Mesolimbic circuits regulate the attribution of motivational significance to incentive cues that predict reward, yet this network also plays a key role in adapting reward-seeking behavior when the ...contingencies linked to a cue unexpectedly change. Here, we asked whether mesoaccumbal GABA (gamma-aminobutyric acid) projections enhance adaptive responding to incentive cues of abruptly altered reward value, and whether these effects were distinct from global activation of all ventral tegmental area GABA circuits.
We used a viral targeting system to chemogenetically activate mesoaccumbal GABA projections in male rats during a novel cue-dependent operant value-shifting task, in which the volume of a sucrose reward associated with a predictive cue is suddenly altered, from the beginning and throughout the session. We compared the results with global activation of ventral tegmental area GABA neurons, which will activate local inhibitory circuits and long loop projections.
We found that activation of mesoaccumbal GABA projections decreases responding to incentive cues associated with smaller-than-expected rewards. This tuning of behavioral responses was specific to cues associated with smaller-than-expected rewards but did not impact measures related to consuming the reward. In marked contrast, activating all ventral tegmental area GABA neurons resulted in a uniform decrease in responding to incentive cues irrespective of changes in the size of the reward.
Targeted activation of mesoaccumbal GABA neurons facilitates adaptation in reward-seeking behaviors. This suggests that these projections may play a very specific role in associative learning processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
AIM To assess the choroidal thickness and choroidal circulatory changes in eyes with myopic choroidal neovascularisation (mCNV). METHODS Retrospective, consecutive, observational case series. ...Forty-two consecutive eyes (17 eyes with newly diagnosed mCNV and 25 eyes without CNV) were included. Choroidal circulation was evaluated by indocyanine green angiography (ICGA), and choroidal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The factors associated with mCNV were evaluated. RESULTS Sixteen (94%) of 17 eyes with mCNV and six (24%) of 25 eyes without mCNV had well-defined hypofluorescence at the macular region on arterial phase ICGA, that is, a choroidal filling delay. Older age (p<0.001), the presence of a choroidal filling delay (p<0.001) and reduced choroidal thickness (p=0.003) were significantly associated with mCNV on univariate analysis. The most important of these three factors associated with mCNV, in order of importance, were the choroidal filling delay (OR=41.5, p<0.001) and choroidal thickness (per 1 microm, OR=0.97, p=0.01). Older age was significantly associated with both choroidal filling delay (per 1 year, OR=1.16, p<0.001) and choroidal thinning (regression coefficient=-1.22, p<0.001). CONCLUSIONS Significant choroidal changes were observed in eyes with mCNV. Ischaemia-induced growth factor expression caused by decreased choroidal perfusion may be related to the development of mCNV.
We studied polyyne formation by gas phase laser-induced breakdown in ethylene and acetylene gas flow using ns and fs lasers. The results show that acetylene is the most efficient target molecule for ...generating polyynes with high selectivity. Of the two lasers, the fs laser achieved higher selectivity for the production of hydrogen-capped polyynes. We also confirmed strong correlations between C2 radical and polyyne production, which have already been observed for larger hydrocarbon targets. In terms of the polyyne formation mechanism, we suggest decomposition of irradiated soot to be a possible pathway, in addition to carbon chain growth by binary collisions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Reward-predictive cues exert powerful control over behavioral choice and may be a critical factor in drug addiction. Reward-seeking elicited by predictive cues is facilitated by the release of ...dopamine in the nucleus accumbens (NAc), yet the contribution of dopamine to the specific NAc firing patterns that underlie goal-directed behavior has remained elusive. We present evidence that subpopulations of NAc neurons that respond to predictive cues require the dopaminergic projection from the ventral tegmental area (VTA) to promote reward-seeking behavior. Rats trained to perform an operant response to a cue to obtain a sucrose reward were implanted with both multiunit recording electrodes in the NAc and microinjection cannulas in the VTA. Both the behavioral response to cues and the cue-evoked firing of NAc neurons were blocked by injection of the GABA(B) agonist baclofen into the VTA. An additional group of rats was trained on the same task and then implanted with microinjection cannulas in the NAc. Like VTA baclofen injection, injection of dopamine receptor antagonists into the NAc profoundly reduced cue-elicited reward seeking. Together, these results support the conclusion that both the behavioral response to the cue and the specific NAc neuronal firing that promotes the response depend on dopamine release within the NAc. Our findings suggest a neural mechanism by which the dopamine-dependent firing of NAc neurons mediates goal-directed behavior.
Recent studies reveal that cocaine experience results in persistent neuroadaptive changes within glutamate (Glu) synapses in brain areas associated with drug reward. However, it remains unclear ...whether cocaine affects Glu release in drug‐naive animals and how it is altered by drug experience. Using high‐speed amperometry with enzyme‐based and enzyme‐free biosensors in freely moving rats, we show that an initial intravenous cocaine injection at a low self‐administering dose (1 mg/kg) induces rapid, small and transient Glu release in the nucleus accumbens shell (NAc), which with subsequent injections rapidly becomes a much stronger, two‐component increase. Using cocaine‐methiodide, cocaine's analog that does not cross the blood–brain barrier, we confirm that the initial cocaine‐induced Glu release in the NAc has a peripheral neural origin. Unlike cocaine, Glu responses induced by cocaine‐methiodide rapidly habituate following repeated exposure. However, after cocaine experience this drug induces cocaine‐like Glu responses. Hence, the interoceptive actions of cocaine, which essentially precede its direct actions in the brain, play a critical role in experience‐dependent alterations in Glu release, cocaine‐induced neural sensitization and may contribute to cocaine addiction.
Using high‐speed amperometry with enzyme‐based biosensors in freely moving rats, we show that initial intravenous cocaine induces rapid, transient glutamate (Glu) release in the Nac (Nucleus accumbens), rapidly becoming a stronger, two‐component increase with subsequent injections. We show that the peripheral actions of cocaine, which precedes its direct central actions, play a critical role in experience‐dependent alterations in Glu release, possibly contributing to cocaine addiction.
Using high‐speed amperometry with enzyme‐based biosensors in freely moving rats, we show that initial intravenous cocaine induces rapid, transient glutamate (Glu) release in the Nac (Nucleus accumbens), rapidly becoming a stronger, two‐component increase with subsequent injections. We show that the peripheral actions of cocaine, which precedes its direct central actions, play a critical role in experience‐dependent alterations in Glu release, possibly contributing to cocaine addiction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Establishing the genetic determinants of niche adaptation by microbial pathogens to specific hosts is important for the management and control of infectious disease. Streptococcus pyogenes is a ...globally prominent human-specific bacterial pathogen that secretes superantigens (SAgs) as 'trademark' virulence factors. SAgs function to force the activation of T lymphocytes through direct binding to lateral surfaces of T cell receptors and class II major histocompatibility complex (MHC-II) molecules. S. pyogenes invariably encodes multiple SAgs, often within putative mobile genetic elements, and although SAgs are documented virulence factors for diseases such as scarlet fever and the streptococcal toxic shock syndrome (STSS), how these exotoxins contribute to the fitness and evolution of S. pyogenes is unknown. Here we show that acute infection in the nasopharynx is dependent upon both bacterial SAgs and host MHC-II molecules. S. pyogenes was rapidly cleared from the nasal cavity of wild-type C57BL/6 (B6) mice, whereas infection was enhanced up to ∼10,000-fold in B6 mice that express human MHC-II. This phenotype required the SpeA superantigen, and vaccination with an MHC -II binding mutant toxoid of SpeA dramatically inhibited infection. Our findings indicate that streptococcal SAgs are critical for the establishment of nasopharyngeal infection, thus providing an explanation as to why S. pyogenes produces these potent toxins. This work also highlights that SAg redundancy exists to avoid host anti-SAg humoral immune responses and to potentially overcome host MHC-II polymorphisms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies show that dense dopamine (DA) innervation from the ventral tegmental area to the olfactory tubercle (OT) may play an important role in processing multisensory information pertaining to ...arousal and reward, yet little is known about DA regulation in the OT. This is mainly due to the anatomical limitations of conventional methods of determining DA dynamics in small heterogeneous OT subregions located in the ventral most part of the brain. Additionally, there is increasing awareness that anteromedial and anterolateral subregions of the OT have distinct functional roles in natural and psychostimulant drug reinforcement as well as in regulating other types of behavioral responses, such as aversion. Here, we compared extracellular DA regulation (release and clearance) in three subregions (anteromedial, anterolateral, and posterior) of the OT of urethane‐anesthetized rats, using in vivo fast‐scan cyclic voltammetry following electrical stimulation of ventral tegmental area dopaminergic cell bodies. The neurochemical, anatomical, and pharmacological evidence confirmed that the major electrically evoked catecholamine in the OT was DA across both its anteroposterior and mediolateral extent. While both D2 autoreceptors and DA transporters play important roles in regulating DA evoked in OT subregions, DA in the anterolateral OT was regulated less by the D2 receptors when compared to other OT subregions. Comparing previous data from other DA rich ventral striatum regions, the slow DA clearance across the OT subregions may lead to a high extracellular DA concentration and contribute towards volume transmission. These differences in DA regulation in the terminals of OT subregions and other limbic structures will help us understand the neural regulatory mechanisms of DA in the OT, which may elucidate its distinct functional contribution in the ventral striatum towards mediating aversion, reward and addiction processes.
Olfactory tubercle (OT)‐dopamine (DA) may play a role in arousal and reward, yet little is known about OT‐DA regulation. Neurochemical, anatomical, and pharmacological evidence confirmed DA as the major electrically evoked catecholamine across the OT. While both D2 autoreceptor and DA transporters regulate evoked DA in OT subregions, anterolateral OT‐DA is regulated less by D2 receptors than other subregions. These differences in OT‐DA regulation may elucidate the distinct roles of OT subregions in diverse natural behavior and psychostimulant drug reinforcement.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems ...and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH's role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Glioblastomas (GBMs) are the most common and aggressive type of brain tumor. GBMs usually show hyperactivation of the PI3K-Akt pathway, a pro-tumorigenic signaling cascade that contributes to ...pathogenesis. Girdin, an actin-binding protein identified as a novel substrate of Akt, regulates the sprouting of axons and the migration of neural progenitor cells during early postnatal-stage neurogenesis in the hippocampus. Here, we show that Girdin is highly expressed in human glioblastoma (GBM). Stable Girdin knockdown in isolated GBM stem cells resulted in decreased expression of stem cell markers, including CD133, induced multilineage neural differentiation, and inhibited in vitro cell motility, ex vivo invasion, sphere-forming capacity and in vivo tumor formation. Furthermore, exogenous expression of the Akt-binding domain of Girdin, which competitively inhibits its Akt-mediated phosphorylation, diminished the expression of stem cell markers, SOX2 and nestin, and migration on the brain slice and induced the expression of neural differentiation markers glial fibrillary acidic protein/βIII Tubulin. Our results reveal that Girdin is required for GBM-initiating stem cells to sustain the stemness and invasive properties.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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