals, and there was a robust effect at the group level. Further, differential response to the signal source had a highly significant interaction with a dog’s general aggressivity as measured by the C-BARQ canine personality assessment. Dogs with greater aggressivity showed a higher differential response to the reward signal versus no-reward signal presented by the unfamiliar human and computer, while dogs with lower aggressivity showed a higher differential response to the reward signal versus no-reward signal from their handler. This suggests that specific facets of canine temperament bear more strongly on the perceived reward value of relevant communication signals than does reinforcement history, as each of the dogs were reinforced similarly for each signal, regardless of the source (familiar human, unfamiliar human, or computer). A group-level psychophysiological interaction (PPI) connectivity analysis showed increased functional coupling between the caudate and a region of cortex associated with visual discrimination and learning on reward versus no-reward trials. Our findings emphasize the sensitivity of the domestic dog to human social interaction, and may have other implications and applications pertinent to the training

  8. Chemoembolization of Extrahepatic Collateral Arteries for Treatment of Hepatocellular Carcinoma in the Caudate Lobe of the Liver

    SciTech Connect

    Woo, Sungmin; Kim, Hyo-Cheol Chung, Jin Wook; Jung, Hyun-Seok; Hur, Saebeom; Lee, Myungsu; Jae, Hwan Jun

    2015-04-15

    PurposeThis study was designed to evaluate the efficacy and safety in performing chemoembolization of extrahepatic collateral arteries (EHC) for hepatocellular carcinoma (HCC) located in the caudate lobe.MethodsBetween January 2006 and November 2013, chemoembolization via EHC was performed in 35 patients with 35 caudate HCCs. Preprocedural and follow-up CT or MR scans, angiographic images, and medical records were reviewed retrospectively in consensus. Chi-square analysis was used to evaluate the relationship between tumor characteristics and type of EHC and that between tumor response and the characteristics of the tumor and chemoembolization.ResultsIn 31 (88.6 %) patients, EHCs supplying the caudate HCC originated from the right inferior phrenic artery (RIPA). The remaining four HCCs were supplied by the gastroduodenal artery, dorsal pancreatic artery, and right and left gastric arteries. Superselective catheterization of tumor-feeding vessels from the EHC was achieved in 27 patients (77.1 %). There were no major complications. Individual tumor response supplied by the EHC at follow-up contrast-enhanced CT were as follows: complete response (n = 18), partial response (n = 9), stable disease (n = 3), and progressive disease (n = 3). Non-RIPA EHCs were significantly more common in patients who had previously received chemoembolization via the RIPA (50 %) than those who had not (6.5 %; P = 0.01). There was no significant predictive factor associated with tumor response.ConclusionsHCC in the caudate lobe can be supplied by several EHCs. Chemoembolization via these arteries can be performed safely and effectively.

  9. One pair of hands is not like another: caudate BOLD response in dogs depends on signal source and canine temperament.

    PubMed

    Cook, Peter F; Spivak, Mark; Berns, Gregory S

    2014-01-01

    Having previously used functional MRI to map the response to a reward signal in the ventral caudate in awake unrestrained dogs, here we examined the importance of signal source to canine caudate activation. Hand signals representing either incipient reward or no reward were presented by a familiar human (each dog's respective handler), an unfamiliar human, and via illustrated images of hands on a computer screen to 13 dogs undergoing voluntary fMRI. All dogs had received extensive training with the reward and no-reward signals from their handlers and with the computer images and had minimal exposure to the signals from strangers. All dogs showed differentially higher BOLD response in the ventral caudate to the reward versus no reward signals, and there was a robust effect at the group level. Further, differential response to the signal source had a highly significant interaction with a dog's general aggressivity as measured by the C-BARQ canine personality assessment. Dogs with greater aggressivity showed a higher differential response to the reward signal versus no-reward signal presented by the unfamiliar human and computer, while dogs with lower aggressivity showed a higher differential response to the reward signal versus no-reward signal from their handler. This suggests that specific facets of canine temperament bear more strongly on the perceived reward value of relevant communication signals than does reinforcement history, as each of the dogs were reinforced similarly for each signal, regardless of the source (familiar human, unfamiliar human, or computer). A group-level psychophysiological interaction (PPI) connectivity analysis showed increased functional coupling between the caudate and a region of cortex associated with visual discrimination and learning on reward versus no-reward trials. Our findings emphasize the sensitivity of the domestic dog to human social interaction, and may have other implications and applications pertinent to the training and

  10. Activity levels in the left hemisphere caudate-fusiform circuit predict how well a second language will be learned.

    PubMed

    Tan, Li Hai; Chen, Lin; Yip, Virginia; Chan, Alice H D; Yang, Jing; Gao, Jia-Hong; Siok, Wai Ting

    2011-02-01

    How second language (L2) learning is achieved in the human brain remains one of the fundamental questions of neuroscience and linguistics. Previous neuroimaging studies with bilinguals have consistently shown overlapping cortical organization of the native language (L1) and L2, leading to a prediction that a common neurobiological marker may be responsible for the development of the two languages. Here, by using functional MRI, we show that later skills to read in L2 are predicted by the activity level of the fusiform-caudate circuit in the left hemisphere, which nonetheless is not predictive of the ability to read in the native language. We scanned 10-y-old children while they performed a lexical decision task on L2 (and L1) stimuli. The subjects' written language (reading) skills were behaviorally assessed twice, the first time just before we performed the fMRI scan (time 1 reading) and the second time 1 y later (time 2 reading). A whole-brain based analysis revealed that activity levels in left caudate and left fusiform gyrus correlated with L2 literacy skills at time 1. After controlling for the effects of time 1 reading and nonverbal IQ, or the effect of in-scanner lexical performance, the development in L2 literacy skills (time 2 reading) was also predicted by activity in left caudate and fusiform regions that are thought to mediate language control functions and resolve competition arising from L1 during L2 learning. Our findings suggest that the activity level of left caudate and fusiform regions serves as an important neurobiological marker for predicting accomplishment in reading skills in a new language.

  11. Encoding of both positive and negative reward prediction errors by neurons of the primate lateral prefrontal cortex and caudate nucleus.

    PubMed

    Asaad, Wael F; Eskandar, Emad N

    2011-12-01

    Learning can be motivated by unanticipated success or unexpected failure. The former encourages us to repeat an action or activity, whereas the latter leads us to find an alternative strategy. Understanding the neural representation of these unexpected events is therefore critical to elucidate learning-related circuits. We examined the activity of neurons in the lateral prefrontal cortex (PFC) and caudate nucleus of monkeys as they performed a trial-and-error learning task. Unexpected outcomes were widely represented in both structures, and neurons driven by unexpectedly negative outcomes were as frequent as those activated by unexpectedly positive outcomes. Moreover, both positive and negative reward prediction errors (RPEs) were represented primarily by increases in firing rate, unlike the manner in which dopamine neurons have been observed to reflect these values. Interestingly, positive RPEs tended to appear with shorter latency than negative RPEs, perhaps reflecting the mechanism of their generation. Last, in the PFC but not the caudate, trial-by-trial variations in outcome-related activity were linked to the animals' subsequent behavioral decisions. More broadly, the robustness of RPE signaling by these neurons suggests that actor-critic models of reinforcement learning in which the PFC and particularly the caudate are considered primarily to be "actors" rather than "critics," should be reconsidered to include a prominent evaluative role for these structures. PMID:22159094

  12. Direct evidence of the left caudate's role in bilingual control: an intra-operative electrical stimulation study.

    PubMed

    Wang, Xin; Wang, Yin-Yan; Jiang, Tao; Wang, Yong-Zhi; Wu, Chen-Xing

    2013-01-01

    Bilinguals need control mechanisms in order to switch between languages in different communication contexts (Green, 1998, Bilingualism: Language and Cognition, 1; Price, Green, & von Studnitz, 1999, Brain, 122). There has been neural evidence showing competition to control output in L2 vs. L1 in both cortical and sub-cortical areas, when language selection is carried out (Abutalebi & Green, 2007, Journal of Neurolinguistics, 20). Here we use intra-operative direct electrical stimulation to demonstrate that the head of the left caudate is critical not only in language switching tasks but other control tasks. A bilingual Chinese-English patient was instructed to perform both language switching and switching in color-shape naming tasks during awake glioma surgery. When stimulation was applied on the left caudate, failures or difficulties in both language switching and color-shape naming were observed, with the effects greater on language switching. Stimulation to neighboring brain regions either did not affect performance or generated mild problems specific to language switching. The results provide direct evidence of the necessary role of the left caudate in language control.

  13. Distinct presynaptic control of dopamine release in striosomal and matrix areas of the cat caudate nucleus

    SciTech Connect

    Kemel, M.L.; Desban, M.; Glowinski, J.; Gauchy, C. )

    1989-11-01

    By use of a sensitive in vitro microsuperfusion method, the cholinergic presynaptic control of dopamine release was investigated in a prominent striosome (areas poor in acetylcholinesterase activity) located within the core of cat caudate nucleus and also in adjacent matrix area. The spontaneous release of ({sup 3}H)dopamine continuously synthesized from ({sup 3}H)tyrosine in the matrix area was found to be twice that in the striosomal area; the spontaneous and potassium-evoked releases of ({sup 3}H)dopamine were calcium-dependent in both compartments. With 10{sup {minus}6} M tetrodotoxin, 5 {times} 10{sup {minus}5} M acetylcholine stimulated ({sup 3}H)dopamine release in both striosomal and matrix areas, effects completely antagonized by atropine, thus showing the involvement of muscarinic receptors located on dopaminergic nerve terminals. Experiments without tetrodotoxin revealed a more complex regulation of dopamine release in the matrix: (i) in contrast to results seen in the striosome, acetylcholine induced only a transient stimulatory effect on matrix dopamine release. (ii) Although 10{sup {minus}6} M atropine completely abolished the cholinergic stimulatory effect on ({sup 3}H)dopamine release in striosomal area, delayed and prolonged stimulation of ({sup 3}H) dopamine release was seen with atropine in the matrix. The latter effect was completely abolished by the nicotinic antagonist pempidine. Therefore, in the matrix, in addition to its direct (tetrodotoxin-insensitive) facilitatory action on ({sup 3}H)dopamine release, acetylcholine exerts two indirect (tetrodotoxin-sensitive) opposing effects: an inhibition and a stimulation of ({sup 3}H)dopamine release mediated by muscarinic and nicotinic receptors, respectively.

  14. Adaptive local multi-atlas segmentation: application to the heart and the caudate nucleus.

    PubMed

    van Rikxoort, Eva M; Isgum, Ivana; Arzhaeva, Yulia; Staring, Marius; Klein, Stefan; Viergever, Max A; Pluim, Josien P W; van Ginneken, Bram

    2010-02-01

    Atlas-based segmentation is a powerful generic technique for automatic delineation of structures in volumetric images. Several studies have shown that multi-atlas segmentation methods outperform schemes that use only a single atlas, but running multiple registrations on volumetric data is time-consuming. Moreover, for many scans or regions within scans, a large number of atlases may not be required to achieve good segmentation performance and may even deteriorate the results. It would therefore be worthwhile to include the decision which and how many atlases to use for a particular target scan in the segmentation process. To this end, we propose two generally applicable multi-atlas segmentation methods, adaptive multi-atlas segmentation (AMAS) and adaptive local multi-atlas segmentation (ALMAS). AMAS automatically selects the most appropriate atlases for a target image and automatically stops registering atlases when no further improvement is expected. ALMAS takes this concept one step further by locally deciding how many and which atlases are needed to segment a target image. The methods employ a computationally cheap atlas selection strategy, an automatic stopping criterion, and a technique to locally inspect registration results and determine how much improvement can be expected from further registrations. AMAS and ALMAS were applied to segmentation of the heart in computed tomography scans of the chest and compared to a conventional multi-atlas method (MAS). The results show that ALMAS achieves the same performance as MAS at a much lower computational cost. When the available segmentation time is fixed, both AMAS and ALMAS perform significantly better than MAS. In addition, AMAS was applied to an online segmentation challenge for delineation of the caudate nucleus in brain MRI scans where it achieved the best score of all results submitted to date.

  15. Habitual action video game playing is associated with caudate nucleus-dependent navigational strategies

    PubMed Central

    West, Greg L.; Drisdelle, Brandi Lee; Konishi, Kyoko; Jackson, Jonathan; Jolicoeur, Pierre; Bohbot, Veronique D.

    2015-01-01

    The habitual playing of video games is associated with increased grey matter and activity in the striatum. Studies in humans and rodents have shown an inverse relationship between grey matter in the striatum and hippocampus. We investigated whether action video game playing is also associated with increased use of response learning strategies during navigation, known to be dependent on the caudate nucleus of the striatum, when presented in a dual solution task. We tested 26 action video game players (actionVGPs) and 33 non-action video game players (nonVGPs) on the 4-on-8 virtual maze and a visual attention event-related potential (ERP) task, which elicits a robust N-2-posterior-controlateral (N2pc) component. We found that actionVGPs had a significantly higher likelihood of using a response learning strategy (80.76%) compared to nonVGPs (42.42%). Consistent with previous evidence, actionVGPs and nonVGPs differed in the way they deployed visual attention to central and peripheral targets as observed in the elicited N2pc component during an ERP visual attention task. Increased use of the response strategy in actionVGPs is consistent with previously observed increases in striatal volume in video game players (VGPs). Using response strategies is associated with decreased grey matter in the hippocampus. Previous studies have shown that decreased volume in the hippocampus precedes the onset of many neurological and psychiatric disorders. If actionVGPs have lower grey matter in the hippocampus, as response learners normally do, then these individuals could be at increased risk of developing neurological and psychiatric disorders during their lifetime. PMID:25994669

  16. Habitual action video game playing is associated with caudate nucleus-dependent navigational strategies.

    PubMed

    West, Greg L; Drisdelle, Brandi Lee; Konishi, Kyoko; Jackson, Jonathan; Jolicoeur, Pierre; Bohbot, Veronique D

    2015-06-01

    The habitual playing of video games is associated with increased grey matter and activity in the striatum. Studies in humans and rodents have shown an inverse relationship between grey matter in the striatum and hippocampus. We investigated whether action video game playing is also associated with increased use of response learning strategies during navigation, known to be dependent on the caudate nucleus of the striatum, when presented in a dual solution task. We tested 26 action video game players (actionVGPs) and 33 non-action video game players (nonVGPs) on the 4-on-8 virtual maze and a visual attention event-related potential (ERP) task, which elicits a robust N-2-posterior-controlateral (N2pc) component. We found that actionVGPs had a significantly higher likelihood of using a response learning strategy (80.76%) compared to nonVGPs (42.42%). Consistent with previous evidence, actionVGPs and nonVGPs differed in the way they deployed visual attention to central and peripheral targets as observed in the elicited N2pc component during an ERP visual attention task. Increased use of the response strategy in actionVGPs is consistent with previously observed increases in striatal volume in video game players (VGPs). Using response strategies is associated with decreased grey matter in the hippocampus. Previous studies have shown that decreased volume in the hippocampus precedes the onset of many neurological and psychiatric disorders. If actionVGPs have lower grey matter in the hippocampus, as response learners normally do, then these individuals could be at increased risk of developing neurological and psychiatric disorders during their lifetime. PMID:25994669

  17. Habitual action video game playing is associated with caudate nucleus-dependent navigational strategies.

    PubMed

    West, Greg L; Drisdelle, Brandi Lee; Konishi, Kyoko; Jackson, Jonathan; Jolicoeur, Pierre; Bohbot, Veronique D

    2015-06-01

    The habitual playing of video games is associated with increased grey matter and activity in the striatum. Studies in humans and rodents have shown an inverse relationship between grey matter in the striatum and hippocampus. We investigated whether action video game playing is also associated with increased use of response learning strategies during navigation, known to be dependent on the caudate nucleus of the striatum, when presented in a dual solution task. We tested 26 action video game players (actionVGPs) and 33 non-action video game players (nonVGPs) on the 4-on-8 virtual maze and a visual attention event-related potential (ERP) task, which elicits a robust N-2-posterior-controlateral (N2pc) component. We found that actionVGPs had a significantly higher likelihood of using a response learning strategy (80.76%) compared to nonVGPs (42.42%). Consistent with previous evidence, actionVGPs and nonVGPs differed in the way they deployed visual attention to central and peripheral targets as observed in the elicited N2pc component during an ERP visual attention task. Increased use of the response strategy in actionVGPs is consistent with previously observed increases in striatal volume in video game players (VGPs). Using response strategies is associated with decreased grey matter in the hippocampus. Previous studies have shown that decreased volume in the hippocampus precedes the onset of many neurological and psychiatric disorders. If actionVGPs have lower grey matter in the hippocampus, as response learners normally do, then these individuals could be at increased risk of developing neurological and psychiatric disorders during their lifetime.

  18. Semi-automatic parcellation of the corpus striatum

    NASA Astrophysics Data System (ADS)

    Al-Hakim, Ramsey; Nain, Delphine; Levitt, James; Shenton, Martha; Tannenbaum, Allen

    2007-03-01

    The striatum is the input component of the basal ganglia from the cerebral cortex. It includes the caudate, putamen, and nucleus accumbens. Thus, the striatum is an important component in limbic frontal-subcortical circuitry and is believed to be relevant both for reward-guided behaviors and for the expression of psychosis. The dorsal striatum is composed of the caudate and putamen, both of which are further subdivided into pre- and post-commissural components. The ventral striatum (VS) is primarily composed of the nucleus accumbens. The striatum can be functionally divided into three broad regions: 1) a limbic; 2) a cognitive and 3) a sensor-motor region. The approximate corresponding anatomic subregions for these 3 functional regions are: 1) the VS; 2) the pre/post-commissural caudate and the pre-commissural putamen and 3) the post-commissural putamen. We believe assessing these subregions, separately, in disorders with limbic and cognitive impairment such as schizophrenia may yield more informative group differences in comparison with normal controls than prior parcellation strategies of the striatum such as assessing the caudate and putamen. The manual parcellation of the striatum into these subregions is currently defined using certain landmark points and geometric rules. Since identification of these areas is important to clinical research, a reliable and fast parcellation technique is required. Currently, only full manual parcellation using editing software is available; however, this technique is extremely time intensive. Previous work has shown successful application of heuristic rules into a semi-automatic platform1. We present here a semi-automatic algorithm which implements the rules currently used for manual parcellation of the striatum, but requires minimal user input and significantly reduces the time required for parcellation.

  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. Nucleus accumbens core lesions enhance two-way active avoidance

    PubMed Central

    Lichtenberg, Nina T.; Kashtelyan, Vadim; Burton, Amanda C.; Bissonette, Gregory B.; Roesch, Matthew R.

    2014-01-01

    The majority of work examining nucleus accumbens core (NAc) has focused on functions pertaining to behaviors guided by appetitive outcomes. These studies have pointed to NAc as being critical for motivating behavior toward desirable outcomes. For example, we have recently shown that lesions of 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 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

  1. Peculiarities of participation of the fronto-thalamo-caudate system in extrapolatory behavior.

    PubMed

    Adrianov, O S; Molodkina, L N; Yamshikova, N G

    1988-06-01

    --frontal, parietal, temporal cortical areas, as well as the caudate nucleus and the association thalamic nuclei--are undergoing a complex evolutionary development in mammals. We see the culmination of their development in man. This paper sums up our research concerning the role of the most important forebrain association structures in realization of extrapolatory reflex. Here we publish the results of our experiments on cats. PMID:3403169

  2. Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure.

    PubMed

    Claussen, Catherine M; Dafny, Nachum

    2015-09-01

    The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long-term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization was also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals were observed for the 2.5 and 10.0mg/kg MPD exposed groups. For 2.5mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and

  3. Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

    PubMed Central

    Claussen, Catherine M; Dafny, Nachum

    2016-01-01

    The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0 mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization were also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals was observed for the 2.5 and 10.0 mg/kg MPD exposed groups. For 2.5 mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0 mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0 mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure

  4. Habenula lesions alter synaptic plasticity within the fimbria-accumbens pathway in the rat.

    PubMed

    Lecourtier, L; Deschaux, O; Arnaud, C; Chessel, A; Kelly, P H; Garcia, R

    2006-08-25

    Both the habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the habenula produce disturbances of memory and attention in experimental animals. As the habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral habenula lesions on the plasticity of the fimbria-nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria-nucleus accumbens pathway is altered by habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the habenula is reported to exhibit exaggerated calcification.

  5. 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

  6. Correlation between decreased motor activity and dopaminergic degeneration in the ventrolateral putamen in monkeys receiving repeated MPTP administrations: a positron emission tomography study.

    PubMed

    Nagai, Yuji; Minamimoto, Takafumi; Ando, Kiyoshi; Obayashi, Shigeru; Ito, Hiroshi; Ito, Nobuhiko; Suhara, Tetsuya

    2012-05-01

    Parkinson's disease (PD) patients have remarkably reduced levels of dopaminergic biomarkers in the caudal putamen. However, the relationship between motor impairments and the localization of intrastriatal dopaminergic degeneration in monkey PD models remains unclear. To identify the striatal areas with dopaminergic dysfunction responsible for motor impairments, we measured changes in both general motor activity and in vivo dopaminergic biomarkers in three cynomolgus monkeys that repeatedly received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), starting in the normal state and continuing until after tremor appearance. Binding of dopamine transporters (DAT) and D(2) receptors were measured by positron emission tomography (PET) using [(11)C]PE2I and [(11)C]raclopride, respectively. Region-of-interest-based regression analysis demonstrated the degree of general motor activity reduction to be explained by striatal DAT binding but not by D(2) receptor binding. Furthermore, voxel-based analysis revealed a significant correlation between reduced general motor activity and decreased DAT binding, specifically in the ventrolateral putamen, which corresponds to the area receiving upper body motor inputs from the primary motor cortex. These results suggest that specific functional deficits in PD models are closely related to the degeneration of dopaminergic terminals in the striatal subregion responsible for these functions and that the level of deficit is dependent on the degree of degeneration.

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

    PubMed Central

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

    2016-01-01

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both rewarding effects of drug and the desire to avoid withdrawal symptoms motivate continued drug use1-3, and the nucleus accumbens (NAc) is important for orchestrating both processes4,5. While multiple inputs to the NAc regulate reward6-9, little is known about the NAc circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus (PVT) as a prominent input to the NAc mediating the expression of opiate withdrawal induced physical signs and aversive memory. Activity in the PVT to NAc pathway is necessary and sufficient to mediate behavioral 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 PVT and D2-receptor-expressing medium spiny neurons (D2-MSNs) via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at PVT→D2-MSNs synapses and robustly suppresses morphine withdrawal symptoms. These results link morphine-evoked pathway- and cell type-specific plasticity in the PVT→NAc circuit to opiate dependence, and suggest that reprogramming this circuit holds promise for treating opiate addiction. PMID:26840481

  8. Further evidence for the role of the caudate nucleus in programming motor and nonmotor behavior in Java monkeys.

    PubMed

    Vrijmoed-de Vries, M C; Cools, A R

    1985-01-01

    This study describes the short-term effects of intracaudate microinjections of carbachol in temporarily isolated and restrained Java monkeys. The monkeys were found to display a series of motor disturbances including blepharoptosis, facial twitches, tongue protrusions, ear flattening, torticollis, and compulsive alternations of rapid flexions and extensions of the extremities. In general, carbachol was found to produce consistent effects as far as it concerns its ability to elicit motor disturbances. Three of the five tested monkeys had previously received another series of carbachol injections when they were freely moving and living in a stabilized social group. Accordingly, the present study enabled us to compare the effectiveness of threshold doses of carbachol in the same monkey in two distinct situations. We concluded first, that motor disturbances and disturbances in social communication were closely coupled in relation to the involvement of a particular cholinoceptive substrate within the caudate nucleus of Java monkeys. Second, the motor disturbances under study appeared to require a larger degree of dysfunctioning of this substrate than did subtle disturbances in the social communication of these monkeys. And, finally, stress inherent to restraint increased the susceptibility of the cholinoceptive substrate within the caudate nucleus. The clinical impact of our findings is discussed in view of differences between the premorbid and manifest phases of Parkinson's disease.

  9. Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans.

    PubMed

    Herringa, Ryan; Phillips, Mary; Almeida, Jorge; Insana, Salvatore; Germain, Anne

    2012-01-01

    Prior studies have examined differences in brain volume between patients with post-traumatic stress disorder (PTSD) and control subjects. Convergent findings include smaller hippocampus and medial prefrontal cortex volumes in PTSD. However, post-traumatic stress symptoms (PTSS) exist on a spectrum, and neural changes may occur beyond the diagnostic threshold of PTSD. We examined the relationship between PTSS and gray matter among combat-exposed U.S. military veterans. Structural brain magnetic resonance imaging (MRI) was obtained on 28 combat veterans from Operations Enduring and Iraqi Freedom. PTSS were assessed using the Clinician-Administered PTSD Scale (CAPS). Thirteen subjects met criteria for PTSD. Subjects were unmedicated, and free of major comorbid psychiatric disorders. Images were analyzed using voxel-based morphometry, and regressed against the total CAPS score and trauma load. Images were subsequently analyzed by diagnosis of PTSD vs. non-PTSD. CAPS scores were inversely correlated with volumes of the subgenual cingulate (sgACC), caudate, hypothalamus, insula, and left middle temporal gyrus (MTG). Group contrast revealed smaller sgACC, caudate, hypothalamus, left insula, left MTG, and right MFG in the PTSD group. PTSS are associated with abnormalities in limbic structures that may underlie the pathophysiology of PTSD. These abnormalities exist on a continuum with PTSS, beyond a diagnosis of PTSD.

  10. Valence-specific conflict moderation in the dorso-medial PFC and the caudate head in emotional speech

    PubMed Central

    Dengler, Reinhard; Wittfoth, Matthias

    2015-01-01

    Emotional speech comprises of complex multimodal verbal and non-verbal information that allows deducting others’ emotional states or thoughts in social interactions. While the neural correlates of verbal and non-verbal aspects and their interaction in emotional speech have been identified, there is very little evidence on how we perceive and resolve incongruity in emotional speech, and whether such incongruity extends to current concepts of task-specific prediction errors as a consequence of unexpected action outcomes (‘negative surprise’). Here, we explored this possibility while participants listened to congruent and incongruent angry, happy or neutral utterances and categorized the expressed emotions by their verbal (semantic) content. Results reveal valence-specific incongruity effects: negative verbal content expressed in a happy tone of voice increased activation in the dorso-medial prefrontal cortex (dmPFC) extending its role from conflict moderation to appraisal of valence-specific conflict in emotional speech. Conversely, the caudate head bilaterally responded selectively to positive verbal content expressed in an angry tone of voice broadening previous accounts of the caudate head in linguistic control to moderating valence-specific control in emotional speech. Together, these results suggest that control structures of the human brain (dmPFC and subcompartments of the basal ganglia) impact emotional speech differentially when conflict arises. PMID:24526187

  11. Task-related functional connectivity of the caudate mediates the association between trait mindfulness and implicit learning in older adults.

    PubMed

    Stillman, Chelsea M; You, Xiaozhen; Seaman, Kendra L; Vaidya, Chandan J; Howard, James H; Howard, Darlene V

    2016-08-01

    Accumulating evidence shows a positive relationship between mindfulness and explicit cognitive functioning, i.e., that which occurs with conscious intent and awareness. However, recent evidence suggests that there may be a negative relationship between mindfulness and implicit types of learning, or those that occur without conscious awareness or intent. Here we examined the neural mechanisms underlying the recently reported negative relationship between dispositional mindfulness and implicit probabilistic sequence learning in both younger and older adults. We tested the hypothesis that the relationship is mediated by communication, or functional connectivity, of brain regions once traditionally considered to be central to dissociable learning systems: the caudate, medial temporal lobe (MTL), and prefrontal cortex (PFC). We first replicated the negative relationship between mindfulness and implicit learning in a sample of healthy older adults (60-90 years old) who completed three event-related runs of an implicit sequence learning task. Then, using a seed-based connectivity approach, we identified task-related connectivity associated with individual differences in both learning and mindfulness. The main finding was that caudate-MTL connectivity (bilaterally) was positively correlated with learning and negatively correlated with mindfulness. Further, the strength of task-related connectivity between these regions mediated the negative relationship between mindfulness and learning. This pattern of results was limited to the older adults. Thus, at least in healthy older adults, the functional communication between two interactive learning-relevant systems can account for the relationship between mindfulness and implicit probabilistic sequence learning.

  12. Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search

    PubMed Central

    Stein, Jason L.; Hibar, Derrek P.; Madsen, Sarah K.; Khamis, Mathew; McMahon, Katie L.; de Zubicaray, Greig I.; Hansell, Narelle K.; Montgomery, Grant W.; Martin, Nicholas G.; Wright, Margaret J.; Saykin, Andrew J.; Jack, Clifford R.; Weiner, Michael W.; Toga, Arthur W.; Thompson, Paul M.

    2011-01-01

    The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural MRI and genome-wide genotypes were acquired from two large cohorts, the Alzheimer’s Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at SNP rs163030 in the ADNI discovery sample (P=2.36×10−6) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79% and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate. PMID:21502949

  13. Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search.

    PubMed

    Stein, J L; Hibar, D P; Madsen, S K; Khamis, M; McMahon, K L; de Zubicaray, G I; Hansell, N K; Montgomery, G W; Martin, N G; Wright, M J; Saykin, A J; Jack, C R; Weiner, M W; Toga, A W; Thompson, P M

    2011-09-01

    The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural magnetic resonance imaging and genome-wide genotypes were acquired from two large cohorts, the Alzheimer's Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at single-nucleotide polymorphism rs163030 in the ADNI discovery sample (P=2.36 × 10⁻⁶) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79 and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate. PMID:21502949

  14. Relationship of Dopamine of the Nucleus Accumbens with Intra-infralimbic Apomorphine Microinjection

    PubMed Central

    Alimoradian, Abbas; Sajedianfard, Javad; Baha-aldini Beigy, Faegheh; Panjehshahin, Mohammad Reza; Owji, Ali Akbar

    2013-01-01

    Objective(s): The dopamine level of the nucleus accumbens changes during some stereotyped behaviors. To study dopamine level of the nucleus accumbens in intra infralimbic apomorphine-induced climbing, microdialysis probes were implanted into the nucleus accumbens shell of male Sprague Dawley rats weighting 275–400 g. Materials and Methods: The rats were divided into two groups (apomorphine and control) of least eleven rats in each group. Apomorphine at dose of 5 μg/0.5 μl or its vehicle was microinjected into the infralimbic in apomorphine and control groups respectively. Then, changes in dopamine levels in the nucleus accumbens shell were monitored. The concentration of dopamine was measured by High-Performance Liquid Chromatography-Electochemical (HPLC-ECD). Finally, the stereotyped behaviors were recorded. Results: The mean of dopamine levels for all of after microinjection period in control and drug groups were 450% and 150% respectively compared to those of before microinjection period. However, there was no significant difference between groups of apomorphine and control. In addition, the return of dopamine level to the baseline was faster in apomorphine group than the control group. Conclusion: The intra infralimbic apomorphine -induced climbing at dose of 5 μg/0.5 μl was not modulated via the increase of dopamine level in the nucleus accumbens area. PMID:23997899

  15. ΔJunD overexpression in the nucleus accumbens prevents sexual reward in female Syrian hamsters.

    PubMed

    Been, L E; Hedges, V L; Vialou, V; Nestler, E J; Meisel, R L

    2013-08-01

    Motivated behaviors, including sexual experience, activate the mesolimbic dopamine system and produce long-lasting molecular and structural changes in the nucleus accumbens. The transcription factor ΔFosB is hypothesized to partly mediate this experience-dependent plasticity. Previous research in our laboratory has demonstrated that overexpressing ΔFosB in the nucleus accumbens of female Syrian hamsters augments the ability of sexual experience to cause the formation of a conditioned place preference. It is unknown, however, whether ΔFosB-mediated transcription in the nucleus accumbens is required for the behavioral consequences of sexual reward. We therefore used an adeno-associated virus to overexpress ΔJunD, a dominant negative binding partner of ΔFosB that decreases ΔFosB-mediated transcription by competitively heterodimerizing with ΔFosB before binding at promotor regions on target genes, in the nucleus accumbens. We found that overexpression of ΔJunD prevented the formation of a conditioned place preference following repeated sexual experiences. These data, when coupled with our previous findings, suggest that ΔFosB is both necessary and sufficient for behavioral plasticity following sexual experience. Furthermore, these results contribute to an important and growing body of literature demonstrating the necessity of endogenous ΔFosB expression in the nucleus accumbens for adaptive responding to naturally rewarding stimuli.

  16. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin.

    PubMed

    Dölen, Gül; Darvishzadeh, Ayeh; Huang, Kee Wui; Malenka, Robert C

    2013-09-12

    Social behaviours in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviours, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin acts as a social reinforcement signal within the nucleus accumbens core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the nucleus accumbens receives oxytocin-receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-hydroxytryptamine; 5-HT) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. Furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-HT1B receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-HT in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism. PMID:24025838

  17. Medial accumbens lesions attenuate testosterone-dependent aggression in male rats.

    PubMed

    Albert, D J; Petrovic, D M; Walsh, M L; Jonik, R H

    1989-10-01

    Male hooded rats were castrated and implanted with testosterone-filled Silastic tubes appropriate for maintaining a normal average serum testosterone concentration. They were then given lesions of the medial accumbens nucleus or sham lesions. Twenty-four hours postoperatively each male was housed with a female. Beginning 7 days following pairing and continuing once each week for 4 weeks, each lesioned or sham-lesioned male was observed for aggression toward an unfamiliar male intruder. On the day following each test of aggression toward an unfamiliar male, each lesioned and sham-lesioned male was assessed for defensiveness toward an experimenter. Rats with medial accumbens lesions displayed significantly less aggression toward an unfamiliar male intruder during each of the weekly tests than did sham-lesioned animals. The attenuation was most pronounced in animals with lesions damaging the posterior part of the medial accumbens nucleus (also designated as anterior portion of the bed nucleus of the stria terminalis) in the region of the crossover of the anterior commissure. Although medial accumbens lesions are known to make individually housed rats hyperdefensive toward an experimenter, lesion-induced hyperdefensiveness was not observed in the pair-housed animals in the present experiment. It is argued that the medial accumbens/bed nucleus of the stria terminalis area is an important region in the anterior forebrain for the modulation of hormone-dependent aggression.

