Safety signals reinforce instrumental avoidance in humans.

Safety signals reinforce instrumental avoidance behavior in nonhuman animals. However, there are no conclusive demonstrations of this phenomenon in humans. Using human participants in an avoidance task, Experiments 1-3 and 5 were conducted online to assess the reinforcing properties of safety signals, and Experiment 4 was conducted in the laboratory. Participants were trained with CSs+ and CSs-, and they could avoid an aversive outcome during presentations of the CSs+ by pressing their space bar at a specific time. If successful, the aversive outcome was not presented but instead a safety signal was. Participants were then tested-whilst on extinction-with two new ambiguous test CSs. If participants made an avoidance response, one of the test CSs produced the trained safety signal and the other was a control. In Experiments 1 and 4, the control was followed by no signal. In Experiment 2, the control was followed by a signal that differed in one dimension (color) with the trained safety signal, and in Experiment 3, the control differed in two dimensions (shape and color) from the trained safety signal. Experiment 5 tested the reinforcing properties of the safety signal using a choice procedure and a new response during test. We observed that participants made more avoidance responses to the ambiguous test CSs when followed by the trained signal in Experiments 1, 3, 4, and 5 (but not in Experiment 2). Overall, these results suggest that trained safety signals can reinforce avoidance behavior in humans.

Modulating reward and aversion: Insights into addiction from the paraventricular nucleus.

BACKGROUND: Drug addiction, characterized by compulsive drug use and high relapse rates, arises from complex interactions between reward and aversion systems in the brain. The paraventricular nucleus (PVN), located in the anterior hypothalamus, serves as a neuroendocrine center and is a key component of the hypothalamic-pituitary-adrenal axis. OBJECTIVE: This review aimed to explore how the PVN impacts reward and aversion in drug addiction through stress responses and emotional regulation and to evaluate the potential of PVN as a therapeutic target for drug addiction. METHODS: We review the current literature, focusing on three main neuron types in the PVN-corticotropin-releasing factor, oxytocin, and arginine vasopressin neurons-as well as other related neurons, to understand their roles in modulating addiction. RESULTS: Existing studies highlight the PVN as a key mediator in addiction, playing a dual role in reward and aversion systems. These findings are crucial for understanding addiction mechanisms and developing targeted therapies. CONCLUSION: The role of PVN in stress response and emotional regulation suggests its potential as a therapeutic target in drug addiction, offering new insights for addiction treatment.

A psychological mechanism for the development of anxiety.

Although numerous behavioral constructs have been proposed to account for anxiety disorders, how these disorders develop within an individual has been difficult to predict. In this perspective, I selectively review clinical and experimental evidence suggesting that avoidance (i.e., safety) behavior increases beliefs of threat or fear. The experimental evidence has been replicated numerous times, with different parameters, and shows that when human participants emit avoidance responses in the presence of a neutral stimulus, they later show heightened expectations of threat in the presence of the neutral stimulus. I interpret these findings as resulting from prediction errors as anticipated by the Rescorla-Wagner model, although other animal learning theories can also predict the phenomenon. I discuss some implications and offer a few novel predictions. The analysis presented here sheds light on a phenomenon of theoretical and clinical relevance which is accommodated by basic associative learning theory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Signal flow in the NMDA receptor-dependent phosphoproteome regulates postsynaptic plasticity for aversive learning.

Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca2+-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.

Protective effects of L-carnitine against beta-amyloid-induced memory impairment and anxiety-like behavior in a rat model of Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of dementia, leads to neurodegeneration and cognitive decline. We investigated the therapeutic effects of L-carnitine on cognitive performance and anxiety-like behavior in a rat model of AD induced by unilateral intracerebroventricular injection of ß-amyloid1-42 (Aß1-42). L-carnitine (100 mg/kg/day) was administered intraperitoneally for 28 consecutive days. Following this, the open-field test, novel object recognition test, elevated plus-maze test, Barnes maze test, and passive avoidance learning test were used to assess locomotor activity, recognition memory, anxiety-like behavior, spatial memory, and passive avoidance memory, respectively. Plasma and hippocampal oxidative stress markers, including total oxidant status (TOS) and total antioxidant capacity (TAC), were examined. In addition, histological investigations were performed in the dentate gyrus of the hippocampus using Congo red staining and hematoxylin and eosin staining. The injection of Aß1-42 resulted in cognitive deficits and increased anxiety-like behavior. These changes were associated with an imbalance of oxidants and antioxidants in plasma and the hippocampus. Also, neuronal death and Aß plaque accumulation were increased in the hippocampal dentate gyrus region. However, injection of L-carnitine improved recognition memory, spatial memory, and passive avoidance memory in AD rats. These findings provide evidence that L-carnitine may alleviate anxiety-like behavior and cognitive deficits induced by Aß1-42 through modulating oxidative-antioxidant status and preventing Aß plaque accumulation and neuronal death.

