scholarly journals Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence

2020 ◽  
Vol 117 (42) ◽  
pp. 26460-26469 ◽  
Author(s):  
Craig T. Werner ◽  
Swarup Mitra ◽  
Benjamin D. Auerbach ◽  
Zi-Jun Wang ◽  
Jennifer A. Martin ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Dorsal Hippocampus ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Activin A ◽  
Lateral Septum ◽  
Self Administration ◽  
Cocaine Seeking ◽  
Prolonged Abstinence

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or “incubates”) during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-β (TGF-β) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

scholarly journals mGlu5 Receptors and Relapse to Cocaine-Seeking: The Role of Receptor Trafficking in Postrelapse Extinction Learning Deficits

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lori A. Knackstedt ◽  
Marek Schwendt
Keyword(s):  
Relapse Prevention ◽  
Operant Chamber ◽  
Treatment Strategies ◽  
Surface Expression ◽  
Self Administration ◽  
Extinction Learning ◽  
Learning Deficits ◽  
Cocaine Seeking ◽  
Mglu5 Receptors

We have previously demonstrated that MTEP, an allosteric antagonist of mGlu5, infused into the nucleus accumbens attenuates relapse after abstinence from cocaine self-administration. MTEP infused into the dorsolateral striatum (dlSTR) does not alter relapse but has long-lasting effects on subsequent extinction learning. Here we tested whether systemic MTEP would prevent relapse after abstinence or alter extinction learning. We also investigated the mechanism of action by which intra-dlSTR MTEP on test day alters extinction on subsequent days. Animals self-administered cocaine for 12 days followed by abstinence for 20-21 days. MTEP (0.5–5 mg/kg IP) was administered prior to placement into the operant chamber for a context-primed relapse test. A separate group of animals received intra-dlSTR MTEP prior to the relapse test and were sacrificed day later. Systemic administration of MTEP attenuated abstinent-relapse without significantly affecting extinction learning. Surface biotinylation analysis of protein expression in the dlSTR revealed that, in cocaine animals, intra-dlSTR MTEP administration decreased mGlu5 surface expression and prevented changes in Arc and GluA1/GluA2 observed in their vehicle counterparts. Thus, blockade of mGlu5 receptors may be utilized in future treatment strategies for relapse prevention in humans, although the effects of chronic blockade on extinction learning should be further evaluated.

scholarly journals Activin A regulates activation of mouse neutrophils by Smad3 signalling

Open Biology ◽  
2017 ◽  
Vol 7 (5) ◽  
pp. 160342 ◽  
Author(s):  
Yan Qi ◽  
Jingyan Ge ◽  
Chunhui Ma ◽  
Na Wu ◽  
Xueling Cui ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Activin A ◽  
Target Cells ◽  
Inflammatory Factor ◽  
Important Regulator ◽  
Growth Factor Beta ◽  
Species Production

Activin A, a member of the transforming growth factor beta superfamily, acts as a pro-inflammatory factor in acute phase response, and influences the pathological progress of neutrophil-mediated disease. However, whether activin A can exert an effect on the activities of neutrophils remains unclear. In this study, we found that the release of activin A was enhanced from neutrophils of mouse when stimulated with lipopolysaccharide. Furthermore, neutrophils were not only the source of activin A but also the target cells in response to activin A, in which canonical activin signalling components existed, and levels of ACTRIIA, SMAD3 and p-SMAD3 proteins were elevated in activin A-treated neutrophils. Next, the role of activin A was determined in regulation of neutrophils activities. Our data revealed that activin A induced O 2 − release and reactive oxygen species production, promoted IL-6 release, and enhanced phagocytosis, but failed to attract neutrophils migrating across the trans-well membrane. Moreover, we found that effect of activin A on IL-6 release from the peritoneal neutrophils of mouse was significantly attenuated by in vivo Smad3 knockdown. In summary, these data demonstrate that activin A can exert an effect on neutrophils activation in an autocrine/paracrine manner through Smad3 signalling, suggesting that activin A is an important regulator of neutrophils.