  18. 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.

  19. Dissociated Accumbens and Hippocampal Structural Abnormalities across Obesity and Alcohol Dependence

    PubMed Central

    Mak, Elijah; Chien, Yee; Voon, Valerie

    2016-01-01

    Background: Processing of food and drug rewards involves specific neurocircuitry, and emerging evidence implicates subcortical abnormalities, particularly the nucleus accumbens and hippocampus. We specifically hypothesized that these 2 established regions in addiction neurocircuitry are associated with distinctive in vivo structural abnormalities in obesity and alcohol dependence. Methods: To specifically investigate anatomically discrete volumetric changes associated with overconsumption of different rewards, we acquired T1 MRI data from 118 subjects in 3 groups comprising obesity (n=42), alcohol dependence (n=32), and healthy volunteer controls (n=44). To exploit novel methods of automated hippocampal subfield segmentation, we used Freesurfer software to generate volumetric data in subject groups for the hippocampal subiculum and its major striatal efferent target, the nucleus accumbens. Hypothesis-led, selective group difference comparisons were analyzed. Results: We found markedly greater accumbens volumes (P=.002) and relatively preserved hippocampal subfield volumes in obesity. Conversely, in alcohol dependence, we found preserved accumbens volumes but atrophy of specific ventral hippocampal subfields, the subiculum and presubiculum. Smaller global subcortical gray-matter volume was found in the alcohol dependence group only. Conclusions: Reward neurocircuitry including the accumbens and ventral hippocampus may show key structural abnormalities in disorders involving processing of both food and drug rewards, although the foci of disruption may vary as a function of reward modality. Structural differences may subserve altered reward and motivational processes in obesity and alcohol dependence and represent a potential biomarker for therapeutic targeting in key public health disorders. PMID:27207916

  20. 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

  1. 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…

  2. 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

  3. Rapid feedback processing in human nucleus accumbens and motor thalamus.

    PubMed

    Schüller, Thomas; Gruendler, Theo O J; Jocham, Gerhard; Klein, Tilmann A; Timmermann, Lars; Visser-Vandewalle, Veerle; Kuhn, Jens; Ullsperger, Markus

    2015-04-01

    The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structures are the NAcc and the ventral anterior and ventro-lateral nuclei (VA/VL) of the thalamus, for OCD and TS, respectively. The feedback related negativity (FRN) is an event-related potential associated with feedback processing reflecting posterior medial frontal cortex (pMFC) activity. Here we report on three cases where we recorded scalp EEG and local field potentials (LFP) from externalized electrodes located in the NAcc or thalamus (VA/VL) while patients engaged in a modified time estimation task, known to engage feedback processing and elicit the FRN. Additionally, scalp EEG were recorded from 29 healthy participants (HP) engaged in the same task. The signal in all structures (pMFC, NAcc, and thalamus) was differently modulated by positive and negative feedback. LFP activity in the NAcc showed a biphasic time course after positive feedback during the FRN time interval. Negative feedback elicited a much weaker and later response. In the thalamus a monophasic modulation was recorded during the FRN time interval. Again, this modulation was more pronounced after positive performance feedback compared to negative feedback. In channels outside the target area no modulation was observed. The surface-FRN was reliably elicited on a group level in HP and showed no significant difference following negative feedback between patients and HP. German Clinical Trial Register: Neurocognitive specification of dysfunctions within basal ganglia-cortex loops and their therapeutic modulation by deep brain stimulation in patients with obsessive compulsive disorder and Tourette syndrome, http://www.drks.de/DRKS00005316. PMID:25726897

  4. Encoding of aversion by dopamine and the nucleus accumbens.

    PubMed

    McCutcheon, James E; Ebner, Stephanie R; Loriaux, Amy L; Roitman, Mitchell F

    2012-01-01

    Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain's reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus - intra-oral infusion of sucrose - has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward. PMID:23055953

  5. 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

  6. A case of musical preference for Johnny Cash following deep brain stimulation of the nucleus accumbens

    PubMed Central

    Mantione, Mariska; Figee, Martijn; Denys, Damiaan

    2014-01-01

    Music is among all cultures an important part of the live of most people. Music has psychological benefits and may generate strong emotional and physiological responses. Recently, neuroscientists have discovered that music influences the reward circuit of the nucleus accumbens (NAcc), even when no explicit reward is present. In this clinical case study, we describe a 60-year old patient who developed a sudden and distinct musical preference for Johnny Cash following deep brain stimulation (DBS) targeted at the NAcc. This case report substantiates the assumption that the NAcc is involved in musical preference, based on the observation of direct stimulation of the accumbens with DBS. It also shows that accumbens DBS can change musical preference without habituation of its rewarding properties. PMID:24834035

  7. Neurons in the Nucleus Accumbens Promote Selection Bias for Nearer Objects

    PubMed Central

    Morrison, Sara E.

    2014-01-01

    Both animals and humans often prefer rewarding options that are nearby over those that are distant, but the neural mechanisms underlying this bias are unclear. Here we present evidence that a proximity signal encoded by neurons in the nucleus accumbens drives proximate reward bias by promoting impulsive approach to nearby reward-associated objects. On a novel decision-making task, rats chose the nearer option even when it resulted in greater effort expenditure and delay to reward; therefore, proximate reward bias was unlikely to be caused by effort or delay discounting. The activity of individual neurons in the nucleus accumbens did not consistently encode the reward or effort associated with specific alternatives, suggesting that it does not participate in weighing the values of options. In contrast, proximity encoding was consistent and did not depend on the subsequent choice, implying that accumbens activity drives approach to the nearest rewarding option regardless of its specific associated reward size or effort level. PMID:25319709

  8. 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

  9. Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats.

    PubMed

    Salti, Ahmad; Kummer, Kai K; Sadangi, Chinmaya; Dechant, Georg; Saria, Alois; El Rawas, Rana

    2015-12-01

    We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens.

  10. Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats

    PubMed Central

    Salti, Ahmad; Kummer, Kai K.; Sadangi, Chinmaya; Dechant, Georg; Saria, Alois; El Rawas, Rana

    2016-01-01

    We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens. PMID:26300300

  11. Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats.

    PubMed

    Salti, Ahmad; Kummer, Kai K; Sadangi, Chinmaya; Dechant, Georg; Saria, Alois; El Rawas, Rana

    2015-12-01

    We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens. PMID:26300300

  12. Functional interactions between the nucleus tractus solitarius (NTS) and nucleus accumbens shell in modulating memory for arousing experiences.

    PubMed

    Kerfoot, Erin C; Chattillion, Elizabeth A; Williams, Cedric L

    2008-01-01

    The shell division of the nucleus accumbens receives noradrenergic input from neurons in the nucleus of the solitary tract (NTS) that transmit information regarding fluctuations in peripheral hormonal and autonomic activity. Accumbens shell neurons also receive converging inputs from limbic areas such as the hippocampus and amygdala that process newly acquired information. However, few studies have explored whether peripheral information regarding changes in emotional arousal contributes to memory processing in the accumbens. The beneficial effects on memory produced by emotional arousal and the corresponding activation of NTS neurons may be mediated through influences on neuronal activity in the accumbens shell during memory encoding. To explore this putative relationship, Experiment 1 examined interactions between the NTS and the accumbens shell in modulating memory for responses acquired after footshock training in a water-motivated inhibitory avoidance task. Memory for the noxious shock was significantly improved by posttraining excitation of noradrenergic NTS neurons. The enhanced retention produced by activating NTS neurons was attenuated by suppressing neuronal activity in the accumbens shell with bupivacaine (0.25%/0.5 microl). Experiment 2 examined the direct involvement of accumbens shell noradrenergic activation in the modulation of memory for psychologically arousing events such as a reduction in perceived reward value. Noradrenergic activation of the accumbens shell with phenylephrine (1.0 microg/0.5 microl) produced an enhancement in memory for the frustrating experience relative to control injections as evidenced by runway performance on an extended seven-day retention test. These findings demonstrate a functional relationship between NTS neurons and the accumbens shell in modulating memory following physiological arousal and identifies a role of norepinephrine in modulating synaptic activity in the accumbens shell to facilitate this process.

  13. Synchronized drumming enhances activity in the caudate and facilitates prosocial commitment--if the rhythm comes easily.

    PubMed

    Kokal, Idil; Engel, Annerose; Kirschner, Sebastian; Keysers, Christian

    2011-01-01

    Why does chanting, drumming or dancing together make people feel united? Here we investigate the neural mechanisms underlying interpersonal synchrony and its subsequent effects on prosocial behavior among synchronized individuals. We hypothesized that areas of the brain associated with the processing of reward would be active when individuals experience synchrony during drumming, and that these reward signals would increase prosocial behavior toward this synchronous drum partner. 18 female non-musicians were scanned with functional magnetic resonance imaging while they drummed a rhythm, in alternating blocks, with two different experimenters: one drumming in-synchrony and the other out-of-synchrony relative to the participant. In the last scanning part, which served as the experimental manipulation for the following prosocial behavioral test, one of the experimenters drummed with one half of the participants in-synchrony and with the other out-of-synchrony. After scanning, this experimenter "accidentally" dropped eight pencils, and the number of pencils collected by the participants was used as a measure of prosocial commitment. Results revealed that participants who mastered the novel rhythm easily before scanning showed increased activity in the caudate during synchronous drumming. The same area also responded to monetary reward in a localizer task with the same participants. The activity in the caudate during experiencing synchronous drumming also predicted the number of pencils the participants later collected to help the synchronous experimenter of the manipulation run. In addition, participants collected more pencils to help the experimenter when she had drummed in-synchrony than out-of-synchrony during the manipulation run. By showing an overlap in activated areas during synchronized drumming and monetary reward, our findings suggest that interpersonal synchrony is related to the brain's reward system. PMID:22110623

  14. Double dissociation of fornix and caudate nucleus lesions on acquisition of two water maze tasks: further evidence for multiple memory systems.

    PubMed

    Packard, M G; McGaugh, J L

    1992-06-01

    The present study examined the effect of lesions of the caudate nucleus or fimbria-fornix on the acquisition of two water maze tasks. In both tasks, two rubber balls with different visual patterns were used as platforms (i.e., cues). The "correct" cue was attached to a submerged rectangular platform and could be mounted by an animal to escape the water. The "incorrect" cue was attached to a thin round pedestal and could not be mounted. In a spatial version of the task, the correct cue was located in the same quadrant of the maze on all trials, whereas the visual pattern on the cue was varied from trial to trial. Lesions of the fornix, but not the caudate nucleus, impaired acquisition of this spatial task in relation to control animals. In a simultaneous visual discrimination version of the task, the correct cue on all trials was one with a specific visual pattern, and the spatial location of the correct cue was varied from trial to trial. Lesions of the caudate nucleus, but not the fornix, impaired acquisition of this visual discrimination task in relation to control animals. The double dissociation observed supports the hypothesis that the hippocampus and caudate nucleus are parts of systems that differ in the type of memory they mediate.

  15. The Role of the Nucleus Accumbens in Knowing when to Respond

    ERIC Educational Resources Information Center

    Singh, Teghpal; McDannald, Michael A.; Takahashi, Yuji K.; Haney, Richard Z.; Cooch, Nisha K.; Lucantonio, Federica; Schoenbaum, Geoffrey

    2011-01-01

    While knowing what to expect is important, it is equally important to know when to expect it and to respond accordingly. This is apparent even in simple Pavlovian training situations in which animals learn to respond more strongly closer to reward delivery. Here we report that the nucleus accumbens core, an area well-positioned to represent…

  16. Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release.

    PubMed

    Lecourtier, Lucas; Defrancesco, Alicia; Moghaddam, Bita

    2008-04-01

    Conditions of increased cognitive or emotional demand activate dopamine release in a regionally selective manner. Whereas the brief millisecond response of dopamine neurons to salient stimuli suggests that dopamine's influence on behaviour may be limited to signalling certain cues, the prolonged availability of dopamine in regions such as the prefrontal cortex and nucleus accumbens is consistent with the well described role of dopamine in maintaining motivation states, associative learning and working memory. The behaviourally elicited terminal release of dopamine is generally attributed to increased excitatory drive on dopamine neurons. Our findings here, however, indicate that this increase may involve active removal of a tonic inhibitory control on dopamine neurons exerted by the lateral habenula (LHb). Inhibition of LHb in behaving animals transiently increased dopamine release in the prefrontal cortex, nucleus accumbens and dorsolateral striatum. The inhibitory influence was more pronounced in the nucleus accumbens and striatum than in the prefrontal cortex. This pattern of regional dopamine activation after LHb inhibition mimicked conditions of reward availability but not increased cognitive demand. Electrical or chemical stimulation of LHb produced minimal reduction of extracellular dopamine, suggesting that in an awake brain the inhibition associated with tonic LHb activity represents a near-maximal influence on dopamine neurotransmission. These data indicate that LHb may be critical for functional differences in dopamine neurons by preferentially modulating dopamine neurons that project to the nucleus accumbens over those neurons that primarily project to the prefrontal cortex.

  17. Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it.

    PubMed

    Rada, P V; Hoebel, B G

    2001-01-01

    Hypothalamic electrodes can generate positive reinforcement, as shown by self-stimulation, and negative reinforcement shown by stimulation-escape. It was hypothesized that acetylcholine (ACh) is released in the nucleus accumbens during the aversive state that underlies stimulation-escape. If this is correct, escape behavior should lower extracellular ACh. Rats were prepared with microdialysis probes in the accumbens (posterior shell region) and electrodes in the perifornical lateral hypothalamus. Animals learned to press a lever for 0.5 s trains of stimulation (typically 3600 responses/h). Then they were given automatic stimulation to determine which animals would also learn to press a lever to turn stimulation off for 5 s at a time (typically 75 responses/h). Accumbens microdialysis showed that automatic stimulation caused extracellular ACh to double, but only in the rats that were motivated to learn stimulation-escape. When allowed to escape stimulation, these animals lowered extracellular ACh significantly. It is concluded that ACh release in the accumbens is related to the neural state that animals work to escape.

  18. Excitant amino acid projections from rat amygdala and thalamus to nucleus accumbens

    SciTech Connect

    Robinson, T.G.; Beart, P.M.

    1988-04-01

    High affinity uptake of D-(/sup 3/H)aspartate, (/sup 3/H)choline and (/sup 3/H)GABA was examined in synaptosomal-containing preparations of rat nucleus accumbens septi 7 to 10 days after unilateral or bilateral N-methyl-D-aspartate lesions confined to the parataenial nucleus of the thalamus or the basolateral nucleus of the amygdala. Uptake of both D-(/sup 3/H)aspartate and (/sup 3/H)choline was significantly reduced (11% and 14% less than control, respectively) by unilateral lesion of the thalamus, whereas (/sup 3/H)GABA uptake was unaffected. Bilateral thalamic lesions significantly reduced D-(/sup 3/H)aspartate uptake (11% less than control) into homogenates of the nucleus accumbens, whilst (/sup 3/H)GABA uptake was unaltered. D-(/sup 3/H)aspartate uptake was significantly reduced (26% less than control) following unilateral lesion of the amygdala, whereas both (/sup 3/H)GABA and (/sup 3/H)choline uptake were unaffected. Bilateral amygdaloid lesions significantly increased D-(/sup 3/H)aspartate uptake (39% greater than control), whilst uptake of (/sup 3/H)GABA was not affected. The results implicate glutamate and/or aspartate as putative neurotransmitters in afferent projections from the basolateral amygdala and the parataenial thalamus to the nucleus accumbens. Thalamic afferents to the nucleus accumbens may also utilize acetylcholine as their transmitter.

  19. Invigoration of reward seeking by cue and proximity encoding in the nucleus accumbens.

    PubMed

    McGinty, Vincent B; Lardeux, Sylvie; Taha, Sharif A; Kim, James J; Nicola, Saleem M

    2013-06-01

    A key function of the nucleus accumbens is to promote vigorous reward seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here, we study cued flexible approach behavior, a form of reward seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and the speed of subsequent flexible approach responses, but not those of stereotyped, inflexible responses. Moreover, the excitation simultaneously signals the subject's proximity to the approach target, a signal that appears to mediate greater response vigor on trials that begin with the subject closer to the target. These results demonstrate a neural mechanism for response invigoration whereby accumbens neuronal encoding of reward availability and target proximity together drive the onset and speed of reward-seeking locomotion. PMID:23764290

  20. 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)…

  1. Individual Differences in Dopamine Efflux in Nucleus Accumbens Shell and Core during Instrumental Learning

    ERIC Educational Resources Information Center

    Cheng, Jingjun; Feenstra, Matthijs G. P.

    2006-01-01

    Combined activation of dopamine D1- and NMDA-glutamate receptors in the nucleus accumbens has been strongly implicated in instrumental learning, the process in which an individual learns that a specific action has a wanted outcome. To assess dopaminergic activity, we presented rats with two sessions (30 trials each) of a one-lever appetitive…

  2. Good Vibrations: Cross-Frequency Coupling in the Human Nucleus Accumbens during Reward Processing

    ERIC Educational Resources Information Center

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

    2009-01-01

    The nucleus accumbens is critical for reward-guided learning and decision-making. It is thought to "gate" the flow of a diverse range of information (e.g., rewarding, aversive, and novel events) from limbic afferents to basal ganglia outputs. Gating and information encoding may be achieved via cross-frequency coupling, in which bursts of…

  3. Invigoration of reward-seeking by cue and proximity encoding in the nucleus accumbens

    PubMed Central

    McGinty, Vincent B.; Lardeux, Sylvie; Taha, Sharif A.; Kim, James J.; Nicola, Saleem M.

    2014-01-01

    Summary A key function of the nucleus accumbens is to promote vigorous reward-seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here we study cued flexible approach behavior, a form of reward-seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and speed of subsequent flexible approach responses, but not of stereotyped, inflexible responses. Moreover, the excitation simultaneously signals the subject’s proximity to the approach target, a signal that appears to mediate greater response vigor on trials that begin with the subject closer to the target. These results demonstrate a neural mechanism for response invigoration whereby accumbens neuronal encoding of reward availability and target proximity together drive the onset and speed of reward-seeking locomotion. PMID:23764290

  4. Accumbens Shell AMPA Receptors Mediate Expression of Extinguished Reward Seeking through Interactions with Basolateral Amygdala

    ERIC Educational Resources Information Center

    Millan, E. Zayra; McNally, Gavan P.

    2011-01-01

    Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B).…

  5. Studies of the biogenic amine transporters. IV. Demonstration of a multiplicity of binding sites in rat caudate membranes for the cocaine analog [125I]RTI-55.

    PubMed

    Rothman, R B; Cadet, J L; Akunne, H C; Silverthorn, M L; Baumann, M H; Carroll, F I; Rice, K C; de Costa, B R; Partilla, J S; Wang, J B

    1994-07-01

    The drug 3 beta-[4'-iodophenyl]tropan-2 beta-carboxylic acid methyl ester (RTI-55) is a cocaine congener with high affinity for the dopamine transporter (Kd < 1 nM). The present study characterized [125I]RTI-55 binding to membranes prepared from rat, monkey and human caudates and COS cells transiently expressing the cloned rat dopamine (DA) transporter. Using the method of binding surface analysis, two binding sites were resolved in rat caudate: a high-capacity binding site (site 1, Bmax = 11,900 fmol/mg of protein) and a low-capacity site (site 2, Bmax = 846 fmol/mg of protein). The Kd (or Ki) values of selected drugs at the two sites were as follows: (Ki for high-capacity site and Ki for low-capacity site, respectively): RTI-55 (0.76 and 0.21 nM), 1-[2-diphenyl-methoxy)ethyl]-4-(3-phenylpropyl)piperazine (0.79 and 358 nM), mazindol (37.6 and 631 nM), 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (45.0 and 540 nM) and cocaine (341 and 129 nM). Nisoxetine, a selective noradrenergic uptake blocker, had low affinity for both sites. Serotonergic uptake blockers had a high degree of selectivity and high affinity for the low-capacity binding site (Ki of citalopram = 0.38 nM; Ki of paroxetine = 0.033 nM). The i.c.v. administration of 5,7-dihydroxytryptamine to rats pretreated with nomifensine (to protect dopaminergic and noradrenergic nerve terminals) selectively decreased the Bmax of site 2, strongly supporting the idea that site 2 is a binding site on the serotonin (5-HT) transporter. This serotonergic lesion also increased the affinity of [125I]RTI-55 for the DA transporter by 10-fold. The ligand selectivity of the caudate 5-HT transporter was different from the [I125]RTI-55 binding site on the 5-HT transporter present in membranes prepared from whole rat brain minus caudate. The [125I]RTI-55 binding to the DA transporter was further resolved into two components, termed sites 1a and 1b, by using human and monkey (Macaca mulatta) caudate membranes but not the

  6. Functional and structural deficits at accumbens synapses in a mouse model of Fragile X

    PubMed Central

    Neuhofer, Daniela; Henstridge, Christopher M.; Dudok, Barna; Sepers, Marja; Lassalle, Olivier; Katona, István; Manzoni, Olivier J.

    2015-01-01

    Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP), a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP) of excitatory afferent inputs of medium spiny neurons (MSN) in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens. These findings

  7. Spatially selective reward site responses in tonically active neurons of the nucleus accumbens in behaving rats.

    PubMed

    Mulder, A B; Shibata, R; Trullier, O; Wiener, S I

    2005-05-01

    To study how hippocampal output signals conveying spatial and other contextual information might be integrated in the nucleus accumbens, tonically active accumbens neurons were recorded in three unrestrained rats as they performed spatial orientation tasks on an elevated round rotatable platform with four identical reward boxes symmetrically placed around the edge. The partially water-deprived rats were required to shuttle either between the pair of reward boxes indicated by beacon cues (lights in the boxes) or between the pair of boxes occupying particular locations in relation to environmental landmark cues. In 43/82 neurons, behaviorally correlated phasic modulations in discharge activity occurred, primarily prior to or after water was provided at the reward boxes. Twenty-two had inhibitory modulation, 12 excitatory, and nine were mixed excitatory and inhibitory. Although tonically active neurons (TANs) have rarely been reported in the rodent, the inhibitory and mixed responses correspond to previously reports in the macaque accumbens of tonically active neurons with activity correlated with reward delivery and, following conditioning, to sensory stimuli associated with rewards. Eighteen of the 43 tonically active accumbens neurons showed spatial selectivity, i.e., behaviorally correlated increases or decreases in firing rate were of different magnitudes at the respective reward boxes. This is the first demonstration that the configuration of environmental sensory cues associated with reward sites are also an effective stimulus for these neurons and that different neurons are selective for different places. These results are consistent with a role for the nucleus accumbens in the initiation of goal-directed displacement behaviors.

  8. 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

  9. 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

  10. Amino acid concentrations in hypothalamic and caudate nuclei during microwave-induced thermal stress: Analysis by microdialysis

    SciTech Connect

    Mason, P.A.; Doyle, J.M.; Escarciga, R.; Romano, W.F.; Donnellan, J.P.; Berger, R.E.

    1997-05-01

    Exposure to radiofrequency radiation (RFR) may produce thermal responses. Extracellular amino acid concentrations in the hypothalamus (Hyp) and caudate nucleus (CN) were measured by using in vivo microdialysis before and during exposure to RFR. Under urethane anesthetic, each rat was implanted stereotaxically with a nonmetallic microdialysis probe and temperature probe guides and then placed in the exposure chamber. The rat laid on its right side with its head and neck placed directly under the wave guide. Temperature probes were placed in the lift brain, right brain, face, left tympanum, and rectum. Each microdialysis sample was collected over a 20 min period. The microdialysis probe was perfused for 2 h before the rat was exposed to 5.02 GHz radiation. The right and left sides of the brain were maintained at approximately 41.2 and 41.7 C, respectively, throughout a 40 min exposure period. Initially when the brain was being heated to these temperatures, the time-averaged specific absorption rates (SARs) for the right and left sides of the brain were 29 and 40 W/kg, respectively. Concentrations of aspartic acid, glutamic acid, serine, glutamine, and glycine in dialysate were determined by using high-pressure liquid chromatography with electrochemical detection. In the Hyp and CN, the concentrations of aspartic acid, serine, and glycine increased significantly during RFR exposure.

  11. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.

    PubMed

    Kupchik, Yonatan M; Brown, Robyn M; Heinsbroek, Jasper A; Lobo, Mary Kay; Schwartz, Danielle J; Kalivas, Peter W

    2015-09-01

    It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.

  12. Directed Communication between Nucleus Accumbens and Neocortex in Humans Is Differentially Supported by Synchronization in the Theta and Alpha Band

    PubMed Central

    Horschig, Jörn M.; Smolders, Ruud; Bonnefond, Mathilde; Schoffelen, Jan-Mathijs; van den Munckhof, Pepijn; Schuurman, P. Richard; Cools, Roshan; Denys, Damiaan; Jensen, Ole

    2015-01-01

    Here, we report evidence for oscillatory bi-directional interactions between the nucleus accumbens and the neocortex in humans. Six patients performed a demanding covert visual attention task while we simultaneously recorded brain activity from deep-brain electrodes implanted in the nucleus accumbens and the surface electroencephalogram (EEG). Both theta and alpha oscillations were strongly coherent with the frontal and parietal EEG during the task. Theta-band coherence increased during processing of the visual stimuli. Granger causality analysis revealed that the nucleus accumbens was communicating with the neocortex primarily in the theta-band, while the cortex was communicating the nucleus accumbens in the alpha-band. These data are consistent with a model, in which theta- and alpha-band oscillations serve dissociable roles: Prior to stimulus processing, the cortex might suppress ongoing processing in the nucleus accumbens by modulating alpha-band activity. Subsequently, upon stimulus presentation, theta oscillations might facilitate the active exchange of stimulus information from the nucleus accumbens to the cortex. PMID:26394404

  13. Ketamine induces dopamine-dependent depression of evoked hippocampal activity in the nucleus accumbens in freely moving rats.

    PubMed

    Hunt, Mark J; Kessal, Karima; Garcia, Rene

    2005-01-12

    Noncompetitive NMDA receptor antagonists, such as ketamine, induce a transient schizophrenia-like state in healthy individuals and exacerbate psychosis in schizophrenic patients. In rodents, noncompetitive NMDA receptor antagonists induce a behavioral syndrome that represents an experimentally valid model of schizophrenia. Current experimental evidence has implicated the nucleus accumbens in the pathophysiology of schizophrenia and the psychomimetic actions of ketamine. In this study, we have demonstrated that acute systemic administration of ketamine, at a dose known to produce hyperlocomotion and stereotypy, depressed the amplitude of the monosynaptic component of fimbria-evoked field potentials recorded in the nucleus accumbens. A similar effect was observed using the more selective antagonist dizocilpine maleate, indicating the depression was NMDA receptor dependent. Paired-pulse facilitation was enhanced concomitantly with, and in proportion to, ketamine-induced depressed synaptic efficacy, indicative of a presynaptic mechanism of action. Notably, the depression of field potentials recorded in the nucleus accumbens was markedly reduced after a focal 6-hydroxydopamine lesioning procedure in the nucleus accumbens. More specifically, pretreatment with the D2/D4 antagonist haloperidol, but not the D1 antagonist SCH23390 blocked ketamine-induced depression of nucleus accumbens responses. Our findings provide supporting evidence for the contemporary theory of schizophrenia as aberrant excitatory neurotransmission at the level of the nucleus accumbens.

  14. 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

  15. Endocannabinoid-Mediated Plasticity in Nucleus Accumbens Controls Vulnerability to Anxiety after Social Defeat Stress.

    PubMed

    Bosch-Bouju, Clémentine; Larrieu, Thomas; Linders, Louisa; Manzoni, Olivier J; Layé, Sophie

    2016-08-01

    Chronic social defeat stress (CSDS) is a clinically relevant model of mood disorders. The relationship between the CSDS model and a physiologically pertinent paradigm of synaptic plasticity is not known. Here, we found that cluster analysis of the emotional behavior states of mice exposed to CSDS allowed their segregation into anxious and non-anxious groups. Endocannabinoid-mediated spike-timing dependent plasticity (STDP) in the nucleus accumbens was attenuated in non-anxious mice and abolished in anxious mice. Anxiety-like behavior in stressed animals was specifically correlated with their ability to produce STDP. Pharmacological enhancement of 2-arachidonoyl glycerol (2-AG) signaling in the nucleus accumbens normalized the anxious phenotype and STDP in anxious mice. These data reveal that endocannabinoid modulation of synaptic efficacy in response to a naturalistic activity pattern is both a molecular correlate of behavioral adaptability and a crucial factor in the adaptive response to chronic stress. PMID:27452462

  16. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Reinstatement through Local and Antidromic Activation

    PubMed Central

    White, Samantha L.; Hopkins, Thomas J.; Guercio, Leonardo A.; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D.; Pierce, R. Christopher

    2013-01-01

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents. PMID:24005296

  17. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation.

    PubMed

    Vassoler, Fair M; White, Samantha L; Hopkins, Thomas J; Guercio, Leonardo A; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D; Pierce, R Christopher

    2013-09-01

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents. PMID:24005296

  18. 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

  19. α2δ-1 Signaling in Nucleus Accumbens Is Necessary for Cocaine-Induced Relapse

    PubMed Central

    Brown, Robyn M.; Quintero, Gabriel C.; Kupchik, Yonatan M.; Thomas, Charles A.; Reissner, Kathryn J.; Kalivas, Peter W.

    2014-01-01

    Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. α2δ-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates α2δ-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that α2δ-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the α2δ-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific α2δ-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that α2δ-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy. PMID:24948814

  20. Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides.

    PubMed

    Torres-Platas, S G; Nagy, C; Wakid, M; Turecki, G; Mechawar, N

    2016-04-01

    There is mounting evidence to suggest aberrant astrocytic function in depression and suicide. Independent studies have reported astrocytic abnormalities in certain brain regions, but it remains unclear whether this is a brain-wide phenomenon. The present study examined this question by measuring glial fibrillary acidic protein (GFAP) expression in postmortem brain samples from suicide completers and matched non-psychiatric controls. Suicide completers were selected based on their recent characterization as low GFAP expressors in the prefrontal cortex, (Brodmann areas 8/9 and 10). Real-time PCR and immunoblotting were used to measure GFAP gene expression and protein levels in BA4 (primary motor cortex), BA17 (primary visual cortex), cerebellar cortex, mediodorsal thalamus and caudate nucleus. We found downregulation of GFAP mRNA and protein in the mediodorsal thalamus and caudate nucleus of depressed suicides compared with controls, whereas GFAP expression in other brain regions was similar between groups. Furthermore, a regional comparison including all samples revealed that GFAP expression in both subcortical regions was, on average, between 11- and 15-fold greater than in cerebellum and neocortex. Examining astrocyte morphology by immunohistochemistry showed that astrocytes in both thalamus and caudate displayed larger cell bodies and extended more ramified processes across larger domains than the previously described cortical astrocytes. This study reveals that astrocytic abnormalities are not brain wide and suggests that they are restricted to cortical and subcortical networks known to be affected in mood disorders. Additionally, our results show a greater diversity in human astrocytic phenotypes than previously thought.

  1. Influences of a DRD2 polymorphism on updating of long-term memory representations and caudate BOLD activity: magnification in aging.

    PubMed

    Persson, Jonas; Rieckmann, Anna; Kalpouzos, Grégoria; Fischer, Håkan; Bäckman, Lars

    2015-04-01

    A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource-modulation hypothesis assumes that aging-related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long-term memory (LTM) updating in younger and older carriers and noncarriers of the A1-allele of the TaqIa polymorphism. We demonstrate that older A1-carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1-carriers exhibited less blood oxygen level-dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non-A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging. PMID:25486867

  2. Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys.

    PubMed

    Bichot, Narcisse P; Heard, Matthew T; Desimone, Robert

    2011-08-15

    It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project. PMID:21704383

  3. Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys.

    PubMed

    Bichot, Narcisse P; Heard, Matthew T; Desimone, Robert

    2011-08-15

    It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.

  4. Dissociated effects of anticipating smoking versus monetary reward in the caudate as a function of smoking abstinence

    PubMed Central

    Sweitzer, Maggie M.; Geier, Charles F.; Joel, Danielle L.; McGurrin, Patrick; Denlinger, Rachel; Forbes, Erika; Donny, Eric C.

    2014-01-01

    Background Theories of addiction suggest that chronic smoking may be associated with both hypersensitivity to smoking and related cues and hyposensitivity to alternative reinforcers. However, neural responses to smoking and non-smoking rewards are rarely evaluated within the same paradigm, leaving the extent to which both processes operate simultaneously uncertain. Furthermore, behavioral evidence and theoretical models suggests that dysregulated reward processing may be more pronounced during deprivation from nicotine, but neuroimaging evidence on the effects of deprivation on reward processing is limited. The current study examined the impact of deprivation from smoking on neural processing of both smoking and monetary rewards. Methods Thirty-eight daily smokers participated in two separate fMRI scans, one after smoking without restriction and one following 24 hours of abstinence. A rewarded guessing task was conducted during each scan to evaluate striatal BOLD response during anticipation of both smoking and monetary rewards. Results A significant reward type X abstinence interaction was observed in the bilateral caudate and medial prefrontal cortex during reward anticipation. BOLD response to anticipation of smoking reward was significantly higher, and anticipation of monetary rewards significantly lower, during abstinence compared with non-abstinence. Furthermore, attenuation of monetary reward-related activation during abstinence was significantly correlated with abstinence-induced increases in craving and withdrawal. Conclusions These results provide the first direct evidence of dissociated effects of smoking versus monetary rewards as a function of abstinence. The findings suggest an important neural pathway that may underlie the choice to smoke in lieu of alternate reinforcement during a quit attempt. PMID:24342923

  5. Differential visualization of dopamine and norepinephrine uptake sites in rat brain using (/sup 3/H)mazindol autoradiography

    SciTech Connect

    Javitch, J.A.; Strittmatter, S.M.; Snyder, S.H.

