Context-dependent Effects Research Articles

Functional diversity increases the resistance of a tritrophic food web to environmental changes

In the light of global climate change and biodiversity loss, understanding the role of functional diversity in the response of food webs to environmental change is growing ever more important. Using a tritrophic food web model, with a variable degree of functional diversity at each trophic level, we studied the role of functional diversity on the resistance of a system against press perturbations. Perturbations affected either nutrient availability or the mortality of the species, which can be interpreted as effects of eutrophication and warming, respectively. We compared food webs with different levels of functional diversity by investigating the species trait and biomass dynamics, the overall changes in the species’ standing biomass as measured by the warping distance, and the duration of the system transients after the onset of a press perturbation (transition time). We found that higher functional diversity increased resistance since it buffered trophic cascading effects and delayed the onset of oscillatory behaviour caused by either bottom-up forcing via perturbations to nutrient concentration or top-down forcing via perturbations to mortality rate. This increased resistance emerged from a higher top-down control of the intermediate species on the basal species. Functional diversity also promoted a higher top biomass, in particular via a higher proportion of top selective species undergoing high mortality rates. Additionally, functional diversity had context-dependent effects on warping distances, and increased transition times. Overall, this study encourages accounting for functional diversity in future investigations about the response of multitrophic systems to global change and in management strategies.

Modulation of opioid overdose susceptibility due to context-dependent tolerance

The US is in the midst of an opioid epidemic, which is primarily being driven by repeat opioid use (ROU). The primary cause of opioid overdose is opioid-induced respiratory depression (OIRD). It has been shown that the risk of overdosing, and subsequently death, can change depending on the environment in which the user takes the drug. This phenomenon is called context-dependent tolerance. However, how OIRD changes depending on the location of drug delivery is not known. The objective of this pilot study is to investigate context-dependent respiratory tolerance to OIRD and overdose. We repeatedly paired an injection of fentanyl (0.7 mg/kg/day i.p.) with a distinctive environmental context (fentanyl-paired (FP) environment) and saline with another distinctive context (saline-paired (SP) environment) in adult mice for five days while monitoring breathing via unrestrained whole-body plethysmography. The ROU protocol was followed by two test days where fentanyl was administered in both environments and breathing was measured. We found that minute ventilation was greater during OIRD in the FP environment as compared to the SP environment (n=4). In the second set of mice (n=6?), we tested overdose susceptibility following ROU by administering a high dose of fentanyl (5mg/kg) in both contexts. In contrast to the FP environment where no mice overdosed (n=0/6), n=4/6 mice overdosed in the SP environment. These data suggest a greater susceptibility to OIRD and overdose when in an environment not previously paired with fentanyl administration. This context-dependent effect on OIRD may be a significant psychophysiological factor driving opioid-related deaths in the ongoing opioid epidemic. NIH: R01NS107421; R01HL163965; R01DA057767. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A novel automated software and video analysis system for quantifying physiological responses of conditioned fear in mice