Drug discrimination learning: Interoceptive stimulus control of behavior and its implications for regulated and dysregulated drug intake.

Drug discrimination research has generated rich evidence for the capacity of interoceptive drug stimuli to control behavior by serving as discriminative cues. Owing to its neuropharmacological specificity, drug discrimination learning has been widely used to characterize the stimulus effects and neuropharmacological underpinning of drugs. Apart from such utility, discriminative drug stimuli may help regulate drug use by disambiguating conditioned associations and post-intake outcomes. First, this review summarizes the evidence supporting interoceptive regulation of drug intake from the literature of exteroceptive discriminative control of drug-related behavior, effects of drug priming, and self-titration of drug intake. Second, an overview of interoceptive control of reward-seeking and the animal model of discriminated goal-tracking is provided to illustrate interoceptive stimulus control of the initiation and patterning of drug intake. Third, we highlight the importance of interoceptive control of aversion-avoidance in the termination of drug-use episodes and describe the animal model of discriminated taste avoidance that supports such a position. In bridging these discriminative functions of drug stimuli, we propose that interoceptive drug stimuli help regulate intake by disambiguating whether intake will be rewarding, nonrewarding, or aversive. The reflection and discussion on current theoretical formulations of interoceptive control of drug intake may further scientific advances to improve animal models to study the mechanisms by which interoceptive stimuli regulate drug intake, as well as how alterations of interoceptive processes may contribute to the transition to dysregulated drug use.

Thirst-driven hygrosensory suppression promotes water seeking in Drosophila.

Survival in animals relies on navigating environments aligned with physiological needs. In Drosophila melanogaster, antennal ionotropic receptors (IRs) sensing humidity changes govern hygrotaxis behavior. This study sheds light on the crucial role of IR8a neurons in the transition from high humidity avoidance to water-seeking behavior when the flies become thirsty. These neurons demonstrate a heightened calcium response toward high humidity stimuli in satiated flies and a reduced response in thirsty flies, modulated by fluctuating levels of the neuropeptide leucokinin, which monitors the internal water balance. Optogenetic activation of IR8a neurons in thirsty flies triggers an avoidance response similar to the moisture aversion in adequately hydrated flies. Furthermore, our study identifies IR40a neurons as associated with dry avoidance, while IR68a neurons are linked to moist attraction. The dynamic interplay among these neurons, each with opposing valences, establishes a preference for approximately 30% relative humidity in well-hydrated flies and facilitates water-seeking behavior in thirsty individuals. This research unveils the intricate interplay between sensory perception, neuronal plasticity, and internal states, providing valuable insights into the adaptive mechanisms governing hygrotaxis in Drosophila.

Direct serotonin release in humans shapes aversive learning and inhibition.

The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function.

Convergent direct and indirect cortical streams shape avoidance decisions in mice via the midline thalamus.

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors.

Network analyses of ecological momentary emotion and avoidance assessments before and after cognitive behavioral therapy for anxiety disorders.

Negative emotions and associated avoidance behaviors are core symptoms of anxiety. Current treatments aim to resolve dysfunctional coupling between them. However, precise interactions between emotions and avoidance in patients' everyday lives and changes from pre- to post-treatment remain unclear. We analyzed data from a randomized controlled trial where patients with anxiety disorders underwent 16 sessions of cognitive behavioral therapy (CBT). Fifty-six patients (68 % female, age: M = 33.31, SD = 12.45) completed ecological momentary assessments five times a day on 14 consecutive days before and after treatment, rating negative emotions and avoidance behaviors experienced within the past 30 min. We computed multilevel vector autoregressive models to investigate contemporaneous and time-lagged associations between anxiety, depression, anger, and avoidance behaviors within patients, separately at pre- and post-treatment. We examined pre-post changes in network density and avoidance centrality, and related these metrics to changes in symptom severity. Network density significantly decreased from pre- to post-treatment, indicating that after therapy, mutual interactions between negative emotions and avoidance were attenuated. Specifically, contemporaneous associations between anxiety and avoidance observed before CBT were no longer significant at post-treatment. Effects of negative emotions on avoidance assessed at a later time point (avoidance instrength) decreased, but not significantly. Reduction in avoidance instrength positively correlated with reduction in depressive symptom severity, meaning that as patients improved, they were less likely to avoid situations after experiencing negative emotions. Our results elucidate mechanisms of successful CBT observed in patients' daily lives and may help improve and personalize CBT to increase its effectiveness.