    1985-06-01

    Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using (/sup 3/H)mazindol autoradiography. At appropriate concentrations, desipramine (DMI) selectively inhibits (/sup 3/H)mazindol binding to NE uptake sites without significantly affecting binding to DA uptake sites. The localization of DMI-insensitive specific (/sup 3/H) mazindol binding, reflecting DA uptake sites, is densest in the caudate-putamen, the nucleus accumbens, the olfactory tubercle, the subthalamic nucleus, the ventral tegmental area, the substantia nigra (SN) pars compacta, and the anterior olfactory nuclei. In contrast, the localization of DMI-sensitive specific (/sup 3/H)mazindol binding, representing NE uptake sites, is densest in the locus coeruleus, the nucleus of the solitary tract, the bed nucleus of the stria terminalis, the paraventricular and periventricular nuclei of the hypothalamus, and the anteroventral thalamus. The distribution of DMI-insensitive specific (/sup 3/H)mazindol binding closely parallels that of dopaminergic terminal and somatodendritic regions, while the distribution of DMI-sensitive specific (/sup 3/H)mazindol binding correlates well with the regional localization of noradrenergic terminals and cell bodies. Injection of 6-hydroxydopamine, ibotenic acid, or colchicine into the SN decreases (/sup 3/H)mazindol binding to DA uptake sites in the ipsilateral caudate-putamen by 85%. In contrast, ibotenic acid lesions of the caudate-putamen do not reduce (/sup 3/H)mazindol binding to either the ipsilateral or contralateral caudate-putamen.

  6. Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats.

    PubMed

    Ding, R; Feng, L; He, L; Chen, Y; Wen, P; Fu, Z; Lin, C; Yang, S; Deng, X; Zeng, J; Sun, G

    2015-06-25

    Hemoglobin (Hb) is a major constituent of blood and a potent mediator of oxidative or nitrative stress after intracerebral hemorrhage (ICH). Our previous study demonstrated that Hb could induce abundant peroxynitrite (ONOO(-)) formation in vivo, which may be involved in the blood-brain barrier (BBB) disruption, however, the drug intervention is absent and also the underlying mechanism. Using an experimental stroke model by injecting Hb into the caudate nucleus of male Sprague-Dawley rats, we assessed the role of ONOO(-) decomposition catalyst, 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) [FeTPPS] in the activation of MMP-9 and Hb-induced neurovascular injuries. 3-Nitrotyrosine (3-NT, as an index of ONOO(-) formation) and NF-κB expression was measured by western blot (WB) and immunohistochemistry (IHC)/immunofluorescence (IF). Activity of MMP was evaluated by in situ zymography. Neurovascular injury was assessed using zonula occludens-1 (ZO-1) by WB and IF, fibronectin (FN) and neuron-specific nuclear protein (NeuN) IHC. Perihematomal cell death was determined by TUNEL assay. Behavioral outcome was measured by modified neurological severity score (mNSS) test. At the injured striata, profuse 3-NT was produced and mainly expressed in neutrophils and microglia/macrophages. 3-NT formation significantly colocalized with nuclear factor-κB (NF-κB) expression. In situ zymography showed that gelatinase activity was mostly co-localized with neurons and blood vessel walls and partly with neutrophils and microglia/macrophages. Enhanced 3-NT production, NF-κB induction and MMP-9 activation were obviously reduced after FeTPPS treatment. Hb-induced injury to tight junction protein (ZO-1), basal lamina of FN-immunopositive microvasculature and neural cells was evidently ameliorated by FeTPPS. In addition, apoptotic cell numbers as well as behavioral deficits were also improved. The present study shows that the administration of the ONOO(-) decomposition

  7. Tickling increases dopamine release in the nucleus accumbens and 50 kHz ultrasonic vocalizations in adolescent rats.

    PubMed

    Hori, Miyo; Shimoju, Rie; Tokunaga, Ryota; Ohkubo, Masato; Miyabe, Shigeki; Ohnishi, Junji; Murakami, Kazuo; Kurosawa, Mieko

    2013-03-27

    Adolescent rats emit 50 kHz ultrasonic vocalizations, a marker of positive emotion, during rough-and-tumble play or on tickling stimulation. The emission of 50 kHz ultrasonic vocalizations in response to tickling is suggested to be mediated by dopamine release in the nucleus accumbens; however, there is no direct evidence supporting this hypothesis. The present study aimed to elucidate whether play behavior (tickling) in adolescent rats can trigger dopamine release in the nucleus accumbens with hedonic 50 kHz ultrasonic vocalizations. The effect of tickling stimulation was compared with light-touch stimulation, as a discernible stimulus. We examined 35-40-day-old rats, which corresponds to the period of midadolescence. Tickling stimulation for 5 min significantly increased dopamine release in the nucleus accumbens (118±7% of the prestimulus control value). Conversely, light-touch stimulation for 5 min did not significantly change dopamine release. In addition, 50 kHz ultrasonic vocalizations were emitted during tickling stimulation but not during light-touch stimulation. Further, tickling-induced 50 kHz ultrasonic vocalizations were significantly blocked by the direct application of SCH23390 (D1 receptor antagonist) and raclopride (D2/D3 receptor antagonist) into the nucleus accumbens. Our study demonstrates that tickling stimulation in adolescent rats increases dopamine release in the nucleus accumbens, leading to the generation of 50 kHz ultrasonic vocalizations.

  8. Evidence for a nucleus accumbens CCK2 receptor regulation of rat ventral pallidal GABA levels: a dual probe microdialysis study.

    PubMed

    Ferraro, L; O'Connor, W T; Glennon, J; Tomasini, M C; Bebe, B W; Tanganelli, S; Antonelli, T

    2000-12-22

    We employed dual probe microdialysis in the nucleus accumbens and ipsilateral ventral pallidum of the halothane anaesthetized rat to investigate the effect of intra-accumbens perfusion with the sulphated octapeptide cholecystokinin (CCK-8S, 10-1000 nM, 60 min) alone and in the presence of the selective CCK1 and CCK2 receptor antagonists L-364,718 (10 and 100 nM) and PD134308 (10 nM), tetrodotoxin (TTX, 1000 nM) and the GABA(A) receptor antagonist bicuculline (1000 nM), on dialysate GABA levels in the ventral pallidum. Intra-accumbens perfusion with the 100 and 1000 nM concentration of CCK-8S was associated with a significant decrease (-16+/-3% and -23+/-3% vs basal, respectively) in ventral pallidum GABA levels. The CCK-8S (1000 nM) induced decrease in ventral pallidal dialysate GABA levels was abolished when PD134308, TTX and bicuculline, but not L-364,718, were included into the perfusion medium of the accumbens probe. The data indicate that nucleus accumbens CCK-8S exerts a CCK2 receptor mediated inhibition of ventral pallidal GABA levels. Furthermore, the TTX and bicuculline sensitivity of this effect suggests that this is possibly mediated via CCK2 receptors probably located on local GABA interneurons.

  9. Disrupted Reinforcement Signaling in Orbital Frontal Cortex and Caudate in Youths with Conduct Disorder/Oppositional Defiant Disorder and High Psychopathic Traits

    PubMed Central

    Finger, Elizabeth C.; Marsh, Abigail A.; Blair, Karina S.; Reid, Marguerite. E.; Sims, Courtney; Ng, Pamela; Pine, Daniel S.; Blair, R. James. R.

    2010-01-01

    OBJECTIVE Dysfunction in amygdala and orbital frontal cortex functioning has been reported in youths and adults with psychopathic traits. However, the specific nature of the computational irregularities within these brain structures remains poorly understood. The current study used the passive avoidance task to examine responsiveness of these systems to early stimulus-reinforcement exposure, when prediction errors are greatest and learning maximized, and to reward in youths with psychopathic traits and comparison youths. METHOD 30 youths (N=15 with conduct disorder or oppositional defiant disorder plus high psychopathic traits and N=15 comparison subjects) completed a 3.0 T fMRI scan while performing a passive avoidance learning task. RESULTS Relative to comparison youth, youths with conduct disorder or oppositional defiant disorder plus psychopathic traits showed reduced orbitofrontal cortex responsiveness both to early stimulus-reinforcement exposure and to rewards, as well as reduced caudate response to early stimulus-reinforcement exposure. Contrary to other predictions, however, there were no group differences in amygdala responsiveness specifically to these two task parameters. However, amygdala responsiveness throughout the task was reduced in the youths with conduct disorder or oppositional defiant disorder plus psychopathic traits. CONCLUSIONS This study demonstrates that youths with conduct disorder or oppositional defiant disorder plus psychopathic traits are marked by a compromised sensitivity to early reinforcement information in both orbitofrontal cortex and caudate and to reward outcome information within orbitofrontal cortex. They further suggest that the integrated functioning of the amygdala, caudate and orbitofrontal cortex may be disrupted in individuals with this disorder. PMID:21078707

  10. Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report.

    PubMed

    Aouizerate, Bruno; Cuny, Emmanuel; Martin-Guehl, Corinne; Guehl, Dominique; Amieva, Helene; Benazzouz, Abdelhamid; Fabrigoule, Colette; Allard, Michele; Rougier, Alain; Bioulac, Bernard; Tignol, Jean; Burbaud, Pierre

    2004-10-01

    Obsessive-compulsive disorder (OCD) is an anxiety disorder associated with recurrent intrusive thoughts and repetitive behaviors. Although conventional pharmacological and/or psychological treatments are well established and effective in treating OCD, symptoms remain unchanged in up to 30% of patients. Deep brain stimulation (DBS) of the anterior limb of the internal capsule has recently been proposed as a possible therapeutic alternative in treatment-resistant OCD. In the present study, the authors tested the hypothesis that DBS of the ventral caudate nucleus might be effective in a patient with intractable severe OCD and concomitant major depression. Psychiatric assessment included the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), and the Global Assessment of Functioning (GAF) Scale for determining the symptom severity of OCD, depression, and anxiety as well as the quality of pychosocial and occupational functioning, respectively. Neuropsychological assessment consisted of a wide range of tests primarily exploring memory and executive functions. Deep brain stimulation of the ventral caudate nucleus markedly improved symptoms of depression and anxiety until their remission, which was achieved at 6 months after the start of stimulation (HDRS < or = 7 and HARS < or = 10). Remission of OCD (Y-BOCS < 16) was also delayed after 12 or 15 months of DBS. The level of functioning pursuant to the GAF scale progressively increased during the 15-month follow-up period. No neuropsychological deterioration was observed, indicating that DBS of the ventral caudate nucleus could be a promising strategy in the treatment of refractory cases of both OCD and major depression. PMID:15481726

  11. Corticosterone Acts in the Nucleus Accumbens to Enhance Dopamine Signaling and Potentiate Reinstatement of Cocaine Seeking

    PubMed Central

    Graf, Evan N.; Wheeler, Robert A.; Baker, David A.; Ebben, Amanda L.; Hill, Jonathan E.; McReynolds, Jayme R.; Robble, Mykel A.; Vranjkovic, Oliver; Wheeler, Daniel S.; Mantsch, John R.

    2013-01-01

    Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may “set the stage” for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake2-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake. PMID:23864669

  12. Variability in nucleus accumbens activity mediates age-related suboptimal financial risk taking

    PubMed Central

    Samanez-Larkin, Gregory R.; Kuhnen, Camelia M.; Yoo, Daniel J.; Knutson, Brian

    2010-01-01

    As human life expectancy continues to rise, financial decisions of aging investors may have an increasing impact on the global economy. In this study, we examined age differences in financial decisions across the adult life span by combining functional neuroimaging with a dynamic financial investment task. During the task, older adults made more suboptimal choices than younger adults when choosing risky assets. This age-related effect was mediated by a neural measure of temporal variability in nucleus accumbens activity. These findings reveal a novel neural mechanism by which aging may disrupt rational financial choice. PMID:20107069

  13. Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning.

    PubMed

    Smith-Roe, S L; Kelley, A E

    2000-10-15

    The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.

  14. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking.

    PubMed

    Bossert, Jennifer M; Stern, Anna L; Theberge, Florence R M; Marchant, Nathan J; Wang, Hui-Ling; Morales, Marisela; Shaham, Yavin

    2012-04-01

    In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse. PMID:22492053

  15. Neural architecture of choice behaviour in a concurrent interval schedule.

    PubMed

    Kalenscher, Tobias; Diekamp, Bettina; Güntürkün, Onur

    2003-11-01

    Concurrent interval schedules are classic experimental paradigms that are traditionally employed in psychological research on choice behaviour. To analyse the neural basis of choice in a concurrent fixed interval schedule, pigeons were trained to peck on two response keys. Responses were differentially rewarded in key specific short or long time intervals (SI vs. LI). Using tetrodotoxin, we reversibly blocked the neostriatum caudolaterale (NCL, the avian functional equivalent of the prefrontal cortex), avian caudate-putamen and nucleus accumbens to examine their contribution. A detailed analysis of baseline choice behaviour revealed that response distribution and key affinity were determined by cued or time-related expectancy for rewards on the SI key. The pigeons' response frequency increased on the SI key and decreased on the LI key with increasing temporal proximity to the SI reward and pigeons switched to the LI key after reward delivery. Pecking bursts on the LI key were negatively correlated with bursts on the SI key. Neostriatum caudolaterale inactivation did not affect pecking activity per se but interfered with reward-related temporal modulation of pecking frequency, switching pattern and coupling of LI to SI pecks. Blockade of caudate-putamen resulted in a complete behavioural halt, while inactivation of nucleus accumbens diminished operant behaviour without affecting consummatory responses. These data suggest that the NCL is tuned via indirect striato-pallial projections to integrate cued or time-related reward expectancy into a response selection process in order to set, maintain or shift goals. The NCL possibly feeds forward the resulting motor commands to the caudate-putamen for execution.

  16. Phenotypical characterization of the rat striatal neurons expressing the D1 dopamine receptor gene.

    PubMed Central

    Le Moine, C; Normand, E; Bloch, B

    1991-01-01

    In situ hybridization experiments were performed in rat brain sections from normal and 6-hydroxydopamine-treated rats in order to map and identify the neurons expressing the D1 receptor gene in the striatum and the substantia nigra. Procedures of combined in situ hybridization, allowing the simultaneous detection of two mRNAs in the same section or in adjacent sections, were used to characterize the phenotypes of the neurons expressing the D1 receptor gene. D1 receptor mRNA was found in neurons all over the caudate-putamen, the accumbens nucleus, and the olfactory tubercle but not in the substantia nigra. In the caudate-putamen and accumbens nucleus, most of the neurons containing D1 receptor mRNA were characterized as medium-sized substance P neurons and distinct from those containing D2 receptor mRNA. Nevertheless, 15-20% of the substance P neurons did not contain D1 receptor mRNA. The neurons containing preproenkephalin A mRNA did not contain D1 receptor mRNA but contained D2 receptor mRNA. A small number of cholinergic and somatostatinergic neurons exhibited a weak reaction for D1 receptor mRNA. These results demonstrate that dopamine acts on efferent striatal neurons through expression of distinct receptors--namely, D1 and D2 in separate cell populations (substance P and preproenkephalin A neurons, respectively)--and can also act on nonprojecting neurons through D1 receptor expression. Images PMID:1827915

  17. A behavioral and micro positron emission tomography imaging study in a rat model of hypothyroidism.

    PubMed

    Yu, Jing; Tang, Yi-Yuang; Feng, Hong-Bo; Cheng, Xiao-Xin

    2014-09-01

    Hypothyroidism leads to somatic, neuropsychological, and psychiatric changes that are similar to depression. The mechanisms underlying the behavioral abnormalities in adult onset hypothyroidism remain ambiguous. Hypothyroidism was induced in adult male Wistar rats by the maintenance of 0.05% propylthiouracil (PTU) in drinking water for 5 weeks (hypothyroid group; HP group); control rats (CON group) received an equivalent amount of water. The open field and sucrose preference tests were employed, and the link between behavioral changes and brain glucose metabolism was evaluated using micro positron emission tomography imaging. The open field test revealed slightly decreased locomotor activity and significantly reduced rearing and defecation in the hypothyroid group. Hypothyroid rats were also characterized by decreased body weight, sucrose preference, and relative sucrose intake compared to control rats. Hypothyroidism induced reduced brain glucose metabolism in the bilateral motor cortex, the caudate putamen, the cortex cingulate, the nucleus accumbens, and the frontal association cortex. A decreased sucrose preference was positively correlated with metabolic glucose changes in the caudate putamen and the nucleus accumbens. The results indicate that the activity pattern in adult onset hypothyroidism is different from the activity pattern when hypothyroidism is induced in the developmental period of the central nervous system. Decreased sucrose preference in hypothyroid rats may be attributed to anhedonia. Furthermore, these findings suggest there may be a common mechanism underlying adult onset hypothyroidism and depression.

  18. Alterations in the hippocampus and thalamus in individuals at high risk for psychosis

    PubMed Central

    Harrisberger, Fabienne; Buechler, Roman; Smieskova, Renata; Lenz, Claudia; Walter, Anna; Egloff, Laura; Bendfeldt, Kerstin; Simon, Andor E; Wotruba, Diana; Theodoridou, Anastasia; Rössler, Wulf; Riecher-Rössler, Anita; Lang, Undine E; Heekeren, Karsten; Borgwardt, Stefan

    2016-01-01

    Reduction in hippocampal volume is a hallmark of schizophrenia and already present in the clinical high-risk state. Nevertheless, other subcortical structures, such as the thalamus, amygdala and pallidum can differentiate schizophrenia patients from controls. We studied the role of hippocampal and subcortical structures in clinical high-risk individuals from two cohorts. High-resolution T1-weighted structural MRI brain scans of a total of 91 clinical high-risk individuals and 64 healthy controls were collected in two centers. The bilateral volume of the hippocampus, the thalamus, the caudate, the putamen, the pallidum, the amygdala, and the accumbens were automatically segmented using FSL-FIRST. A linear mixed-effects model and a prospective meta-analysis were applied to assess group-related volumetric differences. We report reduced hippocampal and thalamic volumes in clinical high-risk individuals compared to healthy controls. No volumetric alterations were detected for the caudate, the putamen, the pallidum, the amygdala, or the accumbens. Moreover, we found comparable medium effect sizes for group-related comparison of the thalamus in the two analytical methods. These findings underline the relevance of specific alterations in the hippocampal and subcortical volumes in the high-risk state. Further analyses may allow hippocampal and thalamic volumes to be used as biomarkers to predict psychosis. PMID:27738647

  19. Accumbens cholinergic interneurons play a role in the regulation of body weight and metabolism.

    PubMed

    Hajnal, A; Székely, M; Gálosi, R; Lénárd, L

    The aims of the present study were (1) to determine whether selective lesions of the accumbens cholinergic interneurons impair feeding and body weight regulation, and (2) to characterize the nature of disturbances using motivational and metabolic challenges. Rats with bilateral cholinotoxic (AF64A) lesions in the nucleus accumbens showed a significant and lasting lag in body weight gain in comparison to the sham-operated controls. This failure to gain weight was not due to a decrease in feeding because lesioned rats actually ate more food and drank more water than controls under basal conditions. Lesion-induced deficits were also exposed when the rats were challenged with food deprivation or cold exposure. Lesioned rats ate less than controls when 24 h food deprived and maintained both a higher core temperature and a higher metabolic rate than controls following either 24-h food deprivation or exposure to cold. Thyroid hormones, insulin, and blood glucose levels were, however, within the physiological range, and no sensory and motor disturbances were observed. The results suggest that the altered body weight regulation is partly due to the enhanced metabolic responsiveness to stress. Possible explanations for the effects of the lesions are also discussed in the context of motivational alterations, including possible dopamine-acetylcholine interactions.

  20. Acute drug-induced spine changes in the nucleus accumbens are dependent on β-adducin.

    PubMed

    Engmann, Olivia; Giralt, Albert; Girault, Jean-Antoine

    2016-11-01

    Chronic modifications of dopamine transmission alter striatal dendritic spines. Here, we show that spine density and length are increased in the nucleus accumbens 24 h after a single injection of caffeine or quinpirole, a dopamine D2/D3 dopamine receptors agonist, whereas the dopamine antagonist haloperidol has opposite effects. These effects are absent in mice lacking β-adducin, a protein that stabilizes actin/spectrin cortical cytoskeleton and modulates synaptic plasticity. Phosphorylation of adducin (Ser713 in β-adducin), which disrupts actin/spectrin interaction, is increased by quinpirole, haloperidol, or caffeine. We previously demonstrated that DARPP-32 interacts with β-adducin and facilitates its phosphorylation. Quinpirole increased DARPP-32 phosphorylation at Thr75 and haloperidol at Ser97, two modifications that can have similar consequences on adducin phosphorylation through distinct mechanisms. Experiments in DARPP-32 mutant mice confirmed that the apparently paradoxical similar effects of quinpirole and haloperidol on adducin phosphorylation may result from differential effects of these drugs on DARPP-32 phosphorylation at Thr75 and Ser97. Our data provide novel insights on how a single dose of widely used psychoactive drugs can affect spine plasticity in the nucleus accumbens, a component of the reward system. PMID:27480796

  1. Understanding the Role α7 Nicotinic Receptors Play in Dopamine Efflux in Nucleus Accumbens

    PubMed Central

    2015-01-01

    Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction. PMID:25147933

  2. Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents.

    PubMed

    Karoly, Hollis C; Bryan, Angela D; Weiland, Barbara J; Mayer, Andrew; Dodd, Andrew; Feldstein Ewing, Sarah W

    2015-12-01

    Numerous questions surround the nature of reward processing in the developing adolescent brain, particularly in regard to polysubstance use. We therefore sought to examine incentive-elicited brain activation in the context of three common substances of abuse (cannabis, tobacco, and alcohol). Due to the role of the nucleus accumbens (NAcc) in incentive processing, we compared activation in this region during anticipation of reward and loss using a monetary incentive delay (MID) task. Adolescents (ages 14-18; 66% male) were matched on age, gender, and frequency of use of any common substances within six distinct groups: cannabis-only (n=14), tobacco-only (n=34), alcohol-only (n=12), cannabis+tobacco (n=17), cannabis+tobacco+alcohol (n=17), and non-using controls (n=38). All groups showed comparable behavioral performance on the MID task. The tobacco-only group showed decreased bilateral nucleus accumbens (NAcc) activation during reward anticipation as compared to the alcohol-only group, the control group, and both polysubstance groups. Interestingly, no differences emerged between the cannabis-only group and any of the other groups. Results from this study suggest that youth who tend toward single-substance tobacco use may possess behavioral and/or neurobiological characteristics that differentiate them from both their substance-using and non-substance-using peers.

  3. Altered CB1 receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects.

    PubMed

    Erdozain, Amaia M; Rubio, Marina; Meana, J Javier; Fernández-Ruiz, Javier; Callado, Luis F

    2015-11-01

    Biochemical, pharmacological and genetic evidence suggests the involvement of the endocannabinoid system in alcohol dependence. The aim of the present study was to evaluate the state of CB1 receptors in post-mortem caudate nucleus, hippocampus and cerebellum of alcoholic subjects.CB1 protein levels were measured by Western blot, CB1 receptor density and affinity by [(3)H]WIN55,212-2 saturation assays and CB1 functionality by [(35)S]GTPγS binding assays. Experiments were performed in samples from 24 subjects classified as non-suicidal alcoholics (n = 6), suicidal alcoholics (n = 6), non-alcoholic suicide victims (n = 6) and control subjects (n = 6).Alcoholic subjects presented hyperfunctional CB1 receptors in the caudate nucleus resulting in a higher maximal effect in both alcoholic groups compared to the non-alcoholic groups (p < 0.001). Conversely, in the cerebellum the non-suicidal alcoholic subjects showed hypofunctional receptors with lower maximal effect and potency (p < 0.001). No changes were found in the CB1 protein expression in either region. In the hippocampus of alcoholic subjects, no changes were observed either in the functionality, density or protein levels.Our data support an association between endocannabinoid system activity and alcoholism. The modifications reported here could be either a consequence of high lifetime ethanol consumption or a vulnerability factor to develop alcohol addiction.

  4. Perinatal undernutrition facilitates morphine sensitization and cross-sensitization to cocaine in adult rats: a behavioral and neurochemical study.

    PubMed

    Velazquez, E E; Valdomero, A; Orsingher, O A; Cuadra, G R

    2010-01-20

    The development of sensitization to the locomotor effects of morphine and cross-sensitization between morphine and cocaine were evaluated in adult rats submitted to a protein malnutrition schedule from the 14th day of gestation up to 30 days of age (D-rats), and compared with well-nourished animals (C-rats). Dose-response curves to morphine-induced locomotor activity (5, 7.5, 10 or 15 mg/kg, i.p., every other day for 5 days) revealed a shift to the left in D-rats compared to C-rats. This implies that D-rats showed behavioral sensitization to the lower dose of morphine used (5 mg/kg), which was ineffective in C-rats. Furthermore, when a cocaine challenge (10 mg/kg, i.p) was given 48 h after the last morphine administration, only D-rats exhibited cross-sensitization in morphine-pretreated animals (7.5 and 10 mg/kg). In order to correlate the differential response observed with the functioning of the mesocorticolimbic dopaminergic system, extracellular dopamine (DA) levels were measured in the nucleus accumbens (core and shell) and the dorsal caudate-putamen. A challenge with cocaine in morphine pre-exposed animals produced an increase in DA release, but only in the nucleus accumbens "core" of D-rats. Similar DA levels were found in the nucleus accumbens "shell" and in the dorsal caudate-putamen of both groups. Finally, these results demonstrate that D-rats had a lower threshold for developing both a progressive behavioral sensitization to morphine and a cross-sensitization to cocaine. In accordance with these behavioral findings, a higher responsiveness of the nucleus accumbens core, expressed by increased DA levels, both basal and after cocaine challenge, was observed in D-rats.

  5. 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

  6. Nucleus accumbens response to gains in reputation for the self relative to gains for others predicts social media use

    PubMed Central

    Meshi, Dar; Morawetz, Carmen; Heekeren, Hauke R.

    2013-01-01

    Our reputation is important to us; we've experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one's character) has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others' behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one's degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior. PMID:24009567

  7. The Role of Nucleus Accumbens Shell in Learning about Neutral versus Excitatory Stimuli during Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Bradfield, Laura A.; McNally, Gavan P.

    2010-01-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning…

  8. A Study on the Role of the Dorsal Striatum and the Nucleus Accumbens in Allocentric and Egocentric Spatial Memory Consolidation

    ERIC Educational Resources Information Center

    De Leonibus, Elvira; Oliverio, Alberto; Mele, Andrea

    2005-01-01

    There is now accumulating evidence that the striatal complex in its two major components, the dorsal striatum and the nucleus accumbens, contributes to spatial memory. However, the possibility that different striatal subregions might modulate specific aspects of spatial navigation has not been completely elucidated. Therefore, in this study, two…

  9. 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…

  10. Neural encoding of psychomotor activation in the nucleus accumbens core, but not the shell, requires cannabinoid receptor signaling

    PubMed Central

    Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

    2010-01-01

    The current study aimed to further elucidate the role of endocannabinoid signaling in methamphetamine-induced psychomotor activation. Rats were treated with bilateral, intracranial microinjections of the cannabinoid CB1 receptor antagonists rimonabant (1 μg; 1 μl) or AM251 (1 μg; 1 μl), or vehicle (1 μl), followed by intravenous methamphetamine (3 mg/kg). Antagonist pretreatment in the nucleus accumbens core, but not shell, attenuated methamphetamine-induced stereotypy, while treatment in either brain region had no effect on drug-induced locomotion. In a parallel experiment, we recorded multiple single-units in the nucleus accumbens of behaving rats treated with intravenous rimonabant (0.3 mg/kg) or vehicle, followed by methamphetamine (0.01, 0.1, 1, 3 mg/kg; cumulative dosing). We observed robust, phasic changes in neuronal firing time-locked to the onset of methamphetamine-induced locomotion and stereotypy. Stereotypy encoding was observed in the core and was attenuated by CB1 receptor antagonism, while locomotor correlates were observed uniformly across the accumbens and were not affected by rimonabant. Psychomotor activation encoding was expressed predominantly by putative fast-spiking interneurons. We therefore propose that endocannabinoid modulation of psychomotor activation is preferentially driven by CB1 receptor-dependent interneuron activity in the nucleus accumbens core. PMID:20371830

  11. Nucleus accumbens response to gains in reputation for the self relative to gains for others predicts social media use.

    PubMed

    Meshi, Dar; Morawetz, Carmen; Heekeren, Hauke R

    2013-01-01

    Our reputation is important to us; we've experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one's character) has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others' behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one's degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior.

  12. Mapping abnormal subcortical brain morphometry in an elderly HIV+ cohort.

    PubMed

    Wade, Benjamin S C; Valcour, Victor G; Wendelken-Riegelhaupt, Lauren; Esmaeili-Firidouni, Pardis; Joshi, Shantanu H; Gutman, Boris A; Thompson, Paul M

    2015-01-01

    Over 50% of HIV + individuals exhibit neurocognitive impairment and subcortical atrophy, but the profile of brain abnormalities associated with HIV is still poorly understood. Using surface-based shape analyses, we mapped the 3D profile of subcortical morphometry in 63 elderly HIV + participants and 31 uninfected controls. The thalamus, caudate, putamen, pallidum, hippocampus, amygdala, brainstem, accumbens, callosum and ventricles were segmented from high-resolution MRIs. To investigate shape-based morphometry, we analyzed the Jacobian determinant (JD) and radial distances (RD) defined on each region's surfaces. We also investigated effects of nadir CD4 + T-cell counts, viral load, time since diagnosis (TSD) and cognition on subcortical morphology. Lastly, we explored whether HIV + participants were distinguishable from unaffected controls in a machine learning context. All shape and volume features were included in a random forest (RF) model. The model was validated with 2-fold cross-validation. Volumes of HIV + participants' bilateral thalamus, left pallidum, left putamen and callosum were significantly reduced while ventricular spaces were enlarged. Significant shape variation was associated with HIV status, TSD and the Wechsler adult intelligence scale. HIV + people had diffuse atrophy, particularly in the caudate, putamen, hippocampus and thalamus. Unexpectedly, extended TSD was associated with increased thickness of the anterior right pallidum. In the classification of HIV + participants vs. controls, our RF model attained an area under the curve of 72%.

  13. Mapping abnormal subcortical brain morphometry in an elderly HIV + cohort

    PubMed Central

    Wade, Benjamin S.C.; Valcour, Victor G.; Wendelken-Riegelhaupt, Lauren; Esmaeili-Firidouni, Pardis; Joshi, Shantanu H.; Gutman, Boris A.; Thompson, Paul M.

    2015-01-01

    Over 50% of HIV + individuals exhibit neurocognitive impairment and subcortical atrophy, but the profile of brain abnormalities associated with HIV is still poorly understood. Using surface-based shape analyses, we mapped the 3D profile of subcortical morphometry in 63 elderly HIV + participants and 31 uninfected controls. The thalamus, caudate, putamen, pallidum, hippocampus, amygdala, brainstem, accumbens, callosum and ventricles were segmented from high-resolution MRIs. To investigate shape-based morphometry, we analyzed the Jacobian determinant (JD) and radial distances (RD) defined on each region's surfaces. We also investigated effects of nadir CD4 + T-cell counts, viral load, time since diagnosis (TSD) and cognition on subcortical morphology. Lastly, we explored whether HIV + participants were distinguishable from unaffected controls in a machine learning context. All shape and volume features were included in a random forest (RF) model. The model was validated with 2-fold cross-validation. Volumes of HIV + participants' bilateral thalamus, left pallidum, left putamen and callosum were significantly reduced while ventricular spaces were enlarged. Significant shape variation was associated with HIV status, TSD and the Wechsler adult intelligence scale. HIV + people had diffuse atrophy, particularly in the caudate, putamen, hippocampus and thalamus. Unexpectedly, extended TSD was associated with increased thickness of the anterior right pallidum. In the classification of HIV + participants vs. controls, our RF model attained an area under the curve of 72%. PMID:26640768

  14. Genetic Variation in the Catechol-O-Methyl Transferase Val108/158Met Is Linked to the Caudate and Posterior Cingulate Cortex Volume in Healthy Subjects: Voxel-Based Morphometry Analysis of Brain Magnetic Resonance Imaging.

    PubMed

    Watanabe, Keita; Kakeda, Shingo; Yoshimura, Reiji; Ide, Satoru; Hayashi, Kenji; Katsuki, Asuka; Umene-Nakano, Wakako; Watanabe, Rieko; Abe, Osamu; Korogi, Yukunori

    2015-01-01

    The effect of the catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain morphology has been investigated but remains controversial. We hypothesized that a comparison between Val/Val and Val/Met individuals, which may represent the most different combinations concerning the effects of the COMT genotype, may reveal new findings. We investigated the brain morphology using 3-Tesla magnetic resonance imaging in 27 Val/Val and 22 Val/Met individuals. Voxel-based morphometry revealed that the volumes of the bilateral caudate and posterior cingulate cortex were significantly smaller in Val/Val individuals than in Val/Met individuals [right caudate: false discovery rate (FDR)-corrected p = 0.048; left caudate: FDR-corrected p = 0.048; and bilateral posterior cingulate cortex: FDR-corrected p = 0.048]. This study demonstrates that interacting functional variants of COMT affect gray matter regional volumes in healthy subjects.