BACKGROUND: Conditioned fear is an aversive learning process that is highly sensitive to sensory conditions such as environmental context, threat intensity and circadian rhythms. To better understand these external variables that impact conditioned fear learning, we developed a novel software application that allows for programmable remote conditioned stimulus (CS, ie., auditory tone) delivery and recording of group-housed mice in a homecage, or familiar environment. The goal of our study was therefore to leverage this technology to examine conditioned fear in the homecage across light-dark (LD) circadian cycles. METHODS: Male C57bl/6J mice underwent Pavlovian auditory fear conditioning (20 CS/US pairings), with a CS-only group as a control (n=4/group). Mice were then returned to the homecage, equipped with speaker and camera. Using a customized open-source software to remotely evoke an enhanced physiological state of fear in the homecage, mice received a select number of conditioned auditory stimuli (30sec. intermittent tones) throughout the LD cycle over 14 days. The software was configured to deliver six tones (6kHz) over a 24hr period (3 light, 3 dark). The first CS during each LD cycle was recorded and percent freezing behavior was manually scored. On day 15, to evaluate whether the HC-specific evoked fear response transfers to a new environment, mice were placed into a novel context and CS-dependent freezing was measured. RESULTS: Over 14 days, compared to controls, fear-conditioned pair-housed mice exhibited strong CS-evoked freezing in the homecage ( total freezing: FC 70.46%, CS-only 3.69%, F(2.29, 11.14)=10.78, p<0.01). Interestingly, when we evaluated CS-specific circadian responses, fear-conditioned mice exhibited enhanced freezing in the light versus the dark phase ( total freezing: light 84.56%, dark 56.36%, F(2.15, 6.46)=11.04, p<0.01). In fear-conditioned mice, there was a 36% reduction in total CS-dependent homecage freezing over 14 days. However, this was a context-dependent effect, as the reduction in freezing on day 14 was not observed in the novel context on day 15 ( t(3)=3.16, p=0.05). CONCLUSIONS: Here we demonstrate for the first time, using an open-source software developed in our laboratory, environment and circadian-dependent conditioned freezing responses in the homecage of group-housed mice. This study provides a proof-of-principle innovative approach for examining physiological outcomes of conditioned fear across ethologically relevant environments, which may help further the understanding for heightened physiological responses in neuropsychiatric diseases such as posttraumatic stress disorder (PTSD). To further elucidate impaired physiological mechanisms of disordered fear, future studies will integrate multimodal behavioral (DeepLabCut TM ) and cardiovascular telemetry-based approaches. Congressionally Directed Medical Research Programs (CDMRP) PR210574 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A rapidly spreading deleterious aphid endosymbiont that uses horizontal as well as vertical transmission

Endosymbiotic bacteria that live inside the cells of insects are typically only transmitted maternally and can spread by increasing host fitness and/or modifying reproduction in sexual hosts. Transinfections of Wolbachia endosymbionts are now being used to introduce useful phenotypes into sexual host populations, but there has been limited progress on applications using other endosymbionts and in asexual populations. Here, we develop a unique pathway to application in aphids by transferring the endosymbiont Rickettsiella viridis to the major crop pest Myzus persicae. Rickettsiella infection greatly reduced aphid fecundity, decreased heat tolerance, and modified aphid body color, from light to dark green. Despite inducing host fitness costs, Rickettsiella spread rapidly through caged aphid populations via plant-mediated horizontal transmission. The phenotypic effects of Rickettsiella were sensitive to temperature, with spread only occurring at 19°C and not 25°C. Body color modification was also lost at high temperatures despite Rickettsiella maintaining a high density. Rickettsiella shows the potential to spread through natural M. persicae populations by horizontal transmission and subsequent vertical transmission. Establishment of Rickettsiella in natural populations could reduce crop damage by modifying population age structure, reducing population growth and providing context-dependent effects on host fitness. Our results highlight the importance of plant-mediated horizontal transmission and interactions with temperature as drivers of endosymbiont spread in asexual insect populations.

Effects of a brief mindfulness meditation practice on Pavlovian-to-instrumental transfer in alcohol use disorder - a pilot study.

Pavlovian conditioned contextual cues have been suggested to modulate instrumental action and might explain maladaptive behavior such as relapse in participants suffering from alcohol use disorder (AUD). Pavlovian-to-Instrumental transfer (PIT) experimentally assesses the magnitude of this context-dependent effect and studies have shown a larger PIT effect in AUD populations. Taken this into account, a reduction of the influence of cues on behavior seems warranted and one approach that could alter such cue reactivity is mindfulness. Mindfulness-based interventions have been shown to be efficient in the treatment of AUD, but underlying mechanisms are yet to be elucidated. Therefore, we aim at investigating the effect of a brief mindful body scan meditation on the magnitude of the PIT effect in AUD subjects and matched controls. Using a randomized within-subjects design, we compared the effect of a short audio guided body scan meditation against a control condition (audio of nature sounds) on PIT in healthy (n = 35) and AUD (n = 27) participants. We found no differences in PIT effect between healthy and AUD participants as well as between conditions. However, a significant interaction effect points to a decreased PIT effect after body scan meditation in AUD subjects only. These pilot results suggest that AUD might be susceptible to mindfulness-induced changes in PIT, with these findings contributing to entangling the underlying mechanisms of the efficacy of mindfulness-based interventions in AUD. However, further investigation should confirm these preliminary results and the efficacy of mindfulness meditation practice in decreasing the PIT effect.

