Tonic Levels Research Articles

Role of Type I Interferon Signaling in Regulating Intestinal γδ IEL Homeostasis and Effector Function

Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) function as a first line of defense against injury or microbial invasion. The majority of the γδ IELs express the Vγ7 T cell receptor (TCR); however, the epithelial compartment also contains Vγ1+ or Vγ4+ cells, which are typically found in peripheral lymphoid organs. Type I interferon (IFN) is a critical immunomodulatory cytokine that contributes to the innate immune response and the maintenance of mucosal homeostasis. Ubiquitously expressed, type I IFNs activate the IFNα/β receptor (IFNAR) and initiate downstream signaling through signal transducer and activator of transcription 1 (STAT1). In response to type I IFN, STAT1 has been shown to inhibit conventional CD8 T cell proliferation. Tonic type I IFN signaling has been shown to shape the intestinal lamina propria immune compartment, yet the role of type I IFN in regulating γδ IEL remains unknown. Thus, we hypothesize that type I IFN modulates γδ IEL proliferation and effector function. Morphometric analysis of γδ T cells in the jejunum of GFP γδ T cell reporter mice (TcrdEGFP, WT) and TcrdEGFP IFNAR‐deficient mice showed a 2.3‐fold increase in the number of γδ T cells in IFNAR KO mice compared to WT (p=0.004). We next investigated the composition of Vγ subsets in the epithelial compartment of IFNAR KO mice. Using flow cytometry, we found a substantial increase in Vγ7− IELs including a 3.4‐fold and 7.6‐fold increase in Vγ1+ and Vγ4+ IEL subsets, respectively. In contrast, Vγ7+ IELs were only increased by 1.8‐fold. To determine if the increased cell number was due to enhanced proliferation, mice were injected with 5‐ethynyl‐2’‐deoxyuridine (EdU). Indeed, all IFNAR KO γδ IEL subsets proliferated more compared to WT; however, proliferation was markedly increased in Vγ7− relative to Vγ7+ IELs (110% vs 30%). Consistent with its anti‐proliferative role, we found that total STAT1 expression was decreased by 45% in IFNAR KO γδ IELs compared to WT (p=0.02). To identify molecular pathways contributing to this phenotype, we performed RNA sequencing on sorted Vγ1+ and Vγ7+ IELs from WT and IFNAR KO mice. Genes associated with cell cycle and PI3K/Akt signaling were significantly increased in IFNAR KO γδ IEL subsets, as was IL‐4, which can activate PI3K signaling and promote CD8 T cell proliferation. Enhanced Il4 expression in IFNAR KO γδ IELs was validated by real‐time PCR. Since IL‐4 activation leads to STAT6 phosphorylation, we next assessed pSTAT6 in ex vivo cultured WT and IFNAR KO γδ IELs by flow cytometry. Basal pSTAT6 was elevated in IFNAR KO γδ IELs compared to WT, and the addition of anti‐IL‐4 antibody to IFNAR KO γδ IELs was sufficient to abrogate this response. Taken together, our findings demonstrate that tonic low level IFNAR signaling maintains γδ IEL homeostasis and regulates their effector function at steady‐state. Loss of IFNAR signaling promotes an expanded Vγ7− IEL compartment, which may result from reduced STAT1 and/or increased IL‐4 signaling.Support or Funding InformationRutgers University Busch Biomedical Research GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Hemispheric Distribution of α-Band EEG Activity During Orienting of Attention in Patients with Reduced Awareness of the Left Side of Space (Spatial Neglect).

