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

The nucleus accumbens (NAC) is a functionally heterogeneous brain region with respect to its involvement in cocaine-seeking behavior triggered by drug-associated explicit conditioned stimuli, foot shock stress, or cocaine itself in the reinstatement animal model of drug relapse. However, it is not known whether the NAC or its subregions are critical for reinstatement of cocaine-seeking behavior produced by re-exposure to a previously cocaine-paired environmental context

Involvement of the Lateral Orbitofrontal Cortex in Drug Context-induced Reinstatement of Cocaine-seeking Behavior in Rats

Orbitofrontal cortex (OFC) damage produces impaired decision-making, impulsivity, and perseveration and potentially contributes to compulsive drug seeking in cocaine users. To further explore this phenomenon, we assessed the role of the lateral OFC (lOFC) in drug context-induced cocaine-seeking behavior in the reinstatement model of drug relapse. Rats were trained to lever press for intravenous cocaine infusions in a distinct environmental context (cocaine-paired context) followed by extinction training in a different context (extinction-paired context). Reinstatement of cocaine seeking (non-reinforced lever presses) was assessed in the cocaine context in the absence of response-contingent stimuli. In experiment 1, we evaluated whether acute inhibition of lOFC output alters context-induced cocaine-seeking behavior by infusing the GABAB+A agonists, baclofen+muscimol, or vehicle into the lOFC immediately before exposure to the cocaine-paired context. In experiments 2–3, we assessed how prolonged loss of lOFC output affects drug context-induced cocaine seeking by administering bilateral NMDA or sham lesions of the lOFC either before or after self-administration and extinction training. Remarkably, OFC functional inactivation attenuated, post-training lesions failed to alter, and pre-training lesions potentiated drug context-induced cocaine seeking without altering responding in the extinction context. These results suggest that neural activity in the lOFC promotes context-induced cocaine-seeking behavior. However, prolonged loss of lOFC output enhances the motivational salience of cocaine-paired contextual stimuli likely by eliciting compensatory neuroadaptations, with the effects of post-training lOFC lesions reflecting an intermediate state of compensatory neuroplasticity. Overall, these findings support the idea that OFC dysfunction may promote cue reactivity and enhance relapse propensity in cocaine users

Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats

The functional integrity of the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine seeking. However, the neuropharmacological mechanisms of this phenomenon are poorly understood

Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking

Understanding the neurobiological underpinnings of putative memory stabilization processes that maintain context-response-cocaine associations in long-term memory and underlie contextual control over addictive behavior is of great interest from an addiction treatment perspective. Using an instrumental animal model of contextual drug relapse, we show that the protein synthesis inhibitor, anisomycin, administered into the basolateral amygdala (BLA) immediately after limited (15- or 60-min) re-exposure to a previously cocaine-paired context subsequently disrupted the ability of the previously cocaine-paired context to reinstate extinguished cocaine-seeking behavior relative to vehicle. Consistent with a BLA-mediated memory reconsolidation deficit, similar impairment in cocaine-seeking behavior was not observed in “no-reactivation” control groups that received anisomycin into the BLA after (re)exposure to either a novel unpaired or an extinction-paired context nor in a neuroanatomical control group that received anisomycin into the posterior caudate-putamen, dorsally adjacent to the BLA, after re-exposure to the cocaine-paired context. Furthermore, anisomycin administered into the BLA after brief (5-min) or extensive (120-min) re-exposure to the cocaine-paired context (which was sufficient to extinguish cocaine-seeking behavior in a vehicle control group) also failed to alter responding. Together, these findings suggest that re-exposure to a cocaine-paired context in the absence of cocaine reinforcement is sufficient to trigger memory reconsolidation processes that support future drug-seeking behavior. The presence and duration of drug-related memory reactivation critically influences and anisomycin-sensitive mechanisms in the BLA selectively control this phenomenon. These findings support the feasibility of novel pharmacotherapeutic approaches that selectively inhibit the reconsolidation of cocaine-related memories in order to prevent drug relapse

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats: Glutamate and cocaine seeking