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies.

In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Large-scale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine.

Mouse model of PRSS1 p.R122H-related hereditary pancreatitis highlights context-dependent effect of autolysis-site mutation

Mutation p.R122H in human cationic trypsinogen (PRSS1) is the most frequently identified cause of hereditary pancreatitis. The mutation blocks protective degradation of trypsinogen by chymotrypsin C (CTRC), which involves an obligatory trypsin-mediated cleavage at Arg122. Previously, we found that C57BL/6N mice are naturally deficient in CTRC, and trypsinogen degradation is catalyzed by chymotrypsin B1 (CTRB1). Here, we used biochemical experiments to demonstrate that the cognate p.R123H mutation in mouse cationic trypsinogen (isoform T7) only partially prevented CTRB1-mediated degradation. We generated a novel C57BL/6N mouse strain harboring the p.R123H mutation in the native T7 trypsinogen locus. T7R123H mice developed no spontaneous pancreatitis, and severity parameters of cerulein-induced pancreatitis trended only slightly higher than those of C57BL/6N mice. However, when treated with cerulein for 2 days, more edema and higher trypsin activity was seen in the pancreas of T7R123H mice compared to C57BL/6N controls. Furthermore, about 40% of T7R123H mice progressed to atrophic pancreatitis in 3 days, whereas C57BL/6N animals showed full histological recovery. Taken together, the observations indicate that mutation p.R123H inefficiently blocks chymotrypsin-mediated degradation of mouse cationic trypsinogen, and modestly increases cerulein-induced intrapancreatic trypsin activity and pancreatitis severity. The findings support the notion that the pathogenic effect of the PRSS1 p.R122H mutation in hereditary pancreatitis is dependent on its ability to defuse chymotrypsin-dependent defenses.

Context-dependent effects of the CB1 receptor antagonist rimonabant on morphine-induced behavioral sensitization in female mice.

Introduction: The endocannabinoid system has been implicated in the neurobiology of opioid use disorder. While the CB1 receptor antagonist rimonabant has been shown to block some of the behavioral effects of opioids, studies suggest that the treatment environment (i.e., receiving treatment in the drug-associated environment, and/or novelty) can influence its effects. In the present study, we investigated the role of the treatment environment in the effects of rimonabant on the expression of morphine-induced behavioral sensitization. Methods: Adult female Swiss mice were submitted to a behavioral sensitization protocol, during which they received morphine (20mg/kg, i.p.) in the open-field apparatus, and were subsequently treated with vehicle or rimonabant (1 or 10mg/kg, i.p.) either in the open-field, in the home-cage or in an activity box (novel environment). The expression of conditioned locomotion (increased locomotor activity in the open-field apparatus in the absence of morphine) and of morphine-induced behavioral sensitization (increased locomotor activity in animals sensitized to morphine) was evaluated during asubsequent saline and morphine challenge, respectively. Results: Animals treated with morphine expressed behavioral sensitization, showing a significant increase in locomotor activity over time. Animals sensitized to morphine and treated with vehicle in the home-cage expressed conditioned locomotion, an effect that was blocked by home-cage treatment with rimonabant. During a saline challenge, only animals sensitized to morphine and treated with saline in the home-cage expressed morphine-induced conditioned locomotion. All morphine-treated animals that received saline during the treatment phase (control groups) expressed behavioral sensitization during the morphine challenge. Treatment with rimonabant in the open-field and in the activity box, but not in the home-cage, blocked the expression of morphine-induced behavioral sensitization. Discussion: Our findings suggest that CB1 receptor antagonism can modulate conditioned responses to morphine even when administered in the home-cage. However, exposure to the drug-associated environment or to a novel environment is necessary for the expression of rimonabant's effects on morphine-induced behavioral sensitization during a morphine challenge.

A universal code for phase separation of prion-like low complexity domains: Insights from quantitative computer simulations.

