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

2015 ◽  
Vol 112 (36) ◽  
pp. 11383-11388 ◽  
Author(s):  
Takashi Yamaguchi ◽  
Akihiro Goto ◽  
Ichiro Nakahara ◽  
Satoshi Yawata ◽  
Takatoshi Hikida ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Critical Role ◽  
D2 Receptor ◽  
Resonance Energy ◽  
Memory Formation ◽  
Memory Retention ◽  
Aversive Learning ◽  
Indirect Pathway ◽  
Specific Expression ◽  
Direct Pathway

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

scholarly journals Circuit-dependent striatal PKA and ERK signaling underlies rapid behavioral shift in mating reaction of male mice

2015 ◽  
Vol 112 (21) ◽  
pp. 6718-6723 ◽  
Author(s):  
Akihiro Goto ◽  
Ichiro Nakahara ◽  
Takashi Yamaguchi ◽  
Yuji Kamioka ◽  
Kenta Sumiyama ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Signaling Cascades ◽  
Male Mice ◽  
Indirect Pathway ◽  
Dynamic Activity ◽  
Reward Seeking ◽  
Electric Shocks

The selection of reward-seeking and aversive behaviors is controlled by two distinct D1 and D2 receptor-expressing striatal medium spiny neurons, namely the direct pathway MSNs (dMSNs) and the indirect pathway MSNs (iMSNs), but the dynamic modulation of signaling cascades of dMSNs and iMSNs in behaving animals remains largely elusive. We developed an in vivo methodology to monitor Förster resonance energy transfer (FRET) of the activities of PKA and ERK in either dMSNs or iMSNs by microendoscopy in freely moving mice. PKA and ERK were coordinately but oppositely regulated between dMSNs and iMSNs by rewarding cocaine administration and aversive electric shocks. Notably, the activities of PKA and ERK rapidly shifted when male mice became active or indifferent toward female mice during mating behavior. Importantly, manipulation of PKA cascades by the Designer Receptor recapitulated active and indifferent mating behaviors, indicating a causal linkage of a dynamic activity shift of PKA and ERK between dMSNs and iMSNs in action selection.

scholarly journals Dopamine receptors mediate strategy abandoning via modulation of a specific prelimbic cortex–nucleus accumbens pathway in mice

2018 ◽  
Vol 115 (21) ◽  
pp. E4890-E4899 ◽  
Author(s):  
Qiaoling Cui ◽  
Qian Li ◽  
Hongyan Geng ◽  
Lei Chen ◽  
Nancy Y. Ip ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Receptors ◽  
Cortical Neurons ◽  
Critical Role ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Prelimbic Cortex ◽  
Dopamine Depletion ◽  
Dopaminergic Tone ◽  
Type Receptor

The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex–nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex–NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.

scholarly journals A conditioned place preference for heroin is signaled by increased dopamine and direct pathway activity and decreased indirect pathway activity in the nucleus accumbens

2021 ◽  
Author(s):  
Timothy J O'Neal ◽  
Mollie X Bernstein ◽  
Derek J MacDougall ◽  
Susan M Ferguson
Keyword(s):  
Nucleus Accumbens ◽  
Conditioned Place Preference ◽  
Place Preference ◽  
Indirect Pathway ◽  
Pathway Activity ◽  
Principal Role ◽  
Direct Pathway ◽  
Dopamine Signaling

Initial drug use promotes the development of conditioned reinforcement, whereby the reinforcing properties of a drug become attributed to drug-associated stimuli, such as cues and contexts. A principal role for the nucleus accumbens (NAc) in the response to drug-associated stimuli has been well-documented. In particular, direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity towards the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement remains unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to address these outstanding questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and activation of the NAc post-conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of addiction.

Dopaminylation in Psychostimulant use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression

2021 ◽  
Vol 09 ◽  
Author(s):  
Kenneth Blum ◽  
Mark S Gold ◽  
Jean L. Cadet ◽  
David Baron ◽  
Abdalla Bowirrat ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Histone H3 ◽  
D2 Receptor ◽  
Reward Processing ◽  
Allelic Polymorphism ◽  
Cocaine Withdrawal ◽  
Src Signaling ◽  
Chronic Cocaine ◽  
Cocaine Seeking ◽  
Seeking Behavior

