Cue Response Research Articles

Sustained brain activation supporting stop‐signal task performance

Stop-signal paradigms operationalize a basic test of goal-directed behaviour whereby an overarching stop goal that is performed intermittently must be maintained throughout ongoing performance of a reaction time go task (go goal). Previous studies of sustained brain activation during stop-signal task performance in humans did not observe activation of the dorsolateral prefrontal cortex (DLPFC) that, in concert with the parietal cortex, is known to subserve goal maintenance. Here we explored the hypothesis that a DLPFC and parietal network has a key role in supporting ongoing stop-signal task performance. We used a blocked functional magnetic resonance imaging design that included blocks of trials containing typical stop-signal paradigm stimuli that were performed under three conditions: Stop condition, which required reaction time responding to go stimuli and inhibition of cued responses upon presentation of a stop signal; Go condition, identical except that the tone was ignored; and Passive condition, which required only quiescent attention to stimuli. We found that, whereas a distributed corticothalamic network was more active in Stop compared with Go, only the right DLPFC and bilateral parietal cortex survived after masking that contrast with Stop compared with Passive. These findings indicate that sustained activation of a right dominant frontoparietal network supports stop goal processes during ongoing performance of the stop-signal task.

Adolescent traumatic stress experience results in less robust conditioned fear and post-extinction fear cue responses in adult rats

Early exposure to a traumatic event may produce lasting effects throughout the lifespan. Traumatic stress during adolescence may deliver a distinct developmental insult compared with more-often studied neonatal or juvenile traumatic stress paradigms. The present study describes the lasting effects of adolescent traumatic stress upon adulthood fear conditioning. Adolescent rats were exposed to a traumatic stressor (underwater trauma, UWT), then underwent fear conditioning during adulthood. Fear extinction was tested over five conditioned suppression extinction sessions three weeks later. The efficacies of two potential extinction-enhancing compounds, endocannabinoid reuptake inhibitor AM404 (10mg/kg) and M1 muscarinic positive allosteric modulator BQCA (10mg/kg), were also assessed. Finally, post-extinction fear responses were examined using a fear cue (light) as a prepulse stimulus. Rats traumatically stressed during adolescence showed blunted conditioned suppression on day 1 of extinction training, and AM404 reversed this effect. Post-extinction startle testing showed that fear conditioning eliminates prepulse inhibition to the light cue. Startle potentiation was observed only in rats without adolescent UWT exposure. AM404 and BQCA both ameliorated this startle potentiation, while BQCA increased startle in the UWT group. These results suggest that exposure to a traumatic stressor during adolescence alters developmental outcomes related to stress response and fear extinction compared to rats without adolescent traumatic stress exposure, blunting the adulthood fear response and reducing residual post-extinction fear expression. Efficacy of pharmacological interventions may also vary as a factor of developmental traumatic stress exposure.

A novel role for the rat retrosplenial cortex in cognitive control

By virtue of its frontal and hippocampal connections, the retrosplenial cortex is uniquely placed to support cognition. Here, we tested whether the retrosplenial cortex is required for frontal tasks analogous to the Stroop Test, i.e., for the ability to select between conflicting responses and inhibit responding to task-irrelevant cues. Rats first acquired two instrumental conditional discriminations, one auditory and one visual, set in two distinct contexts. As a result, rats were rewarded for pressing either the right or left lever when a particular auditory or visual signal was present. In extinction, rats received compound stimuli that either comprised the auditory and visual elements that signaled the same lever response (congruent) or signaled different lever responses (incongruent) during training. On conflict (incongruent) trials, lever selection by sham-operated animals followed the stimulus element that had previously been trained in that same test context, whereas animals with retrosplenial cortex lesions failed to disambiguate the conflicting response cues. Subsequent experiments demonstrated that this abnormality on conflict trials was not due to a failure in distinguishing the contexts. Rather, these data reveal the selective involvement of the rat retrosplenial cortex in response conflict, and so extend the frontal system underlying cognitive control.