Biomolecular phase separation is a critical mechanism that contributes to intracellular spatiotemporal organization via the formation of biomolecular condensates. In addition to their widespread implications in aggregation-related disorders, prion-like low complexity domains (PLCDs) have been shown to exhibit demixing behavior and their aberrant condensation has been linked to disease. Here, we investigate the relationship between amino acid sequence and phase behaviour of the PLCDs exploring an unprecedented set of 140 different protein sequences. To this end, we perform direct coexistence molecular dynamics simulations of our residue-resolution coarse-grained protein model, which we have shown accurately predicts quantitative phase diagrams. For variants where experimental phase behaviors have been characterized, we show that our predictions are in excellent agreement with the experimental results. Analysis of the full simulation set of 140 variants reveals that the identity and patterning of sticker residues (e.g., Y, F) are crucial to define the phase behaviour of PLCDs. Notably, aromatic and charged residues have context-dependent effects on the critical temperature of PLCD condensation. Regarding spacer residues (e.g., S, G, N, T), PLCDs condensates are remarkably stable in front of mutations of glycine and serine but are more sensitive to mutations of asparagine and glutamine. Remarkably, these results extend to the entire family of PLCDs tested and, therefore, reveal universal codes for PLCDs phase behavior. Furthermore, the findings here help shed light on the functions of PLCDs and aid in the design of modifications to counter their aberrant phase separation.

Multivalent interactions between RNA and RNA binding proteins drive differential intra-speckle positioning of RNA transcripts.

Nuclear speckles represent a type of membraneless organelles in higher eukaryotic cells which are rich in snRNP components, certain splicing factors, including SR proteins (a family of RNA binding proteins (RBPs) named for containing regions with repetitive serine and arginine residues), polyA+ RNAs, and certain long noncoding RNAs (lncRNA). Multivalent interactions between RNAs and residing protein components drive the formation, as well as layered organization of components in nuclear speckles. Furthermore, RBPs have differential localization with respect to nuclear speckles; while SRSF1 proteins is enriched in nuclear speckles, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is either uniformly distributed in the nucleoplasm or slightly depleted from nuclear speckles. Using super-resolution imaging we show that the pre-mRNA transcripts containing SRSF1 motifs in the exon and hnRNPA1 motifs in the intron, are orientated in a way such that the regions containing the SRSF1 binding motifs are positioned relatively towards the interior of nuclear speckles and hnRNPA1 binding motifs are placed relatively towards the periphery of speckles. Knocking down of SRSF1 protein leads to the migration of RNA transcripts further towards the periphery of nuclear speckles, whereas knocking down of hnRNPA1 protein leads to the inward migration of RNA transcripts with respect to the speckle center. A similar effect of protein knockdown is seen on the endogenous nuclear speckle associated lncRNA, MALAT1. Our results collectively demonstrate that RNAs can adopt non-random orientation and positioning within the membraneless organelles. These observations might help explain the need for nuclear RNAs for structural integrity of nuclear speckles and the context dependent effect of SR and hnRNP proteins on splicing outcomes.

Variable effects of vegetation characteristics on a recreation service depending on natural and social environment

In this study, we examined roles of three vegetation characteristics in provisioning of a recreation service by applying a machine-learning method to 4,708,229 spatially-explicit records of hiking activity in Japan. Then, expected impacts of land-use changes assessed and mapped based on the model. Associations between a recreation service and three vegetation characteristics were considerably variable depending on the social and natural environment such as accessibility and altitude. As a consequence, expected impacts of unit changes in vegetation characteristics on the service flow were considerably heterogeneous throughout the study area. The signs (positive or negative) of the impact can be reversed depending on the contexts even among nearby sites. Such notable but variable contributions of vegetation on a recreation service should be carefully reflected in landscape management. Even moderate changes in either the quantity or quality of vegetation can have a considerable impact on the frequency of hiking activity. Landscape management for promotion of the recreation service should be carefully designed for each locality on the grounds of the context-dependent effects of vegetation.

EEG complexity during mind wandering: A multiscale entropy investigation

Our attention often drifts away from the ongoing task to task-unrelated thoughts, a phenomenon commonly referred to as mind wandering. Ample studies dedicated to delineating its electrophysiological correlates have revealed distinct event-related potentials (ERP) and spectral patterns associated with mind wandering. It remains less clear whether the complexity of the electroencephalography (EEG) changes when our minds wander, a metric that captures the predictability of the time series at varying timescales. Accordingly, this study investigated whether mind wandering impacts EEG signal complexity. We further explored whether such effects differ across timescales, and change in a context-dependent manner as indexed by global and local levels of processing. To address this, we recorded participants' EEG while they completed Navon's global and local processing task and occasionally reported whether they were on-task or mind wandering throughout the task. We found that brain signal complexity as indexed by multiscale entropy decreased at medium timescales in centro-parietal regions and increased at coarse timescales in anterior and posterior regions during mind wandering, as compared to the on-task state, for global processing. Moreover, global processing showed increased complexity at fine to medium timescales compared to local processing. Finally, behavioral performance revealed a context-dependent effect in accuracy measures, with mind wandering showing lower accuracy compared to the on-task state only during the local condition. Taken together, these results indicate that changes in brain signal complexity across timescales may be an important feature of mind wandering.

The Effect of Chatbots and AI on The Self-Efficacy, Self-Esteem, Problem-Solving and Critical Thinking of Students

This article delves into the multifaceted impacts of chatbots and AI in educational settings. It explores how these technologies, increasingly integrated into learning environments, influence key psychological aspects and cognitive skills among students. The review highlights the potential of chatbots in enhancing academic processes, offering personalized learning experiences, and serving as bridges to educational resources. However, it also raises concerns about the ethical use of such technologies. Focusing on psychological aspects, the article reviews literature suggesting that frequent and satisfying interactions with chatbots can enhance students' self-efficacy and engagement. Studies indicate that chatbots might improve self-efficacy in experimental settings and have indirect effects on health-related self-efficacy. In terms of self-esteem and self-confidence, the research presents mixed findings. While chatbots can positively affect body image and self-esteem among certain demographics, over-reliance on these technologies for social interaction or validation might negatively impact real human connections and individual confidence. The article also examines the impact of chatbots on problem-solving skills. Some studies suggest that AI chatbots can enhance problem-solving abilities, especially when integrated into educational systems. However, there is a risk that reliance on chatbots could limit users' exploration of alternative problem-solving strategies. Critical thinking is another area reviewed, with studies presenting diverse results. While some research indicates a positive influence of chatbots on critical thinking, others suggest limitations or context-dependent effects. The article concludes that while AI and chatbots offer transformative potential for enhancing student learning and engagement, their impact is complex and multifaceted. Future advancements in chatbot technology should aim to enhance their positive impact on users' psychological well-being and cognitive development, balancing the need for independent thinking and adaptability to complex problems.

Mating-induced prolactin surge is not required for subsequent neurogenesis in male mice.

Parenting involves major behavioral transitions that are supported by coordinated neuroendocrine and physiological changes to promote the onset of novel offspring-directed behaviors. In comparison to maternal care, however, the mechanisms underlying the transition to paternal care are less understood. Male laboratory mice are predominantly infanticidal as virgins but show paternal responses 2 weeks after mating. Interestingly, males show a mating-induced surge of prolactin, which we hypothesized may be involved in initiating this behavioral transition. During pregnancy, prolactin stimulates olfactory bulb neurogenesis, which is essential for maternal behavior. Mating induces olfactory bulb neurogenesis in males, but it is unknown whether this is driven by prolactin or is important for subsequent paternal care. New olfactory neurons are generated from cells in the subventricular zone (SVZ) and take about 2 weeks to migrate to the olfactory bulb, which may account for the delayed behavioral change in mated males. We investigated whether mating increases cell proliferation at the SVZ. Males were either mated, exposed to receptive female cues, or left alone (control) and injected with Bromodeoxyuridine (BrdU, a marker of cell division). Contrary to our hypothesis, we found that mating decreased cell proliferation in the caudal lateral portion of the SVZ. Next, we tested whether prolactin itself mediates cell proliferation in the SVZ and/or new cell survival in the olfactory bulb by administering bromocriptine (prolactin inhibitor), vehicle, or bromocriptine + prolactin prior to mating. While suppressing prolactin had no effect on cell proliferation in the SVZ, administering exogenous prolactin resulted in significantly higher BrdU-labeled cells in mated but not virgin male mice. No effects of prolactin were observed on new olfactory cell survival. Taken together, prolactin may have context-dependent effects on new cell division in the SVZ, while other unknown mechanisms may be driving the effects on new olfactory cell survival following mating.

Plant defense synergies and antagonisms affect performance of specialist herbivores of common milkweed.

As a general rule, plants defend against herbivores with multiple traits. The defense synergy hypothesis posits that some traits are more effective when co-expressed with others compared to their independent efficacy. However, this hypothesis has rarely been tested outside of phytochemical mixtures, and seldom under field conditions. We tested for synergies between multiple defense traits of common milkweed (Asclepias syriaca) by assaying the performance of two specialist chewing herbivores on plants in natural populations. We employed regression and a novel application of random forests to identify synergies and antagonisms between defense traits. We found the first direct empirical evidence for two previously hypothesized defense synergies in milkweed (latex by secondary metabolites, latex by trichomes) and identified numerous other potential synergies and antagonisms. Our strongest evidence for a defense synergy was between leaf mass per area and low nitrogen content; given that these "leaf economic" traits typically covary in milkweed, a defense synergy could reinforce their co-expression. We report that each of the plant defense traits showed context-dependent effects on herbivores, and increased trait expression could well be beneficial to herbivores for some ranges of observed expression. The novel methods and findings presented here complement more mechanistic approaches to the study of plant defense diversity and provide some of the best evidence to date that multiple classes of plant defense synergize in their impact on insects. Plant defense synergies against highly specialized herbivores, as shown here, are consistent with ongoing reciprocal evolution between these antagonists.

Dissociating selectivity adjustments from temporal learning-introducing the context-dependent proportion congruency effect.

The list-level proportion congruency effect (PCE) and the context-specific PC (CSPC) effect are typical findings in experimental conflict protocols, which competing explanations attribute to different mechanisms. Of these mechanisms, stimulus-unspecific conflict-induced selectivity adjustments have attracted the most interest, from various disciplines. Recent methodological advances have yielded an experimental procedure for entirely ruling out all stimulus-specific alternatives. However, there is a stimulus-unspecific alternative-temporal learning-which cannot even be ruled out as the sole cause of either effect with any established experimental procedure. That is because it is very difficult to create a scenario in which selectivity adjustments and temporal learning make different predictions-with traditional approaches, it is arguably impossible. Here, we take a step towards solving this problem, and experimentally dissociating the two mechanisms. First, we present our novel approach which is a combination of abstract experimental conditions and theoretical assumptions. As we illustrate with two computational models, given this particular combination, the two mechanisms predict opposite modulations of an as yet unexplored hybrid form of the list-level PCE and the CSPC effect, which we term context-dependent PCE (CDPCE). With experimental designs that implement the abstract conditions properly, it is therefore possible to rule out temporal learning as the sole cause of stimulus-unspecific adaptations to PC, and to unequivocally attribute the latter, at least partially, to selectivity adjustments. Secondly, we evaluate methodological and theoretical aspects of the presented approach. Finally, we report two experiments, that illustrate both the promise of and a potential challenge to this approach.

Whole-brain modeling explains the context-dependent effects of cholinergic neuromodulation