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler’s group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during investigator and selfadministration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. Hypothesis: Hypothesizing that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, results in histone H3 glutamine 5 dopaminylation (H3Q5dop), and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase sig-naling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a “homeostatic brake.” Conclusion: The decrease in Src signaling in NAc D2-MSNs, like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD normalized nucleus accumbens (NAc) dopamine expression and decreased cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

scholarly journals Genome-wide identification of cyclin-dependent kinase (CDK) genes affecting adipocyte differentiation in cattle

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cuili Pan ◽  
Zhaoxiong Lei ◽  
Shuzhe Wang ◽  
Xingping Wang ◽  
Dawei Wei ◽  
...  
Keyword(s):  
Gene Family ◽  
Expression Analysis ◽  
Adipocyte Differentiation ◽  
Bos Taurus ◽  
Adipogenic Differentiation ◽  
Critical Role ◽  
Bos Indicus ◽  
Specific Expression ◽  
Genome Wide ◽  
A Genome

Abstract Background Cyclin-dependent kinases (CDKs) are protein kinases regulating important cellular processes such as cell cycle and transcription. Many CDK genes also play a critical role during adipogenic differentiation, but the role of CDK gene family in regulating bovine adipocyte differentiation has not been studied. Therefore, the present study aims to characterize the CDK gene family in bovine and study their expression pattern during adipocyte differentiation. Results We performed a genome-wide analysis and identified a number of CDK genes in several bovine species. The CDK genes were classified into 8 subfamilies through phylogenetic analysis. We found that 25 bovine CDK genes were distributed in 16 different chromosomes. Collinearity analysis revealed that the CDK gene family in Bos taurus is homologous with Bos indicus, Hybrid-Bos taurus, Hybrid Bos indicus, Bos grunniens and Bubalus bubalis. Several CDK genes had higher expression levels in preadipocytes than in differentiated adipocytes, as shown by RNA-seq analysis and qPCR, suggesting a role in the growth of emerging lipid droplets. Conclusion In this research, 185 CDK genes were identified and grouped into eight distinct clades in Bovidae, showing extensively homology. Global expression analysis of different bovine tissues and specific expression analysis during adipocytes differentiation revealed CDK4, CDK7, CDK8, CDK9 and CDK14 may be involved in bovine adipocyte differentiation. The results provide a basis for further study to determine the roles of CDK gene family in regulating adipocyte differentiation, which is beneficial for beef quality improvement.

scholarly journals The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

2021 ◽  
Author(s):  
Zhanglei Dong ◽  
Bingwu Huang ◽  
Chenchen Jiang ◽  
Jiangfan Chen ◽  
Han Lin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D2 Receptor ◽  
Fixed Ratio ◽  
Receptor Activation ◽  
Addictive Behaviors ◽  
Self Administration ◽  
A2a Receptors ◽  
Mediated Effects ◽  
Seeking Behavior ◽  
Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

scholarly journals Effect of Zishenpingchan Granule on Neurobehavioral Manifestations and the Activity and Gene Expression of Striatal Dopamine D1 and D2 Receptors of Rats with Levodopa-Induced Dyskinesias

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Qing Ye ◽  
Xiao-Lei Yuan ◽  
Jie Zhou ◽  
Can-xing Yuan ◽  
Xu-ming Yang
Keyword(s):  
Gene Expression ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
D2 Receptors ◽  
Striatal Dopamine ◽  
Control Group ◽  
Indirect Pathway ◽  
Dopamine D2 ◽  
D1 And D2 Receptors ◽  
Neurobehavioral Manifestations

This study was performed to observe the effects of Zishenpingchan granule on neurobehavioral manifestations and the activity and gene expression of striatal dopamine D1 and D2 receptors of rats with levodopa-induced dyskinesias (LID). We established normal control group, LID model group, and TCM intervention group. Each group received treatment for 4 weeks. Artificial neural network (ANN) was applied to excavate the main factor influencing variation in neurobehavioral manifestations of rats with LID. The results showed that overactivation in direct pathway mediated by dopamine D1 receptor and overinhibition in indirect pathway mediated by dopamine D2 receptor may be the main mechanism of LID. TCM increased the efficacy time of LD to ameliorate LID symptoms effectively mainly by upregulating dopamine D2 receptor gene expression.

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

2021 ◽  
Vol 118 (40) ◽  
pp. e2111069118
Author(s):  
Theodoros Tsetsenis ◽  
Julia K. Badyna ◽  
Julianne A. Wilson ◽  
Xiaowen Zhang ◽  
Elizabeth N. Krizman ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Hippocampus ◽  
Memory Formation ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Aversive Learning ◽  
Contextual Fear ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

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