scholarly journals Hippocampal efferents to retrosplenial cortex and lateral septum are required for memory acquisition

2020 ◽  
Author(s):  
Ashley N Opalka ◽  
Dong V Wang
Keyword(s):  
Dorsal Hippocampus ◽  
Memory Performance ◽  
Critical Role ◽  
Selective Inhibition ◽  
Brain Regions ◽  
Retrosplenial Cortex ◽  
Contextual Fear Conditioning ◽  
Lateral Septum ◽  
Contextual Fear ◽  
Memory Acquisition

AbstractLearning and memory involves a large neural network of many brain regions, including the notable hippocampus along with the retrosplenial cortex (RSC) and lateral septum (LS). Previous studies have established that the dorsal hippocampus (dHPC) plays a critical role during the acquisition and expression of episodic memories. However, the role of downstream circuitry from the dHPC, including the dHPC-to-RSC and dHPC-to-LS pathways, has come under scrutiny only recently. Here, we employed an optogenetic approach with contextual fear conditioning in mice to determine whether the above two pathways are involved in acquisition and expression of contextual fear memory. We found that a selective inhibition of the dHPC neuronal terminals in either the RSC or LS during acquisition impaired subsequent memory performance, suggesting that both the dHPC-to-RSC and dHPC-to-LS pathways play a critical role in memory acquisition. We also selectively inhibited the two dHPC efferent pathways during memory expression and found a differential effect on memory performance. These results indicate the intricacies of memory processing and that hippocampal efferents to cortical and subcortical regions may be differentially involved in aspects of physiological and cognitive memory processes.

Evidence for the Role of Endogenous Carbon Monoxide in Memory Processing

2007 ◽  
Vol 19 (4) ◽  
pp. 557-562 ◽  
Author(s):  
M. C. Cutajar ◽  
T. M. Edwards
Keyword(s):  
Carbon Monoxide ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Memory Research ◽  
Memory Processing ◽  
Important Target ◽  
Term Potentiation ◽  
Per Se

For a decade and a half, nitric oxide (NO) has been implicated in memory processing across a wide variety of tasks and species. Comparatively, endogenously produced carbon monoxide (CO) has lagged behind as a target for research into the pharmacological processes underlying memory formation. This is surprising given that CO is formed in memory-associated brain regions, is structurally similar to NO, and along with NO can activate guanylate cyclase, which is an enzyme well characterized in memory processing. Nevertheless, a limited number of electrophysiological investigations have concluded that endogenous CO is involved in long-term potentiation. Although not evidence for a role in memory per se, these studies did point to the possible importance of CO in memory processing. In addition, there is now evidence to suggest that endogenous CO is important in avoidance learning and possible for other tasks. This review therefore seeks to promote endogenous CO as a potentially important target for memory research.

scholarly journals Context-induced relapse to drug seeking: a review

2008 ◽  
Vol 363 (1507) ◽  
pp. 3233-3243 ◽  
Author(s):  
Hans S Crombag ◽  
Jennifer M Bossert ◽  
Eisuke Koya ◽  
Yavin Shaham
Keyword(s):  
Basolateral Amygdala ◽  
Dorsal Hippocampus ◽  
Dorsal Striatum ◽  
Self Administration ◽  
Occasion Setting ◽  
Drug Seeking ◽  
Psychological Mechanisms ◽  
History Of ◽  
Study Context

In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies by Bouton & Bolles on context-induced ‘renewal’ of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin–cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking.

scholarly journals Oxytocin regulation of social transmission of fear in zebrafish reveals its evolutionary conserved role in emotional contagion

2021 ◽  
Author(s):  
Ibukun Akinrinade ◽  
Kyriacos Kareklas ◽  
Michael Gliksberg ◽  
Giovanni Petri ◽  
Gil Levkowitz ◽  
...  
Keyword(s):  
Emotional Contagion ◽  
Brain Regions ◽  
Lateral Septum ◽  
Social Transmission ◽  
Proximate Mechanisms ◽  
Action Mechanisms ◽  
Social Fear ◽  
Complex Forms ◽  
Oxytocinergic Neurons

Emotional contagion is the most ancestral form of empathy that relies on simple perception-action mechanisms, on top of which more complex forms of empathic behaviors, such as consolation and helping, have evolved. Here we tested to what extent the proximate mechanisms of emotional contagion are evolutionary conserved by assessing the role of oxytocin, known to regulate empathic behaviors in mammals, in social fear contagion in zebrafish, which represents an evolutionary divergent line to that of tetrapods, within vertebrates. Using mutants for the ligand of the fish oxytocin nonapeptide and both of its receptors in zebrafish we showed that oxytocin is necessary for observer zebrafish to copy the distressed behavior of conspecific demonstrators. Exogeneous administration of oxytocin to the ligand mutant rescued the ability of observers to express social fear transmission, indicating that oxytocin is not only necessary but also sufficient for emotional contagion. The brain regions in the ventral telencephalon that are associated with emotional contagion in zebrafish are homologous to those known to be involved in the same process in rodents (e.g. striatum, lateral septum), and receive direct projections from oxytocinergic neurons located in the preoptic area. Finally, we ruled out the hypothesis that social transmission of fear in zebrafish merely relies on behavior contagion by motor imitation, and we showed that it rather relies on emotion discrimination. Together our results support an evolutionary conserved role for oxytocin as a key regulator of basic empathic behaviors across vertebrates.

scholarly journals Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice

2020 ◽  
Author(s):  
Judit Cabana-Domínguez ◽  
Elena Martín-García ◽  
Ana Gallego-Roman ◽  
Rafael Maldonado ◽  
Noèlia Fernàndez-Castillo ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Short Term Memory ◽  
Long Term Potentiation ◽  
Cocaine Addiction ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Normal Behavior ◽  
Cocaine Seeking ◽  
Seeking Behavior

ABSTRACTBackground and PurposeCocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of PLCB1 gene to cocaine addictive properties in mice.Experimental approachWe used heterozygous Plcb1 knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days. Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq.Key ResultsPlcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation.Conclusions and ImplicationsTo conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

Activin A in Inflammation, Tissue Repair, and Fibrosis: Possible Role as Inflammatory and Fibrotic Mediator of Uterine Fibroid Development and Growth

2017 ◽  
Vol 35 (06) ◽  
pp. 499-509 ◽  
Author(s):  
Olga Protic ◽  
Md Islam ◽  
Stefania Greco ◽  
Stefano Giannubilo ◽  
Pasquale Lamanna ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tissue Repair ◽  
Uterine Leiomyoma ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Hormone Secretion ◽  
Activin A ◽  
Reproductive Age

AbstractThe growth factor activin A belongs to the transforming growth factor-β superfamily and was initially isolated as an inducer of follicle-stimulating hormone secretion. Activin A was later found to play roles in cell proliferation, differentiation, apoptosis, and metabolism. More recently, activin A has also been recognized as a novel player in mediating inflammation, immunity, wound repair, and fibrosis. Elevated levels of activin A during inflammation are responsible for the increased production of extracellular matrix in different pathological conditions, including fibroids. Our group has demonstrated a profibrotic role of activin A in leiomyoma growth. Uterine leiomyoma can be considered as a fibrotic disorder that initiates from myometrial smooth muscle layer of uterus in reproductive-age women and that is driven by a strong inflammatory component. In fertile women, transient inflammation is a physiological and essential process during menstruation, ovulation, and parturition. However, tissue injury from extravasated menstrual blood and/or an altered response to harmful stimuli, such as pathogens, damaged cells, or irritants, can establish chronic inflammation in the uterus, ultimately leading to dysregulated tissue repair. Myofibroblasts are key cells in normal repair and the chronic tissue remodeling characteristic for fibrosis and uterine leiomyoma. In this review, we discuss the role of activin A in inflammation, tissue repair, and fibrosis and we elaborate the hypothesis that it plays a central role in myofibroblast activation and leiomyoma development and growth.

scholarly journals Hippocampal Neuropeptide Y2 receptor blockade improves spatial memory retrieval and modulates limbic brain metabolism

2021 ◽  
Author(s):  
Marta Mendez-Couz ◽  
Hector Gonzalez-Pardo ◽  
Jorge L Arias ◽  
Nelida M Conejo
Keyword(s):  
Spatial Memory ◽  
Brain Metabolism ◽  
Drugs Of Abuse ◽  
Dorsal Hippocampus ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Memory Recall ◽  
Y2 Receptor ◽  
Term Potentiation

Introduction: The neuropeptide Y (NPY) is broadly distributed in the central nervous system (CNS), and it has been related to neuroprotective functions. NPY seems to be an important component to counteract brain damage and cognitive impairment mediated by drugs of abuse and neurodegenerative diseases, and both NPY and its Y2 receptor (Y2R) are highly expressed in the hippocampus, critical for learning and memory. We have recently demonstrated its influence on cognitive functions; however, the specific mechanism and involved brain regions where NPY modulates spatial memory by acting on Y2R remain unclear. Methods: Here, we examined the involvement of the hippocampal NPY Y2R in spatial memory and associated changes in brain metabolism by bilateral administration of the selective antagonist BIIE0246 into the rat dorsal hippocampus. To further evaluate the relationship between memory functions and neuronal activity, we analysed the regional expression of the mitochondrial enzyme cytochrome c oxidase (CCO) as an index of oxidative metabolic capacity in limbic and non-limbic brain regions. Results: The acute blockade of NPY Y2R significantly improved spatial memory recall in rats trained in the Morris water maze that matched metabolic activity changes in spatial memory processing regions. Specifically, CCO activity changes were found in the dentate gyrus of the dorsal hippocampus and CA1 subfield of the ventral hippocampus, the infralimbic region of the PFC and the mammillary bodies. Conclusions: These findings suggest that the NPY hippocampal system, through its Y2R receptor, influences spatial memory recall (retrieval) and exerts control over patterns of brain activation that are relevant for associative learning, probably mediated by Y2R modulation of long-term potentiation and long-term depression.

scholarly journals Pyk2 in dorsal hippocampus plays a selective role in spatial memory and synaptic plasticity

2021 ◽  
Author(s):  
Vincenzo Mastrolia ◽  
Omar al Massadi ◽  
Benoit de Pins ◽  
Jean-Antoine Girault
Keyword(s):  
Synaptic Plasticity ◽  
Spatial Memory ◽  
Dorsal Hippocampus ◽  
Training Session ◽  
Long Term Potentiation ◽  
Object Location ◽  
High Frequency Stimulation ◽  
Novel Object ◽  
Ca1 Region

Pyk2 is a Ca2+-activated non-receptor tyrosine kinase enriched in the forebrain, especially in pyramidal neurons of the hippocampus. Previous reports suggested its role in hippocampal synaptic plasticity and spatial memory but with contradictory findings possibly due to experimental conditions. Here we address this issue and show that novel object location, a simple test of spatial memory induced by a single training session, is altered in Pyk2 KO mice and that re-expression of Pyk2 in the dorsal hippocampus corrects this deficit. Bilateral targeted deletion of Pyk2 in dorsal hippocampus CA1 region also alters novel object location. Long term potentiation (LTP) in CA1 is impaired in Pyk2 KO mice using a high frequency stimulation induction protocol nut not with a theta burst protocol, explaining differences between previous reports. The same selective LTP alteration is observed in mice with Pyk2 deletion in dorsal hippocampus CA1 region. Thus, our results establish the role of Pyk2 in specific aspects of spatial memory and synaptic plasticity and show the dependence of the phenotype on the type of experiments used to reveal it. In combination with other studies they provide evidence for a selective role of non-receptor tyrosine kinases in specific aspects of hippocampal neurons synaptic plasticity.

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