EEG studies in healthy humans have highlighted that alpha-band activity is relatively reduced over the occipital-parietal areas of the hemisphere contralateral to the direction of spatial attention. Here, we investigated the hemispheric distribution of alpha during orienting of attention in male and female right brain-damaged patients with left spatial neglect. Temporal spectral evolution showed that in patients with neglect alpha oscillations over the damaged hemisphere were pathologically enhanced both during the baseline-fixation period that preceded cued orienting (capturing tonic alpha changes) and during orienting with leftward, rightward, or neutral-bilateral spatial cues (reflecting phasic alpha changes). Patients without neglect showed a similar though significantly less enhanced hemispheric asymmetry. Healthy control subjects displayed a conventional decrease of alpha activity over the hemisphere contralateral to the direction of orienting. In right-brain-damaged patients, neglect severity in the line bisection task was significantly correlated both with tonic alpha asymmetry during the baseline period and with phasic asymmetries during orienting of attention with neutral-bilateral and leftward cues. Asymmetries with neutral-bilateral and leftward cues were correlated with lesion of white matter tracts linking frontal with parietal-occipital areas. These findings show that disruption of rostrocaudal white matter connectivity in the right hemisphere interferes with the maintenance of optimal baseline tonic levels of alpha and the phasic modulation of alpha activity during shifts of attention. The hemispheric distribution of alpha activity can be used as a diagnostic tool for acquired pathological biases of spatial attention due to unilateral brain damage.SIGNIFICANCE STATEMENT Alpha desynchronization over the hemisphere contralateral to the attended side of space is a reliable marker of attentional orienting in the healthy human brain: can the same marker be used to spot and quantify acquired disturbances of spatial attention after unilateral brain injuries? Are pathological modifications in the hemispheric distribution of alpha specifically linked to attentional neglect for one side of space? We show that in patients with right brain damage the pathological enhancement of alpha oscillations over the parietal and occipital areas of the injured hemisphere is correlated with reduced awareness for the left side of space and with the lesion of white matter pathways that subserve frontal modulation of alpha activity in posterior brain areas.

Prenatal Effects of Fluoxetine on Adaptive Behavior and the Cognitive Domain in Male Rats During the Prepubertal Period of Development

The effects of injections of the selective serotonin reuptake inhibitor fluoxetine or physiological saline to rats during pregnancy (from day 9 to day 20) on behavioral parameters of the tonic pain system, anxiety levels, depression, and cognitive measures were studied in male offspring during the prepubertal period of development. The results demonstrated decreases in body weight in neonatal and 25-day-old males. Improvements in spatial learning ability were seen, though there were no changes in measures of psychoemotional behavior in males in the prepubertal period of development. Comparison of the effects of prenatal administration of fluoxetine and physiological saline on the functional activity of the nociceptive system showed that the serotonin reuptake inhibitor eliminated the effect of invasive stress due to the injection. Chronic injections of the antidepressant fluoxetine during pregnancy did not increase pain sensitivity in male offspring.

Examining the link between reward and response inhibition in individuals with substance abuse tendencies

BackgroundSubstance use problems are often characterized by dysregulation in reward sensitivity and inhibitory control. In line with this representation, the goal of this investigation was to determine how substance abuse tendencies among university students affect incentivized response inhibition. Additionally, this study examined whether striatal dopamine moderates the impact of substance use on response inhibition performance. MethodsThe sample included ninety-eight university students. Participants completed this prospective experimental study at an on-campus laboratory. All participants completed substance abuse and disinhibition subscales of the Externalizing Spectrum Inventory-Brief Form. Using a within-subjects design, participants then performed the Stop Signal Task under both neutral (unrewarded) and reward conditions, in which correct response cancellations resulted in a monetary reward. Striatal tonic dopamine levels were operationalized using spontaneous eyeblink rate. ResultsThe outcome measures were Stop Signal Reaction Time (SSRT) performance in the unrewarded and rewarded phases of the task. A hierarchical linear regression analysis, controlling for trait disinhibition, age, gender, and cigarette smoking status, identified an interactive effect of substance use and striatal dopamine levels on incentivized SSRT. Substance abuse tendencies were associated with slower SSRT and thus poorer inhibitory control under reward conditions among individuals with low levels of striatal dopamine (F = 7.613, p = .007). ConclusionsThis work has implications for research examining advanced drug use trajectories. In situations in which rewards are at stake, drug users with low tonic dopamine may be more motivated to seek those rewards at the expense of regulating inhibitory control.

Meditation experience predicts negative reinforcement learning and is associated with attenuated FRN amplitude

Focused attention meditation (FAM) practices are cognitive control exercises where meditators learn to maintain focus and attention in the face of distracting stimuli. Previous studies have shown that FAM is both activating and causing plastic changes to the mesolimbic dopamine system and some of its target structures, particularly the anterior cingulate cortex (ACC) and striatum. Feedback-based learning also depends on these systems and is known to be modulated by tonic dopamine levels. Capitalizing on previous findings that FAM practices seem to cause dopamine release, the present study shows that FAM experience predicts learning from negative feedback on a probabilistic selection task. Furthermore, meditators exhibited attenuated feedback-related negativity (FRN) as compared with nonmeditators and this effect scales with meditation experience. Given that reinforcement learning and FRN are modulated by dopamine levels, a possible explanation for our findings is that FAM practice causes persistent increases in tonic dopamine levels which scale with amount of practice, thus altering feedback processing.

Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin

The dopamine system—essential for mood and movement—can be activated in two ways: by excitatory inputs that cause burst firing and stamp-in learning or by slow excitatory or inhibitory inputs—like leptin, insulin, ghrelin, or corticosterone—that decrease or increase single-spike (pacemaker) firing rate and that modulate motivation. In the present study we monitored blood samples taken prior to and during intravenous cocaine or saline self-administration in rats. During cocaine-taking, growth hormone and acetylated ghrelin increased 10-fold; glucagon-like peptide-1 (GLP-1) doubled; non-acetylated ghrelin, insulin-like growth factor-1 (IGF-1), and corticosterone increased by 50% and adiponectin increased by 17%. In the same blood samples, leptin, insulin, gastric inhibitory polypeptide (GIP), and prolactin decreased by 40–70%. On the first day of testing under extinction conditions—where the animals earned unexpected saline instead of cocaine—5-fold increases were seen for growth hormone and acetylated ghrelin and equal changes—in amplitude and latency—were seen in each of the other cases except for IGF-1 (which increased at a slower rate). Single-spike firing affects the tonic activation level of the dopamine system, involving very different controls than those that drive burst firing; thus, the present data suggest interesting new targets for medications that might be used in the early stages of drug abstinence.

A comparative study of cybersickness during exposure to virtual reality and "classic" motion sickness: are they different?

Existing evidence suggests that cybersickness may be clinically different from "classic," motion-induced sickness; this evidence was, however, obtained in separate studies that focused on just one of the two conditions. Our aim was to bring clarity to this issue by directly comparing subjective symptoms and physiological effects of motion sickness induced by physical motion (Coriolis cross-coupling) and by immersion in virtual reality (ride on a roller coaster) in the same subjects. A cohort of 30 young, healthy volunteers was exposed to both stimulations in a counterbalanced order on 2 separate days ≥1 wk apart. Nausea scores were recorded during the exposure, and the Motion Sickness Assessment Questionnaire (MSAQ) was used to profile subjective symptoms postexperiment. Tonic and phasic forehead skin conductance level (SCL) was measured before and during exposure in both stimulation methods. We found that the nausea onset times were significantly correlated in both tests (r = 0.40, P = 0.03). Similarly, the maximum nausea ratings were significantly correlated during both provocations (r = 0.58, P = 0.0012). Symptom-profiling with the MSAQ revealed substantial and significant correlations between total symptom scores (r = 0.69, P < 0.0001) between each of 4 symptom clusters and between 15/18 individual symptoms assessed in both conditions. Both virtual reality and Coriolis cross-coupling provocations caused an increase in tonic SCL associated with nausea [mean difference (mean diff) = 5.1, confidence interval (CI) = (2.59, 6.97), P = 0.007 and mean diff = 1.49, CI = (0.47, 7.08), P = 0.0001, respectively], with a close correlation between the conditions (r = 0.48, P = 0.04). This was accompanied by a significant increase in the amplitude of phasic skin conductance transients in both visual stimulation and Coriolis cross-coupling when participants reported maximum nausea compared with no nausea [mean diff = 0.27, CI = (0.091, 0.63), P < 0.001 and mean diff = 0.235, CI = (0.053, 0.851), P < 0.006, respectively]. We conclude that symptoms and physiological changes occurring during cybersickness and classic motion sickness are quite similar, at least during advanced stages of these malaises.NEW & NOTEWORTHY Expansion of virtual reality (VR) technology has provoked an interest in cybersickness, a subtype of motion sickness induced by immersion in VR. Finding means for preventing and managing cybersickness requires good understanding of its nature, including its relationship to "classic" motion sickness. The knowledge about this relationship is controversial, partly because there were no studies where the same cohort was exposed to the two provocations. With this approach, we demonstrate that symptoms and physiological manifestations of the two conditions are identical.

Does the Neuroimmune Modulator Ibudilast Alter Food Craving? Results in a Sample With Alcohol Use Disorder.

Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. A randomized, placebo-control, crossover human laboratory trial advanced IBUD development for alcohol use disorder and found that IBUD reduced tonic levels of alcohol craving. Given the importance of considering medication effects on other appetitive behavior, the present study tested the effect of IBUD (50 mg bid) on food craving. The present study was a secondary data analysis of the trial of IBUD in non-treatment seekers with alcohol use disorder (N = 19). High-fat/high-sugar food craving was measured daily. Moreover, because substantial literatures show that small alcohol doses and psychological stress increase eating of high-fat/high-sugar food, craving for high-fat/high-sugar food was measured after alcohol infusion and stress reactivity. Results indicated that IBUD did not alter tonic high-fat/high-sugar food craving. Alcohol infusion did not generally increase high-fat/high-sugar food craving but psychological stress did. Likewise, IBUD did not affect high-fat/high-sugar food craving after alcohol infusion but IBUD did increase high-fat/high-sugar food craving after psychological stress. Follow-up analyses revealed that, among individuals with lower depressive symptomatology, IBUD compared to placebo heightened the effect of psychological stress on high-fat/high-sugar food craving. These results advance the development of IBUD for addiction indications by demonstrating that IBUD compared to placebo does not suppress other appetitive responses, namely craving for high-fat/high-sugar food among individuals with alcohol use disorder.

Tracking tonic dopamine levels in vivo using multiple cyclic square wave voltammetry

For over two decades, fast-scan cyclic voltammetry (FSCV) has served as a reliable analytical method for monitoring dopamine release in near real-time in vivo. However, contemporary FSCV techniques have been limited to measure only rapid (on the order of seconds, i.e. phasic) changes in dopamine release evoked by either electrical stimulation or elicited by presentation of behaviorally salient stimuli, and not slower changes in the tonic extracellular levels of dopamine (i.e. basal concentrations). This is because FSCV is inherently a differential method that requires subtraction of prestimulation tonic levels of dopamine to measure phasic changes relative to a zeroed baseline. Here, we describe the development and application of a novel voltammetric technique, multiple cyclic square wave voltammetry (M-CSWV), for analytical quantification of tonic dopamine concentrations in vivo with relatively high temporal resolution (10 s). M-CSWV enriches the electrochemical information by generating two dimensional voltammograms which enable high sensitivity (limit of detection, 0.17 nM) and selectivity against ascorbic acid, and 3,4-dihydroxyphenylacetic acid (DOPAC), including changes in pH. Using M-CSWV, a tonic dopamine concentration of 120 ± 18 nM (n = 7 rats, ± SEM) was determined in the striatum of urethane anethetized rats. Pharmacological treatments to elevate dopamine by selectively inhibiting dopamine reuptake and to reduce DOPAC by inhibition of monoamine oxidase supported the selective detection of dopamine in vivo. Overall, M-CSWV offers a novel voltammetric technique to quantify levels and monitor changes in tonic dopamine concentrations in the brain to further our understanding of the role of dopamine in normal behavior and neuropsychiatric disorders.

GABA beyond the synapse: defining the subtype-specific pharmacodynamics of non-synaptic GABAA receptors.

Physiologically relevant combinations of recombinant GABAA receptor (GABAR) subunits were expressed in HEK293 cells. Using whole-cell voltage clamp and rapid drug application, we measured the GABAR-subtype-specific properties to convey either synaptic or extrasynaptic signalling in a range of physiological contexts. α4βδ GABARs are optimally tuned to submicromolar tonic GABA and transient surges of micromolar GABA concentrations. α5β2γ2l GABARs are better suited to higher tonic GABA levels, but also convey robust responses to brief synaptic and perisynaptic GABA fluctuations. α1β2/3δ GABARs function well at prolonged, micromolar (>2μm) GABA levels, but not to low tonic (<1μm GABA) or synaptic/transient GABAergic signalling. These results help illuminate the context- and isoform-specific modes of GABAergic signalling in the brain. GABAA receptors (GABARs) mediate a remarkable diversity of signalling modalities in vivo. Yet most published work characterizing responses to GABA has focused on the properties needed to convey fast, phasic synaptic inhibition. We therefore aimed to characterize the most prevalent (α4βδ, α5β3γ2L) and least prevalent (α1β2δ) non-synaptic GABAR currents, using whole-cell voltage clamp recordings of recombinant GABAR expressed in HEK293 cells and drug application protocols to recapitulate the GABA concentration profiles occurring during both fast synaptic and slow extrasynaptic signalling. We found that α4βδ GABARs were very sensitive to submicromolar GABA, with a rank order potency of α4β2δ ≥ α4β1δ ≈ α4β3δ GABARs. In comparison, the GABA EC50 was up to 20 times higher for α1β2γ2L GABARs, with α1β2δ and α5β3γ2L GABARs having intermediate GABA potency. Both α4βδ and α5β3γ2L GABAR currents exhibited slow, but substantial, desensitization as well as prolonged rates of deactivation. These GABAR current properties defined distinct 'dynamic ranges' of responsiveness to changing GABA for α4β2δ (0.1-1μm), α5β3γ2L (0.5-7μm) and α1β2γ2L (0.6-9μm) GABARs. Finally, α1β2δ GABARs were notable for their relative lack of desensitization and extremely quick deactivation. In summary, our results help delineate the roles that specific GABARs may play in mediating non-synaptic GABA signals. Since ambient GABA levels may be altered during development as well as by drugs and disease states, these findings may help future efforts to understand disrupted inhibition underlying a variety of neurological illnesses, such as epilepsy.

Nicotine-Induced Conditional Place Preference Is Affected by Head Injury: Correlation with Dopamine Release in the Nucleus Accumbens Shell.

BackgroundTraumatic brain injury is known to impact dopamine-mediated reward pathways, but the underlying mechanisms have not been fully established.MethodsNicotine-induced conditional place preference was used to study rats exposed to a 6-psi fluid percussion injury with and without prior exposure to nicotine. Preference was quantified as a score defined as (C1 − C2) / (C1 + C2), where C1 is time in the nicotine-paired compartment and C2 is time in the saline-paired compartment. Subsequent fast-scan cyclic voltammetry was used to analyze the impact of nicotine infusion on dopamine release in the shell portion of the nucleus accumbens. To further determine the influence of brain injury on nicotine withdrawal, nicotine infusion was administered to the rats after fluid percussion injury. The effects of fluid percussion injury on conditional place preference after prior exposure to nicotine and abstinence or withdrawal from nicotine were also assessed.ResultsAfter traumatic brain injury, dopamine release was reduced in the nucleus accumbens shell, and nicotine-induced conditional place preference preference was significantly impaired. Preference scores of control, sham-injured, and fluid percussion injury groups were 0.1627±0.04204, 0.1515±0.03806, and -0.001300±0.04286, respectively. Nicotine-induced conditional place preference was also seen in animals after nicotine pretreatment, with a conditional place preference score of 0.07805±0.02838. Nicotine preexposure substantially increased tonic dopamine release in sham-injured animals, but it did not change phasic release; nicotine exposure after fluid percussion injury enhanced phasic release, though not to the same levels seen in sham-injured rats. Conditioned preference was related not only to phasic dopamine release (r=0.8110) but also to the difference between tonic and phasic dopamine levels (r=0.9521).ConclusionsTraumatic brain injury suppresses dopamine release from the shell portion of the nucleus accumbens, which in turn significantly alters reward-seeking behavior. These results have important implications for tobacco and drug use after traumatic brain injury.

Inhibiting Basal Ganglia Regions Reduces Syllable Sequencing Errors in Parkinson's Disease: A Computer Simulation Study.

Background: Parkinson's disease affects many motor processes including speech. Besides drug treatment, deep brain stimulation (DBS) in the subthalamic nucleus (STN) and globus pallidus internus (GPi) has developed as an effective therapy.Goal: We present a neural model that simulates a syllable repetition task and evaluate its performance when varying the level of dopamine in the striatum, and the level of activity reduction in the STN or GPi.Method: The Neural Engineering Framework (NEF) is used to build a model of syllable sequencing through a cortico-basal ganglia-thalamus-cortex circuit. The model is able to simulate a failing substantia nigra pars compacta (SNc), as occurs in Parkinson's patients. We simulate syllable sequencing parameterized by (i) the tonic dopamine level in the striatum and (ii) average neural activity in STN or GPi.Results: With decreased dopamine levels, the model produces syllable sequencing errors in the form of skipping and swapping syllables, repeating the same syllable, breaking and restarting in the middle of a sequence, and cessation (“freezing”) of sequences. We also find that reducing (inhibiting) activity in either STN or GPi reduces the occurrence of syllable sequencing errors.Conclusion: The model predicts that inhibiting activity in STN or GPi can reduce syllable sequencing errors in Parkinson's patients. Since DBS also reduces syllable sequencing errors in Parkinson's patients, we therefore suggest that STN or GPi inhibition is one mechanism through which DBS reduces syllable sequencing errors in Parkinson's patients.