  15. Genetic Variation in the Catechol-O-Methyl Transferase Val108/158Met Is Linked to the Caudate and Posterior Cingulate Cortex Volume in Healthy Subjects: Voxel-Based Morphometry Analysis of Brain Magnetic Resonance Imaging

    PubMed Central

    Watanabe, Keita; Kakeda, Shingo; Yoshimura, Reiji; Ide, Satoru; Hayashi, Kenji; Katsuki, Asuka; Umene-Nakano, Wakako; Watanabe, Rieko; Abe, Osamu; Korogi, Yukunori

    2015-01-01

    The effect of the catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain morphology has been investigated but remains controversial. We hypothesized that a comparison between Val/Val and Val/Met individuals, which may represent the most different combinations concerning the effects of the COMT genotype, may reveal new findings. We investigated the brain morphology using 3-Tesla magnetic resonance imaging in 27 Val/Val and 22 Val/Met individuals. Voxel-based morphometry revealed that the volumes of the bilateral caudate and posterior cingulate cortex were significantly smaller in Val/Val individuals than in Val/Met individuals [right caudate: false discovery rate (FDR)-corrected p = 0.048; left caudate: FDR-corrected p = 0.048; and bilateral posterior cingulate cortex: FDR-corrected p = 0.048]. This study demonstrates that interacting functional variants of COMT affect gray matter regional volumes in healthy subjects. PMID:26566126

  16. Dual effects of limbic seizures on psychosis-relevant behaviors shown by nucleus accumbens kindling in rats

    PubMed Central

    Ma, Jingyi; Leung, L. Stan

    2016-01-01

    Background A paradox in epilepsy and psychiatry is that temporal lobe epilepsy is often predisposed to schizophrenic-like psychosis, whereas convulsive therapy can relieve schizophrenic symptoms. We have previously demonstrated that the nucleus accumbens is a key structure in mediating postictal psychosis induced by a hippocampal electrographic seizure. Objective/Hypothesis The purpose of this study is to test a hypothesis that accumbens kindling cumulating in a single (1-time) or repeated (5-times) convulsive seizures have different effects on animal models of psychosis. Methods Electrical stimulation at 60 Hz was applied to nucleus accumbens to evoke afterdischarges until one, or five, convulsive seizures that involved the hind limbs (stage 5 seizures) were attained. Behavioral tests, performed at 3 days after the last seizure, included gating of hippocampal auditory evoked potentials (AEP) and prepulse inhibition to an acoustic startle response (PPI), tested without drug injection or after ketamine (3 mg/kg s.c.) injection, as well as locomotion induced by ketamine or methamphetamine (1 mg/kg i.p.). Results Compared to non-kindled control rats, 1-time, but not 5-times, convulsive seizures induced PPI deficit and decreased gating of hippocampal AEP, without drug injection. Compared to non-kindled rats, 5-times, but not 1-time, convulsive seizures antagonized ketamine-induced hyperlocomotion, ketamine-induced PPI deficit and AEP gating decrease. However, both 1- and 5-times convulsive seizures, significantly enhanced methamphetamine-induced locomotion as compared to non-kindled rats. Conclusions Accumbens kindling ending with 1 convulsive seizure may induce schizophrenic-like behaviors, while repeated (≥ 5) convulsive seizures induced by accumbens kindling may have therapeutic effects on dopamine independent psychosis. PMID:27267861

  17. 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

  18. 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

  19. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking in Rats

    PubMed Central

    Vassoler, F.M.; Schmidt, H.D.; Gerard, M.E.; Famous, K.R.; Ciraulo, D.A.; Kornetsky, C.; Knapp, C.M.; Pierce, R.C.

    2008-01-01

    Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 hours daily for 21 days and then cocaine seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 μAmps. DBS began immediately after a priming injection of cocaine (0, 5, 10 or 20 mg/kg, i.p.) and continued throughout each 2-hour reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer-specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Taken together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction. PMID:18753374

  20. Modifications in glutamatergic transmission after dopamine depletion of the nucleus accumbens. A combined in vivo/in vitro electrophysiological study in the rat.

    PubMed

    Mulder, A B; Manshanden, I; Vos, P E; Wolterink, G; van Ree, J M; Lopes da Silva, F H

    1996-06-01

    The interaction between the glutamatergic and dopaminergic input in the nucleus accumbens was examined by studying the effects of dopamine depletion of the nucleus accumbens on the local field potentials, and the L-glutamate elicited responses of the nucleus accumbens in anaesthetized rats in vivo. A characteristic field potential in the nucleus accumbens is evoked by electrical stimulation of the fornix/fimbria fibres, with a monosynaptic positive peak at 10 ms (P10). Rats were unilaterally injected with 6-hydroxydopamine in the nucleus accumbens. The contralateral accumbens was sham lesioned. The rats were divided into short-term and long-term survival groups of one to two weeks and 24 weeks, respectively. In the short-term group, a striking increase (up to three times) of the amplitude of the P10 components, at the site of the lesion, compared with the sham lesioned contralateral accumbens and untreated rats, was found. The long-term group could still display a slight increase although on average this was not significantly different from controls. In the short-term group, at the centre of the lesion, the paired-pulse facilitation ratio was significantly smaller than at the more ventral, less denervated, border of the accumbens. These differences were no longer visible in the long-term group. Single-unit activity of the accumbens, elicited by the iontophoretical application of L-glutamate showed, in controls, a maximal firing frequency ranging from 5 to 40 Hz (mean 25 Hz), whereas in the short-term group more than 50% of the accumbens neurons fired with higher frequencies, reaching up to 90 Hz (mean 55 Hz). In the long-term group the firing frequency varied from 5 to 60 Hz (mean 41 Hz). No changes in threshold ejection glutamate current were found for both lesioned groups. In control rats the L-glutamate elicited responses of six cells tested could be suppressed by dopamine whereas in lesioned rats three of the six cells tested were unresponsive to dopamine

  1. Satiating effects of cocaine are controlled by dopamine actions in the nucleus accumbens core

    PubMed Central

    Suto, Nobuyoshi; Wise, Roy A.

    2012-01-01

    Intravenous cocaine intake in laboratory animals is characterized by periods of apparent drug satiety between regularly spaced earned injections. The reinforcing properties of cocaine are linked primarily to dopaminergic neurotransmission in the shell and not the core of nucleus accumbens. To determine if the satiating effects of cocaine are similarly mediated, we perfused dopamine receptor agonists into the core or the shell during intravenous cocaine self-administrations by rats. Neither D1-type (SKF38393) nor D2-type (quinpirole) agonist was effective when given alone. However, a combination of the two agonists perfused into the core but not the shell significantly increased the time between cocaine self-injections, decreasing the amount of earned intake. Together with previous findings, the current data suggest that the satiating and reinforcing effects of cocaine are mediated by different ventral striatal output neurons. PMID:22159106

  2. 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

  3. 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

  4. Emotional environments retune the valence of appetitive versus fearful functions in nucleus accumbens

    PubMed Central

    Reynolds, Sheila M; Berridge, Kent C

    2009-01-01

    The nucleus accumbens mediates both appetitive motivation for rewards and fearful motivation toward threats, which are generated in part by glutamate-related circuits organized in a keyboard fashion. At rostral sites of the medial shell, localized glutamate disruptions typically generate intense appetitive behaviors in rats, but the disruption incrementally generates fearful behaviors as microinjection sites move more caudally. We found that exposure to stressful environments caused caudal fear-generating zones to expand rostrally, filling ~90% of the shell. Conversely, a preferred home environment caused fear-generating zones to shrink and appetitive-generating zones to expand caudally, filling ~90% of the shell. Thus, the emotional environments retuned the generation of motivation in corticolimbic circuits. PMID:18344996

  5. Ventral-striatal/nucleus-accumbens sensitivity to prediction errors during classification learning.

    PubMed

    Rodriguez, P F; Aron, A R; Poldrack, R A

    2006-04-01

    A prominent theory in neuroscience suggests reward learning is driven by the discrepancy between a subject's expectation of an outcome and the actual outcome itself. Furthermore, it is postulated that midbrain dopamine neurons relay this mismatch to target regions including the ventral striatum. Using functional MRI (fMRI), we tested striatal responses to prediction errors for probabilistic classification learning with purely cognitive feedback. We used a version of the Rescorla-Wagner model to generate prediction errors for each subject and then entered these in a parametric analysis of fMRI activity. Activation in ventral striatum/nucleus-accumbens (Nacc) increased parametrically with prediction error for negative feedback. This result extends recent neuroimaging findings in reward learning by showing that learning with cognitive feedback also depends on the same circuitry and dopaminergic signaling mechanisms.

  6. 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

  7. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

    PubMed

    LaPlant, Quincey; Vialou, Vincent; Covington, Herbert E; Dumitriu, Dani; Feng, Jian; Warren, Brandon L; Maze, Ian; Dietz, David M; Watts, Emily L; Iñiguez, Sergio D; Koo, Ja Wook; Mouzon, Ezekiell; Renthal, William; Hollis, Fiona; Wang, Hui; Noonan, Michele A; Ren, Yanhua; Eisch, Amelia J; Bolaños, Carlos A; Kabbaj, Mohamed; Xiao, Guanghua; Neve, Rachael L; Hurd, Yasmin L; Oosting, Ronald S; Fan, Gouping; Morrison, John H; Nestler, Eric J

    2010-09-01

    Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

  8. Mefloquine in the nucleus accumbens promotes social avoidance and anxiety-like behavior in mice.

    PubMed

    Heshmati, Mitra; Golden, Sam A; Pfau, Madeline L; Christoffel, Daniel J; Seeley, Elena L; Cahill, Michael E; Khibnik, Lena A; Russo, Scott J

    2016-02-01

    Mefloquine continues to be a key drug used for malaria chemoprophylaxis and treatment, despite reports of adverse events like depression and anxiety. It is unknown how mefloquine acts within the central nervous system to cause depression and anxiety or why some individuals are more vulnerable. We show that intraperitoneal injection of mefloquine in mice, when coupled to subthreshold social defeat stress, is sufficient to produce depression-like social avoidance behavior. Direct infusion of mefloquine into the nucleus accumbens (NAc), a key brain reward region, increased stress-induced social avoidance and anxiety behavior. In contrast, infusion into the ventral hippocampus had no effect. Whole cell recordings from NAc medium spiny neurons indicated that mefloquine application increases the frequency of spontaneous excitatory postsynaptic currents, a synaptic adaptation that we have previously shown to be associated with increased susceptibility to social defeat stress. Together, these data demonstrate a role for the NAc in mefloquine-induced depression and anxiety-like behaviors.

  9. Sulpiride infused into the nucleus accumbens posttraining impairs memory of spatial water maze training.

    PubMed

    Setlow, B; McGaugh, J L

    1998-06-01

    A variety of nucleus accumbens (NA) manipulations induce deficits in spatial learning and memory tasks. It is not known, however, if these deficits reflect influences on memory or on other processes affecting performance. The experiments in this article were undertaken to examine the involvement of the NA in memory consolidation in a spatial task. Rats were given 1 training session in a spatial water maze immediately followed by intra-NA infusions of sulpiride or saline vehicle. A probe test 2 days later revealed an impairing effect of sulpiride on several retention measures. Sulpiride infused into the NA either 2 hr posttraining in the spatial task or immediately posttraining in a cued water maze task did not affect retention performance. These findings suggest that the impairing effects of immediate posttraining sulpiride in the spatial task are due to interference with spatial water maze-specific consolidation processes involving the NA.

  10. Cocaine exposure reorganizes cell type- and input-specific connectivity in the nucleus accumbens.

    PubMed

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

    2014-09-01

    Repeated 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 used whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine exposure alters connectivity in the mouse NAc medial shell. Cocaine selectively enhanced amygdala innervation of MSNs expressing D1 dopamine receptors (D1-MSNs) relative to D2-MSNs. We also found that amygdala activity was required for cocaine-induced changes to behavior and connectivity. Finally, we established how heightened amygdala innervation can explain the structural and functional changes evoked by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell type- and input-specific connectivity in the NAc.

  11. 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

  12. 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

  13. [A comparison of the effects of single and chronic microinjections of GABA and picrotoxin into the caudate nucleus on the conditioned reflexes of dogs].

    PubMed

    Iakimovskiĭ, A F

    1990-01-01

    The effects on Pavlovian alimentary conditioned reflexes realization of two methods of intrastriatal microinjections--acute (separate) and long-term (chronic) one--are compared in experiments on dogs. Bilateral acute administration and the first week of chronic injection of 45 mcg of GABA into the caudate nuclei produced in dogs a manifest improvement of parameters of the conditioned differentiation inhibition, but only in the next period of chronic treatment an improvement of the positive Pavlovian alimentary conditioned reflex was obtained. The both ways of picrotoxin treatment impaired conditioned behaviour, and this effect was observed after the end of injection. No withdrawal effects were recorded. The data obtained give ground for discussion of the role of striatal GABAergic system in the positive modulation of adaptive alimentary behaviour. The application of novel psychopharmacological method in experimental and clinical fields of investigation is discussed.

  14. Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens.

    PubMed

    Tzeng, Wen-Yu; Cherng, Chian-Fang G; Wang, Shyi-Wu; Yu, Lung

    2016-06-01

    This study aimed to assess the impact of companions on the rewarding effects of cocaine. Three cage mates, serving as companions, were housed with each experimental mouse throughout cocaine-place conditioning in a cocaine-induced conditioned place preference (CPP) paradigm using conditioning doses of 10 and 20mg/kg. The presence of companions decreased the magnitude of the CPP. At 20mg/kg, cocaine stimulated dopamine (DA) release in the nucleus accumbens as evidenced by a significant decrease in total (spontaneous and electrical stimulation-provoked) DA release in accumbal superfusate samples. The presence of companions prevented this cocaine-stimulated DA release; such a reduction in cocaine-induced DA release may account for the reduction in the magnitude of the CPP in the presence of the companions. Furthermore, cocaine pretreatment (2.5mg/kg) was found to prevent the companion-produced decreases in cocaine (10mg/kg/conditioning)-induced CPP as well as the cocaine (10mg/kg)-stimulated DA release. Moreover, the presence of methamphetamine (MA) (1mg/kg)-treated companions decreased cocaine (20mg/kg/conditioning)-induced CPP and prevented the cocaine (20mg/kg)-stimulated DA release. Finally, the presence of companions decreased the magnitude of the CPP could not seem to be accounted for by cocaine-stimulated corticosterone (CORT) release. Taken together, these results indicate that familiar companions, regardless of their pharmacological status, may exert dampening effects on CPP induced by moderate to high conditioning doses of cocaine, at least in part, by preventing cocaine-stimulated DA release in the nucleus accumbens. PMID:27001454

  15. Serotonergic antidepressants decrease hedonic signals but leave learning signals in the nucleus accumbens unaffected.

    PubMed

    Graf, Heiko; Metzger, Coraline D; Walter, Martin; Abler, Birgit

    2016-01-01

    Investigating the effects of serotonergic antidepressants on neural correlates of visual erotic stimulation revealed decreased reactivity within the dopaminergic reward network along with decreased subjective sexual functioning compared with placebo. However, a global dampening of the reward system under serotonergic drugs is not intuitive considering clinical observations of their beneficial effects in the treatment of depression. Particularly, learning signals as coded in prediction error processing within the dopaminergic reward system can be assumed to be rather enhanced as antidepressant drugs have been demonstrated to facilitate the efficacy of psychotherapeutic interventions relying on learning processes. Within the same study sample, we now explored the effects of serotonergic and dopaminergic/noradrenergic antidepressants on prediction error signals compared with placebo by functional MRI. A total of 17 healthy male participants (mean age: 25.4 years) were investigated under the administration of paroxetine, bupropion and placebo for 7 days each within a randomized, double-blind, within-subject cross-over design. During functional MRI, we used an established monetary incentive task to explore neural prediction error signals within the bilateral nucleus accumbens as region of interest within the dopaminergic reward system. In contrast to diminished neural activations and subjective sexual functioning under the serotonergic agent paroxetine under visual erotic stimulation, we revealed unaffected or even enhanced neural prediction error processing within the nucleus accumbens under this antidepressant along with unaffected behavioural processing. Our study provides evidence that serotonergic antidepressants facilitate prediction error signalling and may support suggestions of beneficial effects of these agents on reinforced learning as an essential element in behavioural psychotherapy. PMID:26555033

  16. Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

    PubMed

    Singer, Bryan F; Guptaroy, Bipasha; Austin, Curtis J; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A; Gnegy, Margaret E; Robinson, Terry E; Aragona, Brandon J

    2016-03-01

    Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not.

  17. Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

    PubMed

    Singer, Bryan F; Guptaroy, Bipasha; Austin, Curtis J; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A; Gnegy, Margaret E; Robinson, Terry E; Aragona, Brandon J

    2016-03-01

    Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not. PMID:26613374

  18. The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent.

    PubMed

    Barrot, M; Marinelli, M; Abrous, D N; Rougé-Pont, F; Le Moal, M; Piazza, P V

    2000-03-01

    The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core. This effect was observed in basal conditions, after a mild stress (vehicle injection), as well as after subcutaneous administration of morphine (2 mg/kg, s.c. ) or intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine observed in the shell had a postsynaptic impact, as shown by less induction of Fos-like proteins selectively in the shell in response to cocaine. However, the induction of Fos-like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.) remained unchanged after adrenalectomy, suggesting that the changes in Fos expression after cocaine injection were likely to depend on changes in extracellular dopamine levels rather than on changes in postsynaptic sensitivity to dopamine. The effects of adrenalectomy were glucocorticoid-specific given that they were prevented by corticosterone treatment. This anatomical specificity in the control of neuronal activity by a hormonal input highlights the role of steroid hormones in shaping the functional activity of the brain. PMID:10762327

  19. Characterization of the effects of serotonin on the release of (/sup 3/H)dopamine from rat nucleus accumbens and striatal slices

    SciTech Connect

    Nurse, B.; Russell, V.A.; Taljaard, J.J.

    1988-05-01

    The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of (/sup 3/H)dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal /sup 3/H overflow and reduced K+-induced release of (/sup 3/H)DA from nucleus accumbens slices. The effect of serotonin on basal /sup 3/H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of (/sup 3/H)DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of (/sup 3/H)DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens.

  20. Abnormal striatal resting-state functional connectivity in adolescents with obsessive-compulsive disorder.

    PubMed

    Bernstein, Gail A; Mueller, Bryon A; Schreiner, Melinda Westlund; Campbell, Sarah M; Regan, Emily K; Nelson, Peter M; Houri, Alaa K; Lee, Susanne S; Zagoloff, Alexandra D; Lim, Kelvin O; Yacoub, Essa S; Cullen, Kathryn R

    2016-01-30

    Neuroimaging research has implicated abnormalities in cortico-striatal-thalamic-cortical (CSTC) circuitry in pediatric obsessive-compulsive disorder (OCD). In this study, resting-state functional magnetic resonance imaging (R-fMRI) was used to investigate functional connectivity in the CSTC circuitry in adolescents with OCD. Imaging was obtained with the Human Connectome Project (HCP) scanner using newly developed pulse sequences which allow for higher spatial and temporal resolution. Fifteen adolescents with OCD and 13 age- and gender-matched healthy controls (ages 12-19) underwent R-fMRI on the 3T HCP scanner. Twenty-four minutes of resting-state scans (two consecutive 12-min scans) were acquired. We investigated functional connectivity of the striatum using a seed-based, whole brain approach with anatomically-defined seeds placed in the bilateral caudate, putamen, and nucleus accumbens. Adolescents with OCD compared with controls exhibited significantly lower functional connectivity between the left putamen and a single cluster of right-sided cortical areas including parts of the orbitofrontal cortex, inferior frontal gyrus, insula, and operculum. Preliminary findings suggest that impaired striatal connectivity in adolescents with OCD in part falls within the predicted CSTC network, and also involves impaired connections between a key CSTC network region (i.e., putamen) and key regions in the salience network (i.e., insula/operculum). The relevance of impaired putamen-insula/operculum connectivity in OCD is discussed. PMID:26674413

  1. The implication of frontostriatal circuits in young smokers: A resting-state study.

    PubMed

    Yuan, Kai; Yu, Dahua; Bi, Yanzhi; Li, Yangding; Guan, Yanyan; Liu, Jixin; Zhang, Yi; Qin, Wei; Lu, Xiaoqi; Tian, Jie

    2016-06-01

    The critical roles of frontostriatal circuits had been revealed in addiction. With regard to young smokers, the implication of frontostriatal circuits resting-state functional connectivity (RSFC) in smoking behaviors and cognitive control deficits remains unclear. In this study, the volume of striatum subsets, i.e., caudate, putamen, and nucleus accumbens, and corresponding RSFC differences were investigated between young smokers (n1  = 60) and nonsmokers (n2  = 60), which were then correlated with cigarette smoking measures, such as pack_years-cumulative effect of smoking, Fagerström Test for Nicotine Dependence (FTND)-severity of nicotine addiction, Questionnaire on Smoking Urges (QSU)-craving state, and Stroop task performances. Additionally, mediation analysis was carried out to test whether the frontostriatal RSFC mediates the relationship between striatum morphometry and cognitive control behaviors in young smokers when applicable. We revealed increased volume of right caudate and reduced RSFC between caudate and dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex in young smokers. Significant positive correlation between right caudate volume and QSU as well as negative correlation between anterior cingulate cortex-right caudate RSFC and FTND were detected in young smokers. More importantly, DLPFC-caudate RSFC strength mediated the relationship between caudate volume and incongruent errors during Stroop task in young smokers. Our results demonstrated that young smokers showed abnormal interactions within frontostriatal circuits, which were associated with smoking behaviors and cognitive control impairments. It is hoped that our study focusing on frontostriatal circuits could provide new insights into the neural correlates and potential novel therapeutic targets for treatment of young smokers. Hum Brain Mapp 37:2013-2026, 2016. © 2016 Wiley Periodicals, Inc. PMID:26918784

  2. The NMDA receptor antagonist CPP suppresses long-term potentiation in the rat hippocampal-accumbens pathway in vivo.

    PubMed

    Feasey-Truger, K J; ten Bruggencate, G

    1994-08-01

    Excitation of afferent fibres originating in the ventral subiculum of the hippocampus through stimulation of the fimbria elicits field potentials in the nucleus accumbens. When recorded in the dorsomedial aspect of the nucleus accumbens, the evoked field responses consisted of an early, negative-going component (N1) with a peak latency of 8-10 ms, followed by a second negative-going peak (N2) with a latency of 22-24 ms. The N1 response reflects monosynaptic activation of nucleus accumbens neurons; the N2 component appears to be polysynaptic in origin. In control rats, high-frequency stimulation of the fimbria (three trains at 250 Hz, 250 ms, delivered at 50 min intervals) resulted in a long-lasting potentiation of both the N1 and N2 components. The magnitude of potentiation exhibited by the polysynaptic N2 response was typically greater than that of the monosynaptically evoked N1 response. Following delivery of the first train, the amplitude of the N1 and N2 components was increased by approximately 20 and 50% respectively. Administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.) had no significant effects on the evoked nucleus accumbens responses. High-frequency stimulation failed to produce a significant increase in the amplitude of either the N1 or the N2 response when delivered 45-60 min after CPP administration. To test whether the suppressant effects of CPP were time-dependent, two further high-frequency trains were applied 90 and 180 min after administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7981867

  3. κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats.

    PubMed

    Nealey, Kathryn A; Smith, Alexander W; Davis, Seth M; Smith, Daniel G; Walker, Brendan M

    2011-01-01

    Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable

  4. Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens

    PubMed Central

    Rose, Jamie H.; Karkhanis, Anushree N.; Chen, Rong; Gioia, Dominic; Lopez, Marcelo F.; Becker, Howard C.; McCool, Brian A.

    2016-01-01

    Background: Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. Methods: Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens. Results: Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group. Conclusions: These data suggest that the chronic intermittent ethanol-induced increase

  5. Excessive disgust caused by brain lesions or temporary inactivations: Mapping hotspots of nucleus accumbens and ventral pallidum

    PubMed Central

    Ho, Chao-Yi; Berridge, Kent C.

    2014-01-01

    Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense ‘disgust reactions’ (e.g., gapes) to a normally pleasant sensation such as sweetness. Here we aimed to map forebrain candidates more precisely to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol-baclofen microinjections) caused rats to emit excessive sensory disgust reactions to sucrose. Our study compared subregions of nucleus accumbens shell, ventral pallidum, lateral hypothalamus and adjacent extended amygdala. Results indicated the posterior half of ventral pallidum to be the only forebrain site where intense sensory disgust gapes to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness ‘liking’). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust but lesions never did at any site. Further, even inactivations failed to induce disgust in the rostral half of accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior versus rostral halves of medial shell. PMID:25229197

  6. The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens.

    PubMed

    Velázquez-Sánchez, Clara; García-Verdugo, José M; Murga, Juan; Canales, Juan J

    2013-07-01

    Benztropine (BZT) analogs, a family of agents with high affinity for the dopamine transporter have been postulated as potential treatments in stimulant abuse due to their ability to attenuate a wide range of effects evoked by psychomotor stimulants such as cocaine and amphetamine (AMPH). Repeating administration of drugs, including stimulants, can result in behavioral sensitization, a progressive increase in their psychomotor activating effects. We examined in mice the sensitizing effects and the neuroplasticity changes elicited by chronic AMPH exposure, and the modulation of these effects by the BZT derivative and atypical dopamine uptake inhibitor, JHW007, a candidate medication for stimulant abuse. The results indicated that JHW007 did not produce sensitized locomotor activity when given alone but prevented the sensitized motor behavior induced by chronic AMPH administration. Morphological analysis of medium spiny neurons of the nucleus accumbens revealed that JHW 007 prevented the neuroadaptations induced by chronic AMPH exposure, including increments in dendritic arborization, lengthening of dendritic processes and increases in spine density. Furthermore, data revealed that AMPH produced an increase in the density of asymmetric, possibly glutamatergic synapses in the nucleus accumbens, an effect that was also blocked by JHW007 pretreatment. The present observations demonstrate that JHW007 is able to prevent not only AMPH-induced behavioral sensitization but also the long-term structural changes induced by chronic AMPH in the nucleus accumbens. Such findings support the development and evaluation of BZT derivatives as possible leads for treatment in stimulant addiction.

  7. Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of schizophrenia.

    PubMed

    Holahan, Matthew R; Madularu, Dan; McConnell, Erin M; Walsh, Ryan; DeRosa, Maria C

    2011-01-01

    Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

  8. 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

  9. 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

  10. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor.

    PubMed

    Zernig, Gerald; Pinheiro, Barbara S

    2015-09-01

    Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus

  11. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor

    PubMed Central

    Pinheiro, Barbara S.

    2015-01-01

    Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus

  12. The striatum in the hedgehog tenrec: histochemical organization and cortical afferents.

    PubMed

    Künzle, Heinz

    2005-02-01

    In order to get insight into the striopallidal organization in mammals with little differentiated brain the striatum of the lesser hedgehog tenrec (Afrotheria) was characterized histochemically and analysed with regard to its cortical afferents using axonal tracer substances. The majority of neocortical cells projecting to the striatum were found bilaterally in the layers 2 and 3 of the frontal hemisphere; caudalwards the relative number of cells increased somewhat in the upper layer 5. There was a topographical organization as far as the allocortical projections appeared confined to the ventral striatum, and the efferents from hippocampal, posterior paleocortical, somatosensory and audiovisual areas were distributed in largely different striatal territories. Projections from the anterior frontal cortex, on the other hand, terminated extensively upon the caudate-putamen and also involved the nucleus accumbens and the olfactory tubercle. In the latter region the molecular layer was especially involved. The entorhinal cortex also projected heavily to the olfactory tubercle but unlike other species it scarcely involved the nucleus accumbens. The cortical fibers were distributed in a relatively homogenous fashion within their striatal territory and there was little evidence for patches of high density terminations. Islands of low density labeling, however, were noted occasionally in the caudate-putamen. These islands were partly similar in size as the patches of neuropil staining obtained with anti-calretinin and anti-substance P. There were also hints for the presence of a shell-like region in the nucleus accumbens stained with anti-dopamine transporter and NADPh-diaphorase. The classical striosome-matrix markers such as calbindin, acetylcholinesterase and enkephalin, however, failed to reveal any compartmental organization.

  13. Nucleus accumbens deep brain stimulation in a rat model of binge eating

    PubMed Central

    Doucette, W T; Khokhar, J Y; Green, A I

    2015-01-01

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a ‘chronic BE' model as well as in a ‘relapse to chronic BE' model. Male Sprague–Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5–7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior. PMID:26670280

  14. Cocaine must enter the brain to evoke unconditioned dopamine release within the nucleus accumbens shell.

    PubMed

    Porter-Stransky, Kirsten A; Wescott, Seth A; Hershman, Molly; Badrinarayan, Aneesha; Vander Weele, Caitlin M; Lovic, Vedran; Aragona, Brandon J

    2011-10-17

    In addition to blocking dopamine (DA) uptake, cocaine also causes an unconditioned increase in DA release. In drug naive rats, this effect is most robust within the nucleus accumbens (NAc) shell. Recent studies have shown that, in rats trained to self-administer cocaine, cocaine may act in the periphery to enhance mesolimbic DA release. Further, these studies have suggested that peripheral cocaine action may also enhance unconditioned DA release. Here, we test if it is necessary for cocaine to enter the brain to evoke unconditioned increases in DA release within the NAc shell. Administration of a cocaine analogue that crosses the blood brain barrier (cocaine HCl) enhances electrically evoked DA release and the number of cocaine-evoked phasic DA release events (i.e., DA transients) within the NAc shell. However, administration of a cocaine analogue that does not cross the blood brain barrier (cocaine MI) does not alter either measure. We therefore conclude that cocaine must act within the central nervous system to evoke unconditioned DA release within the NAc shell. PMID:21888949

  15. Extinction and reinstatement of phasic dopamine signals in the nucleus accumbens core during Pavlovian conditioning.

    PubMed

    Sunsay, Ceyhun; Rebec, George V

    2014-10-01

    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, which plays a key role in reward processing. Following at least 4 daily sessions of 16 tone-food pairings, fast-scan cyclic voltammetry was performed while rats received additional tone-food pairings followed by tone alone presentations (i.e., extinction). Acquisition memory was reinstated with noncontingent presentations of reward and then tested with cue presentation. Tone-food pairings produced transient (1- to 3-s) DA release in response to tone. During extinction, the amplitude of the DA response decreased significantly. Following presentation of 2 noncontingent food pellets, subsequent tone presentation reinstated the DA signal. Our results support the prediction-error model for appetitive Pavlovian extinction but not for reinstatement.

  16. 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

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

    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.

  18. Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit.

    PubMed

    Ramaekers, J G; Evers, E A; Theunissen, E L; Kuypers, K P C; Goulas, A; Stiers, P

    2013-09-01

    Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.

  19. Effects of nucleus accumbens core and shell lesions on autoshaped lever-pressing

    PubMed Central

    Chang, Stephen E.; Holland, Peter C.

    2013-01-01

    Certain Pavlovian conditioned stimuli (CSs) paired with food unconditioned stimuli (USs) come to elicit approach and even consumption-like behaviors in rats (sign-tracking). We investigated the effects of lesions of the nucleus accumbens core (ACbC) or shell (ACbS) on the acquisition of sign-tracking in a discriminative autoshaping procedure in which presentation of one lever CS was followed by delivery of sucrose, and another was not. Although we previously found that bilateral lesions of the whole ACb disrupted the initial acquisition of sign-tracking, neither ACbC or ACbS lesions affected the rate or percentage of trials in which rats pressed the CS+. In addition, detailed video analysis showed no effect of either lesion on the topography of the sign-tracking conditioned response (CR). These and other results from lesion studies of autoshaping contrast with those from previous sign-tracking experiments that used purely visual cues (Parkinson, Robbins, and Everitt, 2000a; Parkinson, Willoughby, Robbins, and Everitt, 2000b), suggesting that the neural circuitry involved in assigning incentive value depends upon the nature of the CS. PMID:23933141

  20. 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

  1. Phasic dopamine release in the rat nucleus accumbens symmetrically encodes a reward prediction error term.

    PubMed

    Hart, Andrew S; Rutledge, Robb B; Glimcher, Paul W; Phillips, Paul E M

    2014-01-15

    Making predictions about the rewards associated with environmental stimuli and updating those predictions through feedback is an essential aspect of adaptive behavior. Theorists have argued that dopamine encodes a reward prediction error (RPE) signal that is used in such a reinforcement learning process. Recent work with fMRI has demonstrated that the BOLD signal in dopaminergic target areas meets both necessary and sufficient conditions of an axiomatic model of the RPE hypothesis. However, there has been no direct evidence that dopamine release itself also meets necessary and sufficient criteria for encoding an RPE signal. Further, the fact that dopamine neurons have low tonic firing rates that yield a limited dynamic range for encoding negative RPEs has led to significant debate about whether positive and negative prediction errors are encoded on a similar scale. To address both of these issues, we used fast-scan cyclic voltammetry to measure reward-evoked dopamine release at carbon fiber electrodes chronically implanted in the nucleus accumbens core of rats trained on a probabilistic decision-making task. We demonstrate that dopamine concentrations transmit a bidirectional RPE signal with symmetrical encoding of positive and negative RPEs. Our findings strengthen the case that changes in dopamine concentration alone are sufficient to encode the full range of RPEs necessary for reinforcement learning.

  2. 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

  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. 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

  5. Selecting danger signals: dissociable roles of nucleus accumbens shell and core glutamate in predictive fear learning.

    PubMed

    Li, Susan S Y; McNally, Gavan P

    2015-06-01

    Conditioned stimuli (CSs) vary in their reliability as predictors of danger. Animals must therefore select among CSs those that are appropriate to enter into an association with the aversive unconditioned stimulus (US). The actions of prediction error instruct this stimulus selection so that when prediction error is large, attention to the CS is maintained and learning occurs but when prediction is small attention to the CS is withdrawn and learning is prevented. Here we studied the role of glutamate acting at rat nucleus accumbens shell (AcbSh) and core (AcbC) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in this selection of danger signals. Using associative blocking and unblocking designs in rats, we show that antagonizing AcbSh AMPA receptors via infusions of 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX; 0.5 μg) prevents the unblocking of fear learning, whereas antagonizing AcbC AMPA receptors via infusions of NBQX (0.5 μg) prevents both the blocking and unblocking of fear learning. These results identify dissociable but complementary roles for AcbSh and AcbC glutamate acting at AMPA receptors in selecting danger signals: AcbSh AMPA receptors upregulate attention and learning to CSs that signal surprising USs, whereas AcbC AMPA receptors encode the predicted outcome of each trial.

  6. Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration.