The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 μl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 μg/0.3 μl/hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual cocaine-seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity, or food-reinforced instrumental behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon

Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats

Exposure to a cocaine-paired context increases the propensity for relapse in cocaine users and prompts cocaine-seeking behavior in rats. According to the reconsolidation hypothesis, upon context re-exposure, established cocaine-related associations are retrieved and can become labile. These associations must undergo reconsolidation into long-term memory to effect enduring stimulus control. The dorsal hippocampus (DH), dorsolateral caudate-putamen, and dorsomedial prefrontal cortex are critical for the expression of context-induced cocaine seeking, and these brain regions may also play a role in the reconsolidation of cocaine-related memories that promote this behavior. To test this hypothesis, rats were trained to press a lever for un-signaled cocaine infusions (0.2 mg/infusion, IV) in a distinct environmental context (cocaine-paired context), followed by extinction training in a different context (extinction context). Rats were then re-exposed to the cocaine-paired context for 15 min in order to reactivate cocaine-related memories or received comparable exposure to a novel unpaired context. Immediately thereafter, rats received bilateral microinfusions of the protein synthesis inhibitor anisomycin, the sodium channel blocker tetrodotoxin, or vehicle into one of the above brain regions. After additional extinction training in the extinction context, reinstatement of cocaine-seeking behavior (i.e., non-reinforced lever presses) was assessed in the cocaine-paired context. Tetrodotoxin, but not anisomycin, administered into the DH inhibited drug context-induced cocaine-seeking behavior in a memory reactivation-dependent manner. Other manipulations failed to alter this behavior. These findings suggest that the DH facilitates the reconsolidation of associative memories that maintain context-induced cocaine-seeking behavior, but it is not the site of anisomycin-sensitive memory re-stabilization per se

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Dietary plasticity linked to divergent growth trajectories in a critically endangered sea turtle

Foraging habitat selection and diet quality are key factors that influence individual fitness and meta-population dynamics through effects on demographic rates. There is growing evidence that sea turtles exhibit regional differences in somatic growth linked to alternative dispersal patterns during the oceanic life stage. Yet, the role of habitat quality and diet in shaping somatic growth rates is poorly understood. Here, we evaluate whether diet variation is linked to regional growth variation in hawksbill sea turtles (Eretmochelys imbricata), which grow significantly slower in Texas, United States versus Florida, United States, through novel integrations of skeletal growth, gastrointestinal content (GI), and bulk tissue and amino acid (AA)-specific stable nitrogen (δ15N) and carbon (δ13C) isotope analyses. We also used AA δ15N ΣV values (heterotrophic bacterial re-synthesis index) and δ13C essential AA (δ13CEAA) fingerprinting to test assumptions about the energy sources fueling hawksbill food webs regionally. GI content analyses, framed within a global synthesis of hawksbill dietary plasticity, revealed that relatively fast-growing hawksbills stranded in Florida conformed with assumptions of extensive spongivory for this species. In contrast, relatively slow-growing hawksbills stranded in Texas consumed considerable amounts of non-sponge invertebrate prey and appear to forage higher in the food web as indicated by isotopic niche metrics and higher AA δ15N-based trophic position estimates internally indexed to baseline nitrogen isotope variation. However, regional differences in estimated trophic position may also be driven by unique isotope dynamics of sponge food webs. AA δ15N ΣV values and δ13CEAA fingerprinting indicated minimal bacterial re-synthesis of organic matter (ΣV < 2) and that eukaryotic microalgae were the primary energy source supporting hawksbill food webs. These findings run contrary to assumptions that hawksbill diets predominantly comprise high microbial abundance sponges expected to primarily derive energy from bacterial symbionts. Our findings suggest alternative foraging patterns could underlie regional variation in hawksbill growth rates, as divergence from typical sponge prey might correspond with increased energy expenditure and reduced foraging success or diet quality. As a result, differential dispersal patterns may infer substantial individual and population fitness costs and represent a previously unrecognized challenge to the persistence and recovery of this critically endangered species

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts