Tonic Levels Research Articles

Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

Valence-dependent dopaminergic modulation during reversal learning in Parkinson’s disease: A neurocomputational approach

Reinforcement learning, crucial for behavior in dynamic environments, is driven by rewards and punishments, modulated by dopamine (DA) changes. This study explores the dopaminergic system’s influence on learning, particularly in Parkinson’s disease (PD), where medication leads to impaired adaptability. Highlighting the role of tonic DA in signaling the valence of actions, this research investigates how DA affects response vigor and decision-making in PD. DA not only influences reward and punishment learning but also indicates the cognitive effort level and risk propensity in actions, which are essential for understanding and managing PD symptoms.In this work, we adapt our existing neurocomputational model of basal ganglia (BG) to simulate two reversal learning tasks proposed by Cools et al. We first optimized a Hebb rule for both probabilistic and deterministic reversal learning, conducted a sensitivity analysis (SA) on parameters related to DA effect, and compared performances between three groups: PD-ON, PD-OFF, and control subjects.In our deterministic task simulation, we explored switch error rates after unexpected task switches and found a U-shaped relationship between tonic DA levels and switch error frequency. Through SA, we classify these three groups. Then, assuming that the valence of the stimulus affects the tonic levels of DA, we were able to reproduce the results by Cools et al.As for the probabilistic task simulation, our results are in line with clinical data, showing similar trends with PD-ON, characterized by higher tonic DA levels that are correlated with increased difficulty in both acquisition and reversal tasks.Our study proposes a new hypothesis: valence, signaled by tonic DA levels, influences learning in PD, confirming the uncorrelation between phasic and tonic DA changes. This hypothesis challenges existing paradigms and opens new avenues for understanding cognitive processes in PD, particularly in reversal learning tasks.

Human physiological responses to different types of human-dog interactions: A randomised crossover study

Previous studies of human-dog interventions vary in terms of type of interaction, which is rarely quantified, leading to contradictory findings and limited comparability. To uncover the influence of different types of interactions, the present study investigated if it was possible to detect differences in immediate physiological measurements of healthy humans during different standardised types of interaction with a dog. Thirty-three healthy participants (women = 25, men = 8, >18 years) were exposed to four different test situations with standardised types of interaction intensity with a dog in random order: no dog present (CONTROL), looking at a dog (VISUAL), petting a dog (TACTILE) or performing tricks with a dog (ACTIVE). Each test situation lasted 10 min with a 30-min break between each. Heart rate (HR), heart rate variability (HRV) and skin conductance (tonic level (SCL) and peak counts (SCR)) were continuously recorded. Blood pressure (BP) and salivary cortisol (s-cortisol) were measured before and after each test situation. Linear Mixed Models were applied. HR, HRV, BP, SCL and SCR increased with increased interaction with the dog (for all: p < 0.001). HRV increased with decreased HR (p = 0.002), increased SCL (p = 0.027), and SCR (p < 0.001) depending on the type of interaction. Generally, s-cortisol increased with increased HR (p = 0.042), SCL increased with increased SCR (p < 0.001), and SCR increased with increased HRV (p = 0.013), depending on type of interaction. The physiological measurements HR, HRV, BP, SCL and SCR are influenced by different types of dog interaction, and thus it is important to quantify and report the type of interaction in human-dog interaction studies. (ClinicalTrials.gov ID:NCT04696419).

Convergent Comodulation Reduces Interindividual Variability of Circuit Output.

Ionic current levels of identified neurons vary substantially across individual animals. Yet, under similar conditions, neural circuit output can be remarkably similar, as evidenced in many motor systems. All neural circuits are influenced by multiple neuromodulators, which provide flexibility to their output. These neuromodulators often overlap in their actions by modulating the same channel type or synapse, yet have neuron-specific actions resulting from distinct receptor expression. Because of this different receptor expression pattern, in the presence of multiple convergent neuromodulators, a common downstream target would be activated more uniformly in circuit neurons across individuals. We therefore propose that a baseline tonic (non-saturating) level of comodulation by convergent neuromodulators can reduce interindividual variability of circuit output. We tested this hypothesis in the pyloric circuit of the crab, Cancer borealis Multiple excitatory neuropeptides converge to activate the same voltage-gated current in this circuit, but different subsets of pyloric neurons have receptors for each peptide. We quantified the interindividual variability of the unmodulated pyloric circuit output by measuring the activity phases, cycle frequency, and intraburst spike number and frequency. We then examined the variability in the presence of different combinations and concentrations of three neuropeptides. We found that at mid-level concentration (30 nM) but not at near-threshold (1 nM) or saturating (1 µM) concentrations, comodulation by multiple neuropeptides reduced the circuit output variability. Notably, the interindividual variability of response properties of an isolated neuron was not reduced by comodulation, suggesting that the reduction of output variability may emerge as a network effect.

Thermoregulatory differences in sex and time-of-day within naturally ventilated office environments

Thermal comfort research lacks continuous data collection on thermoregulation and adaptive behavior in real-world environments. This paper presents the findings of a field study that aimed at understanding the temporal and individual differences between humans’ thermoregulation and adaptation within a dynamic thermal environment. The dataset contains a 6-week long summer field study of 2022 observing nine participants in a naturally ventilated office without a cooling system. The data collection comprises a total of 43 measurement days (22,776 data points at 60s frequency). The results indicate that the overall trend in clothing insulation deviates from standard assumptions (0.5 clo), especially above air temperatures of 26 °C. The mean clothing insulation was 0.29 clo ±0.08, overall ranging from 0.20 to 0.73 clo. The data showed significant sex differences in tonic levels of electrodermal activity, the low-frequency to high-frequency heart rate variability ratio, and clothing insulation. Other heart rate variability data, like the root mean square of successive differences and beats per minute, as well as the distal skin temperature of the wrist, show significant sex differences and time-of-day variations in morning-to-afternoon comparisons. The findings indicate a nuanced relationship between air temperature and thermoregulatory responses, highlighting the need for future research with larger, more diverse participant cohorts and enhanced environmental monitoring to strengthen the validity and generalizability of the findings.

Does dual‐tasking affect the ability to generate anticipatory postural adjustments in young adults?

AbstractThe aim of this study was to investigate how additional cognitive tasks (Stroop test and counting backwards task) influence young adults' ability to generate appropriate postural responses while standing on a continuously oscillating platform. Twenty young adults (25.95 ± 2.97 years) stood on a moving platform which was translated in the anterior–posterior direction at three different frequencies (0.10, 0.25 and 0.50 Hz) in three dual‐task conditions (counting backwards task, a Stroop task or no additional cognitive task). Postural muscle onset latencies and tonic activity levels of the leg muscles were measured through surface electromyography; the number of steps taken and cognitive errors made were recorded. Results showed no significant differences in muscle activity between dual and single‐tasking conditions nor between the two dual tasking conditions. Cognitive errors were made in the counting backwards task but not the Stroop task. A frequency effect was identified with participants showing greater tonic activity in rectus femoris (p = 0.012), gastrocnemius medialis (p = 0.016) and bicep femoris (p = 0.043) at 0.5 Hz, as well as earlier muscle activation in tibialis anterior, gastrocnemius medialis and bicep femoris (p &lt; 0.001) at 0.50 Hz. Transition and steady state muscle onset latencies were only significantly different for gastrocnemius medialis at 0.25 Hz (p = 0.001). Dual tasking did not seem to influence anticipatory postural adjustments in young adults; however, perturbation intensities did. The differences observed in the number of cognitive errors made could be indicative of the regional cortical activations and overlapping demand for resources interfering with balance control, though cortical activation was not recorded. Future research should include detailed cognitive behavior, including cortical activations and task reaction times to better understand the allocation of attentional resources during perturbed balance dual tasking.

Simulated Dopamine Modulation of a Neurorobotic Model of the Basal Ganglia.

The vertebrate basal ganglia play an important role in action selection-the resolution of conflicts between alternative motor programs. The effective operation of basal ganglia circuitry is also known to rely on appropriate levels of the neurotransmitter dopamine. We investigated reducing or increasing the tonic level of simulated dopamine in a prior model of the basal ganglia integrated into a robot control architecture engaged in a foraging task inspired by animal behaviour. The main findings were that progressive reductions in the levels of simulated dopamine caused slowed behaviour and, at low levels, an inability to initiate movement. These states were partially relieved by increased salience levels (stronger sensory/motivational input). Conversely, increased simulated dopamine caused distortion of the robot's motor acts through partially expressed motor activity relating to losing actions. This could also lead to an increased frequency of behaviour switching. Levels of simulated dopamine that were either significantly lower or higher than baseline could cause a loss of behavioural integration, sometimes leaving the robot in a 'behavioral trap'. That some analogous traits are observed in animals and humans affected by dopamine dysregulation suggests that robotic models could prove useful in understanding the role of dopamine neurotransmission in basal ganglia function and dysfunction.

Comparing tonic and phasic dendritic calcium in cholinergic pedunculopontine neurons and dopaminergic substantia nigra neurons.

Several brainstem nuclei degenerate in Parkinson's disease (PD). In addition to the well-characterized dopaminergic neurons of the substantia nigra pars compacta (SNc), the cholinergic neurons of the pedunculopontine nucleus (PPN) also degenerate in PD. One leading hypothesis of selective vulnerability is that pacemaking activity and the activation of low-threshold L-type calcium current are major contributors to tonic calcium load and cellular stress in SNc dopaminergic neurons. However, it is not yet clear whether the vulnerable PPN cholinergic neurons share this property. Therefore, we used two-photon dendritic calcium imaging and whole-cell electrophysiology to evaluate the role of L-type calcium channels in tonic and phasic dendritic calcium signals in PPN and SNc neurons. In addition, we investigated N- and P/Q-type calcium channel regulation of firing properties and dendritic calcium in PPN neurons. We found that blocking L-type channels reduces tonic firing rate and dendritic calcium levels in SNc neurons. By contrast, the tonic calcium load in PPN neurons did not depend on L-, N- or P/Q-type channels. However, we found that blocking either L-type (with nifedipine) or N- and P/Q-type (with omega-conotoxin MVIIC) channels reducesphasic calcium influx in PPN dendrites. Together, these findings show that L-type calcium channels play different roles in the activity of SNc and PPN neurons, and suggest that low-threshold L-type channels are not responsible for tonic calcium levels in PPN cholinergic neurons and are therefore not likely to be a source of selective vulnerability in these cells.

Continuous long-range measurement of tonic dopamine with advanced FSCV for pharmacodynamic analysis of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa, a dopamine prodrug, alleviates the motor symptoms of Parkinson's disease (PD), but its chronic use gives rise to levodopa-induced dyskinesia (LID). However, it remains unclear whether levodopa pharmacodynamics is altered during the progressive onset of LID. Using in vivo fast-scan cyclic voltammetry and second-derivative-based background drift removal, we continuously measured tonic dopamine levels using high temporal resolution recording over 1-h. Increases to tonic dopamine levels following acute levodopa administration were slow and marginal within the naïve PD model. However, these levels increased faster and higher in the LID model. Furthermore, we identified a strong positive correlation of dyskinetic behavior with the rate of dopamine increase, but much less with its cumulative level, at each time point. Here, we identified the altered signature of striatal DA dynamics underlying LID in PD using an advanced FSCV technique that demonstrates the long-range dynamics of tonic dopamine following drug administration.

Recalled protective childhood experiences are associated with positive emotional expression in active-duty firefighters.

There is a wealth of research linking adverse childhood experiences (ACEs) with negative outcomes later in life, but less research has focused on the effects of protective childhood experiences (PCEs). PCEs have been shown broadly to promote resilience, but the precise nature of this association is not clear, particularly in studies of at-risk adults. The current investigation explored the association between recollection of early life experiences and in vivo emotional responses in at-risk adults. In 2018, 56 active-duty firefighters reported childhood experiences via a questionnaire. Using a semistructured interview, firefighters then responded to questions about recent emotionally evocative experiences (positive and negative) as a firefighter. Emotion was measured in vivo via sympathetic arousal and recorded facial expressions of emotion. Individuals who reported more PCEs expressed significantly more facial expressions of positive emotion across contexts, sr2 = .11-.14. Early childhood experiences were not significantly associated with negative facial expressions or changes in sympathetic reactivity, but ACEs were associated with tonic levels of arousal in a negative context, r = -.36. Given the adaptive role of positive emotions in adjustment to adverse events, the current investigation suggests a potential protective association between PCEs and the expression of emotion even within a high-risk context, which could help explain the resilience promoting role of PCEs.

Pivotal role of Slitrk1 in adult striatal cholinergic neurons in mice: Implication in Tourette syndrome.

The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1-2% of total neurons but send dense arbors of fibers in the stratum, making it the most ACh-abundant brain region. Here, mice receiving Slitrk1 siRNA bilateral microinjection in the dorsal striatum, Slitrk1-knockdown (KD) mice, exhibit TS-like haloperidol-sensitive stereotypic tic behaviors and impaired prepulse inhibition, as well as delayed sensorimotor response, compared with scrambled siRNA-treated controls. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls. These results suggest that Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. This article is protected by copyright. All rights reserved.

Linear integration of multisensory signals in the pupil.

The pupil of the eye responds to various salient signals from different modalities, but there is no consensus on how these pupillary responses are integrated when multiple signals appear simultaneously. Both linear and nonlinear integration have been found previously. The current study aimed to reexamine the nature of pupillary integration, and specifically focused on the early, transient pupillary responses due to its close relationship with orienting. To separate the early pupillary responses out of the pupil time series, we adopted a pupil oscillation paradigm in which sensory stimuli were periodically presented. The simulation analysis confirmed that the amplitude of the pupil oscillation, induced by stimuli repeatedly presented at relatively high rates, can precisely reflect the early, transient pupillary responses without involving the late and sustained pupillary responses. The experimental results then showed that the amplitude of pupil oscillation induced by a series of simultaneous audiovisual stimuli equaled to a linear summation of the oscillatory amplitudes when unisensory stimuli were presented alone. Moreover, the tonic arousal levels, indicated by the baseline pupil size, cannot shift the summation from linear to nonlinear. These findings together support the additive nature of multisensory pupillary integration for the early, orienting-related pupillary responses. The additive nature of pupillary integration further implies that multiple pupillary responses may be independent of each other, irrespective of their potential cognitive and neural drivers.

Amperometric bio-sensing of lactate and oxygen concurrently with local field potentials during status epilepticus

Epilepsy is a prevalent neurological disorder with a complex pathogenesis and unpredictable nature, presenting limited treatment options in >30 % of affected individuals. Neurometabolic abnormalities have been observed in epilepsy patients, suggesting a disruption in the coupling between neural activity and energy metabolism in the brain. In this study, we employed amperometric biosensors based on a modified carbon fiber microelectrode platform to directly and continuously measure lactate and oxygen dynamics in the brain extracellular space. These biosensors demonstrated high sensitivity, selectivity, and rapid response time, enabling in vivo measurements with high temporal and spatial resolution. In vivo recordings in the cortex of anaesthetized rats revealed rapid and multiphasic fluctuations in extracellular lactate and oxygen levels following neuronal stimulation with high potassium. Furthermore, real-time measurement of lactate and oxygen concentration dynamics concurrently with network electrical activity during status epilepticus induced by 4-aminopyridine (4-AP) demonstrated phasic changes in lactate levels that correlated with bursts of electrical activity, while tonic levels of lactate remained stable during seizures. This study highlights the complex interplay between lactate dynamics, electrical activity, and oxygen utilization in epileptic seizures.

Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson’s disease (PD) and following the development of l-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of l-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of l-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg l-DOPA doses. However, after reaching the 72 mg/kg l-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of l-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.

Tourism destination advertising: effect of storytelling and sensory stimuli on arousal and memorability

PurposeTourism destination marketers use videos that incorporate storytelling and visual and audio components to evoke emotional arousal and memorability. This study aims to examine the increase in participants’ level of arousal and the degree of memorability after watching two different videos.Design/methodology/approachA quasi-experimental study was conducted with 45 participants who watched two destination promotional videos. One video used storytelling whereas the other used scenic images and music. The level of arousal was measured using both tonic and phasic electrodermal activity levels. The memorability of each video was measured after seven days by testing the recall accuracy.FindingsScenic imagery and music videos were associated with higher-than-average arousal levels, while storytelling videos generated larger-amplitude arousal peaks and a greater number of arousal-evoking events. After a week, the respondents recalled more events from the storytelling video than from the scenery and musical advertisements. This finding reveals that the treatment, storytelling and sensory stimuli in advertising moderate the impact of arousal peaks and memorability.Originality/valueThese results indicate that nonnarrative videos using only sceneries and music evoked a higher average level of arousal. However, memorability was associated with higher peak levels of arousal only in narrative storytelling. This is the first tourism study to report the effects of large arousal peaks on improved memorability in advertising.

Delivery Mode Affects the Sympathetic Nervous System in Healthy Term Newborns

Abstract Background Spontaneous delivery represents an important way triggering the physiological mechanisms essential for a proper postnatal adaptation of a newborn. Autonomic nervous system (ANS) plays a crucial role in this process. There is insufficient data concerning the impact of different delivery mode on ANS in newborns. Therefore, we aimed to study the effect of delivery mode on sympathetic nervous system (SNS) in healthy term newborns measured by electrodermal activity (EDA). Material &amp; Methods The study conducted 50 healthy full – term newborns divided into two groups: the spontaneous delivery group (SD, n=27) and the caesarean section group (CS, n=23). EDA parameters (SCL – tonic level of skin conductance; NS.SCRs – non – specific phasic responses of skin conductance) were evaluated during three measurements: 2nd (M1), 24th (M2), and 72nd (M3) hours of life. Results SCL significantly decreased during the first day of life (M1 vs. M2 – p &lt; 0.001). The lowest NS.SCRs values were demonstrated in M1 in both groups with significant differences in CS group between measurements – M1 vs. M2 (p=0.001) and M1 vs. M3 (p=0.005). However, a significantly lower NS.SCRs was found in CS group (p=0.01) early after birth (M1). Conclusion Our findings revealed a reduced NS.SCRs indicating potential decreased „arousal“ in CS group – it seems that the attenuated „arousal“ could reflect the absence of physiological labor mechanisms as well as the effect of anesthesia leading to discrete early functional abnormalities in CS group. Further research is needed to validate these findings.