    PubMed

    Wise, R A; Leone, P; Rivest, R; Leeb, K

    1995-10-01

    Extracellular dopamine and DOPAC (3,4-dihydroxyphenylacetic acid) levels in nucleus accumbens were sampled by microdialysis and quantified with high-performance liquid chromatography during intravenous heroin self-administration sessions in rats. Dopamine levels in 10 and 20 min samples were elevated following the first injection of each session, reaching a plateau of elevation within the first two or three injections and falling back toward baseline only when drug access was terminated. Elevations were in the range of 150-300% when unit dosages of 0.05-0.2 mg/kg were given. Increasing the work requirement from FR-1 to FR-10 did not appear to alter the degree of elevation of dopamine levels, and dopamine levels fell during extinction while lever-pressing rates increased 20-fold. While animals compensated for unit dose changes between 0.05 and 0.2 mg/kg/injection, adjusting their response rate such that the same hourly drug intake and the same asymptotic dopamine levels were maintained across these conditions, at 0.4 mg/kg/injection hourly drug intake and asymptotic dopamine levels were elevated beyond the levels sustained by the lower doses. These findings confirm that self-administered doses of intravenous heroin are sufficient to activate the mesolimbic dopamine system and suggest that significant heroin "craving" can emerge when dopamine levels are still moderately elevated, long before the development of dopamine depletion associated with opiate withdrawal.

  7. Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning.

    PubMed

    Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M

    2014-10-01

    Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models) or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of 2 neutral stimuli (e.g., tone [A] and light [X]; "Paired"), or random noncontingent presentations ("Unpaired"). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in Phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during test. Further, these effects were only seen in Paired rats that showed successful behavior during test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior.

  8. Activation in the VTA and Nucleus Accumbens Increases in Anticipation of Both Gains and Losses

    PubMed Central

    Carter, R. McKell; MacInnes, Jeff J.; Huettel, Scott A.; Adcock, R. Alison

    2009-01-01

    To represent value for learning and decision making, the brain must encode information about both the motivational relevance and affective valence of anticipated outcomes. The nucleus accumbens (NAcc) and ventral tegmental area (VTA) are thought to play key roles in representing these and other aspects of valuation. Here, we manipulated the valence (i.e., monetary gain or loss) and personal relevance (i.e., self-directed or charity-directed) of anticipated outcomes within a variant of the monetary incentive delay task. We scanned young-adult participants using functional magnetic resonance imaging (fMRI), utilizing imaging parameters targeted for the NAcc and VTA. For both self-directed and charity-directed trials, activation in the NAcc and VTA increased to anticipated gains, as predicted by prior work, but also increased to anticipated losses. Moreover, the magnitude of responses in both regions was positively correlated for gains and losses, across participants, while an independent reward-sensitivity covariate predicted the relative difference between and gain- and loss-related activation on self-directed trials. These results are inconsistent with the interpretation that these regions reflect anticipation of only positive-valence events. Instead, they indicate that anticipatory activation in reward-related regions largely reflects the motivational relevance of an upcoming event. PMID:19753142

  9. Prefrontal cortex modulates desire and dread generated by nucleus accumbens glutamate disruption

    PubMed Central

    Richard, Jocelyn M.; Berridge, Kent. C

    2012-01-01

    Background Corticolimbic circuits, including direct projections from prefrontal cortex to nucleus accumbens (NAc), permit “top-down” control of intense motivations generated by subcortical circuits. In rats, localized disruptions of glutamate signaling within medial shell of NAc generate desire or dread, anatomically organized along a rostrocaudal gradient analogous to a limbic “keyboard”. At rostral locations in shell these disruptions generate appetitive eating, but at caudal locations the disruptions generate progressively fearful behaviors (distress vocalizations, escape attempts and antipredator reactions). Here we asked whether medial prefrontal cortex can modulate intense motivations generated by subcortical NAc disruptions. Methods We used simultaneous microinjections in medial prefrontal cortex regions and in NAc shell to examine whether the desire or dread generated by NAc shell disruptions is modulated by activation/inhibition of three specific regions of prefrontal cortex: medial orbitofrontal cortex, infralimbic cortex (homologous to area 25 or subgenual anterior cingulate in the human), or prelimbic cortex (midventral anterior cingulate). Results We found that activation of medial orbitofrontal cortex biased intense bivalent motivation in an appetitive direction by amplifying generation of eating behavior by middle to caudal NAc disruptions, without altering fear. In contrast, activation of infralimbic prefrontal cortex powerfully and generally suppressed both appetitive eating and fearful behaviors generated by NAc shell disruptions. Conclusions These results suggest that corticolimbic projections from discrete prefrontal regions can either bias motivational valence or generally suppress subcortically-generated intense motivations of desire or fear. PMID:22981656

  10. Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens

    SciTech Connect

    Goeders, N.E.; Kuhar, M.J.

    1987-01-01

    A variety of clinical and animal data suggest that the repeated administration of cocaine and related psychomotor stimulants may be associated with a behavioral sensitization whereby the same dose of the drug results in increasing behavioral pathology. This investigation was designed to determine the effects of chronic cocaine administration on the binding of (/sup 3/H)sulpiride, a relatively specific ligand for D2 dopaminergic receptors, in the rat brain using in vitro homogenate binding and light microscopic quantitative autoradiographic methodologies. Chronic daily injections of cocaine (10 mg/kg, i.p.) for 15 days resulted in a significant decrease in the maximum concentration of sulpiride binding sites in the striatum and a significant increase in the maximum number of these binding sites in the nucleus accumbens. No significant differences in binding affinity were observed in either brain region. These data suggest that chronic cocaine administration may result in differential effects on D2 receptors in the nigro-striatal and mesolimbic dopaminergic systems.

  11. 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

  12. 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

  13. Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats.

    PubMed

    Wallin-Miller, Kathryn; Li, Grace; Kelishani, Diana; Wood, Ruth I

    2016-08-25

    Recent studies have demonstrated that anabolic-androgenic steroids (AAS) modify cognitive processes such as decision making and behavioral flexibility. However, the neural mechanisms underlying these AAS-induced cognitive changes remain poorly understood. The mesocorticolimbic dopamine (DA) system, particularly the nucleus accumbens (Acb), is important for reward, motivated behavior, and higher cognitive processes such as decision making. Therefore, AAS-induced plasticity in the DA system is a potential structural substrate for the observed cognitive alterations. High doses of testosterone (the most commonly-used AAS) increase dendritic spine density in limbic regions including the amygdala and hippocampus. However, effects on Acb are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically for 8weeks with high-dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc. Brains were stained by Golgi-Cox to analyze neuronal morphology in medium spiny neurons of the shell region of Acb (AcbSh). Eightweeks of testosterone treatment significantly decreased spine density in AcbSh compared to brains of vehicle-treated rats (F1,14=5.455, p<0.05). Testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results show that AAS alter neuronal morphology in AcbSh by decreasing spine density throughout the dendritic tree, and provides a potential mechanism for AAS to modify cognition and decision-making behavior.

  14. Nucleus accumbens deep brain stimulation in a rat model of binge eating.

    PubMed

    Doucette, W T; Khokhar, J Y; Green, A I

    2015-01-01

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5-7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior. PMID:26670280

  15. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.

    PubMed

    Trifilieff, P; Feng, B; Urizar, E; Winiger, V; Ward, R D; Taylor, K M; Martinez, D; Moore, H; Balsam, P D; Simpson, E H; Javitch, J A

    2013-09-01

    A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc. PMID:23711983

  16. Reduced nucleus accumbens reactivity and adolescent depression following early-life stress.

    PubMed

    Goff, B; Gee, D G; Telzer, E H; Humphreys, K L; Gabard-Durnam, L; Flannery, J; Tottenham, N

    2013-09-26

    Depression is a common outcome for those having experienced early-life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youths without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, functional magnetic resonance imaging results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention. PMID:23262241

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

    PubMed

    Resendez, Shanna L; Keyes, Piper C; Day, Jeremy J; Hambro, Caely; Austin, Curtis J; Maina, Francis K; Eidson, Lori; 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. PMID:27371827

  18. Nucleus Accumbens Mediates Relative Motivation for Rewards in the Absence of Choice

    PubMed Central

    Clithero, John A.; Reeck, Crystal; Carter, R. McKell; Smith, David V.; Huettel, Scott A.

    2011-01-01

    To dissociate a choice from its antecedent neural states, motivation associated with the expected outcome must be captured in the absence of choice. Yet, the neural mechanisms that mediate behavioral idiosyncrasies in motivation, particularly with regard to complex economic preferences, are rarely examined in situations without overt decisions. We employed functional magnetic resonance imaging in a large sample of participants while they anticipated earning rewards from two different modalities: monetary and candy rewards. An index for relative motivation toward different reward types was constructed using reaction times to the target for earning rewards. Activation in the nucleus accumbens (NAcc) and anterior insula (aINS) predicted individual variation in relative motivation between our reward modalities. NAcc activation, however, mediated the effects of aINS, indicating the NAcc is the likely source of this relative weighting. These results demonstrate that neural idiosyncrasies in reward efficacy exist even in the absence of explicit choices, and extend the role of NAcc as a critical brain region for such choice-free motivation. PMID:21941472

  19. Reduced Nucleus Accumbens Reactivity and Adolescent Depression following Early-life Stress

    PubMed Central

    Goff, Bonnie; Gee, Dylan G.; Telzer, Eva H.; Humphreys, Kathryn L.; Gabard-Durnam, Laurel; Flannery, Jessica; Tottenham, Nim

    2013-01-01

    Depression is a common outcome for those having experienced early life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youth without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, fMRI results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention. PMID:23262241

  20. Resting state functional connectivity of the nucleus accumbens in youth with a family history of alcoholism

    PubMed Central

    Cservenka, Anita; Casimo, Kaitlyn; Fair, Damien; Nagel, Bonnie

    2014-01-01

    Adolescents with a family history of alcoholism (FHP) are at heightened risk for developing alcohol use disorders (AUDs). The nucleus accumbens (NAcc), a key brain region for reward processing, is implicated in the development of AUDs. Thus, functional connectivity of the NAcc may be an important marker of risk in FHP youth. Resting state functional magnetic resonance imaging (rs-fcMRI) was used to examine the intrinsic connectivity of the NAcc in 47 FHP and 50 family history negative (FHN) youth, ages 10–16 years old. FHP and FHN adolescents showed significant group differences in resting state synchrony between the left NAcc and bilateral inferior frontal gyri and the left postcentral gyrus (PG). Additionally, FHP youth differed from FHN youth in right NAcc functional connectivity with the left orbitofrontal cortex (OFC), left superior temporal gyrus, right cerebellum, left PG, and right occipital cortex. These results indicate that FHP youth have less segregation between the NAcc and executive functioning brain regions, and less integration with reward-related brain areas, such as the OFC. The findings of the current study highlight that premorbid atypical connectivity of appetitive systems, in the absence of heavy alcohol use, may be a risk marker in FHP adolescents. PMID:24440571

  1. Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning.

    PubMed

    Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M

    2014-10-01

    Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models) or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of 2 neutral stimuli (e.g., tone [A] and light [X]; "Paired"), or random noncontingent presentations ("Unpaired"). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in Phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during test. Further, these effects were only seen in Paired rats that showed successful behavior during test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior. PMID:25244086

  2. Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens.

    PubMed

    Mátyás, Ferenc; Watanabe, Masahiko; Mackie, Ken; Katona, István; Freund, Tamás F

    2007-03-30

    Several abused drugs are known to alter glutamatergic signaling in reward pathways of the brain, and these plastic changes may contribute to the establishment of addiction-related behaviour. Glutamatergic synapses of the prefrontal cortical projections to the nucleus accumbens (nAcb)--which are suggested to be under endocannabinoid (eCB) control - play a central role in the addiction process. The most abundant eCB in the brain is 2-arachi-donoyl-glycerol (2-AG). It is synthesized by diacylglycerol lipase alpha (DGL-alpha), and exerts its action via type 1 cannabinoid receptors (CB1). However, the precise localization of DGL-alpha and CB1 - i.e. the sites of synthesis and action of 2AG - is still unknown. At the light microscopic level, immunocytochemistry revealed a granular pattern of DGL-alpha distribution in the core of the nAcb. Electron microscopic analysis confirmed that these granules corresponded to the heads of dendritic spines. On the other hand, presynaptic axon terminals forming excitatory synapses on these spineheads were found to express CB1 receptors. Our results demonstrate that the molecular constituents for a retrograde endocannabinoid control of glutamatergic transmission are available in the core of the nAcb, and their relative subcellular location is consistent with a role of 2-AG in addiction-related plasticity of cortical excitatory synapses in this reward area.

  3. CHRONIC INTERMITTENT ETHANOL EXPOSURE REDUCES PRESYNAPTIC DOPAMINE NEUROTRANSMISSION IN THE MOUSE NUCLEUS ACCUMBENS

    PubMed Central

    Karkhanis, Anushree N.; Rose, Jamie H.; Huggins, Kimberly N.; Konstantopoulos, Joanne K.; Jones, Sara R.

    2015-01-01

    BACKGROUND Increasing evidence suggests that chronic ethanol exposure decreases dopamine (DA) neurotransmission in the nucleus accumbens (NAc), contributing to a hypodopaminergic state during withdrawal. However, few studies have investigated adaptations in presynaptic DA terminals after chronic intermittent ethanol (CIE) exposure. In monkeys and rats, chronic ethanol exposure paradigms have been shown to increase DA uptake and D2 autoreceptor sensitivity. METHODS The current study examined the effects of ethanol on DA terminals in CIE exposed mice during two time-points after the cessation of CIE exposure. DA release and uptake were measured using fast scan cyclic voltammetry in NAc core slices from C57BL/6J mice, 0 and 72 hours following three weekly cycles (4 days of 16 hrs ethanol vapor/8 hrs room air/day + 3 days withdrawal) of CIE vapor exposure. RESULTS Current results showed that DA release was reduced, uptake rates were increased, and inhibitory D2-type autoreceptor activity was augmented following CIE exposure in mice. CONCLUSIONS Overall, these CIE-induced adaptations in the accumbal DA system reduce DA signaling and therefore reveal several potential mechanisms contributing to a functional hypodopaminergic state during alcohol withdrawal. PMID:25765483

  4. Bidirectional modulation of cocaine-expectancy by phasic glutamate fluctuations in the nucleus accumbens

    PubMed Central

    Suto, Nobuyoshi; Elmer, Greg I.; Wang, Bin; You, Zhi-Bing; Wise, Roy A.

    2013-01-01

    While glutamate in the nucleus accumbens (NAS) contributes to the promotion of drug-seeking by drug-predictive cues, it also appears to play a role in the inhibition of drug-seeking following extinction procedures. Thus we measured extracellular fluctuations of NAS glutamate in response to discriminative stimuli that signaled either cocaine availability or cocaine omission. We trained rats to self-administer intravenous cocaine and then to recognize discriminative odor cues that predicted either sessions where cocaine was available or alternating sessions where it was not (saline substituted for cocaine). Whereas responding in cocaine availability sessions remained stable, responding in cocaine omission sessions progressively declined to chance levels. We then determined the effects of each odor cue on extracellular glutamate in the core and shell subregions of NAS preceding and accompanying lever-pressing under an extinction condition. Glutamate levels were elevated in both core and shell by the availability odor and depressed in the core but not the shell by the omission odor. Infusion of kynurenic acid (an antagonist for ionotropic glutamate receptors) into core but not shell suppressed responding associated with the availability odor, but had no effect on the suppression associated with the omission odor. Thus cocaine-predictive cues appear to promote cocaine-seeking in part by elevating glutamatergic neurotransmission in the core of NAS, whereas cocaine-omission cues appear to suppress cocaine-seeking in part by depressing glutamatergic receptor activation in the same region. PMID:23699516

  5. Differential contributions of infralimbic prefrontal cortex and nucleus accumbens during reward-based learning and extinction.

    PubMed

    Francois, Jennifer; Huxter, John; Conway, Michael W; Lowry, John P; Tricklebank, Mark D; Gilmour, Gary

    2014-01-01

    Using environmental cues for the prediction of future events is essential for survival. Such cue-outcome associations are thought to depend on mesolimbic circuitry involving the nucleus accumbens (NAc) and prefrontal cortex (PFC). Several studies have identified roles for both NAc and PFC in the expression of stable goal-directed behaviors, but much remains unknown about their roles during learning of such behaviors. To further address this question, we used in vivo oxygen amperometry, a proxy for blood oxygen level-dependent (BOLD) signal measurement in human functional magnetic resonance imaging, in rats performing a cued lever-pressing task requiring discrimination between a rewarded and nonrewarded cue. Simultaneous oxygen recordings were obtained from infralimbic PFC (IFC) and NAc throughout both acquisition and extinction of this task. Activation of NAc was specifically observed following rewarded cue onset during the entire acquisition phase and also during the first days of extinction. In contrast, IFC activated only during the earliest periods of acquisition and extinction, more specifically to the nonrewarded cue. Thus, in vivo oxygen amperometry permits a novel, stable form of longitudinal analysis of brain activity in behaving animals, allowing dissociation of the roles of different brain regions over time during learning of reward-driven instrumental action. The present results offer a unique temporal perspective on how NAc may promote actions directed toward anticipated positive outcome throughout learning, while IFC might suppress actions that no longer result in reward, but only during critical periods of learning. PMID:24403158

  6. Nucleus accumbens deep brain stimulation in a rat model of binge eating.

    PubMed

    Doucette, W T; Khokhar, J Y; Green, A I

    2015-01-01

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5-7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior.

  7. Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis.

    PubMed

    Zhang, Yi; Cheng, Yan; Ren, Xingcong; Hori, Tsukasa; Huber-Keener, Kathryn J; Zhang, Li; Yap, Kai Lee; Liu, David; Shantz, Lisa; Qin, Zheng-Hong; Zhang, Suping; Wang, Jianrong; Wang, Hong-Gang; Shih, Ie-Ming; Yang, Jin-Ming

    2012-08-15

    Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1-/- cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment.

  8. 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

  9. Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens

    PubMed Central

    du Hoffmann, Johann

    2014-01-01

    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. HIV-1 Transgenic Female Rat: Synaptodendritic Alterations of Medium Spiny Neurons in the Nucleus Accumbens

    PubMed Central

    Roscoe, Robert F.; Mactutus, Charles F.

    2015-01-01

    HIV-1 associated neurocognitive deficits are increasing in prevalence, although the neuronal basis for these deficits is unclear. HIV-1 Tg rats constitutively express 7 of 9 HIV-associated proteins, and may be useful for studying the neuropathological substrates of HIV-1 associated neurocognitive disorders (HAND). In this study, adult female HIV-1 Tg rats and F344 control rats had similar growth rates, estrous cyclicity and startle reflex inhibition to a visual prepulse stimulus. Medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) were ballistically-labeled utilizing the indocarbocyanine dye DiI. The branching complexity of MSNs in the NAcc was significantly decreased in HIV-1 Tg rats, relative to controls; moreover, the shorter length and decreased volume of dendritic spines, but unchanged head diameter, in HIV-1 Tg rats suggested a reduction of longer spines and an increase in shorter, less projected spines, indicating a population shift to a more immature spine phenotype. Collectively, these results from HIV-1 Tg female rats indicated significant synaptodendritic alterations of MSNs in the NAcc occur as a consequence of chronic, low-level, exposure to HIV-1 associated proteins. PMID:25037595

  11. Morphine conditioned place preference depends on glucocorticoid receptors in both hippocampus and nucleus accumbens.

    PubMed

    Dong, Zhifang; Han, Huili; Wang, Meina; Xu, Lin; Hao, Wei; Cao, Jun

    2006-01-01

    Learned association between drugs of abuse and context is essential for the formation of drug conditioned place preference (CPP), which is believed to engage many brain regions including hippocampus and nucleus accumbens (NAc). The underlying mechanisms are not fully understood. Here, we examined whether glucocorticoid receptors (GRs) of hippocampus and NAc influenced the formation of morphine CPP in Sprague Dawley rats. We found that systemic or intrahippocampal infused DMSO vehicle (DMSO 20% in saline) 30 min before daily morphine (10 mg/kg, s.c.) conditioning did not affect the formation of morphine CPP. In contrast, systemic administration (5 mg/kg, s.c.) or intrahippocampal infusion (0, 0.1, 1.0, 10, 20 microg per side) of the GR antagonist RU38486 blocked or impaired the formation of CPP in a dose-dependent manner, respectively. Furthermore, intra-NAc infused RU38486 (10 microg per side) but not DMSO vehicle also prevented the formation of CPP. These results demonstrate that both the GRs of hippocampus and NAc are necessary for the formation of morphine CPP, suggesting a neural network function of the GRs in forming the opiate-associated memory.

  12. 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.

  13. 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

  14. Individual Variations in Nucleus Accumbens Responses Associated with Major Depressive Disorder Symptoms

    PubMed Central

    Misaki, Masaya; Suzuki, Hideo; Savitz, Jonathan; Drevets, Wayne C.; Bodurka, Jerzy

    2016-01-01

    Abnormal reward-related responses in the nucleus accumbens (NAcc) have been reported for major depressive disorder (MDD) patients. However, variability exists in the reported results, which could be due to heterogeneity in neuropathology of depression. To parse the heterogeneity of MDD we investigated variation of NAcc responses to gain and loss anticipations using fMRI. We found NAcc responses to monetary gain and loss were significantly variable across subjects in both MDD and healthy control (HC) groups. The variations were seen as a hyperactive response subtype that showed elevated activation to the anticipation of both gain and loss, an intermediate response with greater activation to gain than loss, and a suppressed-activity with reduced activation to both gain and loss compared to a non-monetary condition. While these response variability were seen in both MDD and HC subjects, specific symptoms were significantly associated with the right NAcc variation in MDD. Both the hyper- and suppressed-activity subtypes of MDD patients had severe suicidal ideation and anhedonia symptoms. The intermediate subjects had less severity in these symptoms. These results suggest that differing propensities in reward responsiveness in the NAcc may affect the development of specific symptoms in MDD. PMID:26880358

  15. Individual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone.

    PubMed

    Rougé-Pont, F; Deroche, V; Le Moal, M; Piazza, P V

    1998-12-01

    Stressful experiences, glucocorticoids hormones and dopaminergic neurons seems to interact in determining a higher propensity to develop drug abuse. In this report, we studied the acute interaction between these three factors. For this purpose, we compared stress-induced dopamine release in intact rats and in rats in which stress-induced corticosterone secretion was experimentally blocked. Ten-minute tail-pinch was used as a stressor and dopamine release estimated in the nucleus accumbens by using the microdialysis technique. Individual differences were also taken into account by comparing rats identified as either predisposed (HRs) or resistant (LRs) to develop self-administration of drugs of abuse, on the basis of their locomotor response to novelty. It was found that suppression of stress-induced corticosterone secretion significantly decreased stress-induced dopamine release. However, such an effect greatly differed between HR and LR rats. When corticosterone secretion was intact HR animals had a higher and longer dopamine release in response to stress than LRs. The blockade of stress-induced corticosterone secretion selectively reduced the dopaminergic response of HRs that did not differ from LRs anymore. These findings strength the idea that glucocorticoids could be involved in determining propensity to develop drug self-administration. In particular, these hormones could play a role in determining the higher dopaminergic activity that characterizes drug proned individuals. PMID:9875367

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

    PubMed

    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

  17. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons

    PubMed Central

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J.; Miranda-Barrientos, Jorge; Morales, Marisela

    2016-01-01

    The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens-glutamatergic pathway remains unknown. Here, we report that nAcc photoactivation of mesoaccumbens-glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens-glutamate-fibers lack GABA, the aversion evoked by their photoactivation depends on glutamate and GABA receptor signaling, and not on dopamine receptor signaling. We found that mesoaccumbens-glutamatergic-fibers establish multiple asymmetric synapses on single parvalbumin-GABAergic interneurons, and that nAcc photoactivation of these fibers drives AMPA-mediated cellular firing of parvalbumin-GABAergic interneurons. These parvalbumin-GABAergic-interneurons, in turn, inhibit nAcc medium spiny output neurons, as such, controlling inhibitory neurotransmission within nAcc. The mesoaccumbens-glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion, instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin-GABAergic interneurons. PMID:27019014

  18. Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats.

    PubMed

    Wallin-Miller, Kathryn; Li, Grace; Kelishani, Diana; Wood, Ruth I

    2016-08-25

    Recent studies have demonstrated that anabolic-androgenic steroids (AAS) modify cognitive processes such as decision making and behavioral flexibility. However, the neural mechanisms underlying these AAS-induced cognitive changes remain poorly understood. The mesocorticolimbic dopamine (DA) system, particularly the nucleus accumbens (Acb), is important for reward, motivated behavior, and higher cognitive processes such as decision making. Therefore, AAS-induced plasticity in the DA system is a potential structural substrate for the observed cognitive alterations. High doses of testosterone (the most commonly-used AAS) increase dendritic spine density in limbic regions including the amygdala and hippocampus. However, effects on Acb are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically for 8weeks with high-dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc. Brains were stained by Golgi-Cox to analyze neuronal morphology in medium spiny neurons of the shell region of Acb (AcbSh). Eightweeks of testosterone treatment significantly decreased spine density in AcbSh compared to brains of vehicle-treated rats (F1,14=5.455, p<0.05). Testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results show that AAS alter neuronal morphology in AcbSh by decreasing spine density throughout the dendritic tree, and provides a potential mechanism for AAS to modify cognition and decision-making behavior. PMID:27238893

  19. Subsecond dopamine release in the nucleus accumbens predicts conditioned punishment and its successful avoidance.

    PubMed

    Oleson, Erik B; Gentry, Ronny N; Chioma, Vivian C; Cheer, Joseph F

    2012-10-17

    The mesolimbic dopamine system is believed to be a pathway that processes rewarding information. While previous studies have also implicated a general role for dopamine in punishment and its avoidance, the precise nature of subsecond dopamine release during these phenomena remains unknown. Here, we used fast-scan cyclic voltammetry to investigate whether subsecond dopamine release events in the nucleus accumbens encode cues predicting the avoidance of punishment during behavior maintained in a signaled footshock avoidance procedure. In this task, rats could initiate an avoidance response by pressing a lever within a warning period, preventing footshock. Alternatively, once footshocks commenced, animals could initiate an escape response by pressing the lever, terminating footshock. This design allowed us to assess subsecond dopamine release events during the presentation of a warning signal, safety periods, and two distinct behavioral responses. We found that release consistently increased upon presentation of the warning signal in a manner that reliably predicted successful punishment avoidance. We also observed subsecond dopamine release during the safety period, as occurs following the receipt of reward. Conversely, we observed a decrease in release at the warning signal during escape responses. Because of this finding, we next assessed dopamine release in a conditioned fear model. As seen during escape responses, we observed a time-locked decrease in dopamine release upon presentation of a cue conditioned to inescapable footshock. Together, these data show that subsecond fluctuations in mesolimbic dopamine release predict when rats will successfully avoid punishment and differentially encode cues related to aversive outcomes.

  20. 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

  1. Reduction of 3-methoxytyramine concentrations in the caudate nucleus of rats after exposure to high-energy iron particles: Evidence for deficits in dopaminergic neurons

    SciTech Connect

    Hunt, W.A.; Dalton, T.K.; Joseph, J.A.; Rabin, B.M.

    1990-01-01

    The prospect of long-term space travel raises a number of questions about the safety of astronauts asked to venture on prolonged journeys. The problems of microgravity are well known, but the hazards of exposure to radation are less understood. Most space travel has involved a few days to many months in low-altitude, equatorial orbits, where the dangers of radiation are lessened by the magnetic field surrounding the earth. Travel to polar or geostationary orbits or travel to the moon or the planets has a far greater radiation hazard. Almost nothing is known about possible risks to behavior and brain function after radiation exposure, such as found after the emission of solar flares or from long-term exposure from galactic cosmic radiation. Exposure to low doses of high-energy iron particles can alter motor behavior. The ability of rats to hang from a wire has been reported to be significantly degraded after exposure to doses as low as 0.5 Gy. In addition, deficits in the ability of acetylcholine to regulate dopamine release in the caudate nucleus (an area in the brain important for motor function) have been found. These results provide further evidence that exposure to heavy particles can degrade motor behavior through an action on dopaminergic mechanisms and that this can occur after doses much lower than those needed for low-LET radiation.

  2. Re-examination of topographic distribution of thalamic neurons projecting to the caudate nucleus. A retrograde labeling study in the cat.

    PubMed

    de las Heras, S; Mengual, E; Velayos, J L; Giménez-Amaya, J M

    1998-08-01

    The distribution of thalamic neurons projecting directly to the caudate nucleus (CN) was examined using the retrograde labeling method. Horseradish peroxidase conjugated with wheat germ agglutinin (HRP-WGA) or a fluorescent tracer (either Fast Blue (FB) or Diamidino Yellow (DY)) was injected into various parts of the CN. The main findings were as follows: (1) labeled neurons were distributed most densely in the intralaminar nuclei, midline thalamic nuclei and centre median-parafascicular complex, and less densely in the ventroanterior (VA), ventrolateral (VL) and ventromedial (VM) nuclei. (2) After injections into the rostral parts of the CN, a moderate number of retrogradely labeled neuronal cell bodies was observed in VA, VL and VM. However, only very few, if any, labeled neurons were found in these nuclei after injections into the caudal parts of the CN. (3) After injections into the most dorsolateral parts of the CN, labeled neurons were seen in the lateralmost part of the VA and VL. (4) Many retrogradely labeled neurons were consistently found in the lateral wing of the rhomboid nucleus after injections into the CN. (5) No clear topography was detected in the arrangement of labeled neurons in the rhomboid, dorsal mediodorsal, centrolateral or paracentral nuclei. (6) After injections into the rostral parts of the CN, the most prominent labeling was observed in the ventral part of the centre médian-parafascicular complex.

  3. Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

    SciTech Connect

    Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

    1986-06-01

    The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

  4. Estradiol and brain serotonin reuptake transporter in long-term ovariectomized parkinsonian monkeys.

    PubMed

    Sánchez, Maria Gabriela; Morissette, Marc; Di Paolo, Thérèse

    2013-08-01

    This study evaluated the effect of a one month 17β-estradiol treatment on brain serotonin (5-HT) reuptake transporter (SERT) in long-term ovariectomized (OVX) female monkeys (Macaca fascicularis) bearing a unilateral lesion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injected directly into the left substantia nigra modeling Parkinson disease (PD). Ovariectomy and MPTP lesion were performed four years before the estrogen treatment to model postmenopausal PD patients. SERT was measured by autoradiography using the radioligand [(3)H]Citalopram. Specific binding to SERT decreased in anterior cerebral cortex, nucleus accumbens, caudate nucleus and putamen on the lesioned side of 17β-estradiol and vehicle-treated monkeys compared to the intact side. In caudate nucleus and putamen the lesioned-induced decrease of [(3)H]Citalopram specific binding was more extensive in anterior and middle than posterior parts. [(3)H]Citalopram specific binding was increased in the cortex anterior cingulate gyrus of monkeys treated with 17β-estradiol in both brain hemispheres and was unchanged in the other brain regions investigated including the raphe nucleus. Positive correlations between [(3)H]Citalopram specific binding and 5-HT as well as 5-HIAA concentrations (reported previously) were obtained in the caudate nucleus and putamen and a negative correlation between SERT binding and 5-HIAA/5-HT concentration ratio suggesting MPTP lesion-induced 5-HT neuronal loss and lower 5-HT neurotransmission controlling and decreasing SERT for homeostasis. 17β-estradiol treatment initiated four years after ovariectomy of monkeys modeling hormonal conditions of post-menopause shows that SERT still displays some responsiveness to estrogens as observed in the anterior cingulate cortex. These results support a role of estrogens in 5-HT activity in PD. PMID:23719069

  5. Chromatin alterations in response to forced swimming underlie increased prodynorphin transcription.

    PubMed

    Reed, B; Fang, N; Mayer-Blackwell, B; Chen, S; Yuferov, V; Zhou, Y; Kreek, M J

    2012-09-18

    Antagonism of the kappa opioid receptor (KOR) has been reported to have anti-depressant-like properties. The dynorphin/KOR system is a crucial neurochemical substrate underlying the pathologies of addictive diseases, affective disorders and other disease states. However, the molecular underpinnings and neuroanatomical localization of the dysregulation of this system have not yet been fully elucidated. Utilizing the Porsolt Forced Swim Test (FST), an acute stressor commonly used as in rodent models measuring antidepressant efficacy, male Sprague-Dawley rats were subject to forced swimming for 15 min, treated 1h with vehicle or norbinaltorphimine (nor-BNI) (5 or 10mg/kg), and then 1 day later subject to FST for 5 min. In accordance with previous findings, nor-BNI dose dependently increased climbing time and reduced immobility. In comparison to control animals not exposed to FST, we observed a significant elevation in prodynorphin (pDyn) mRNA levels following FST using real-time optical polymerase chain reaction (PCR) in the caudate putamen but not in the nucleus accumbens, hypothalamus, amygdala, frontal cortex, or hippocampus. nor-BNI treatment did not affect pDyn mRNA levels in comparison to animals that received vehicle. The corresponding brain regions from the opposite hemisphere were analyzed for underlying chromatin modifications of the prodynorphin gene promoter region using chromatin immunoprecipitation with antibodies against specifically methylated histones H3K27Me2, H3K27Me3, H3K4Me2, and H3K4Me3, as well as CREB-1 and MeCP2. Significant alterations in proteins bound to DNA in the Cre-3, Cre-4, and Sp1 regions of the prodynorphin promoter were found in the caudate putamen of the FST saline-treated animals compared to control animals, with no changes observed in the hippocampus. Epigenetic changes resulting in elevated dynorphin levels specifically in the caudate putamen may in part underlie the enduring effects of stress.