Spatial Variability in Serial Response Learning and Performance by Pigeons (Columba livia)

Pigeons can learn structured sequences of cued responses and perform them quickly, even when random variability is later introduced into the originally learned sequence, making some cue locations unpredictable. In order to determine if initial learning shows the same tolerance of spatial variability as steady-state performance, naïve pigeons were trained on random distortions around a structured sequence without having seen the original sequence itself. Learning was possible, but accommodated less variability than did performance of the same sequence previously learned in an undistorted context. Analysis of results indicated that performance of a randomly distorted sequence is best when birds are initially trained with little or no variability, and randomness is later introduced in a gradual fashion.

Nucleus accumbens responses differentiate execution and restraint in reward-directed behavior

Our behavior is powerfully driven by environmental cues that signal the availability of rewarding stimuli. We frequently encounter stimuli-a bowl of candy or an alert from our smartphone-that trigger actions to obtain those rewards, even though there may be positive outcomes associated with not acting. The inability to restrain one's action in the presence of reward-associated cues is one type of impulsive behavior and a component of such maladaptive behaviors as overeating, gambling, and substance abuse. The nucleus accumbens (NAc) is ideally situated to integrate multiple cognitive and affective inputs to bias action via outputs through the basal ganglia. NAc neurons have been shown to respond to cues that predict reward availability, goal-directed behaviors aimed at obtaining them, and delivery of the reward itself. As these processes are typically associated, it is difficult to discern whether signals in the NAc are more closely related to processing reward-predictive aspects of goal-directed behavior or selection of behavioral response. To dissociate these possibilities, we recorded the activity of NAc neurons while rats performed a task in which two different cues both informed rats of reward availability but required them to either press a lever (Go) or withhold pressing (NoGo) to obtain the reward. Individual cue-responsive neurons showed either increases or decreases in activity at cue onset. Increases in activity were larger, and decreases smaller, when rats withheld lever pressing, whether correctly for NoGo trials or in error on Go trials. Thus NAc cue responses correlated with action, regardless of cue type or accuracy.

FTY720, Sphingosine 1-Phosphate Receptor Modulator, Attenuates Radiation-Induced Neurocognitive Deficits in Young Mice

Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural stem cells (NSCs) in the hippocampus. Previously, we showed that FTY720, an agent recently approved by the FDA for treatment of multiple sclerosis, provided radioprotection for NSCs but not tumor cells in vitro. We now examined the ability of fingolimod to mitigate neurocognitive deficits, induced by whole brain irradiation (WBI), in a mouse model. Six-week-old C57/Bl/6J mice were randomized to four experimental groups: (1) WBI + FTY720, (2) WBI + drug vehicle control, (3) sham irradiation + FTY720, and (4) sham irradiation + vehicle. There were 12 mice in each group. Following a single dose of radiation, 7 Gy or 0 Gy (sham), FTY720 or vehicle was given to mice via i.p. injections three times a week for six weeks. Spatial memory was tested using Morris water maze studies. The mice were trained to locate a submerged hidden platform in daily sessions for five days; this was followed by a single probe trial with no platform. The average latency time (length of time to find the platform in water) was calculated for each animal in each trial. Additional behavioral studies included open field, elevated plus maze, and cued fear conditioning studies, testing locomotor activity, anxiety, and amygdala-driven cued response respectively. All data were analyzed using STATA statistical software. In irradiated mice (WBI + vehicle), spatial memory deficits were manifested by significantly longer latency times compared to the non-irradiated controls (sham + vehicle), p < 0.05. Administration of FTY720 fully attenuated radiation-induced memory dysfunction: latency times of irradiated mice treated with FTY720 (WBI + FTY720) were not significantly different from those of non-irradiated controls (sham + vehicle). The latency times of non-irradiated mice treated with FTY720 (sham + FTY720) were equal to those of the non-irradiated vehicle controls (sham + vehicle) as well as of the irradiated FTY720-treated group (WBI + FTY720). There were no statistically significant differences between any of the groups in the open field, elevated plus maze, or fear conditioning studies. We found FTY720 to attenuate radiation-induced spatial memory dysfunction in vivo. Combined with our previous data demonstrating the radioprotective effects of FTY720 on hippocampal neural precursor cells but not tumor cells in vitro, these results provide a strong rationale for testing the efficacy of this FDA-approved agent as a neuroprotector in patients undergoing whole brain radiation therapy.

β-Endorphin via the Delta Opioid Receptor is a Major Factor in the Incubation of Cocaine Craving

Cue-induced cocaine craving intensifies, or 'incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid β-endorphin. In the present study, we examined the possible involvement of β-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in β-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while β-endorphin levels remained unchanged. Intra-NAc infusion of an anti-β-endorphin antibody (4 μg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic β-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the δ opioid receptor antagonist naltrindole (1 μg) on day 1 and naltrindole together with β-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the μ opioid receptor antagonist CTAP (30 ng and 3 μg) had no behavioral effect. Altogether, these results demonstrate a novel role for β-endorphin and the δ opioid receptor in the development of the incubation of cocaine craving.

Abstract 4607: Expression of Bcl-2 pro-survival family proteins predicts pharmacological responses to ABT-199, a novel and selective Bcl-2 antagonist, in multiple myeloma models.

Abstract A hallmark feature of cancer is the ability to evade cell death signals induced by stress response cues mediated, in part, by the the Bcl-2 family of pro-apoptotic and pro-survival proteins. ABT-199 is a potent BH3-only mimetic that selectively antagonizes the pro-survival function of Bcl-2. The work presented describes the efficacy of ABT-199 as a single agent and in combination with bortezomib in preclinical models of Multiple Myeloma (MM). Expression of Bcl-2 protein was detected in 95% of MM cell lines (n=21) evaluated and ABT-199 reduced cell viability in a sub-set of these lines (7/21) with EC50 values less than 0.5 μM. Expression of Bcl-xL and Mcl-1 at the mRNA and protein levels were also evaluated to determine predictors of drug sensitivity and resistance to ABT-199. MM lines that expressed higher levels of Bcl-2 relative to Bcl-xL and Mcl-1 were the most sensitive to ABT-199 treatment while those that were less sensitive expressed higher levels of Mcl-1 or Bcl-xL. Other predictors of sensitivity to ABT-199 included higher levels of Bcl-2/Bim complexes and t(11;14) status. Ex vivo, 75% of the MM bone marrow biopsies and aspirates (n=27) had high Bcl-2 levels whereas 50% had high Bcl-xL expression, demonstrating that a subset of patient samples (33%) have a favorable biomarker profile (Bcl-2-high/Bcl-xL-low) that may be predictive of ABT-199 activity. Efficacy of ABT-199 as a single agent and in combination with bortezomib was evaluated in vivo in MM xenograft models that expressed Bcl-2 (OPM-2, KMS-11, RPMI-8226, H929 and MM.1s). Bortezomib treatment alone at maximum tolerated doses resulted in tumor regressions or stasis in all xenograft models tested. ABT-199 at maximum tolerated doses was efficacious as a single agent in xenograft models that expressed higher protein levels of Bcl-2 but relatively lower levels of Bcl-xL. The combination of ABT-199 with bortezomib increased overall response rates, durability of anti-tumor activity and levels of apoptotic markers such as cleaved caspase 3 and PARP when compared to bortezomib alone even in MM xenograft models that also express relatively high levels of Mcl-1. Treatment with bortezomib in vivo increased levels of Noxa; a pro-apoptotic BH3-only protein that selectively antagonizes Mcl-1. Therefore, greater efficacy may be achieved when ABT-199 is combined with bortezomib due to inhibition of Bcl-2 by ABT-199 and neutralization of Mcl-1 by Noxa in tumors that express both pro-survival proteins. Our preclinical data supports the evaluation of ABT-199 as a single agent and in combination with bortezomib in MM patients in which relative expression of the Bcl-2 pro-survival proteins may serve as predictive biomarkers of drug activity. Citation Format: Deepak Sampath, Elizabeth Punnoose, Erwin Boghaert, Lisa Belmont, Franklin Peale, Nguyen Tan, Jun Chen, Walter Darbonne, Peng Yue, Jason Oeh, Leslie Lee, Wayne J. Fairbrother, Andrew J. Souers, Steven W. Elmore, Joel D. Leverson. Expression of Bcl-2 pro-survival family proteins predicts pharmacological responses to ABT-199, a novel and selective Bcl-2 antagonist, in multiple myeloma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4607. doi:10.1158/1538-7445.AM2013-4607

Cortical Cholinergic Input Is Required for Normal Auditory Perception and Experience-Dependent Plasticity in Adult Ferrets

The nucleus basalis (NB) in the basal forebrain provides most of the cholinergic input to the neocortex and has been implicated in a variety of cognitive functions related to the processing of sensory stimuli. However, the role that cortical acetylcholine release plays in perception remains unclear. Here we show that selective loss of cholinergic NB neurons that project to the cortex reduces the accuracy with which ferrets localize brief sounds and prevents them from adaptively reweighting auditory localization cues in response to chronic occlusion of one ear. Cholinergic input to the cortex was disrupted by making bilateral injections of the immunotoxin ME20.4-SAP into the NB. This produced a substantial loss of both p75 neurotrophin receptor (p75(NTR))-positive and choline acetyltransferase-positive cells in this region and of acetylcholinesterase-positive fibers throughout the auditory cortex. These animals were significantly impaired in their ability to localize short broadband sounds (40-500 ms in duration) in the horizontal plane, with larger cholinergic cell lesions producing greater performance impairments. Although they localized longer sounds with normal accuracy, their response times were significantly longer than controls. Ferrets with cholinergic forebrain lesions were also less able to relearn to localize sound after plugging one ear. In contrast to controls, they exhibited little recovery of localization performance after behavioral training. Together, these results show that cortical cholinergic inputs contribute to the perception of sound source location under normal hearing conditions and play a critical role in allowing the auditory system to adapt to changes in the spatial cues available.

Understanding variation in behavioural responses to human-induced rapid environmental change: a conceptual overview

A key issue in animal behaviour is the need to understand variation in behavioural responses to human-induced rapid environmental change (HIREC) such as habitat loss, exotic species, pollution, human harvesting and climate change. Why do some individuals show maladaptive behaviours, while others show adaptive responses to evolutionarily novel situations? At present, we lack a unified conceptual framework for generating predictions and guiding empirical and theoretical work on this critical question. Drawing from the concept of ecological traps, I suggest that a conceptual framework for explaining this variation should include four main points: (1) behavioural responses (adaptive or not) are the result of cue–response systems, or behavioural ‘rules of thumb’; (2) limited or imprecise, unreliable information often underlies suboptimal behaviour; (3) the organism’s behavioural flexibility affects its response to novel situations; and (4) evolution (and development) in past environments has shaped cue–response systems, responses to imperfect information and degree of behavioural flexibility to be adaptive in past environments, but not necessarily in novel environments. The degree of match/mismatch between past environments and novel environments altered by HIREC is thus a key to explaining adaptive versus maladaptive behaviours. I suggest several existing frameworks that address these four points, and are thus potentially useful for explaining behavioural responses to HIREC: signal detection theory, adaptive plasticity theory, extended reaction norms and cost–benefit theory on variation in learning. I further discuss more complex aspects of reality that would be useful to add to these existing frameworks.

Spatial Orienting of Attention in Dyslexic Adults using Directional and Alphabetic Cues

Spatial attention performance was investigated in adults with dyslexia. Groups with and without dyslexia completed literacy/phonological tasks as well as two spatial cueing tasks, in which attention was oriented in response to a centrally presented pictorial (arrow) or alphabetic (letter) cue. Cued response times and orienting effects were largely similar in dyslexic and nonimpaired readers. The one distinct pattern that emerged showed dyslexic adults to have smaller orienting effects in the right than left visual field for letter cues, whereas typical readers showed the opposite pattern. These smaller orienting effects appeared to characterize the dyslexic group as a whole and not only one or two individuals. Our results suggest that dyslexic adults may have a subtle impairment in orienting visual attention when processing alphabetic (but not pictorial) cues. Several interpretations of these findings are considered, including links with a phonological deficit and/or a difficulty in shifting attention in the direction of reading.

Appetitive traits from infancy to adolescence: Using behavioral and neural measures to investigate obesity risk

We come into the world with enduring predispositions towards food, which interact with environmental factors to influence our eating behaviors and weight trajectories. But our fates are not sealed — by learning more about this process we can identify ways to intervene. To advance this goal this we need to be able to assess appetitive traits such as food cue responsiveness and satiety sensitivity at different developmental stages. Assessment methods might include behavioral measures (e.g. eating behavior tests, psychometric questionnaires), but also biomarkers such as brain responses to food cues measured using fMRI. Evidence from infants, children and adolescents suggests that these indices of appetite differ not only with body weight, but also with familial obesity risk as assessed by parent weight, which reflects both genetic and environmental influences, and may provide a useful predictor of obesity development. Behavioral and neural approaches have great potential to inform each other: examining eating behavior can help us identify meaningful appetitive endophenotypes whose neural bases can be probed, while increasing knowledge of the shared neurobiology underlying appetite, obesity, and related behaviors and disorders may ultimately lead to innovative generalized interventions. Another challenge will be to combine comprehensive behavioral and neural assessments of appetitive traits with measures of relevant genetic and environmental factors within long-term prospective studies. This approach may help to identify the biobehavioral precursors of obesity, and lay the foundations for targeted neurobehavioral interventions that can interrupt the pathway to excess weight.

Differences in response initiation and behavioral flexibility between adolescent and adult rats.

Adolescence is a period of increased vulnerability to psychiatric illnesses such as addiction, mood disorders, and schizophrenia. Rats provide a useful animal model for investigating the differences in behavior and biology between adults and adolescents that stem from ongoing brain development. We developed the Cued Response Inhibition Task, or CRIT, to assess response inhibition and initiation processes by measuring the ability of rodents to withhold a response during an inhibitory cue and then to respond promptly after cue termination. We found no difference between adult and adolescent rats in the ability to appropriately inhibit a response during cue presentation. Adolescents, however, were unable to initiate a response as quickly as adults after cue termination. Further, we observed that this difference in responding was abolished after adolescent rats aged to adulthood with no additional training. In a separate experiment, adult and adolescent rats were trained in CRIT and then trained in another protocol in which the response inhibitory cue from CRIT was used as a Pavlovian cue predictive of reward. Adolescents demonstrated more reward-seeking behavior during the previously inhibitory Pavlovian cue than adults, indicative of greater behavioral flexibility. Taken together, these data suggest that, compared with adults, adolescent rats (a) are less able to initiate a response after response inhibition, (b) equally inhibit behavioral responses, and (c) are more adept at flexibly switching behavioral patterns. Furthermore, this study characterizes a task that is well suited for future pharmacological and electrophysiological investigations for assessing neuronal processing differences between adolescents and adults.

Changes in alcohol-related brain networks across the first year of college: A prospective pilot study using fMRI effective connectivity mapping

The upsurge in alcohol use that often occurs during the first year of college has been convincingly linked to a number of negative psychosocial consequences and may negatively affect brain development. In this longitudinal functional magnetic resonance imaging (fMRI) pilot study, we examined changes in neural responses to alcohol cues across the first year of college in a normative sample of late adolescents. Participants (N=11) were scanned three times across their first year of college (summer, first semester, second semester), while completing a go/no-go task in which images of alcoholic and non-alcoholic beverages were the response cues. A state-of-the-art effective connectivity mapping technique was used to capture spatiotemporal relations among brain regions of interest (ROIs) at the level of the group and the individual. Effective connections among ROIs implicated in cognitive control were greatest at the second assessment (when negative consequences of alcohol use increased), and effective connections among ROIs implicated in emotion processing were lower (and response times were slower) when participants were instructed to respond to alcohol cues compared to non-alcohol cues. These preliminary findings demonstrate the value of a prospective effective connectivity approach for understanding adolescent changes in alcohol-related neural processes.

Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning

Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.

Clarifying Response Processes and Efficiency in a Cued Continuous Performance Test

Event Abstract Back to Event Clarifying Response Processes and Efficiency in a Cued Continuous Performance Test Robert J. Barry1, Diana Karamacoska1* and Genevieve Z. Steiner1 1 University Of Wollongong, School of Psychology, Australia Background The cued Continuous Performance Test (CPT) is known to elicit the contingent negative variation (CNV), which facilitates response preparation to upcoming Targets/NonTargets (imperative stimuli). Less prevalent in the literature is the examination of ERP responses to the cues, and how the preparatory activity these stimuli elicit influences the subsequent processing of imperative stimuli. Our study aimed to clarify whether the response processes to the imperatives were similar to those occurring to the cue, and determine if physiological and behavioural response efficiency was facilitated by this preparatory activity. Methods Continuous EEG was recorded from 70 participants during a computerised version of the Gordon-CPT that involved a fixed series of digits presented on a monitor with 1000 ms SOA. Subjects were required to press a button to the Target, 9, when cued by 1, and refrain from responses to cued NonTarget numbers. Single trial ERPs were extracted for the cue and two imperatives, and were analysed via Principal Components Analysis (PCA). Response components to cues and imperatives were assessed for similarity using the coefficient of congruence (rc); latencies were also assessed. For behavioural performance, reaction time (RT) was measured from Target onset and correlated with CNV amplitude. Results PCA identified 7 response components for the cue and imperatives: N1, PN, P2, N2c, N2b, P3, and SW. All were deemed to be similar between the stimulus types (rc > .80), except the N2cs, which showed little resemblance (rc < .80). Peak latencies strongly correlated between cue and imperatives (r = .99), with shorter latencies apparent for imperative components. RTs reduced as a function of increasing CNV amplitude. Discussion The response components to imperatives are strongly related to cue response components, suggesting that similar response processes are occurring for these stimuli during the task. The preparatory activity elicited by the cue enhances both electrophysiological and behavioural response efficiency in this cued paradigm. Keywords: Continuous Performance Test (CPT), event-related potentials (ERPs), Principal Components Analysis (PCA), response processes, response efficiency Conference: ACNS-2013 Australasian Cognitive Neuroscience Society Conference, Clayton, Melbourne, Australia, 28 Nov - 1 Dec, 2013. Presentation Type: Poster Topic: Attention Citation: Barry RJ, Karamacoska D and Steiner GZ (2013). Clarifying Response Processes and Efficiency in a Cued Continuous Performance Test. Conference Abstract: ACNS-2013 Australasian Cognitive Neuroscience Society Conference. doi: 10.3389/conf.fnhum.2013.212.00142 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Sep 2013; Published Online: 25 Nov 2013. * Correspondence: Miss. Diana Karamacoska, University Of Wollongong, School of Psychology, Wollongong, Australia, d.karamacoska@westernsydney.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Robert J Barry Diana Karamacoska Genevieve Z Steiner Google Robert J Barry Diana Karamacoska Genevieve Z Steiner Google Scholar Robert J Barry Diana Karamacoska Genevieve Z Steiner PubMed Robert J Barry Diana Karamacoska Genevieve Z Steiner Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Anticipation and the control of voluntary action

Anticipation and the control of voluntary action

Sorbic acid stress activates the Candida glabrata high osmolarity glycerol MAP kinase pathway

Weak organic acids such as sorbic acid are important food preservatives and powerful fungistatic agents. These compounds accumulate in the cytosol and disturb the cellular pH and energy homeostasis. Candida glabrata is in many aspects similar to Saccharomyces cerevisiae. However, with regard to confrontation to sorbic acid, two of the principal response pathways behave differently in C. glabrata. In yeast, sorbic acid stress causes activation of many genes via the transcription factors Msn2 and Msn4. The C. glabrata homologs CgMsn2 and CgMsn4 are apparently not activated by sorbic acid. In contrast, in C. glabrata the high osmolarity glycerol (HOG) pathway is activated by sorbic acid. Here we show that the MAP kinase of the HOG pathway, CgHog1, becomes phosphorylated and has a function for weak acid stress resistance. Transcript profiling of weak acid treated C. glabrata cells suggests a broad and very similar response pattern of cells lacking CgHog1 compared to wild type which is over lapping with but distinct from S. cerevisiae. The PDR12 gene was the highest induced gene in both species and it required CgHog1 for full expression. Our results support flexibility of the response cues for general stress signaling pathways, even between closely related yeasts, and functional extension of a specific response pathway.

Expression of Bcl-2 Pro-Survival Family Proteins Predicts Pharmacological Responses to ABT-199, a Novel and Selective Bcl-2 Antagonist, in Multiple Myeloma Models

AbstractAbstract 5028Multiple myeloma (MM) is a hematological malignancy of the bone marrow caused by the dysregulated proliferation of monoclonal antibody producing plasma cells. A hallmark feature of cancer is the ability to evade cell death signals induced by stress response cues. The Bcl-2 family of proteins regulates the intrinsic apoptosis pathways and consists of pro-apoptotic (Bax, Bak, Bad, Bim, Noxa, Puma) and pro-survival (Bcl-2, Bcl-xL, Mcl-1); the balance of which dictates the life or death status of MM tumor cells. Thus, there is a strong rationale to target members of the Bcl-2 proteins for the treatment of MM. ABT-199 is a potent BH3-only mimetic that selectively antagonizes Bcl-2 and is currently in phase I clinical trials for the treatment of hematological malignancies. Therefore, we evaluated the efficacy of ABT-199 as a single agent and in combination with standard of care drugs such as Velcade (bortezomib) in preclinical models of MM.A panel of 21 human MM cell lines was evaluated in vitro for to sensitivity to ABT-199. ABT-199 potently inhibited cell viability in a sub-set of MM cell lines (7/21) with EC50 values less than 1 μM. Expression of Bcl-2, Bcl-xL, Mcl-1, Bim and other Bcl-2 family proteins were evaluated by protein and mRNA. Cell line modeling identified thresholds for expression of Bcl-2, Bcl-xL and Mcl-1 that best predicted sensitivity and resistance to ABT-199 and the dual Bcl-2/Bcl-xL antagonist, navitoclax. Consistent with the target inhibition profile of these drugs, we found that MM lines that were Bcl-2high/Bcl-xLlow/Mcl-1low are the most sensitive to ABT-199 treatment. Whereas cell lines that are Bcl-xLhigh remain sensitive to navitoclax but not ABT-199. MM cell lines that are Mcl-1high are less sensitive to both ABT-199 and navitoclax, suggesting that Mcl-1 is a resistance factor to both drugs. Utilizing a novel Mesoscale Discovery based immunoassay we determined that levels of Bcl-2/Bim complexes also correlated with sensitivity of ABT-199 in the MM cell lines tested. In addition, the t(11;14) status in these cell lines associated with sensitivity to ABT-199. The clinical relevance of the Bcl-2 pro-survival expression pattern in MM cell lines, was determined by a collection of bone marrow biopsies and aspirates (n=27) from MM patients by immunohistochemistry for prevalence of Bcl-2 and Bcl-xL. Similar to our in vitro observations, the majority (75%) of the MM bone marrow biopsies and aspirates had high Bcl-2 levels whereas 50% had high Bcl-xL expression. Therefore, a subset of patient samples (33%) were identified with a favorable biomarker profile (Bcl-2high/Bcl-xLlow) that may predict ABT-199 single agent activity.ABT-199 synergized with bortezomib in decreasing cell viability in the majority of MM cell lines tested in vitro based on the Bliss model of independence analyses (Bliss score range = 10 to 40). However the window of combination activity was reduced due to high degree of sensitivity to bortezomib alone. Therefore, the combination efficacy of ABT-199 and bortezomib was further evaluated in vivo in MM xenograft models that expressed high levels of Bcl-2 protein (OPM-2, KMS-11, RPMI-8226, H929 and MM. 1s). Bortezomib treatment alone at a maximum tolerated dose resulted in tumor regressions or stasis in all xenograft models tested. ABT-199 at a maximum tolerated dose was moderately efficacious (defined by tumor growth delay) as a single agent in xenograft models that expressed high protein levels of Bcl-2 but relatively lower levels of Bcl-xL. However, the combination of ABT-199 with bortezomib significantly increased the overall response rate and durability of anti-tumor activity when compared to bortezomib, resulting in increased cell death in vivo. Treatment with bortezomib increased levels of the pro-apoptotic BH3-only protein, Noxa, in MM xenograft models that expressed high levels of Mcl-1. Given that the induction of Noxa by bortezomib results in neutralization of Mcl-1 pro-survival activity in MM models [Gomez-Bougie et al; Cancer Res. 67:5418–24 (2007)], greater efficacy may be achieved when Bcl-2 is antagonized by ABT-199 thereby inhibiting pro-survival activity occurring through either Bcl-2 or Mcl-1 and increasing cell death. Thus, our preclinical data support the clinical evaluation of ABT-199 in combination with bortezomib in MM patients in which relative expression of the Bcl-2 pro-survival proteins may serve as predictive biomarkers of drug activity. Disclosures:Sampath:Genentech: Employment, Equity Ownership. Punnoose:Genentech: Employment, Equity Ownership. Boghaert:Abbott Pharmaceuticals: Employment, Equity Ownership. Belmont:Genentech: Employment, Equity Ownership. Chen:Abbott Pharmaceuticals: Employment, Equity Ownership. Peale:Genentech: Employment, Equity Ownership. Tan:Genentech: Employment, Equity Ownership. Darbonne:Genentech: Employment, Equity Ownership. Yue:Genentech: Employment, Equity Ownership. Oeh:Genentech: Employment, Equity Ownership. Lee:Genentech: Employment, Equity Ownership. Fairbrother:Genentech: Employment, Equity Ownership. Souers:Abbott Pharmaceuticals: Employment, Equity Ownership. Elmore:Abbott Pharmaceuticals: Employment, Equity Ownership. Leverson:Abbott Pharmaceuticals: Employment, Equity Ownership.

Prefrontal cortex contributions to controlled memory judgment: fMRI evidence from adolescents and young adults

Cortical regions supporting cognitive control and memory judgment are structurally immature in adolescents. Here we studied adolescents (13–15 y.o.) and young adults (20–22 y.o.) using a recognition memory paradigm that modulates cognitive control demands through cues that probabilistically forecast memory probe status. Behaviorally, adolescence was associated with quicker responding in the presence of invalid cues compared to young adulthood. fMRI data demonstrated that while both groups increasingly activated posterior dorsolateral prefrontal (dlPFC), midline, and lateral parietal regions for invalidly compared to validly cued trials, this differential invalid cueing response ended sooner in adolescents, consistent with their quicker responding on invalidly cued trials. Critically, dlPFC also demonstrated reversed brain–behavior associations across the groups. Increased mean dlPFC activation during invalid cueing was linked to improved performance in young adults, whereas increases within adolescents were linked to impaired performance. Resting state connectivity analysis revealed greater connectivity between dlPFC and episodic retrieval linked regions in young adults relative to adolescents. These data demonstrate that the functional interpretation of dlPFC activation hinges on its physical maturation and suggest that the pattern of behavioral and neural response in adolescents reflects different functional integration of cognitive control and memory systems.