Profiling transcriptomic responses of human stem cell-derived medium spiny neuron-like cells to exogenous phasic and tonic neurotransmitters

Transcriptomic responses to neurotransmitters contribute to the complex processes driving memory and addiction. Advances in both measurement methods and experimental models continue to improve our understanding of this regulatory layer. Here we focus on the experimental potential of stem cell derived neurons, currently the only ethical model that can be used in reductionist and experimentally perturbable studies of human cells. Prior work has focused on generating distinct cell types from human stem cells, and has also shown their utility in modeling development and cellular phenotypes related to neurodegeneration. Here we seek an understanding of how stem cell derived neural cultures respond to perturbations experienced during development and disease progression. This work profiles transcriptomic responses of human medium spiny neuron-like cells with three specific goals. We first characterize transcriptomic responses to dopamine and dopamine receptor agonists and antagonists presented in dosing patterns mimicking acute, chronic, and withdrawal regimens. We also assess transcriptomic responses to low and persistent tonic levels of dopamine, acetylcholine, and glutamate to better mimic the in vivo environment. Finally, we identify similar and distinct responses between hMSN-like cells derived from H9 and H1 stem cell lines, providing some context for the extent of variability these types of systems will likely pose for experimentalists. The results here suggest future optimizations of human stem cell derived neurons to increase their in vivo relevance and the biological insights that can be garnered from these models.

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Introduction: Women are more vulnerable to cocaine’s reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine. Here, we asked if sex chromosome complement (SCC) influences vulnerability to cocaine use. Methods: We used the four-core genotype mouse that produces gonadal males and females with either XX or XY SCC. Mice were gonadectomized and implanted with either an estradiol (E2) or cholesterol-filled pellet. This allowed us to determine the effects of SCC in the absence (cholesterol-treated) and presence of tonic high physiological hormone levels (estradiol). Acquisition of cocaine self-administration was determined over a 12-day period using an escalated dose procedure (0.3 mg/kg/infusion, sessions 1–6; 0.6 mg/kg/infusion, sessions 6–12). Results: Without estradiol treatment, a greater percentage of castrated XY mice acquired cocaine self-administration and did so at a faster rate than XX castrates and ovariectomized XY females. These same XY males acquired sooner, infused more cocaine, and directed more nose pokes to the rewarded nose-poke hole than XX castrates and XY males receiving E2. Conclusion: Our results suggest that in gonadal male mice, SCC and estradiol can modulate the reinforcing effects of cocaine which may influence the likelihood of cocaine use.

Tonic and phasic cardiac vagal activity predict cognitive-affective processing in an emotional stop-signal task

Both the Neurovisceral Integration Model and the Vagal Tank Theory propose cardiac vagal activity (CVA) as proxy for self-regulatory or processing resources required for attentional and top-down control as key mechanisms in executive functioning or emotion-regulation. These resources have, according to the Dual Competition Model, limited capacity and are prioritized for processing the most salient of different competing stimuli. As such, emotional and especially negative or threatening stimuli attract these self-regulatory/processing resources, and may thus interfere with ongoing cognitive processes if not integrated adaptively. Here, we investigated whether tonic and phasic CVA represent self-regulatory/processing resources and thus predict response inhibition in an emotional stop-signal task as a measure of cognitive-affective integration. Thereby, we examined not only the independent effects of tonic and phasic CVA, but whether and how the interaction of both variables predicts response inhibition. We assumed that the effects of CVA on response inhibition would be more pronounced in negatively-valenced trials compared to positive or neutral ones. Our results show that CVA significantly predicted response inhibition, with higher tonic CVA predicting faster, and larger phasic withdrawal CVA predicting slower stop-signal reaction times. The interactive effects of tonic and phasic CVA revealed that high tonic CVA levels prevented the negative effects of CVA withdrawal on response inhibition. Contrary to our assumption, we did not find differential effects of tonic and phasic CVA on trials with different valences. Our results support the notion of CVA as index for self-regulatory/processing resources. However, further research is needed to investigate how CVA is related to specific neural processes of cognitive-affective processing.