  6. Chromatin Alterations in Response to Forced Swimming Underlie Increased Prodynorphin Transcription

    PubMed Central

    Reed, Brian; Fang, Nancy; Blackwell-Mayer, Brandan; Chen, Shasha; Yuferov, Vadim; Zhou, Yan; Kreek, Mary Jeanne

    2012-01-01

    Antagonism of the kappa opioid receptor (KOR) has been reported to have anti-depressant-like properties. The dynorphin/KOR system is a crucial neurochemical substrate underlying the pathologies of addictive diseases, affective disorders and other disease states. However, the molecular underpinnings and neuroanatomical localization of the dysregulation of this system have not yet been fully elucidated. Utilizing the Porsolt Forced Swim Test (FST), an acute stressor commonly used as in rodent models measuring antidepressant efficacy, male Sprague-Dawley rats were subject to forced swimming for 15 minutes, treated 1 hour with vehicle or nor-BNI (5 or 10 mg/kg), and then 1 day later subject to FST for five minutes. In accordance with previous findings, nor-BNI dose dependently increased climbing time and reduced immobility. In comparison to control animals not exposed to FST, we observed a significant elevation in prodynorphin (pDyn) mRNA levels following FST using real-time optical PCR in the caudate putamen but not in the nucleus accumbens, hypothalamus, amygdala, frontal cortex, or hippocampus. Nor-BNI treatment did not affect pDyn mRNA levels in comparison to animals that received vehicle. The corresponding brain regions from the opposite hemisphere were analyzed for underlying chromatin modifications of the prodynorphin gene promoter region using chromatin immunoprecipitation with antibodies against specifically methylated histones H3K27Me2, H3K27Me3, H3K4Me2, and H3K4Me3, as well as CREB-1 and MeCP2. Significant alterations in proteins bound to DNA in the Cre-3, Cre-4, and Sp1 regions of the prodynorphin promoter were found in the caudate putamen of the FST saline-treated animals compared to control animals, with no changes observed in the hippocampus. Epigenetic changes resulting in elevated dynorphin levels specifically in the caudate putamen may in part underlie the enduring effects of stress. PMID:22698692

  7. Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats.

    PubMed

    Guercio, Leonardo A; Schmidt, Heath D; Pierce, R Christopher

    2015-03-15

    Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 days, with each infusion of cocaine being paired with a cue light. After 21 days of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer. PMID:25529183

  8. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cue-Induced Reinstatement of Both Cocaine and Sucrose Seeking in Rats

    PubMed Central

    Guercio, Leonardo A.; Schmidt, Heath D.; Pierce, R. Christopher

    2015-01-01

    Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 d, with each infusion of cocaine being paired with a cue light. After 21 d of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer. PMID:25529183

  9. Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate.

    PubMed

    Rothman, R B; Silverthorn, M L; Glowa, J R; Matecka, D; Rice, K C; Carroll, F I; Partilla, J S; Uhl, G R; Vandenbergh, D J; Dersch, C M

    1998-04-01

    [125I]RTI-55 is a cocaine analog with high affinity for dopamine (DA) and serotonin (5-HT) transporters. Quantitative ligand binding studies revealed a novel high affinity [125I]RTI-55 binding site assayed under 5-HT transporter (SERT) conditions which has low affinity for almost all classic biogenic amine transporter ligands, including high affinity 5-HT transporter inhibitors such as paroxetine, but which retains high affinity for cocaine analogs. This site, termed SERT(site2) for its detection under 5-HT transporter conditions (not for an association with the SERT) occurs in monkey caudate, human caudate, and guinea pig caudate membranes, but not in rat caudate membranes. SERT(site2) is distinguished from the DA transporter (DAT) and SERT by several criteria, including a distinct ligand-selectivity profile, the inability to detect SERT(site2) in cells stably expressing the cloned human DAT, and insensitivity to irreversible ligands which inhibit [125I]RTI-55 binding to the DAT and SERT. Perhaps the most striking finding about SERT(site2) is that a wide range of representative antidepressant agents have very low affinity for SERT(site2). The affinity of cocaine for this site is not very different from the concentration cocaine achieves in the brain at pharmacological doses. Viewed collectively with the observation that ligands with high affinity for SERT(site2) are mostly cocaine analogs, these data lead us to speculate that actions of cocaine which differ from those of classic biogenic amine uptake inhibitors may be mediated in part via SERT(site2).

  10. Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

    ERIC Educational Resources Information Center

    Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

    2009-01-01

    Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

  11. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior.

    PubMed

    Christoffel, Daniel J; Golden, Sam A; Heshmati, Mitra; Graham, Ami; Birnbaum, Shari; Neve, Rachael L; Hodes, Georgia E; Russo, Scott J

    2012-11-01

    Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.

  12. 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

  13. Targeting Dopamine D2 and Cannabinoid-1 (CB1) Receptors in Rat Nucleus Accumbens

    PubMed Central

    PICKEL, VIRGINA M.; CHAN, JANE; KEARN, CHRISTOPHER S.; MACKIE, KENNETH

    2006-01-01

    The nucleus accumbens (Acb) shell and core are essential components of neural circuitry mediating the reward and motor effects produced by activation of dopamine D2 or cannabinoid-1 (CB1) receptors. D2 receptors can form heterodimeric complexes with cannabinoid-1 (CB1) receptors and are also involved in control of the availability of both dopamine and endocannabinoids. Thus, the subcellular locations of D2 and CB1 receptors with respect to each other are implicit to their physiological actions in the Acb. We used electron microscopic immunocytochemistry to determine these locations in the Acb shell and core of rat brain. In each region, many neuronal profiles showed endomembrane and plasmalemmal distributions of one or both receptors. Approximately one-third of the labeled profiles were somata and dendrites, some of which showed overlapping subcellular distributions of D2 and CB1 immunoreactivities. The remaining labeled profiles were small axons and axon terminals containing CB1 and/or D2 receptors. Of the labeled terminals forming recognizable synapses, ~20% of those containing CB1 receptors contacted D2-labeled dendrites, while conversely, almost 15% of those containing D2 receptors contacted CB1-labeled dendrites. These results provide the first ultrastructural evidence that D2 and CB1 receptors in the Acb shell and core have subcellular distributions supporting both intracellular associations and local involvement of D2 receptors in making available endocannabinoids that are active on CB1 receptors in synaptic neurons. These distributions have direct relevance to the rewarding and euphoric as well as motor effects produced by marijuana and by addictive drugs enhancing dopamine levels in the Acb. PMID:16440297

  14. Neonatal Masculinization Blocks Increased Excitatory Synaptic Input in Female Rat Nucleus Accumbens Core.

    PubMed

    Cao, Jinyan; Dorris, David M; Meitzen, John

    2016-08-01

    Steroid sex hormones and genetic sex regulate the phenotypes of motivated behaviors and relevant disorders. Most studies seeking to elucidate the underlying neuroendocrine mechanisms have focused on how 17β-estradiol modulates the role of dopamine in striatal brain regions, which express membrane-associated estrogen receptors. Dopamine action is an important component of striatal function, but excitatory synaptic neurotransmission has also emerged as a key striatal substrate and target of estradiol action. Here, we focus on excitatory synaptic input onto medium spiny neurons (MSNs) in the striatal region nucleus accumbens core (AcbC). In adult AcbC, miniature excitatory postsynaptic current (mEPSC) frequency is increased in female compared with male MSNs. We tested whether increased mEPSC frequency in female MSNs exists before puberty, whether this increased excitability is due to the absence of estradiol or testosterone during the early developmental critical period, and whether it is accompanied by stable neuron intrinsic membrane properties. We found that mEPSC frequency is increased in female compared with male MSNs before puberty. Increased mEPSC frequency in female MSNs is abolished after neonatal estradiol or testosterone exposure. MSN intrinsic membrane properties did not differ by sex. These data indicate that neonatal masculinization via estradiol and/or testosterone action is sufficient for down-regulating excitatory synaptic input onto MSNs. We conclude that excitatory synaptic input onto AcbC MSNs is organized long before adulthood via steroid sex hormone action, providing new insight into a mechanism by which sex differences in motivated behavior and other AbcC functions may be generated or compromised.

  15. Nucleus Accumbens-Specific Interventions in RGS9-2 Activity Modulate Responses to Morphine

    PubMed Central

    Gaspari, Sevasti; Papachatzaki, Maria M; Koo, Ja Wook; Carr, Fiona B; Tsimpanouli, Maria-Efstratia; Stergiou, Eugenia; Bagot, Rosemary C; Ferguson, Deveroux; Mouzon, Ezekiell; Chakravarty, Sumana; Deisseroth, Karl; Lobo, Mary Kay; Zachariou, Venetia

    2014-01-01

    Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc. PMID:24561386

  16. 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

  17. 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

  18. Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction.

    PubMed

    del Castillo, Carmen; Morales, Lidia; Alguacil, Luis F; Salas, Elisabet; Garrido, Elisa; Alonso, Elba; Pérez-García, Carmen

    2009-07-01

    Vulnerability to the addictive effects of drugs of abuse varies among individuals, but the biological basis of these differences are poorly known. This work tries to increase this knowledge by comparing the brain proteome of animals with different rate of extinction of cocaine-seeking behaviour. To achieve this goal, we used a place-preference paradigm to separate Sprague Dawley rats in two groups: rats that extinguished (E) and rats that did not extinguish (NE) cocaine-seeking behaviour after a five-day period of drug abstinence. Once the phenotype was established, we compared the protein expression in the nucleus accumbens (NAC) of these animals after a single injection of either saline (SAL) or cocaine (COC, 15 mg/kg). The analysis of protein expression was performed by 2-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization time of flight mass spectrometry. When comparing E SAL and NE SAL animals we found significant differences in the expression level of 5 proteins: ATP synthase subunit alpha, fumarate hydratase, transketolase, NADH dehydrogenase [ubiquinone] flavoprotein 2 and glutathione transferase omega-1. A single injection of COC differently alters the NAC proteome of E and NE rats; thus in E COC animals there was an alteration in the expression of 6 proteins, including dihydropyrimidinase-related protein 2 and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10; whereas in NE COC rats 9 proteins were altered (including alpha-synuclein, peroxiredoxin-2 and peroxiredoxin-5). These proteins could be potential biomarkers of individual vulnerability to cocaine abuse and may be helpful in designing new treatments for cocaine addiction.

  19. 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

  20. Cue-Evoked Cocaine “Craving”: Role of Dopamine in the Accumbens Core

    PubMed Central

    Saunders, Benjamin T.; Yager, Lindsay M.

    2013-01-01

    Drug-associated cues can acquire powerful motivational control over the behavior of addicts, and can contribute to relapse via multiple, dissociable mechanisms. Most preclinical models of relapse focus on only one of these mechanisms: the ability of drug cues to reinforce drug-seeking actions following a period of extinction training. However, in addicts, drug cues typically do not follow seeking actions; they precede them. They often produce relapse by evoking a conditioned motivational state (“wanting” or “craving”) that instigates and/or invigorates drug-seeking behavior. Here we used a conflict-based relapse model to ask whether individual variation in the propensity to attribute incentive salience to reward cues predicts variation in the ability of a cocaine cue to produce conditioned motivation (craving) for cocaine. Following self-administration training, responding was curtailed by requiring rats to cross an electrified floor to take cocaine. The subsequent response-independent presentation of a cocaine-associated cue was sufficient to reinstate drug-seeking behavior, despite the continued presence of the adverse consequence. Importantly, there were large individual differences in the motivational properties of the cocaine cue, which were predicted by variation in the propensity to attribute incentive salience to a food cue. Finally, a dopamine antagonist injected into the nucleus accumbens core attenuated, and amphetamine facilitated, cue-evoked cocaine seeking, implicating dopamine signaling in cocaine cue-evoked craving. These data provide a promising preclinical approach for studying sources of individual variation in susceptibility to relapse due to conditioned craving and implicate mesolimbic dopamine in this process. PMID:23986236

  1. Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

    PubMed

    LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A

    2016-02-01

    Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux. PMID:26706696

  2. Plasticity of GABAA receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats

    PubMed Central

    Liang, Jing; Lindemeyer, A. Kerstin; Suryanarayanan, Asha; Meyer, Edward M.; Marty, Vincent N.; Ahmad, S. Omar; Shao, Xuesi Max; Olsen, Richard W.

    2014-01-01

    Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABAARs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABAARs, which mediate the picrotoxin-sensitive tonic current (Itonic), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both Itonic and mIPSCs was decreased by CIE treatment. The average magnitude of Itonic was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABAAR subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission. PMID:24694935

  3. NPY mediates reward activity of morphine, via NPY Y1 receptors, in the nucleus accumbens shell.

    PubMed

    Desai, Sagar J; Upadhya, Manoj A; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2013-06-15

    Although the interaction between endogenous neuropeptide Y (NPY) and opioidergic systems in processing of reward has been speculated, experimental evidence is lacking. We investigated the role of NPY, and its Y1 receptors, in the nucleus accumbens shell (AcbSh) in morphine induced reward and reinforcement behavior. Rats were implanted with cannulae targeted at AcbSh for drug administration, and with stimulating electrode in the medial forebrain bundle (MFB). The rats were then conditioned in an operant conditioning chamber for electrical self-stimulation of the MFB. Increased rate of lever pressings was evaluated against the frequency of the stimulating current. Increase in rate of lever presses was considered as a measure of reward and reinforcement. About 30-70% increase in self-stimulation was observed following bilateral intra-AcbSh treatment with morphine, NPY or [Leu(31), Pro(34)]-NPY (NPY Y1/Y5 receptors agonist), however, BIBP3226 (selective NPY Y1 receptors antagonist) produced opposite effect. The reward effect of morphine was significantly potentiated by NPY or [Leu(31), Pro(34)]-NPY, but antagonized by BIBP3226. NPY-immunoreactivity in the AcbSh, arcuate nucleus (ARC) and lateral part of bed nucleus of stria terminalis (BNSTl) was significantly more in the operant conditioned rats than in naïve control. However, morphine administration to the conditioned rats resulted in significant decrease in the NPY-immunoreactivity in all these anatomical regions. Since the role of morphine in modulation of mesolimbic-dopaminergic pathway is well established, we suggest that NPY system in AcbSh, ARC and BNSTl, perhaps acting via Y1-receptor system, may be an important component of the mesolimbic-AcbSh reward circuitry triggered by endogenous opioids.

  4. Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.

    PubMed

    Larson, Erin B; Graham, Danielle L; Arzaga, Rose R; Buzin, Nicole; Webb, Joseph; Green, Thomas A; Bass, Caroline E; Neve, Rachael L; Terwilliger, Ernest F; Nestler, Eric J; Self, David W

    2011-11-01

    Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

  5. κ-Opioid receptors within the nucleus accumbens shell mediate pair bond maintenance.

    PubMed

    Resendez, Shanna L; Kuhnmuench, Morgan; Krzywosinski, Tarin; Aragona, Brandon J

    2012-05-16

    The prairie vole is a socially monogamous species in which breeder pairs typically show strong and selective pair bonds. The establishment of a pair bond is associated with a behavioral transition from general affiliation to aggressive rejection of novel conspecifics. This "selective aggression" is indicative of mate guarding that is necessary to maintain the initial pair bond. In the laboratory, the neurobiology of this behavior is studied using resident-intruder testing. Although it is well established that social behaviors in other species are mediated by endogenous opioid systems, opiate regulation of pair bond maintenance has never been studied. Here, we used resident-intruder testing to determine whether endogenous opioids within brain motivational circuitry mediate selective aggression in prairie voles. We first show that peripheral blockade of κ-opioid receptors with the antagonist norbinaltorphimine (nor-BNI; 100 mg/kg), but not with the preferential μ-opioid receptor antagonist naloxone (1, 10, or 30 mg/kg), decreased selective aggression in males. We then provide the first comprehensive characterization of κ- and μ-opioid receptors in the prairie vole brain. Finally, we demonstrate that blockade of κ-opioid receptors (500 ng nor-BNI) within the nucleus accumbens (NAc) shell abolishes selective aggression in both sexes, but blockade of these receptors within the NAc core enhances this behavior specifically in females. Blockade of κ-opioid receptors within the ventral pallidum or μ-opioid receptors with the specific μ-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH2 (1 ng CTAP) within the NAc shell had no effect in either sex. Thus, κ-opioid receptors within the NAc shell mediate aversive social motivation that is critical for pair bond maintenance. PMID:22593047

  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. Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

    PubMed

    LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A

    2016-02-01

    Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux.

  8. 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.

  9. Cocaine withdrawal-induced trafficking of delta-opioid receptors in rat nucleus accumbens.

    PubMed

    Ambrose-Lanci, Lisa M; Peiris, Niluk B; Unterwald, Ellen M; Van Bockstaele, Elisabeth J

    2008-05-19

    Interactions between the opioidergic and dopaminergic systems in the nucleus accumbens (NAcb) play a critical role in mediating cocaine withdrawal-induced effects on cell signaling and behavior. In support of this, increased activation of striatal dopamine-D1 receptors (D1R) results in desensitization of delta-opioid receptor (DOR) signaling through adenylyl cyclase during early cocaine withdrawal. A potential cellular substrate underlying receptor desensitization is receptor internalization. The present study examined the effect of cocaine withdrawal on subcellular localization of DOR in dendrites of the NAcb core (NAcbC) and shell (NAcbS) using immunoelectron microscopy. Female and male rats received binge-pattern cocaine or saline for 14 days and subsequently underwent 48 h withdrawal. Animals were transcardially perfused and tissue sections were processed for immunogold-silver localization of DOR. Semi-quantitative analysis revealed that cocaine withdrawal caused an increase in the percentage of DOR localized intracellularly in the NAcbS of male and female rats and the NAcbC of male rats compared to saline controls. In contrast, in the NAcbC of female rats, there was an increase in DOR associated with the plasma membrane following cocaine withdrawal. To determine whether modulation of D1R could directly impact DOR containing neurons, the hypothesis that DOR and D1R co-exist in common neurons of the NAcb was examined in naïve rats. Semi-quantitative analysis revealed a subset of profiles containing both DOR and D1R immunoreactivities. The present findings demonstrate a redistribution of DOR in the NAcb following cocaine withdrawal and provide anatomical evidence supporting D1R regulation of DOR function in a subset of NAcb neurons. PMID:18417105

  10. Exposure to Cocaine Dynamically Regulates the Intrinsic Membrane Excitability of Nucleus Accumbens Neurons

    PubMed Central

    Mu, Ping; Moyer, Jason T.; Ishikawa, Masago; Zhang, Yonghong; Panksepp, Jaak; Sorg, Barbara A.; Schlüter, Oliver M.; Dong, Yan

    2010-01-01

    Drug-induced malfunction of nucleus accumbens (NAc) neurons underlies a key pathophysiology of drug addiction. Drug-induced changes in intrinsic membrane excitability of NAc neurons are thought to be critical for producing behavioral alterations. Previous studies demonstrate that following short-term (2d) or long-term (21d) withdrawal from non-contingent cocaine injection, the intrinsic membrane excitability of NAc shell (NAcSh) neurons is decreased, and decreased membrane excitability of NAcSh neurons increases the acute locomotor response to cocaine. However, animals exhibit distinct cellular and behavioral alterations at different stages of cocaine exposure, suggesting that the decreased membrane excitability of NAc neurons may not be a persistent change. Here, we demonstrate that the membrane excitability of NAcSh neurons is differentially regulated depending on whether cocaine is administered contingently or non-contingently. Specifically, the membrane excitability of NAcSh MSNs was decreased at 2d after withdrawal from either 5-day intraperitoneal (i.p.) injections (15 mg/kg) or cocaine self-administration (SA). At 21d of withdrawal, the membrane excitability of NAcSh MSNs, which remained low in i.p.-pretreated rats, returned to a normal level in SA-pretreated rats. Furthermore, upon a re-exposure to cocaine after long-term withdrawal, the membrane excitability of NAcSh MSNs instantly returned to a normal level in i.p.-pretreated rats. On the other hand, in SA-pretreated rats, the re-exposure elevated the membrane excitability of NAcSh MSMs beyond the normal level. These results suggest that the dynamic alterations in membrane excitability of NAcSh MSNs, together with the dynamic changes in synaptic input, contribute differentially to the behavioral consequences of contingent and non-contingent cocaine administration. PMID:20220002

  11. 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

  12. SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens.

    PubMed

    Ferguson, Deveroux; Shao, Ningyi; Heller, Elizabeth; Feng, Jian; Neve, Rachael; Kim, Hee-Dae; Call, Tanessa; Magazu, Samantha; Shen, Li; Nestler, Eric J

    2015-02-18

    Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action. PMID:25698746

  13. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

    PubMed

    Gaspari, Sevasti; Papachatzaki, Maria M; Koo, Ja Wook; Carr, Fiona B; Tsimpanouli, Maria-Efstratia; Stergiou, Eugenia; Bagot, Rosemary C; Ferguson, Deveroux; Mouzon, Ezekiell; Chakravarty, Sumana; Deisseroth, Karl; Lobo, Mary Kay; Zachariou, Venetia

    2014-07-01

    Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

  14. Oscillatory Activity in the Medial Prefrontal Cortex and Nucleus Accumbens Correlates with Impulsivity and Reward Outcome

    PubMed Central

    Rich, P. Dylan; Nevado-Holgado, Alejo J.; Fernando, Anushka B. P.; Van Dijck, Gert; Holzhammer, Tobias; Paul, Oliver; Ruther, Patrick; Paulsen, Ole; Robbins, Trevor W.; Dalley, Jeffrey W.

    2014-01-01

    Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50–60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7–9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour. PMID:25333512

  15. Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons.

    PubMed

    Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan

    2011-01-01

    Homeostatic response is an endowed self-correcting/maintaining property for living units, ranging from subcellular domains, single cells, and organs to the whole organism. Homeostatic responses maintain stable function through the ever-changing internal and external environments. In central neurons, several forms of homeostatic regulation have been identified, all of which tend to stabilize the functional output of neurons toward their prior "set-point." Medium spiny neurons (MSNs) within the forebrain region the nucleus accumbens (NAc) play a central role in gating/regulating emotional and motivational behaviors including craving and seeking drugs of abuse. Exposure to highly salient stimuli such as cocaine administration not only acutely activates a certain population of NAc MSNs, but also induces long-lasting changes in these neurons. It is these long-lasting cellular alterations that are speculated to mediate the increasingly strong cocaine-craving and cocaine-seeking behaviors. Why do the potentially powerful homeostatic mechanisms fail to correct or compensate for these drug-induced maladaptations in neurons? Based on recent experimental results, this review proposes a hypothesis of homeostatic dysregulation induced by exposure to cocaine. Specifically, we hypothesize that exposure to cocaine generates false molecular signals which misleads the homeostatic regulation process, resulting in maladaptive changes in NAc MSNs. Thus, many molecular and cellular alterations observed in the addicted brain may indeed result from homeostatic dysregulation. This review is among the first to introduce the concept of homeostatic neuroplasticity to understanding the molecular and cellular maladaptations following exposure to drugs of abuse. PMID:20708038

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

    PubMed

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

    2014-04-22

    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 10days 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 10mg/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 10.0mg/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 population 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 analyses 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 animal's behavior concomitantly with neuronal recordings.

  17. Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.

    PubMed

    Massart, Renaud; Barnea, Royi; Dikshtein, Yahav; Suderman, Matthew; Meir, Oren; Hallett, Michael; Kennedy, Pamela; Nestler, Eric J; Szyf, Moshe; Yadid, Gal

    2015-05-27

    One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0.75 mg/kg, 6 h/d, 10 d), and cue-induced cocaine-seeking was examined in an extinction test after 1 or 30 d of withdrawal. We show that the withdrawal periods, as well as cue-induced cocaine seeking, are associated with broad, time-dependent enhancement of DNA methylation alterations in the nucleus accumbens (NAc). These gene methylation alterations were partly negatively correlated with gene expression changes. Furthermore, intra-NAc injections of a DNA methyltransferase inhibitor (RG108, 100 μm) abolished cue-induced cocaine seeking on day 30, an effect that persisted 1 month, whereas the methyl donor S-adenosylmethionine (500 μm) had an opposite effect on cocaine seeking. We then targeted two proteins whose genes were demethylated by RG108-estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with an intra-NAc injection of the ESR1 agonist propyl pyrazole triol (10 nm) or the CDK5 inhibitor roscovitine (28 μm) on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results demonstrate a role for NAc DNA methylation, and downstream targets of DNA demethylation, in incubation of cocaine craving.

  18. Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli

    PubMed Central

    Cone, Jackson J.; Roitman, Jamie D.; Roitman, Mitchell F.

    2015-01-01

    Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e. hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS−). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS−, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. PMID:25708523

  19. 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.

  20. Imipramine Treatment and Resiliency Exhibit Similar Chromatin Regulation in the Mouse Nucleus Accumbens in Depression Models

    PubMed Central

    Wilkinson, Matthew B.; Xiao, Guanghua; Kumar, Arvind; LaPlant, Quincey; Renthal, William; Sikder, Devanjan; Kodadek, Thomas J.; Nestler, Eric J.

    2009-01-01

    Though it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use ChIP-chip assays—chromatin immunoprecipitation (ChIP) followed by genome wide promoter array analyses—to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that most of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice—those resistant to the deleterious effects of defeat stress—show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress. PMID:19535594

  1. Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

    PubMed Central

    Christoffel, Daniel J; Golden, Sam A; Heshmati, Mitra; Graham, Ami; Birnbaum, Shari; Neve, Rachael L; Hodes, Georgia E; Russo, Scott J

    2012-01-01

    Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses. PMID:22781845

  2. The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

    PubMed

    Jean, A; Laurent, L; Bockaert, J; Charnay, Y; Dusticier, N; Nieoullon, A; Barrot, M; Neve, R; Compan, V

    2012-12-11

    In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this 'paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT(4) receptors (5-HTR(4)) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR(1B) self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR(4) in the absence of 5-HTR(1B), associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR(4) overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR(4) knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR(4). Additionally, inactivating NAc-5-HTR(4) suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR(4)/CART pathway establishes a 'tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules.

  3. Nucleus accumbens GABAergic inhibition generates intense eating and fear that resists environmental retuning and needs no local dopamine.

    PubMed

    Richard, Jocelyn M; Plawecki, Andrea M; Berridge, Kent C

    2013-06-01

    Intense fearful behavior and/or intense appetitive eating behavior can be generated by localized amino acid inhibitions along a rostrocaudal anatomical gradient within medial shell of nucleus accumbens of the rat. This can be produced by microinjections in medial shell of either the γ-aminobutyric acid (GABA)A agonist muscimol (mimicking intrinsic GABAergic inputs) or the AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione), disrupting corticolimbic glutamate inputs). At rostral sites in medial shell, each drug robustly stimulates appetitive eating and food intake, whereas at more caudal sites the same drugs instead produce increasingly fearful behaviors such as escape, distress vocalizations and defensive treading (an antipredator behavior rodents emit to snakes and scorpions). Previously we showed that intense motivated behaviors generated by glutamate blockade require local endogenous dopamine and can be modulated in valence by environmental ambience. Here we investigated whether GABAergic generation of intense appetitive and fearful motivations similarly depends on local dopamine signals, and whether the valence of motivations generated by GABAergic inhibition can also be retuned by changes in environmental ambience. We report that the answer to both questions is 'no'. Eating and fear generated by GABAergic inhibition of accumbens shell does not need endogenous dopamine. Also, the appetitive/fearful valence generated by GABAergic muscimol microinjections resists environmental retuning and is determined almost purely by rostrocaudal anatomical placement. These results suggest that nucleus accumbens GABAergic release of fear and eating are relatively independent of modulatory dopamine signals, and more anatomically pre-determined in valence balance than release of the same intense behaviors by glutamate disruptions.

  4. 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

  5. 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.

  6. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    PubMed

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.

  7. The role of the medial caudate nucleus, but not the hippocampus, in a matching-to sample task for a motor response.

    PubMed

    Kesner, Raymond P; Gilbert, Paul E

    2006-04-01

    A delayed-match-to-sample task was used to assess memory for motor responses in rats with control, hippocampus, or medial caudate nucleus (MCN) lesions. All testing was conducted on a cheeseboard maze in complete darkness using an infrared camera. A start box was positioned in the centre of the maze facing a randomly determined direction on each trial. On the sample phase, a phosphorescent object was randomly positioned to cover a baited food well in one of five equally spaced positions around the circumference of the maze forming a 180-degree arc 60 cm from the box. The rat had to displace the object to receive food and return to the start box. The box was then rotated to face a different direction. An identical baited phosphorescent object was placed in the same position relative to the start box. A second identical object was positioned to cover a different unbaited well. On the choice phase, the rat must remember the motor response made on the sample phase and make the same motor response on the choice phase to receive a reward. Hippocampus lesioned and control rats improved as a function of increased angle separation used to separate the correct object from the foil (45, 90, 135, and 180 degrees) and matched the performance of controls. However, rats with MCN lesions were impaired across all separations. Results suggest that the MCN, but not the hippocampus, supports working memory and/or a process aimed at reducing interference for motor response selection based on vector angle information.

  8. Subcortical brain segmentation of two dimensional T1-weighted data sets with FMRIB's Integrated Registration and Segmentation Tool (FIRST).

    PubMed

    Amann, Michael; Andělová, Michaela; Pfister, Armanda; Mueller-Lenke, Nicole; Traud, Stefan; Reinhardt, Julia; Magon, Stefano; Bendfeldt, Kerstin; Kappos, Ludwig; Radue, Ernst-Wilhelm; Stippich, Christoph; Sprenger, Till

    2015-01-01

    Brain atrophy has been identified as an important contributing factor to the development of disability in multiple sclerosis (MS). In this respect, more and more interest is focussing on the role of deep grey matter (DGM) areas. Novel data analysis pipelines are available for the automatic segmentation of DGM using three-dimensional (3D) MRI data. However, in clinical trials, often no such high-resolution data are acquired and hence no conclusions regarding the impact of new treatments on DGM atrophy were possible so far. In this work, we used FMRIB's Integrated Registration and Segmentation Tool (FIRST) to evaluate the possibility of segmenting DGM structures using standard two-dimensional (2D) T1-weighted MRI. In a cohort of 70 MS patients, both 2D and 3D T1-weighted data were acquired. The thalamus, putamen, pallidum, nucleus accumbens, and caudate nucleus were bilaterally segmented using FIRST. Volumes were calculated for each structure and for the sum of basal ganglia (BG) as well as for the total DGM. The accuracy and reliability of the 2D data segmentation were compared with the respective results of 3D segmentations using volume difference, volume overlap and intra-class correlation coefficients (ICCs). The mean differences for the individual substructures were between 1.3% (putamen) and -25.2% (nucleus accumbens). The respective values for the BG were -2.7% and for DGM 1.3%. Mean volume overlap was between 89.1% (thalamus) and 61.5% (nucleus accumbens); BG: 84.1%; DGM: 86.3%. Regarding ICC, all structures showed good agreement with the exception of the nucleus accumbens. The results of the segmentation were additionally validated through expert manual delineation of the caudate nucleus and putamen in a subset of the 3D data. In conclusion, we demonstrate that subcortical segmentation of 2D data are feasible using FIRST. The larger subcortical GM structures can be segmented with high consistency. This forms the basis for the application of FIRST in large 2D

  9. Knockdown of Dopamine D2 Receptors in the Nucleus Accumbens Core Suppresses Methamphetamine-Induced Behaviors and Signal Transduction in Mice

    PubMed Central

    Miyamoto, Yoshiaki; Iida, Asako; Sato, Keiji; Muramatsu, Shin-ichi

    2015-01-01

    Background: Addictive drugs lead to reinforcing properties by increasing dopamine in the nucleus accumbens, which is composed of a core and shell regions. Neurons in the nucleus accumbens are divided into 2 subtypes based on the differential gene expression of the dopamine D1 receptors and D2 receptors. Methods: In the present study, we investigated the role of D2 receptors in the nucleus accumbens core in behaviors and signal transduction induced by psychostimulant methamphetamine in mice that were microinjected with adeno-associated virus vectors containing a microRNA (miRNA) sequence for D2 receptor (adeno-associated virus-miD2r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D2 receptor-treated mice (miD2r mice) were assessed at a reduction in D2 receptor, but at no change in dopamine D1 receptor, in the nucleus accumbens core compared with the adeno-associated virus-Mock vectors-treated mice (Mock mice). Results: miD2r mice exhibited a reduction in hyperlocomotion that was induced by a single treatment with methamphetamine. The development of locomotor sensitization induced by repeated treatment with methamphetamine exhibited less extension in miD2r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD2r mice than in Mock mice. Furthermore, the single treatment with methamphetamine-induced phosphorylation of extracellular signal regulated kinase and cyclic adenosine monophosphate response element-binding protein in the nucleus accumbens core of miD2r mice was decreased compared with that in Mock mice. Repeated treatment with methamphetamine-induced delta FBJ murine osteosarcoma viral oncogene homolog B accumulation in the nucleus accumbens core of miD2r mice was also attenuated. Conclusions: These findings suggest that a D2 receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of

  10. Value and probability coding in a feedback-based learning task utilizing food rewards.

    PubMed

    Tricomi, Elizabeth; Lempert, Karolina M

    2015-01-01

    For the consequences of our actions to guide behavior, the brain must represent different types of outcome-related information. For example, an outcome can be construed as negative because an expected reward was not delivered or because an outcome of low value was delivered. Thus behavioral consequences can differ in terms of the information they provide about outcome probability and value. We investigated the role of the striatum in processing probability-based and value-based negative feedback by training participants to associate cues with food rewards and then employing a selective satiety procedure to devalue one food outcome. Using functional magnetic resonance imaging, we examined brain activity related to receipt of expected rewards, receipt of devalued outcomes, omission of expected rewards, omission of devalued outcomes, and expected omissions of an outcome. Nucleus accumbens activation was greater for rewarding outcomes than devalued outcomes, but activity in this region did not correlate with the probability of reward receipt. Activation of the right caudate and putamen, however, was largest in response to rewarding outcomes relative to expected omissions of reward. The dorsal striatum (caudate and putamen) at the time of feedback also showed a parametric increase correlating with the trialwise probability of reward receipt. Our results suggest that the ventral striatum is sensitive to the motivational relevance, or subjective value, of the outcome, while the dorsal striatum codes for a more complex signal that incorporates reward probability. Value and probability information may be integrated in the dorsal striatum, to facilitate action planning and allocation of effort.

  11. Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis.

    PubMed

    Burgaleta, Miguel; Sanjuán, Ana; Ventura-Campos, Noelia; Sebastian-Galles, Núria; Ávila, César

    2016-01-15

    Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes.

  12. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    SciTech Connect

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. )

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  13. Quantitative autoradiography of /sup 3/H-nomifensine binding sites in rat brain

    SciTech Connect

    Scatton, B.; Dubois, A.; Dubocovich, M.L.; Zahniser, N.R.; Fage, D.

    1985-03-04

    The distribution of /sup 3/H-nomifensine binding sites in the rat brain has been studied by quantitative autoradiography. The binding of /sup 3/H-nomifensine to caudate putamen sections was saturable, specific, of a highly affinity (Kd = 56 nM) and sodium-dependent. The dopamine uptake inhibitors benztropine, nomifensine, cocaine, bupropion and amfonelic acid were the most potent competitors of /sup 3/H-nomifensine binding to striatal sections. The highest levels of (benztropine-displaceable) /sup 3/H-nomifensine binding sites were found in the caudate-putamen, the olfactory tubercle and the nucleus accumbens. 6-Hydroxy-dopamine-induced lesion of the ascending dopaminergic bundle resulted in a marked decrease in the /sup 3/H-ligand binding in these areas. Moderately high concentrations of the /sup 3/H-ligand were observed in the bed nucleus of the stria terminalis, the anteroventral thalamic nucleus, the cingulate cortex, the lateral septum, the hippocampus, the amygdala, the zona incerta and some hypothalamic nuclei. There were low levels of binding sites in the habenula, the dorsolateral geniculate body, the substantia nigra, the ventral tegmental area and the periaqueductal gray matter. These autoradiographic data are consistent with the hypothesis that /sup 3/H-nomifensine binds primarily to the presynaptic uptake site for dopamine but also labels the norepinephrine uptake site. 33 references, 2 figures, 1 table.

  14. Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis.

    PubMed

    Burgaleta, Miguel; Sanjuán, Ana; Ventura-Campos, Noelia; Sebastian-Galles, Núria; Ávila, César

    2016-01-15

    Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes. PMID:26505300

  15. 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

  16. 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.

  17. 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

  18. Differential activation of accumbens shell and core dopamine by sucrose reinforcement with nose poking and with lever pressing.

    PubMed

    Bassareo, V; Cucca, F; Frau, R; Di Chiara, G

    2015-11-01

    In order to investigate the role of modus operandi in the changes of nucleus accumbens (NAc) dopamine (DA) transmission in sucrose reinforcement, extracellular DA was monitored by microdialysis in the NAc shell and core of rats trained on a fixed-ratio 1 schedule to respond for sucrose pellets by nose poking and lever pressing respectively. After training, rats were tested on three different sessions: sucrose reinforcement, extinction and passive sucrose presentation. In rats responding by nose poking dialysate DA increased in the shell but not in the core under reinforced as well as under extinction sessions. In contrast, in rats responding by lever pressing dialysate DA increased both in the accumbens shell and core under reinforced and extinction sessions. Response non-contingent sucrose presentation increased dialysate DA in the shell and core of rats trained to respond for sucrose by nose poking as well as in those trained by lever pressing. In rats trained to respond for sucrose by nose poking on a FR5 schedule dialysate DA also increased selectively in the NAc shell during reinforced responding and in both the shell and core under passive sucrose presentation. These findings, while provide an explanation for the discrepancies existing in the literature over the responsiveness of shell and core DA in rats responding for food, are consistent with the notion that NAc shell and core DA encode different aspects of reinforcement.

  19. BAZ1B in Nucleus Accumbens Regulates Reward-Related Behaviors in Response to Distinct Emotional Stimuli

    PubMed Central

    Sun, HaoSheng; Martin, Jennifer A.; Werner, Craig T.; Wang, Zi-Jun; Damez-Werno, Diane M.; Scobie, Kimberly N.; Shao, Ning-Yi; Dias, Caroline; Rabkin, Jacqui; Koo, Ja Wook; Gancarz, Amy M.; Mouzon, Ezekiell A.; Neve, Rachael L.; Shen, Li; Dietz, David M.

    2016-01-01

    ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins. SIGNIFICANCE STATEMENT We show that BAZ1B, a component of chromatin remodeling complexes, in the nucleus accumbens regulates reward-related behaviors in response to chronic exposure to both rewarding and aversive stimuli by regulating largely distinct subsets of genes. PMID:27053203

  20. Reward-guided learning beyond dopamine in the nucleus accumbens: The integrative functions of cortico-basal ganglia networks

    PubMed Central

    Yin, Henry H.; Ostlund, Sean B.; Balleine, Bernard W.

    2009-01-01

    Here we challenge the view that reward-guided learning is solely controlled by the mesoaccumbens pathway arising from dopaminergic neurons in the ventral tegmental area and projecting to the nucleus accumbens. This widely accepted view assumes that reward is a monolithic concept, but recent work has suggested otherwise. It now appears that, in reward-guided learning, the functions of ventral and dorsal striata, and the cortico-basal ganglia circuitry associated with them, can be dissociated. Whereas the nucleus accumbens is necessary for the acquisition and expression of certain appetitive Pavlovian responses and contributes to the motivational control of instrumental performance, the dorsal striatum is necessary for the acquisition and expression of instrumental actions. Such findings suggest the existence of multiple independent yet interacting functional systems that are implemented in iterating and hierarchically organized cortico-basal ganglia networks engaged in appetitive behaviors ranging from Pavlovian approach responses to goal-directed instrumental actions controlled by action-outcome contingencies. PMID:18793321

  1. 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

  2. Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress

    PubMed Central

    Hodes, Georgia E.; Pfau, Madeline L.; Purushothaman, Immanuel; Ahn, H. Francisca; Golden, Sam A.; Christoffel, Daniel J.; Magida, Jane; Brancato, Anna; Takahashi, Aki; Flanigan, Meghan E.; Ménard, Caroline; Aleyasin, Hossein; Koo, Ja Wook; Lorsch, Zachary S.; Feng, Jian; Heshmati, Mitra; Wang, Minghui; Turecki, Gustavo; Neve, Rachel; Zhang, Bin; Shen, Li; Nestler, Eric J.

    2015-01-01

    Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. SIGNIFICANCE STATEMENT Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic

  3. 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

  4. Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression

    PubMed Central

    Barr, Jeffrey L.; Forster, Gina L.; Unterwald, Ellen M.

    2014-01-01

    Dopaminergic neurotransmission in the nucleus accumbens is important for various reward-related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In the present study, in vivo microdialysis in freely moving adult male Sprague-Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus-mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N-methyl-D-aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A:NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal-nucleus accumbens communication, in part through changes in glutamate receptor composition. PMID:24832868

  5. 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…

  6. Lesions of the dopaminergic innervation of the nucleus accumbens medial shell delay the generation of preference for sucrose, but not of sexual pheromones.

    PubMed

    Martínez-Hernández, José; Lanuza, Enrique; Martínez-García, Fernando

    2012-01-15

    Male sexual pheromones are rewarding stimuli for female mice, able to induce conditioned place preference. To test whether processing these natural reinforcing stimuli depends on the dopaminergic innervation of the nucleus accumbens, as for other natural rewards, we compare the effects of specific lesions of the dopaminergic innervation of the medial shell of the nucleus accumbens on two different appetitive behaviours, 'pheromone seeking' and sucrose preferential intake. Female mice, with no previous experience with either adult male chemical stimuli or with sucrose, received injections of 6-hydroxydopamine (or vehicle) in the medial shell of the accumbens. Then, we analyzed their preference for male soiled-bedding and their preferential intake of a sucrose solution, with particular emphasis on the dynamics of acquisition of both natural rewards. The results indicate that both lesioned and sham animals showed similar preference for male sexual pheromones, which was constant along the test (linear dynamics). In contrast, lesioned animals differed from sham operated mice in the dynamics of sucrose consumption in their first test of sucrose preference. Sham animals showed an initial sucrose preference followed by preference for water, which can be interpreted as sucrose neophobia. Lesioned animals showed no preference at the beginning of the test, and a delayed sucrose preference appeared followed by a delayed neophobia. The next day, during a second sucrose-preference test, both groups displayed comparable and sustained preferential sucrose intake. Therefore, dopamine in the medial shell of the nucleus accumbens has a different role on the reward of sexual pheromones and sucrose.

  7. 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…

  8. 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…

  9. No Evidence for Sex Differences in the Electrophysiological Properties and Excitatory Synaptic Input onto Nucleus Accumbens Shell Medium Spiny Neurons123

    PubMed Central

    Will, Tyler; Hauser, Caitlin A.; Cao, Jinyan

    2016-01-01

    Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. These investigations yield accumulating evidence of sexually different electrophysiological properties, excitatory synaptic input, and sensitivity to neuromodulator/hormone action in select striatal regions both before and after puberty. It is unknown whether the electrical properties of neurons in the nucleus accumbens shell differ by sex, and whether sex differences in excitatory synaptic input are present before puberty. To test the hypothesis that these properties differ by sex, we performed whole-cell patch-clamp recordings on male and female medium spiny neurons (MSNs) in acute brain slices obtained from prepubertal rat nucleus accumbens shell. We analyzed passive and active electrophysiological properties, and miniature EPSCs (mEPSCs). No sex differences were detected; this includes those properties, such as intrinsic excitability, action potential afterhyperpolarization, threshold, and mEPSC frequency, that have been found to differ by sex in other striatal regions and/or developmental periods. These findings indicate that, unlike other striatal brain regions, the electrophysiological properties of nucleus accumbens shell MSNs do not differ by sex. Overall, it appears that sex differences in striatal function, including motivated behavior and reward, are likely mediated by other factors and striatal regions. PMID:27022621

  10. Effects of alpha-methyl-p-tyrosine on extracellular dopamine levels in the nucleus accumbens and the dorsal striatum of freely moving rats.

    PubMed

    Watanabe, Shu; Fusa, Koichi; Takada, Koji; Aono, Yuri; Saigusa, Tadashi; Koshikawa, Noriaki; Cools, Alexander R

    2005-12-01

    Alpha-methyl-p-tyrosine (AMPT) is known to inhibit the formation of dopamine (DA) in the cytosol of dopaminergic neurons and is therefore used to study the role of the cytosolic DA pools. AMPT is usually administered systemically. In the present study, however, the effects of locally infused AMPT on the efflux of DA from the nucleus accumbens and dorsal striatum were analyzed, using in vivo brain microdialysis in unanesthetized rats. The administration of AMPT (100 microM, 4 h) into the nucleus accumbens reduced accumbal DA output to 30% of its baseline level. When it was infused into the dorsal striatum, however, it reduced striatal DA output to 60% of its baseline level. At first sight, these data suggest that the amount of DA available from the AMPT-sensitive pool is larger in the nucleus accumbens than in the striatum. However, this cannot be the case, as the decrease in accumbal and striatal DA efflux induced by systemic administration of AMPT (250 mg/kg given intra-peritoneally) was identical. These results show that local infusion of AMPT is a valuable tool for analyzing the role of AMPT-sensitive pools within a particular brain area, but it cannot be used to compare effects across different brain structures because a fixed dose of AMPT differentially affected the nucleus accumbens and the dorsal striatum.

  11. DeltaFosB is increased in the nucleus accumbens by amphetamine but not social housing or isolation in the prairie vole.

    PubMed

    Hostetler, C M; Bales, K L

    2012-05-17

    The nucleus accumbens is a key region that mediates aspects of immediate and long-term adaptations to various stimuli. For example, both repeated amphetamine and pair-bonding increase dopamine D1 receptor binding in the nucleus accumbens of the monogamous prairie vole (Microtus ochrogaster). This upregulation has significant and stimulus-dependent behavioral consequences. A promising candidate for these and other adaptations is the transcription factor ΔfosB. ΔfosB is a highly stable protein that persists in the brain over long periods of time, leading to increasing and accumulating levels with repeated or continuous exposure to specific stimuli. Within the nucleus accumbens, ΔfosB is specifically increased in medium spiny neurons containing D1 receptors. To explore whether ΔfosB is altered by drug and social experience in prairie voles, we performed three separate experiments. In the first experiment, animals were treated with repeated injections of amphetamine and then brain tissue was analyzed for ΔfosB expression. As expected, 4 days of amphetamine treatment increased ΔfosB in the nucleus accumbens, consistent with previous findings in other laboratory species. In the second experiment, animals were housed for 10 days with one of three social partners: a familiar same-sex sibling, an unfamiliar same-sex partner, or an unfamiliar opposite-sex partner. Here, we predicted that 10 days of housing with an opposite-sex partner would act as a "social reward," leading to upregulation of ΔfosB expression in the nucleus accumbens. In a third experiment, we also investigated whether 10 days of social isolation would result in altered ΔfosB activity. We hypothesized that isolation would lead to decreased levels of nucleus accumbens ΔfosB, as seen in other studies. However, neither opposite-sex cohabitation nor social isolation affected ΔfosB expression in the nucleus accumbens. These findings suggest that social stimuli, in contrast to drugs of abuse, are not

  12. Autoradiographic visualization of CNS receptors for vasoactive intestinal peptide

    SciTech Connect

    Shaffer, M.M.; Moody, T.W.

    1986-03-01

    Receptors for VIP were characterized in the rat CNS. /sup 125/I-VIP bound with high affinity to rat brain slices. Binding was time dependent and specific. Pharmacology studies indicated that specific /sup 125/I-VIP binding was inhibited with high affinity by VIP and low affinity by secretin and PHI. Using in vitro autoradiographic techniques high grain densities were present in the dentate gyrus, pineal gland, supraoptic and suprachiasmatic nuclei, superficial gray layer of the superior colliculus and the area postrema. Moderate grain densities were present in the olfactory bulb and tubercle, cerebral cortex, nucleus accumbens, caudate putamen, interstitial nucleus of the stria terminalis, paraventricular thalamic nucleus, medial amygdaloid nucleus, subiculum and the medial geniculate nucleus. Grains were absent in the corpus callosum and controls treated with 1 microM unlabeled VIP. The discrete regional distribution of VIP receptors suggest that it may function as an important modulator of neural activity in the CNS.

  13. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward.

    PubMed

    Stouffer, Melissa A; Woods, Catherine A; Patel, Jyoti C; Lee, Christian R; Witkovsky, Paul; Bao, Li; Machold, Robert P; Jones, Kymry T; de Vaca, Soledad Cabeza; Reith, Maarten E A; Carr, Kenneth D; Rice, Margaret E

    2015-01-01

    Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. PMID:26503322

  14. Autoradiographic localization of adenosine receptors in rat brain using (/sup 3/H)cyclohexyladenosine

    SciTech Connect

    Goodman, R.R.; Synder, S.H.

    1982-09-01

    Adenosine (A1) receptor binding sites have been localized in rat brain by an in vitro light microscopic autoradiographic method. The binding of (/sup 3/H)N6-cyclohexyladenosine to slide-mounted rat brain tissue sections has the characteristics of A1 receptors. It is saturable with high affinity and has appropriate pharmacology and stereospecificity. The highest densities of adenosine receptors occur in the molecular layer of the cerebellum, the molecular and polymorphic layers of the hippocampus and dentate gyrus, the medial geniculate body, certain thalamic nuclei, and the lateral septum. High densities also are observed in certain layers of the cerebral cortex, the piriform cortex, the caudate-putamen, the nucleus accumbens, and the granule cell layer of the cerebellum. Most white matter areas, as well as certain gray matter areas, such as the hypothalamus, have negligible receptor concentrations. These localizations suggest possible central nervous system sites of action of adenosine.

  15. Microinjections of a nicotinic agonist into dopamine terminal fields: effects on locomotion.

    PubMed

    Museo, E; Wise, R A

    1990-09-01

    Nicotine induces locomotion, a behavior associated with the mesocorticolimbic dopamine system. The present study determined the effects on locomotion of direct microinjections of the nicotinic agonist cytisine into four DA terminal fields were nicotinic receptors have been localized: nucleus accumbens (NAS, n = 20), caudate putamen (CPU, n = 9), olfactory tubercle (OT, n = 8), and medial prefrontal cortex (MPC, n = 12). Male Long-Evans rats were injected with cytisine (0.1, 1, 10 and 100 nanomoles per 0.5 microliters per side) or vehicle through indwelling cannulae, and locomotor activity was recorded during a 60-minute test session; each animal was tested with each dose in counterbalanced order. NAS injections of the three highest doses of cytisine increased locomotion relative to vehicle injections; injections in the CPU, dorsal to the NAS, were ineffective, as were MPC and OT injections. The data support the notion that systemic nicotine may interact with dopaminergic projections to the NAS to produce increases in locomotor activity.

  16. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward.

    PubMed

    Stouffer, Melissa A; Woods, Catherine A; Patel, Jyoti C; Lee, Christian R; Witkovsky, Paul; Bao, Li; Machold, Robert P; Jones, Kymry T; de Vaca, Soledad Cabeza; Reith, Maarten E A; Carr, Kenneth D; Rice, Margaret E

    2015-10-27

    Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices.

  17. Autoradiographic localization of adenosine uptake sites in rat brain using (/sup 3/H)nitrobenzylthioinosine

    SciTech Connect

    Bisserbe, J.C.; Patel, J.; Marangos, P.J.

    1985-02-01

    The adenosine uptake site has been localized in rat brain by an in vitro light microscopic autoradiographic method, using (/sup 3/H)nitrobenzylthioinosine ((/sup 3/H)NBI) as the probe. The binding characteristics of (/sup 3/H)NBI on slide-mounted sections are comparable to those seen in studies performed on brain homogenates. A very high density of uptake sites occurs in the nucleus tractus solitarius, in the superficial layer of the superior colliculus, in several thalamic nuclei, and also in geniculate body nuclei. A high density of sites are also observed in the nucleus accumbens, the caudate putamen, the dorsal tegmentum area, the substantia nigra, and the central gray. The localization of the adenosine uptake site in brain may provide information on the functional activity of the site and suggests the involvement of the adenosine system in the central regulation of cardiovascular function.

  18. 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

  19. Changes in benzodiazepine-GABA receptor coupling in an accumbens-habenula circuit after chronic diazepam treatment.

    PubMed Central

    Brett, R. R.; Pratt, J. A.

    1995-01-01

    1. The effects of subacute and of chronic diazepam treatment upon binding to the GABAA receptor have been examined by use of receptor autoradiography for determining flunitrazepam (FNZP) binding, GABA enhancement of FNZP binding. SR 95531 2-(3'-carboxy-2',propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding and GABA binding in parallel sections from rat brain. Prior to the autoradiographic procedures, a behavioural assessment of the rats was made in the elevated plus-maze test of anxiety. 2. Rats receiving diazepam either subacutely (3 days) or chronically (28 days) by both continuous release, from previously implanted subcutaneous silastic capsules, or by daily injection (5 mg kg-1) did not display changes in FNZP or GABA binding in any of the 47 brain structures analysed. Similarly, there were no significant effects of treatment upon mean total entries or on the open:total ratio for entries in the elevated plus-maze. 3. There were reductions in the GABA enhancement of FNZP binding in the nucleus accumbens and central grey after subacute diazepam treatment. This effect persisted in the nucleus accumbens after chronic treatment. Less marked effects occurred in the lateral habenula, dorsal raphe and substantia nigra pars compacta. In the dorsal tegmental nucleus, GABA enhancement of FNZP binding was enhanced after chronic treatment and this was accompanied by reductions in SR 95531 binding. Treatment did not otherwise affect SR 95531 binding, with the exception of the dorsal raphe where binding was decreased after subacute treatment. 4. In general, the patterns of binding produced by the two different treatment routes were very similar. However, SR 95531 binding was lower in certain hippocampal fields in the i.p. treated animals compared to the rats implanted with silastic capsules. 5. It is concluded that repeated administration of diazepam evokes changes in benzodiazepine and GABA receptor coupling, and to a lesser extent changes in low affinity GABA

  20. Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions.

    PubMed

    Sheu, Yi-Shin; Polcari, Ann; Anderson, Carl M; Teicher, Martin H

    2010-11-01

    Harsh corporal punishment (HCP) was defined as frequent parental administration of corporal punishment (CP) for discipline, with occasional use of objects such as straps, or paddles. CP is linked to increased risk for depression and substance abuse. We examine whether long-term exposure to HCP acts as sub-traumatic stressor that contributes to brain alterations, particularly in dopaminergic pathways, which may mediate their increased vulnerability to drug and alcohol abuse. Nineteen young adults who experienced early HCP but no other forms of maltreatment and twenty-three comparable controls were studied. T2 relaxation time (T2-RT) measurements were performed with an echo planar imaging TE stepping technique and T2 maps were calculated and analyzed voxel-by-voxel to locate regional T2-RT differences between groups. Previous studies indicated that T2-RT provides an indirect index of resting cerebral blood volume. Region of interest (ROI) analyses were also conducted in caudate, putamen, nucleus accumbens, anterior cingulate cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus and cerebellar hemispheres. Voxel-based relaxometry showed that HCP was associated with increased T2-RT in right caudate and putamen. ROI analyses also revealed increased T2-RT in dorsolateral prefrontal cortex, substantia nigra, thalamus and accumbens but not globus pallidus or cerebellum. There were significant associations between T2-RT measures in dopamine target regions and use of drugs and alcohol, and memory performance. Alteration in the paramagnetic or hemodynamic properties of dopaminergic cell body and projection regions were observed in subjects with HCP, and these findings may relate to their increased risk for drug and alcohol abuse.

  1. Recombinant human nerve growth factor is biologically active and labels novel high-affinity binding sites in rat brain

    SciTech Connect

    Altar, C.A.; Burton, L.E.; Bennett, G.L.; Dugich-Djordjevic, M. )

    1991-01-01

    Iodinated recombinant human nerve growth factor (125I-rhNGF) stimulated neurite formation in PC12 cell cultures with a half-maximal potency of 35-49 pg/ml, compared with 39-52 pg/ml for rhNGF. In quantitative ligand autoradiography, the in vitro equilibrium binding of 125I-rhNGF to brain sections showed a 10-fold regional variation in density and was saturable, reversible, and specifically displaced by up to 74% with rhNGF or murine NGF (muNGF). At equilibrium, 125I-rhNGF bound to these sites with high affinity and low capacity (Bmax less than or equal to 13.2 fmol/mg of protein). Calculation of 125I-rhNGF binding affinity by kinetic methods gave average Kd values of 24 and 31 pM. Computer-generated maps revealed binding in brain regions not identified previously with 125I-muNGF, including hippocampus; dentate gyrus; amygdala; paraventricular thalamus; frontal, parietal, occipital, and cingulate cortices; nucleus accumbens; olfactory tubercle; subiculum; pineal gland; and medial geniculate nucleus. NGF binding sites were distributed in a 2-fold increasing medial-lateral gradient in the caudate-putamen and a 2-fold lateral-medial gradient in the nucleus accumbens. 125I-rhNGF binding sites were also found in most areas labeled by 125I-muNGF, including the interpedunucular nucleus, cerebellum, forebrain cholinergic nuclei, caudoventral caudate-putamen, and trigeminal nerve nucleus. 125I-rhNGF binding sites were absent from areas replete with low-affinity NGF binding sites, including circumventricular organs, myelinated fiber bundles, and choroid plexus. The present analysis provides an anatomical differentiation of high-affinity 125I-rhNGF binding sites and greatly expands the number of brain structures that may respond to endogenous NGF or exogenously administered rhNGF.

  2. Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats

    SciTech Connect

    Neisewander, J.L.; Lucki, I.; McGonigle, P. )

    1991-05-01

    Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with ({sup 3}H)SCH-23390 and D2 receptors labeled with ({sup 3}H)spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.

  3. The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

    PubMed

    Bradfield, Laura A; McNally, Gavan P

    2010-07-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

  4. A Single Intra-PFC Infusion of BDNF Prevents Cocaine-Induced Alterations in Extracellular Glutamate within the Nucleus Accumbens

    PubMed Central

    Berglind, William J.; Whitfield, Timothy W.; LaLumiere, Ryan T.; Kalivas, Peter W.; McGinty, Jacqueline F.

    2009-01-01

    The glutamatergic pathway arising in the dorsomedial prefrontal cortex (dmPFC) and projecting to the nucleus accumbens (NAc) core is a critical component of the reward circuitry that underlies reinstatement to cocaine-seeking behavior. Brain derived neurotrophic factor (BDNF) is expressed by and modulates PFC-NAc neurons. BDNF infusion into the dmPFC attenuates reinstatement to cocaine-seeking behavior as well as some cocaine-induced molecular adaptations within the NAc. In the present study, it is demonstrated that a single intra-dmPFC infusion of BDNF prevents cocaine self administration-induced reduction in basal extracelluar glutamate, as well as cocaine prime-induced increases in extracellular glutamate levels within the NAc. These data suggest that intra-PFC BDNF attenuates reinstatement to cocaine-seeking behavior by normalizing cocaine-induced neuroadaptations that alter glutamate neurotransmission within the NAc. PMID:19321768

  5. 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.

  6. Comparative analysis of oxytocin receptor density in the nucleus accumbens: an adaptation for female and male alloparental care?

    PubMed

    Olazábal, Daniel E

    2014-01-01

    Parental behavior is commonly displayed by progenitors. However, other individuals, genetically related (e.g. siblings, aunts, uncles) or not with the newborns, also display parental behavior (commonly called alloparental, or adoptive behavior). I hypothesize that species that live in family or social groups where other non-reproductive members (males and females) take care of infants, have brain adaptations to promote or facilitate that behavioral response. The present work revises the evidence supporting the hypothesis that high density of oxytocin receptors (OXTR) in the nucleus accumbens (NA) is one of those adaptations. All species known to have high NA OXTR show not only female, but also male alloparental care. Therefore, I predict that high NA OXTR could be present in all species in which juvenile and adult male alloparental behavior have been observed. Strategies to test this and other alternative working hypothesis and its predictions are presented. PMID:25446893

  7. White-Matter Tract Connecting Anterior Insula to Nucleus Accumbens Correlates with Reduced Preference for Positively Skewed Gambles

    PubMed Central

    Leong, Josiah K.; Pestilli, Franco; Wu, Charlene C.; Samanez-Larkin, Gregory R.; Knutson, Brian

    2016-01-01

    SUMMARY Individuals sometimes show inconsistent risk preferences, including excessive attraction to gambles featuring small chances of winning large amounts (called “positively skewed” gambles). While functional neuroimaging research indicates that nucleus accumbens (NAcc) and anterior insula (AIns) activity inversely predict risky choice, structural connections between these regions have not been described in humans. By combining diffusion-weighted MRI with tractography, we identified the anatomical trajectory of white-matter tracts projecting from the AIns to the NAcc and statistically validated these tracts using Linear Fascicle Evaluation (LiFE) and virtual lesions. Coherence of the right AIns-NAcc tract correlated with reduced preferences for positively skewed gambles. Further, diminished NAcc activity during gamble presentation mediated the association between tract structure and choice. These results identify an unreported tract connecting the AIns to the NAcc in humans and support the notion that structural connections can alter behavior by influencing brain activity as individuals weigh uncertain gains against uncertain losses. PMID:26748088

  8. Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp): implications for alcohol-induced behavioral plasticity.

    PubMed

    Ary, Alexis W; Cozzoli, Debra K; Finn, Deborah A; Crabbe, John C; Dehoff, Marlin H; Worley, Paul F; Szumlinski, Karen K

    2012-06-01

    Neuronal activity dependent pentraxin (Narp) interacts with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors to facilitate excitatory synapse formation by aggregating them at established synapses. Alcohol is well-characterized to influence central glutamatergic transmission, including AMPA receptor function. Herein, we examined the influence of injected and ingested alcohol upon Narp protein expression, as well as basal Narp expression in mouse lines selectively bred for high blood alcohol concentrations under limited access conditions. Alcohol up-regulated accumbens Narp levels, concomitant with increases in levels of the GluR1 AMPA receptor subunit. However, accumbens Narp or GluR1 levels did not vary as a function of selectively bred genotype. We next employed a Narp knock-out (KO) strategy to begin to understand the behavioral relevance of alcohol-induced changes in protein expression in several assays of alcohol reward. Compared to wild-type mice, Narp KO animals: fail to escalate daily intake of high alcohol concentrations under free-access conditions; shift their preference away from high alcohol concentrations with repeated alcohol experience; exhibit a conditioned place-aversion in response to the repeated pairing of 3 g/kg alcohol with a distinct environment and fail to exhibit alcohol-induced locomotor hyperactivity following repeated alcohol treatment. Narp deletion did not influence the daily intake of either food or water, nor did it alter any aspect of spontaneous or alcohol-induced motor activity, including the development of tolerance to its motor-impairing effects with repeated treatment. Taken together, these data indicate that Narp induction, and presumably subsequent aggregation of AMPA receptors, may be important for neuroplasticity within limbic subcircuits mediating or maintaining the rewarding properties of alcohol.

  9. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release.

    PubMed

    Melchior, James R; Ferris, Mark J; Stuber, Garret D; Riddle, David R; Jones, Sara R

    2015-09-01

    The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse microenvironments. Local electrical stimulation excites all of the neuronal processes in the stimulation field, potentially modulating the dopamine signal - measured using cyclic voltammetry. Optogenetically targeting light stimulation to dopamine

  10. Differential effects of acute and repeated stress on hippocampus and amygdala inputs to the nucleus accumbens shell

    PubMed Central

    Gill, Kathryn M.; Grace, Anthony A.

    2013-01-01

    The basolateral amygdala (BLA) and ventral subiculum (vSub) of the hippocampus convey emotion and context information, respectively, to the nucleus accumbens (NAc). Using in vivo extracellular recordings from NAc neurons, we examined how acute and repeated restraint stress alters the plasticity of the vSub and BLA afferent pathways. High frequency (HFS) and low frequency (LFS) stimulation was applied to the vSub to assess the impact on NAc responses to vSub and BLA inputs. In addition, iontophoretic application of the D2-antagonist sulpiride was used to explore the role of dopamine in the NAc in mediating the effects of stress on plasticity. Acute and repeated restraint caused disparate effects on BLA- and vSub-evoked responses in the NAc. Following repeated restraint, but not after acute restraint, HFS of the vSub failed to potentiate the vSub-NAc pathway while instead promoting a long lasting reduction of the BLA-NAc pathway, and these effects were independent of D2-receptor activity. In contrast, LFS to the vSub pathway after acute restraint resulted in potentiation in the vSub-NAc pathway while BLA-evoked responses were unchanged. When sulpiride was applied prior to LFS of the vSub after acute stress, there was a pronounced decrease in vSub-evoked responses similar to control animals. This work provides new insight into the impact of acute and repeated stress on the integration of context and emotion inputs in the nucleus accumbens. These data support a model of stress whereby the hippocampus is inappropriately activated and dominates the information processing within this circuit via a dopaminergic mechanism after acute bouts of stress. PMID:23745764

  11. Plasminogen.

    PubMed

    Sharon, R; Abramovitz, R; Miskin, R

    2001-08-01

    Plasminogen activator inhibitor-2 (PAI-2) specifically inhibits plasminogen activators, extracellular fibrinolytic serine proteases that are also implicated in brain plasticity and toxicity. Primarily localized intracellularly, PAI-2 is thought to also counteract apoptosis mediated by a currently undefined intracellular protease. Here we localized PAI-2 mRNA through in situ hybridization in brain cryosections derived from normal adult mice or after kainate excitation. We found that in the normal brain PAI-2 mRNA was confined to an area within the accumbens nucleus shell. After kainate was injected (i.p.), PAI-2 mRNA was substantially and rapidly (within 2 h) induced in neuron-like cells primarily in layers II-III of the neocortex; the cingulate, piriform, entorhinal and perirhinal cortices; the olfactory bulb, nucleus and tubercle; in the accumbens nucleus, shell and core; throughout the caudate putamen and the amygdaloid complex; in the CA1 and CA3 areas of the hippocampus, and in the parasubiculum. These findings suggest that PAI-2 could play a role in the accumbens nucleus as well as in activity-related events associated with olfactory, striatal, and limbic structures.

  12. Alterations of BDNF and trkB mRNA Expression in the 6-Hydroxydopamine-Induced Model of Preclinical Stages of Parkinson’s Disease: An Influence of Chronic Pramipexole in Rats

    PubMed Central

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson’s disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively. PMID:25739024

  13. Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat.

    PubMed

    Millan, M J; Brocco, M; Gobert, A; Joly, F; Bervoets, K; Rivet, J; Newman-Tancredi, A; Audinot, V; Maurel, S

    1999-12-01

    In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.

  14. [REACTIVE CHANGES IN THE ASTROCYTES OF FOREBRAIN NUCLEUS ACCUMBENS AFTER RESTRICTION OF BLOOD FLOW IN THE BASIN OF BOTH COMMON CAROTID ARTERIES IN RATS].

    PubMed

    Naumov, N G

    2016-01-01

    Reactive changes of astrocytes were studied in forebrain nucleus accumbens in rats (n = 12) after global cerebral ischemia induced by bilateral occlusion of both common carotid arteries, which is a frequently used model to assess the effectiveness of pharmacological agents that have anti-ischemic and neuroprotective properties. Under these conditions, the nucleus accumbens was in the area of partial ischemia. Morphometric study of nucleus accumbens was performed in three groups of rats (4 animals in each group) after ligation of both common carotid arteries, after a sham operation and in healthy animals. Astrocytes were demonstrated in serial sections using the reaction to glial fibrillary acidic protein counterstained with hematoxylin. 7 days after the surgery, in each animal the number of astrocytes was counted in the sections in 7 successiive squares of 0.01 mm2 each, the distance between their bodies and the capillary wall was measured within the circle of 20 μm radius, the cell body area and the length of their main processes were determined. It is found that astrocytes in the nucleus accumbens in the model of bilateral occlusion of the common carotid arteries for 7 days experienced a partial state of ischemia. Their reactive changes were manifested by the signs of the cytotoxic edema, damaging intermediate filament proteins in their bodies, processes and in the perivascular glial membranes. The concentration of the astrocyte cell bodies near blood capillaries is the adaptation mechanism and is a condition for the survival of cells under the restriction of blood flow in the brain. PMID:27487658

  15. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism

    PubMed Central

    Graves, Steven M.; Clark, Mary J.; Traynor, John R.; Hu, Xiu-Ti; Napier, T. Celeste

    2014-01-01

    Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq–mediated signaling pathways. PMID:25229719

  16. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism.

    PubMed

    Graves, Steven M; Clark, Mary J; Traynor, John R; Hu, Xiu-Ti; Napier, T Celeste

    2015-02-01

    Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq-mediated signaling pathways.