Distress tolerance across self-report, behavioral and psychophysiological domains in women with eating disorders, and healthy controls

Background and objectivesThe tendency to engage in impulsive behaviors when distressed is linked to disordered eating. The current study comprehensively examines emotional responses to a distress tolerance task by utilizing self-report, psychophysiological measures (respiratory sinus arrhythmia [RSA], skin conductance responses [SCRs] and tonic skin conductance levels [SCLs]), and behavioral measures (i.e., termination of task, latency to quit task). Methods26 healthy controls (HCs) and a sample of treatment-seeking women with Bulimia Nervosa (BN), Binge Eating Disorder (BED) and Anorexia Nervosa (AN) (N = 106) completed the Paced Auditory Serial Addition Task- Computerized (PASAT-C). Psychophysiological measurements were collected during baseline, PASAT-C, and recovery, then averaged for each time period. Self-reported emotions were collected at baseline, post-PASAT-C and post-recovery. ResultsOverall, we found an effect of Time, with all participants reporting greater negative emotions, less happiness, lower RSA, more SCRs and higher tonic SCLs after completion of the PASAT-C relative to baseline. There were no differences in PASAT-C performance between groups. There was an effect of Group for negative emotions, with women with BN, BED and AN reporting overall higher levels of negative emotions relative to HCs. Furthermore, we found an effect of Group for greater urges to binge eat and lower RSA values among BED, relative to individuals with BN, AN and HCs. LimitationsThis study is cross-sectional and lacked an overweight healthy control group. ConclusionDuring the PASAT-C, individuals with eating disorders (EDs) compared to HCs report higher levels of negative emotions, despite similar physiological and behavioral manifestations of distress.

Executive and arousal vigilance decrement in the context of the attentional networks: The ANTI-Vea task

BackgroundVigilance is generally understood as the ability to detect infrequent critical events through long time periods. In tasks like the Sustained Attention to Response Task (SART), participants tend to detect fewer events across time, a phenomenon known as “vigilance decrement”. However, vigilance might also involve sustaining a tonic arousal level. In the Psychomotor Vigilance Test (PVT), the vigilance decrement corresponds to an increment across time in both mean and variability of reaction time. New MethodThe present study aimed to develop a single task –Attentional Networks Test for Interactions and Vigilance – executive and arousal components (ANTI-Vea)– to simultaneously assess both components of vigilance (i.e., the executive vigilance as in the SART, and the arousal vigilance as in the PVT), while measuring the classic attentional functions (phasic alertness, orienting, and executive control). ResultsIn Experiment #1, the executive vigilance decrement was found as an increment in response bias. In Experiment #2, this result was replicated, and the arousal vigilance decrement was simultaneously observed as an increment in reaction time. Comparison with Existing MethodThe ANTI-Vea solves some issues observed in the previous ANTI-V task with the executive vigilance measure (e.g., a low hit rate and no vigilance decrement). Furthermore, the new ANTI-Vea task assesses both components of vigilance together with others typical attentional functions. ConclusionsThe new attentional networks test developed here may be useful to provide a better understanding of the human attentional system. The role of sensitivity and response bias in the executive vigilance decrement are discussed.

The opportunity cost of time modulates cognitive effort

A spate of recent work demonstrates that humans seek to avoid the expenditure of cognitive effort, much like physical effort or economic resources. Less is clear, however, about the circumstances dictating how and when people decide to expend cognitive effort. Here we adopt a popular theory of opportunity costs and response vigor and to elucidate this question. This account, grounded in Reinforcement Learning, formalizes a trade-off between two costs: the harder work assumed necessary to emit faster actions and the opportunity cost inherent in acting more slowly (i.e., the delay that results to the next reward and subsequent rewards). Recent work reveals that the opportunity cost of time—operationalized as the average reward rate per unit time, theorized to be signaled by tonic dopamine levels, modulates the speed with which a person responds in a simple discrimination tasks. We extend this framework to cognitive effort in a diverse range of cognitive tasks, for which 1) the amount of cognitive effort demanded from the task varies from trial to trial and 2) the putative expenditure of cognitive effort holds measureable consequences in terms of accuracy and response time. In the domains of cognitive control, perceptual decision-making, and task-switching, we found that subjects tuned their level of effort exertion in accordance with the experienced average reward rate: when the opportunity cost of time was high, subjects made more errors and responded more quickly, which we interpret as a withdrawal of cognitive effort. That is, expenditure of cognitive effort appeared to be modulated by the opportunity cost of time. Further, and consistent with our account, the strength of this modulation was predicted by individual differences in efficacy of cognitive control. Taken together, our results elucidate the circumstances dictating how and when people expend cognitive effort.