Integration and segregation are two fundamental principles of brain organization. The brain manages the transitions and balance between different functional segregated or integrated states through neuromodulatory systems. Recently, computational and experimental studies suggest a pro-segregation effect of cholinergic neuromodulation. Here, we studied the effects of the cholinergic system on brain functional connectivity using both empirical fMRI data and computational modeling. First, we analyzed the effects of nicotine on functional connectivity and network topology in healthy subjects during resting-state conditions and during an attentional task. Then, we employed a whole-brain neural mass model interconnected using a human connectome to simulate the effects of nicotine and investigate causal mechanisms for these changes. The drug effect was modeled decreasing both the global coupling and local feedback inhibition parameters, consistent with the known cellular effects of acetylcholine. We found that nicotine incremented functional segregation in both empirical and simulated data, and the effects are context-dependent: observed during the task, but not in the resting state. In-task performance correlates with functional segregation, establishing a link between functional network topology and behavior. Furthermore, we found in the empirical data that the regional density of the nicotinic acetylcholine α4β2 correlates with the decrease in functional nodal strength by nicotine during the task. Our results confirm that cholinergic neuromodulation promotes functional segregation in a context-dependent fashion, and suggest that this segregation is suited for simple visual-attentional tasks.

SOX9 and TCF transcription factors associate to mediate Wnt/β-catenin target gene activation in colorectal cancer

Activation of the Wnt/β-catenin pathway regulates gene expression by promoting the formation of a β-catenin-T-cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/β-catenin pathway at different levels to produce tissue-specific patterns of Wnt target gene expression. The transcription factor SOX9 potently represses many Wnt target genes by downregulating β-catenin protein levels. Here, we find using colony formation and cell growth assays that SOX9 surprisingly promotes the proliferation of Wnt-driven colorectal cancer (CRC) cells. In contrast to how it indirectly represses Wnt targets, SOX9 directly co-occupies and activates multiple Wnt-responsive enhancers in CRC cells. Our examination of the binding site grammar of these enhancers shows the presence of TCF and SOX9 binding sites that are necessary for transcriptional activation. In addition, we identify a physical interaction between the DNA-binding domains of TCFs and SOX9 and show that TCF-SOX9 interactions are important for target gene regulation and CRC cell growth. Our work demonstrates a highly context-dependent effect of SOX9 on Wnt targets, with the presence or absence of SOX9-binding sites on Wnt-regulated enhancers determining whether they are directly activated or indirectly repressed by SOX9.

CNSC-35. CANCERS GOT THE NERVE

Abstract Brain cancers carry a bleak prognosis despite the increase in our understanding of the disease. Brain tumours are in some ways a distinct entity in comparison to other types of tumours due to the distinct type of cell population in the brain tumour microenvironment. Sympathetic and parasympathetic nervous systems have been shown to exert a context-dependent effect on tumourigenesis. In 2021, I proposed neuronal signalling as a hallmark of cancer, albeit resection of specific nerves to hinder tumourigenesis is both challenging and may not result in the desired outcome. In order to add the nervous system to our armamentarium of therapeutic strategies against cancer, we may need to look beyond conventional methods of reducing synaptic plasticity such as with the use of anti-epileptic drugs. One among the strategy I propose is to utilize epigenetics to our advantage. Using lysine demethylase 5 specifically KDM5C to alter the synapticity in the brain tumour microenvironment is one way of exploiting the synaptic plasticity to our advantage against cancers. Additionally, metabolism intertwines the effects mediated by the nervous system which can be exploited to pivot the tumour-promoting effects of the nervous system towards tumour elimination.

A comparison of renewal, spontaneous recovery, and reacquisition after punishment and extinction.

Punishment and extinction are both effective methods of reducing instrumental responding and may involve similar learning mechanisms. To characterize the similarities and differences between them, we examined three well-established recovery or "relapse" effects -renewal, spontaneous recovery, and reacquisition - following either punishment or extinction of an instrumental response. In Experiment 1a, both punished and extinguished responses renewed to similar degrees following a context change at test (ABA renewal). In Experiment 1b, responding spontaneously recovered to similar degrees following punishment or extinction. In Experiment 2, responding was rapidly reacquired when the response was reinforced again following extinction but not following punishment, as predicted by the idea that the reinforcer delivered in reacquisition is part of the context of punishment, but not extinction. The results collectively suggest that both punishment and extinction produce similar context-dependent retroactive interference effects. More broadly, they also suggest that punished and extinguished responses may be equally likely to return following a change of context despite the intuition that punishment might provide a more extreme and effective means of suppressing behavior. To our knowledge, this is the first direct behavioral comparison of response recovery after punishment and extinction within individual experiments.