  17. Phosphorylation of the N-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal.

    PubMed

    Anderson, Ethan M; Reeves, Turi; Kapernaros, Katherine; Neubert, John K; Caudle, Robert M

    2015-12-01

    Opioid withdrawal causes a dysphoric state that can lead to complications in pain patients and can propagate use in drug abusers and addicts. Opioid withdrawal changes the activity of neurons in the nucleus accumbens, an area rich in both opioid-binding mu opioid receptors and glutamate-binding NMDA receptors. Because the accumbens is an area important for reward and aversion, plastic changes in this area during withdrawal could alter future behaviors in animals. We discovered an increase in phosphorylation of serine 897 in the NR1 subunit of the NMDA receptor (pNR1) during acute morphine withdrawal. This serine can be phosphorylated by protein kinase A (PKA) and dephosphorylated by calcineurin. We next demonstrated that this increased pNR1 change is associated with an increase in NR1 surface expression. NR1 surface expression and pNR1 levels during acute withdrawal were both reduced by the NMDA receptor antagonist MK-801 (dizocilpine hydrogen maleate) and the PKA inhibitor H-89(N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride hydrate). We also found that pNR1 levels remained high after an extended morphine withdrawal period of 2 months, correlated with reward-seeking behavior for palatable food, and were associated with a decrease in accumbal calcineurin levels. These data suggest that NR1 phosphorylation changes during the acute withdrawal phase can be long lasting and may reflect a permanent change in NMDA receptors in the accumbens. These altered NMDA receptors in the accumbens could play a role in long-lasting behaviors associated with reward and opioid use.

  18. Nucleus accumbens response to food cues predicts subsequent snack consumption in women and increased body mass index in those with reduced self-control.

    PubMed

    Lawrence, Natalia S; Hinton, Elanor C; Parkinson, John A; Lawrence, Andrew D

    2012-10-15

    Individuals have difficulty controlling their food consumption, which is due in part to the ubiquity of tempting food cues in the environment. Individual differences in the propensity to attribute incentive (motivational) salience to and act on these cues may explain why some individuals eat more than others. Using fMRI in healthy women, we found that food cue related activity in the nucleus accumbens, a key brain region for food motivation and reward, was related to subsequent snack food consumption. However, both nucleus accumbens activation and snack food consumption were unrelated to self-reported hunger, or explicit wanting and liking for the snack. In contrast, food cue reactivity in the ventromedial prefrontal cortex was associated with subjective hunger/appetite, but not with consumption. Whilst the food cue reactivity in the nucleus accumbens that predicted snack consumption was not directly related to body mass index (BMI), it was associated with increased BMI in individuals reporting low self-control. Our findings reveal a neural substrate underpinning automatic environmental influences on consumption in humans and demonstrate how self-control interacts with this response to predict BMI. Our data provide support for theoretical models that advocate a 'dual hit' of increased incentive salience attribution to food cues and poor self-control in determining vulnerability to overeating and overweight. PMID:22776461

  19. Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study.

    PubMed

    Rougé-Pont, F; Piazza, P V; Kharouby, M; Le Moal, M; Simon, H

    1993-01-29

    Individual vulnerability to the reinforcing effects of drugs appears to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with high locomotor responses to novelty (high responders, HR) acquire amphetamine SA, while animals with low responses (low responders, LR) do not. In this study we examined by microdialysis whether stress-induced extracellular dopamine (DA) concentrations in the nucleus accumbens differed between these two groups of animals. This neurotransmitter was studied because it is thought to be involved in the reinforcing effects of psychostimulants. Furthermore, previous studies have shown that HR animals have a higher basal DOPAC/DA ratio in the nucleus accumbens and higher extracellular concentrations of dopamine in this structure in response to cocaine. The stress procedure used in this experiment consisted of a 10 min tail-pinch. HR animals displayed a higher and longer stress-induced changes in DA concentrations than the LR group. Regression analysis showed that stress-induced changes in DA levels accounted for 75% of the variance observed in the locomotor response to a novel environment. Since higher DA activity in the nucleus accumbens has been reported in animals in which the propensity to psychostimulant SA is induced by brain lesions or life events, this biochemical modification may be one neurobiological substrate of the predisposition to acquire psychostimulant self-administration. PMID:8448654

  20. Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats.

    PubMed

    Kitamura, Yoshihisa; Yagi, Takahiko; Kitagawa, Kouhei; Shinomiya, Kazuaki; Kawasaki, Hiromu; Asanuma, Masato; Gomita, Yutaka

    2010-08-01

    The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

  1. The decrease of dopamine D₂/D₃ receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB₁ cannabinoid receptors in Parkinson's disease: a preliminary autoradiographic study with the selective dopamine D₂/D₃ antagonist [³H]raclopride and the novel CB₁ inverse agonist [¹²⁵I]SD7015.

    PubMed

    Farkas, Szabolcs; Nagy, Katalin; Jia, Zhisheng; Harkany, Tibor; Palkovits, Miklós; Donohou, Sean R; Pike, Victor W; Halldin, Christer; Máthé, Domokos; Csiba, László; Gulyás, Balázs

    2012-04-10

    Cannabinoid type-1 receptors (CB₁Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB₁Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB₁R and dopamine receptor density in case of Parkinson's disease (PD). Post mortem putamen, nucleus caudatus and medial frontal gyrus samples obtained from PD patients were used for CB₁R and dopamine D₂/D₃ receptor autoradiography. [¹²⁵I]SD7015, a novel selective CB₁R inverse agonist, developed by a number of the present co-authors, and [³H]raclopride, a dopamine D₂/D₃ antagonist, were used as radioligands. Our results demonstrate unchanged CB₁R density in the putamen and nucleus caudatus of deceased PD patients, treated with levodopa (L-DOPA). At the same time dopamine D₂/D₃ receptors displayed significantly decreased density levels in case of PD putamen (control: 47.97 ± 10.00 fmol/g, PD: 3.73 ± 0.07 fmol/g (mean ± SEM), p<0.05) and nucleus caudatus (control: 30.26 ± 2.48 fmol/g, PD: 12.84 ± 5.49 fmol/g, p<0.0005) samples. In contrast to the putamen and the nucleus caudatus, in the medial frontal gyrus neither receptor densities were affected. Our data suggest the presence of an unaltered CB₁R population even in late stages of levodopa treated PD. This further supports the presence of an intact CB₁R population which, in line with the conclusion of earlier publications, may be utilized as a pharmacological target in the treatment of PD. Furthermore we found discrepancy between a maintained CB₁R population and a decreased dopamine D₂/D₃ receptor population in PD striatum. The precise explanation of this conundrum requires further studies with simultaneous examination of the central cannabinoid and dopaminergic systems in PD using higher sample size.

  2. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

    PubMed Central

    Peciña, Susana; Schulkin, Jay; Berridge, Kent C

    2006-01-01

    Background Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl) or amphetamine (20 μg/0.2 μl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Results Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 μg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent

  3. 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

  4. Violence as a source of pleasure or displeasure is associated with specific functional connectivity with the nucleus accumbens

    PubMed Central

    Porges, Eric C.; Decety, Jean

    2013-01-01

    The appraisal of violent stimuli is dependent on the social context and the perceiver's individual characteristics. To identify the specific neural circuits involved in the perception of violent videos, forty-nine male participants were scanned with functional MRI while watching video-clips depicting Mixed Martial Arts (MMA) and Capoeira as a baseline. Prior to scanning, a self-report measure of pleasure or displeasure when watching MMA was collected. Watching MMA was associated with activation of the anterior insula (AI), brainstem, ventral tegmental area (VTA), striatum, medial, and lateral prefrontal cortex, orbitofrontal cortex, somatosensory cortex, and supramarginal gyrus. While this pattern of brain activation was not related to participants' reported experience of pleasure or displeasure, pleasurable ratings of MMA predicted increased functional connectivity (FC) seeded in the nucleus accumbens (NAcc) (a structure known to be responsive to anticipating both positive and negative outcomes) with the subgenual anterior cingulate cortex (ACC) and anterior insular cortex (AIC) (regions involved in positive feelings and visceral somatic representations). Displeasure ratings of MMA were related to increased FC with regions of the prefrontal cortex and superior parietal lobule, structures implicated in cognitive control and executive attention. These data suggest that functional connectivity is an effective approach to investigate the relationship between subjective feelings of pleasure and pain of neural structures known to respond to both the anticipation of positive and negative outcomes. PMID:23964226

  5. Violence as a source of pleasure or displeasure is associated with specific functional connectivity with the nucleus accumbens.

    PubMed

    Porges, Eric C; Decety, Jean

    2013-01-01

    The appraisal of violent stimuli is dependent on the social context and the perceiver's individual characteristics. To identify the specific neural circuits involved in the perception of violent videos, forty-nine male participants were scanned with functional MRI while watching video-clips depicting Mixed Martial Arts (MMA) and Capoeira as a baseline. Prior to scanning, a self-report measure of pleasure or displeasure when watching MMA was collected. Watching MMA was associated with activation of the anterior insula (AI), brainstem, ventral tegmental area (VTA), striatum, medial, and lateral prefrontal cortex, orbitofrontal cortex, somatosensory cortex, and supramarginal gyrus. While this pattern of brain activation was not related to participants' reported experience of pleasure or displeasure, pleasurable ratings of MMA predicted increased functional connectivity (FC) seeded in the nucleus accumbens (NAcc) (a structure known to be responsive to anticipating both positive and negative outcomes) with the subgenual anterior cingulate cortex (ACC) and anterior insular cortex (AIC) (regions involved in positive feelings and visceral somatic representations). Displeasure ratings of MMA were related to increased FC with regions of the prefrontal cortex and superior parietal lobule, structures implicated in cognitive control and executive attention. These data suggest that functional connectivity is an effective approach to investigate the relationship between subjective feelings of pleasure and pain of neural structures known to respond to both the anticipation of positive and negative outcomes. PMID:23964226

  6. Long-lasting deficits in hedonic and nucleus accumbens reactivity to sweet rewards by sugar overconsumption during adolescence.

    PubMed

    Naneix, Fabien; Darlot, Florence; Coutureau, Etienne; Cador, Martine

    2016-03-01

    Adolescence is a critical period characterized by major neurobiological changes. Chronic stimulation of the reward system might constitute an important factor in vulnerability to pathological development. In spite of the dramatic increase in the consumption of sweet palatable foods during adolescence in our modern societies, the long-term consequences of such exposure on brain reward processing remain poorly understood. Here, we investigated in rats the long-lasting effects of sugar overconsumption during their adolescence on their adult reactivity to the hedonic properties of sweet rewards. Adolescent rats with continuous access to 5% sucrose solution (from postnatal day 30-46) showed escalating intake. At adulthood (post-natal day 70), using two-bottle free choice tests, sucrose-exposed rats showed lower intake than non-exposed rats suggesting decreased sensitivity to the rewarding properties of sucrose. In Experiment 1, we tested their hedonic-related orofacial reactions to intraoral infusion of tasty solutions. We showed that sucrose-exposed rats presented less hedonic reactions in response to sweet tastes leaving the reactivity to water or quinine unaltered. Hence, in Experiment 2, we observed that this hedonic deficit is associated with lower c-Fos expression levels in the nucleus accumbens, a brain region known to play a central role in hedonic processing. These findings demonstrate that a history of high sucrose intake during the critical period of adolescence induces long-lasting deficits in hedonic treatment that may contribute to reward-related disorders.

  7. Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness "liking" and "wanting".

    PubMed

    Castro, Daniel C; Berridge, Kent C

    2014-03-19

    A specialized cubic-millimeter hotspot in the rostrodorsal quadrant of medial shell in nucleus accumbens (NAc) of rats may mediate opioid enhancement of gustatory hedonic impact or "liking". Here, we selectively stimulated the three major subtypes of opioid receptors via agonist microinjections [mu (DAMGO), delta (DPDPE), or kappa (U50488H)] and constructed anatomical maps for functional localizations of consequent changes in hedonic "liking" (assessed by affective orofacial reactions to sucrose taste) versus "wanting" (assessed by changes in food intake). Results indicated that the NAc rostrodorsal quadrant contains a shared opioid hedonic hotspot that similarly mediates enhancements of sucrose "liking" for mu, delta, and kappa stimulations. Within the rostrodorsal hotspot boundaries each type of stimulation generated at least a doubling or higher enhancement of hedonic reactions, with comparable intensities for all three types of opioid stimulation. By contrast, a negative hedonic coldspot was mapped in the caudal half of medial shell, where all three types of opioid stimulation suppressed "liking" reactions to approximately one-half normal levels. Different anatomical patterns were produced for stimulation of food "wanting", reflected in food intake. Altogether, these results indicate that the rostrodorsal hotspot in medial shell is unique for generating opioid-induced hedonic enhancement, and add delta and kappa signals to mu as hedonic generators within the hotspot. Also, the identification of a separable NAc caudal coldspot for hedonic suppression, and separate NAc opioid mechanisms for controlling food "liking" versus "wanting" further highlights NAc anatomical heterogeneity and localizations of function within subregions of medial shell.

  8. Neuronal calcium sensor-1 deletion in the mouse decreases motivation and dopamine release in the nucleus accumbens.

    PubMed

    Ng, Enoch; Varaschin, Rafael K; Su, Ping; Browne, Caleb J; Hermainski, Joanna; Le Foll, Bernard; Pongs, Olaf; Liu, Fang; Trudeau, Louis-Eric; Roder, John C; Wong, Albert H C

    2016-03-15

    Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior.

  9. Certain or uncertain cocaine expectations influence accumbens dopamine responses to self-administered cocaine and non-rewarded operant behavior.

    PubMed

    D'Souza, Manoranjan S; Duvauchelle, Christine L

    2008-09-01

    Uncertainty and errors in predicting natural rewards influence associative learning and dopamine activity. The present study was conducted to determine the influence of cue-induced cocaine uncertainty, certainty and prediction error on nucleus accumbens dopamine (NAcc DA) in rats. For Certainty training, distinctive sensory cues were present during cocaine availability and alternate cues were paired with non-reinforced (saline) operant sessions. For Uncertainty training, all cues were equally associated with both cocaine and non-reinforcement. After training, animals self-administered cocaine or saline in the presence of conditioned cues while NAcc DA responses were assessed using in vivo microdialysis. Findings revealed cocaine-stimulated NAcc DA increased significantly less in Certainty--compared to Uncertainty-trained animals, and cocaine-paired cues in the absence of cocaine (Negative Prediction Error) resulted in a significant depression of baseline NAcc DA. These findings provide support for enhanced DA activity during cocaine uncertainty or the development of conditioned cocaine tolerance in subjects certain of a cocaine outcome.

  10. TrkB in the hippocampus and nucleus accumbens differentially modulates depression-like behavior in mice.

    PubMed

    De Vry, Jochen; Vanmierlo, Tim; Martínez-Martínez, Pilar; Losen, Mario; Temel, Yasin; Boere, Janneke; Kenis, Gunter; Steckler, Thomas; Steinbusch, Harry W M; De Baets, Marc; Prickaerts, Jos

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) exerts antidepressant-like effects in the hippocampus and pro-depressant effects in the nucleus accumbens (NAc). It is thought that downstream signaling of the BDNF receptor TrkB mediates the effects of BDNF in these brain structures. Here, we evaluate how TrkB regulates affective behavior in the hippocampus and NAc. We overexpressed TrkB by electroporating a non-viral plasmid in the NAc or hippocampus in mice. Depression- and anxiety-like behaviors were evaluated in the sucrose test (anhedonia), the forced swim test (despair) and the elevated zero maze (anxiety). Targeted brain tissue was biochemically analyzed to identify molecular mechanisms responsible for the observed behavior. Overexpressing TrkB in the NAc increased the number of young neuronal cells and decreased despair and basal corticosterone levels. TrkB overexpression in the hippocampus increased astrocyte production and activation of the transcription factor CREB, yet without altering affective behavior. Our data suggest antidepressant effects of BDNF-TrkB in the NAc, which could not be explained by activation of the transcription factors CREB or β-catenin. The effects TrkB has on depression-related behavior in different brain regions appear to critically depend on the targeted cell type.

  11. 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.

  12. Cocaine-Induced Plasticity in the Nucleus Accumbens is Cell-Specific and Develops Without Prolonged Withdrawal

    PubMed Central

    Dobi, Alice; Seabold, Gail K.; Christensen, Christine H.; Bock, Roland; Alvarez, Veronica A.

    2011-01-01

    Cocaine induces plasticity at glutamatergic synapses in the nucleus accumbens (NAc). Withdrawal was suggested to play an important role in the development of this plasticity by studies showing that some changes only appear several weeks after the final cocaine exposure. In this study, the requirement for prolonged withdrawal was evaluated by comparing the changes in glutamatergic transmission induced by two different non-contingent cocaine treatments: a short treatment followed by prolonged withdrawal, and a longer treatment without prolonged withdrawal. Recordings were performed from mouse medium spiny neurons (MSNs) in the NAc at the same time after the first cocaine injection under both treatments. A similar increase in the frequency of glutamate-mediated miniature excitatory postsynaptic currents (mEPSCs) was observed in D1-expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPAR to NMDAR ratios, higher spine density and enlarged spine heads were observed in the absence of withdrawal following a long cocaine treatment. These synaptic adaptations expressed in D1-containing MSNs of the NAc core were not further enhanced by protracted withdrawal. In conclusion, a few repeated cocaine injections are enough to trigger adaptations at glutamatergic synapses in D1-expressing MSNs, which although they take time to develop, do not require prolonged cocaine withdrawal. PMID:21289199

  13. Cocaine-Induced Behavioral Sensitization in Mice: Effects of Microinjection of Dopamine D2 Receptor Antagonist into the Nucleus Accumbens

    PubMed Central

    Jung, Eun-Sol; Lee, Hyo Jin; Sim, Hye-Ri

    2013-01-01

    To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R-/- mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R-/-) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R-/- mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization. PMID:24167417

  14. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

    PubMed

    Sakae, D Y; Marti, F; Lecca, S; Vorspan, F; Martín-García, E; Morel, L J; Henrion, A; Gutiérrez-Cuesta, J; Besnard, A; Heck, N; Herzog, E; Bolte, S; Prado, V F; Prado, M A M; Bellivier, F; Eap, C B; Crettol, S; Vanhoutte, P; Caboche, J; Gratton, A; Moquin, L; Giros, B; Maldonado, R; Daumas, S; Mameli, M; Jamain, S; El Mestikawy, S

    2015-11-01

    Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse. PMID:26239290

  15. Glycogen synthase kinase 3β in the nucleus accumbens core is critical for methamphetamine-induced behavioral sensitization.

    PubMed

    Xu, Chun-Mei; Wang, Jun; Wu, Ping; Xue, Yan-Xue; Zhu, Wei-Li; Li, Qian-Qian; Zhai, Hai-Feng; Shi, Jie; Lu, Lin

    2011-07-01

    As a ubiquitous serine/threonine protein kinase, glycogen synthase kinase 3β (GSK-3β) has been considered to be important in the synaptic plasticity that underlies dopamine-related behaviors and diseases. We recently found that GSK-3β activity in the nucleus accumbens (NAc) core is critically involved in cocaine-induced behavioral sensitization. The present study further explored the association between the changes in GSK-3β activity in the NAc and the chronic administration of methamphetamine. We also examined whether blocking GSK-3β activity in the NAc could alter the initiation and expression of methamphetamine (1 mg/kg, i.p.)-induced locomotor sensitization in rats using systemic administration of lithium chloride (LiCl, 100 mg/kg, i.p) and brain region-specific administration of the GSK-3β inhibitor SB216763 (1 ng/side). We found that GSK-3β activity increased in the NAc core, but not NAc shell, after chronic methamphetamine administration. The initiation and expression of methamphetamine-induced locomotor sensitization was attenuated by systemic administration of LiCl and direct infusion of SB216763 into the NAc core, but not NAc shell. These results indicate that GSK-3β activity in the NAc core mediates the initiation and expression of methamphetamine-induced locomotor sensitization, suggesting that GSK-3β may be a potential target for the treatment of psychostimulant addiction.

  16. Sex differences in interactions between nucleus accumbens and visual cortex by explicit visual erotic stimuli: an fMRI study.

    PubMed

    Lee, S W; Jeong, B S; Choi, J; Kim, J-W

    2015-01-01

    Men tend to have greater positive responses than women to explicit visual erotic stimuli (EVES). However, it remains unclear, which brain network makes men more sensitive to EVES and which factors contribute to the brain network activity. In this study, we aimed to assess the effect of sex difference on brain connectivity patterns by EVES. We also investigated the association of testosterone with brain connection that showed the effects of sex difference. During functional magnetic resonance imaging scans, 14 males and 14 females were asked to see alternating blocks of pictures that were either erotic or non-erotic. Psychophysiological interaction analysis was performed to investigate the functional connectivity of the nucleus accumbens (NA) as it related to EVES. Men showed significantly greater EVES-specific functional connection between the right NA and the right lateral occipital cortex (LOC). In addition, the right NA and the right LOC network activity was positively correlated with the plasma testosterone level in men. Our results suggest that the reason men are sensitive to EVES is the increased interaction in the visual reward networks, which is modulated by their plasma testosterone level. PMID:25971857

  17. The nucleus accumbens is involved in both the pursuit of social reward and the avoidance of social punishment

    PubMed Central

    Kohls, Gregor; Perino, Michael T.; Taylor, James M.; Madva, Elizabeth N.; Cayless, Sarah J.; Troiani, Vanessa; Price, Elinora; Faja, Susan; Herrington, John D.; Schultz, Robert T.

    2013-01-01

    Human social motivation is characterized by the pursuit of social reward and the avoidance of social punishment. The ventral striatum/nucleus accumbens (VS/Nacc), in particular, has been implicated in the reward component of social motivation, i.e., the ‘wanting’ of social incentives like approval. However, it is unclear to what extent the VS/Nacc is involved in avoiding social punishment like disapproval, an intrinsically pleasant outcome. Thus, we conducted an event-related functional magnetic resonance imaging (fMRI) study using a social incentive delay task with dynamic video stimuli instead of static pictures as social incentives in order to examine participants' motivation for social reward gain and social punishment avoidance. As predicted, the anticipation of avoidable social punishment (i.e., disapproval) recruited the VS/Nacc in a manner that was similar to VS/Nacc activation observed during the anticipation of social reward gain (i.e., approval). Stronger VS/Nacc activity was accompanied by faster reaction times of the participants to obtain those desired outcomes. This data support the assumption that dynamic social incentives elicit robust VS/Nacc activity, which likely reflects motivation to obtain social reward and to avoid social punishment. Clinical implications regarding the involvement of the VS/Nacc in social motivation dysfunction in autism and social phobia are discussed. PMID:23911778

  18. Role of melanin-concentrating hormone in the nucleus accumbens shell in rats behaviourally sensitized to methamphetamine.

    PubMed

    Sun, Li-Li; Zhang, Yan; Liu, Jian-feng; Wang, Jun; Zhu, Wei-li; Zhao, Li-yan; Xue, Yan-xue; Lu, Lin; Shi, Jie

    2013-09-01

    Melanin-concentrating hormone (MCH) is a neuropeptide and its receptor is extensively expressed throughout the brain. MCH has been suggested to regulate the rewarding and reinforcing effects of psychostimulants by potentiating the dopaminergic system within the midbrain. Moreover, MCH and its receptor can regulate ERK activity. The present study investigated the role of MCH in the nucleus accumbens (NAc) in rats behaviourally sensitized to methamphetamine (Meth). We found that the development of Meth-induced locomotor sensitization was attenuated by MCH infused into the NAc shell but not core. Moreover, the elevation of ERK phosphorylation in the NAc shell induced by Meth was inhibited by locally infused MCH. Infusion of the MCH receptor 1 (MCHR1) antagonist SNAP 94847 into the NAc shell but not core augmented the initiation of locomotor sensitization and amplitude of elevated phosphorylated ERK levels induced by Meth. The expression of Meth-induced locomotor sensitization and ERK alterations after 1 wk withdrawal were not affected by either MCH or SNAP 94847 infused into the NAc shell or core. These results indicate that MCH in the NAc shell plays a critical role in the development but not expression of Meth-induced locomotor sensitization in rats, which might be mediated by the ERK signalling pathway. Our study suggests that MCH might be a potential target for the treatment of Meth addiction.

  19. 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

  20. 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

  1. α-1 Adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission.

    PubMed

    Mitrano, Darlene A; Schroeder, Jason P; Smith, Yoland; Cortright, James J; Bubula, Nancy; Vezina, Paul; Weinshenker, David

    2012-08-01

    Brainstem noradrenergic neurons innervate the mesocorticolimbic reward pathway both directly and indirectly, with norepinephrine facilitating dopamine (DA) neurotransmission via α1-adrenergic receptors (α1ARs). Although α1AR signaling in the prefrontal cortex (PFC) promotes mesolimbic transmission and drug-induced behaviors, the potential contribution of α1ARs in other parts of the pathway, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc), has not been investigated before. We found that local blockade of α1ARs in the medial NAc shell, but not the VTA, attenuates cocaine- and morphine-induced locomotion. To determine the neuronal substrates that could mediate these effects, we analyzed the cellular, subcellular, and subsynaptic localization of α1ARs and characterized the chemical phenotypes of α1AR-containing elements within the mesocorticolimbic system using single and double immunocytochemical methods at the electron microscopic (EM) level. We found that α1ARs are found mainly extra-synaptically in axons and axon terminals in the NAc and are enriched in glutamatergic and dopaminergic elements. α1ARs are also abundant in glutamatergic terminals in the PFC, and in GABA-positive terminals in the VTA. In line with these observations, microdialysis experiments revealed that local blockade of α1ARs attenuated the increase in extracellular DA in the medial NAc shell following administration of cocaine. These data indicate that local α1ARs control DA transmission in the medial NAc shell and behavioral responses to drugs of abuse.

  2. 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

  3. Involvement of the nucleus accumbens shell glutamatergic system in ACPA-induced impairment of inhibitory avoidance memory consolidation.

    PubMed

    Rasekhi, Khalil; Oryan, Shahrbanoo; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

    2014-08-01

    Interactions between cannabinoid and glutamate systems have been demonstrated in some brain areas associated with mnemonic functions. This study investigates the effects of bilateral post-training intra-nucleus accumbens (NAc) shell administrations of glutamate NMDA receptor agents on memory impairment induced by cannabinoid CB1 receptor activation during a step-through inhibitory avoidance (IA) task. Our results showed post-training administration of ACPA (CB1 receptor agonist; 3 ng/side) impairs IA memory consolidation, whereas AM251 (CB1 receptor antagonist; 0.3, 3 and 30 ng/side), NMDA (0.3, 3 and 30 ng/side), and d-AP7 (NMDA receptor antagonist; 3, 30 and 300 ng/side) were ineffective. However, co-administration of AM251 (30 ng/side) or NMDA (30 ng/side) with ACPA (3 ng/side) prevented the memory-impairing effect of ACPA. Meanwhile, co-administration of NMDA (30 ng/side) and a subthreshold dose of ACPA (0.15 ng/side) decreased memory consolidation. Moreover, post-training microinjection of AM251 (30 ng/side) or d-AP7 (300 ng/side) prevented memory impairment induced by co-administration of subthreshold doses of NMDA and ACPA. The data indicated that NMDA receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the NAc shell.

  4. Positive Reinforcement Mediated by Midbrain Dopamine Neurons Requires D1 and D2 Receptor Activation in the Nucleus Accumbens

    PubMed Central

    Steinberg, Elizabeth E.; Boivin, Josiah R.; Saunders, Benjamin T.; Witten, Ilana B.; Deisseroth, Karl; Janak, Patricia H.

    2014-01-01

    The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement. PMID:24733061

  5. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

    PubMed

    Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2014-01-01

    The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  6. 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

  7. No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

    PubMed

    Stenner, Max-Philipp; Rutledge, Robb B; Zaehle, Tino; Schmitt, Friedhelm C; Kopitzki, Klaus; Kowski, Alexander B; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J

    2015-08-01

    Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. PMID:26019312

  8. Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons.

    PubMed

    Jedynak, Jakub; Hearing, Matthew; Ingebretson, Anna; Ebner, Stephanie R; Kelly, Matthew; Fischer, Rachel A; Kourrich, Saïd; Thomas, Mark J

    2016-01-01

    Repeated exposure to psychostimulant drugs such as cocaine or amphetamine can promote drug-seeking and -taking behavior. In rodent addiction models, persistent changes in excitatory glutamatergic neurotransmission in the nucleus accumbens (NAc) appear to drive this drug-induced behavioral plasticity. To study whether changes in glutamatergic signaling are shared between or exclusive to specific psychostimulant drugs, we examined synaptic transmission from mice following repeated amphetamine or cocaine administration. Synaptic transmission mediated by AMPA-type glutamate receptors was potentiated in the NAc shell 10-14 days following repeated amphetamine or cocaine treatment. This synaptic enhancement was depotentiated by re-exposure to amphetamine or cocaine. By contrast, in the NAc core only repeated cocaine exposure enhanced synaptic transmission, which was subsequently depotentiated by an additional cocaine but not amphetamine injection during drug abstinence. To better understand the drug-induced depotentiation, we replicated these in vivo findings using an ex vivo model termed 'challenge in the bath,' and showed that drug-induced decreases in synaptic strength occur rapidly (within 30 min) and require activation of metabotropic glutamate receptor 5 (mGluR5) and protein synthesis in the NAc shell, but not NAc core. Overall, these data demonstrate the specificity of neuronal circuit changes induced by amphetamine, introduce a novel method for studying drug challenge-induced plasticity, and define NAc shell medium spiny neurons as a primary site of persistent AMPA-type glutamate receptor plasticity by two widely used psychostimulant drugs.

  9. Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats.

    PubMed

    Spiga, Saturnino; Talani, Giuseppe; Mulas, Giovanna; Licheri, Valentina; Fois, Giulia R; Muggironi, Giulia; Masala, Nicola; Cannizzaro, Carla; Biggio, Giovanni; Sanna, Enrico; Diana, Marco

    2014-09-01

    Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that "long thin" but not "mushroom" spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence, suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal and thus the whole addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence.

  10. Genetic reconstruction of dopamine D1 receptor signaling in the nucleus accumbens facilitates natural and drug reward responses.

    PubMed

    Gore, Bryan B; Zweifel, Larry S

    2013-05-15

    The dopamine D1 receptor (D1R) facilitates reward acquisition and its alteration leads to profound learning deficits. However, its minimal functional circuit requirement is unknown. Using conditional reconstruction of functional D1R signaling in D1R knock-out mice, we define distinct requirements of D1R in subregions of the nucleus accumbens (NAc) for specific dimensions of reward. We demonstrate that D1R expression in the core region of the NAc (NAc(Core)), but not the shell (NAc(Shell)), enhances selectively a unique form of pavlovian conditioned approach and mediates D1R-dependent cocaine sensitization. However, D1R expression in either the NAc(Core) or the NAc(Shell) improves instrumental responding for reward. In contrast, neither NAc(Core) nor NAc(Shell) D1R is sufficient to promote motivation to work for reward in a progressive ratio task or for motor learning. These results highlight dissociated circuit requirements of D1R for dopamine-dependent behaviors. PMID:23678109

  11. No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

    PubMed

    Stenner, Max-Philipp; Rutledge, Robb B; Zaehle, Tino; Schmitt, Friedhelm C; Kopitzki, Klaus; Kowski, Alexander B; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J

    2015-08-01

    Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods.

  12. An examination of nucleus accumbens cell firing during extinction and reinstatement of water reinforcement behavior in rats.

    PubMed

    Hollander, Jonathan A; Ijames, Stephanie G; Roop, Richard G; Carelli, Regina M

    2002-03-01

    Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats (n = 13) during water reinforcement sessions consisting of three phases. During phase one (maintenance), a lever press resulted in water reinforcement (fixed ratio 1; 0.05 ml/press) paired with an auditory stimulus (0.5 s). Of 128 Acb neurons recorded during maintenance, 40 cells (31%) exhibited one of three types of neuronal firing patterns described previously [J. Neurosci. 14 (12) (1994) 7735-7746; J. Neurosci. 20 (11) (2000) 4255-4266]. Briefly, Acb neurons exhibited increases in firing rate within seconds preceding the reinforced response (type PR) or increases (type RFe) or decreases (type RFi) in activity seconds following response completion. In phase two (extinction), subsequent lever pressing had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, animals were given water reinforcement/auditory stimulus 'primes' to reestablish lever pressing behavior during the third phase (reinstatement). Results indicated that all types of phasic neurons (PR, RFe and RFi) exhibited an attenuated firing rate during extinction, and in some cases recovery of patterned discharges were observed during reinstatement. No significant changes in cell firing were observed for any cell type during presentation of the stimulus prime used to reestablish operant responding following extinction. These findings are discussed in terms of how Acb neurons process information related to 'natural' reinforcers versus drugs of abuse.

  13. No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients

    PubMed Central

    Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Kopitzki, Klaus; Kowski, Alexander B.; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.

    2015-01-01

    Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. PMID:26019312

  14. The medial prefrontal cortex and nucleus accumbens mediate the motivation for voluntary wheel running in the rat.

    PubMed

    Basso, Julia C; Morrell, Joan I

    2015-08-01

    Voluntary wheel running in rats provides a preclinical model of exercise motivation in humans. We hypothesized that rats run because this activity has positive incentive salience in both the acquisition and habitual stages of wheel running and that gender differences might be present. Additionally, we sought to determine which forebrain regions are essential for the motivational processes underlying wheel running in rats. The motivation for voluntary wheel running in male and female Sprague-Dawley rats was investigated during the acquisition (Days 1-7) and habitual phases (after Day 21) of running using conditioned place preference (CPP) and the reinstatement (rebound) response after forced abstinence, respectively. Both genders displayed a strong CPP for the acquisition phase and a strong rebound response to wheel deprivation during the habitual phase, suggesting that both phases of wheel running are rewarding for both sexes. Female rats showed a 1.5 times greater rebound response than males to wheel deprivation in the habitual phase of running, while during the acquisition phase, no gender differences in CPP were found. We transiently inactivated the medial prefrontal cortex (mPFC) or the nucleus accumbens (NA), hypothesizing that because these regions are involved in the acquisition and reinstatement of self-administration of both natural and pharmacological stimuli, they might also serve a role in the motivation to wheel run. Inactivation of either structure decreased the rebound response in the habitual phase of running, demonstrating that these structures are involved in the motivation for this behavior.

  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. Dopamine release and metabolism in the rat frontal cortex, nucleus accumbens, and striatum: a comparison of acute clozapine and haloperidol.

    PubMed Central

    Karoum, F.; Egan, M