A CARD10-Dependent Tonic Signalosome Activates MALT1 Paracaspase and Regulates IL-17/TNF-α–Driven Keratinocyte Inflammation

The paracaspase MALT1 (Mucosa associated lymphoid tissue lymphoma translocation protein 1) controls signaling downstream of several cell surface receptors, such as C-type lectin receptors on myeloid cells and antigen receptors on lymphocytes. Upon receptor engagement, MALT1, BCL10 (B-cell lymphoma/leukemia 10) and a CARD (Caspase recruitment domain) family member assemble into a ‘CBM’ complex, which is required to trigger MALT1 paracaspase activity and downstream transcriptional activation mechanisms (Meininger and Krappmann 2016; Rosebeck et al. 2011). Here, we found that CARD10 is highly expressed in proliferating keratinocytes and is responsible for a tonic level of paracaspase activity, driven by MALT1 isoform A. Furthermore, using the potent and selective MALT1 inhibitor MLT-827 (Bardet et al. 2018; Unterreiner et al. 2017), we reveal that MALT1 activity regulates pro-inflammatory responses downstream of IL-17/TNF-α.

Relationship between tonic and phasic craving for alcohol

BackgroundMultiple measures are utilized to assess alcohol craving, often interchangeably. Little is known about the relationship between tonic and phasic craving. This study fills this gap in the literature by examining the association between tonic levels of alcohol craving and phasic craving for alcohol that is provoked by alcohol administration. MethodsForty-three non-treatment seeking problem drinkers underwent an initial interview and two laboratory testing sessions, where either alcohol or a saline placebo was administered intravenously. Tonic craving was assessed via the Penn Alcohol Craving Scale (PACS) and Obsessive Compulsive Drinking Scale (OCDS) at the initial interview. Phasic craving was assessed during the laboratory sessions (i.e., alcohol and saline administrations, single blinded) at baseline and at 3 subsequent breath alcohol concentrations (0.02, 0.04, and 0.06 g/dl). ResultsThere was a main effect of PACS in predicting phasic craving across both saline and alcohol administration conditions (p < 0.05). The OCDS was predictive of phasic craving when alcohol, but not saline, was administered (p = 0.058); the obsessive subscale (p = 0.01), but not the compulsive subscale (p > 0.10), predicted phasic craving during alcohol, as compared to saline administration. ConclusionIn sum, tonic craving captured by the OCDS was predictive of phasic craving during alcohol administration whereas the PACS more generally captured the increase in phasic craving. Therefore, these measures of tonic craving may function differently in capturing the experience of phasic craving. Implications for the utilization of the PACS and OCDS as well as assessments of craving in alcoholism research are discussed.

Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD

Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention-deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD.

Electrodermal Response and Automation Trust during Simulated Self-Driving Car Use

The integration of self-driving vehicles may expose individuals with health concerns to undue amounts of stress. Psychophysiological indicators of stress were used to determine changes in tonic and phasic stress levels brought about by a high-fidelity autonomous vehicle simulation. Twenty-eight participants completed one manual driving task and two automated driving tasks. Participants reported their subjective level of trust in the automated systems using the Automation Trust Survey. Psychophysiological stress was indexed using skin conductance and trapezius muscle tension. Results indicate that users show more signs of physiological stress when the vehicle drives autonomously than when the users is in control. Results also indicate that users show an additional increase in stress when the user reports low trust in the autonomous vehicle. These findings suggest that health-care professionals and manufactures should be aware of additional stress associated with self-driving technology.

Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes.

Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomerular filtration rate. or electrolyte excretion rates between the Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex-treated fetuses was significantly lower (12.9 ± 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 ± 1.0 nl/min). This resetting of TGF sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TGF sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TGF response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.