Embryonic alcohol exposure alters cholinergic neurotransmission and memory in adult zebrafish.

Alcohol is the most consumed addictive substance worldwide that elicits multiple health problems. Consumption of alcoholic beverages by pregnant women is of great concern because pre-natal exposure can trigger fetal alcohol spectrum disorder (FASD). This disorder can significantly change the embryo's normal development, mainly by affecting the central nervous system (CNS), leading to neurobehavioral consequences that persist until adulthood. Among the harmful effects of FASD, the most reported consequences are cognitive and behavioral impairments. Alcohol interferes with multiple pathways in the brain, affecting memory by impairing neurotransmitter systems, increasing the rate of oxidative stress, or even activating neuroinflammation. Here, we aimed to evaluate the deleterious effects of alcohol on the cholinergic signaling and memory in a FASD zebrafish model, using inhibitory avoidance and novel object recognition tests. Four months after the embryonic exposure to ethanol, the behavioral tests indicated that ethanol impairs memory. While both ethanol concentrations tested (0.5 % and 1 %) disrupted memory acquisition in the inhibitory avoidance test, 1 % ethanol impaired memory in the object recognition test. Regarding the cholinergic system, 0.5 % ethanol decreased ChAT and AChE activities, but the relative gene expression did not change. Overall, we demonstrated that FASD model in zebrafish impairs memory in adult individuals, corroborating the memory impairment associated with embryonic exposure to ethanol. In addition, the cholinergic system was also affected, possibly showing a relation with the cognitive impairment observed.

The Effects of a VR Training Program for Walker Avoidance Skill Improvement: A Randomized Controlled Trial.

This study aimed to evaluate the effectiveness of our newly developed virtual reality head-mounted display (VR-HMD) "walker avoidance" game in reducing step-aside reaction time (SART) and enhancing agility in collision avoidance. Fifteen young adults in experimental group (EG) engaged in the "walker avoidance" game, while another 15 young adults in the control group (CG) played the "first touch" tutorial. The results showed the EG had significant decreases (p < 0.01) in both SART-standing and SART-walking when compared with pre-intervention measurements. Compared with the CG, the EG SART-standing exhibited significant decreases in both the first (p = 0.001) and second (p < 0.001) measurements post-intervention; the EG SART-walking demonstrated significant decreases in all (p < 0.05) measurements, except for pre-intervention measurement. One-dimensional statistical parametric mapping (spm1d) also demonstrated significant differences in most of the electromyography and forefoot/hindfoot ground reaction force results because the step-aside movement became quicker in the EG following training. After pushing the leg-heel contact, the EG participants made a toe-off sooner than the CG participants. Following two sessions of our newly developed "walker avoidance" game, conducted 1 week apart, the EG exhibited less collisions with virtual pedestrians and reduced reaction times to unpredictable directional change measurements compared with the CG. This study demonstrated the effectiveness of this targeted VR training program in improving motor function, which introduced a novel approach to rehabilitation as a digital therapy. It offers innovative perspectives and an approach for clinical rehabilitation, while also providing new ideas for the VR content development industry.

Experiential Avoidance During Mealtimes Among Individuals With Eating Disorders.

The relationship between negative emotions and avoidance is widely theorized as a bidirectional cycle implicated in a range of psychopathology. Historically, research on this cycle has examined one type of negative emotion: anxiety. Yet, a broader range of internal experiences may be implicated in the maintenance of unhealthy avoidance cycles in psychopathology. This study examines prospective relationships among anxiety, guilt, physical discomfort, and experiential avoidance during mealtimes for individuals with eating disorders (EDs). Participants (N = 108) completed ecological momentary assessments four times a day for 25 days. We computed multilevel models to examine between- and within-person effects of negative emotions and physical discomfort on experiential avoidance. When including guilt and anxiety in one model, guilt, but not anxiety, explained the significant variance in experiential avoidance at the next meal. Mealtime physical discomfort and experiential avoidance evidenced reciprocal prospective relationships. Future research should test whether interventions targeting experiential avoidance and physical discomfort at mealtimes disrupt guilt.

Self-Critical Perfectionism and Anxious and Depressive Symptoms Over 2 Years: Moderated Mediation Models of Anxiety Sensitivity and Experiential Avoidance.

This three-wave longitudinal study of 297 community adults (mean age = 38.66 years, 67% female) examined how anxiety sensitivity and experiential avoidance work together to explain the relation between perfectionism and anxious and depressive symptoms over 2 years. Participants completed measures of self-critical (SC) and personal standards (PS) higher-order dimensions of perfectionism, anxiety sensitivity, experiential avoidance, and anxious and depressive symptoms at Time 1. Participants completed measures of anxiety sensitivity, experiential avoidance, and symptoms again at Time 2 one year later, and symptoms measures again at Time 3 two years after baseline. Moderated mediation analyses showed that for those with higher Time 1 experiential avoidance, Time 1 SC perfectionism was indirectly related to Time 3 anxious arousal symptoms through Time 2 anxiety sensitivity. For those with moderate to higher Time 1 anxiety sensitivity, Time 1 SC perfectionism was indirectly associated with Time 3 general distress and anxious arousal symptoms through Time 2 experiential avoidance. These moderated mediation effects were not found for PS perfectionism. These results support anxiety sensitivity and experiential avoidance as moderating and mediating processes that may be important treatment targets for reducing vulnerability to anxious and depressive symptoms over the longer-term in SC perfectionistic individuals.

Neural correlates of proactive avoidance deficits and alcohol use motives in problem drinking.

Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance, in contrast, can reduce consumption in response to these motives but appears to be impaired in those with problem drinking. Despite such evidence, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task featuring proactive avoidance of painful outcomes. We identified the brain responses to proactive avoidance and contrasted the neural correlates of drinking to avoid negative emotions vs. physical pain. Behavioral results confirmed proactive avoidance deficits in problem drinking individuals' learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in the problem drinking group showed that negative emotions as a drinking motive predicted attenuated right anterior insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions' activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in alcohol misuse and establish the link between their neural underpinnings and drinking behavior.

Renewal of instrumental avoidance in humans.

The ABA renewal effect occurs when behavior is trained in one context (A), extinguished in a second context (B), and the test occurs in the training context (A). Two mechanisms that explain ABA renewal are context summation at the test and contextual modulation of extinction learning, with the former being unlikely if both contexts have a similar associative history. In two experiments, we used within-subjects designs in which participants learned to avoid a loud noise (unconditioned stimulus) signaled by discrete visual stimuli (conditioned stimuli [CSs]), by pressing the space bar on the computer keyboard. The training was conducted in two contexts, with a different pair of CSs (CS+ and CS-) trained in each context. During extinction, CS+ and CS- stimuli were presented in the alternative context from that of training, and participants were allowed to freely respond, but no loud noise was presented. Finally, all CSs were tested in both contexts, resulting in a within-subjects ABA versus ABB comparison. Across experiments, participants increased avoidance responses during training and decreased them during extinction, although Experiment 2 revealed less extinction. During the test, responding was higher when CS+ were tested in the training context (ABA) versus the extinction context (ABB), revealing the renewal of instrumental avoidance. Experiment 2 also measured expectancy after the avoidance test and revealed a remarkable similarity between avoidance responses and expectancy ratings. This study shows the renewal of instrumental avoidance in humans, and the results suggest the operation of a modulatory role for the context in renewal, similar to the occasion setting of extinction learning by the context. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Avoidance and Rumination as Predictors of Substance Use, Mental Health, and Pain Outcomes Among People Living With HIV.

Pain, substance use, and mental health conditions are common among people living with HIV (PLWH), and avoidance and rumination may influence the co-occurrence of these conditions. The present study examined longitudinal associations between avoidance/rumination and pain outcomes, anxiety, anger, and substance use among PLWH. Participants (N = 187) with chronic pain and depressive symptoms completed self-report assessments over a 1-year period. Greater avoidance/rumination was positively associated with mental health outcomes (anxiety, anger), pain interference, and alcohol use across participants after controlling for depression severity. At time points with greater avoidance/rumination than average, participants also reported increased pain severity and interference, anxiety and anger symptoms, and alcohol use. No associations were found between avoidance/rumination and cannabis use. Results suggest a mechanistic effect of avoidance/rumination, such that increases in avoidance/rumination correspond with poorer health outcomes among PLWH over time. Targeting avoidance/rumination through intervention approaches may be beneficial for addressing comorbid health conditions among PLWH. Additional research is necessary to investigate this possibility and further characterize the effects of avoidance/rumination on health outcomes for PLWH.

Taste aversion training can educate free-ranging crocodiles against toxic invaders.

Apex predators play critical ecological roles, making their conservation a high priority. In tropical Australia, some populations of freshwater crocodiles (Crocodylus johnstoni) have plummeted by greater than 70% due to lethal ingestion of toxic invasive cane toads (Rhinella marina). Laboratory-based research has identified conditioned taste aversion (CTA) as a way to discourage consumption of toads. To translate those ideas into landscape-scale management, we deployed 2395 baits (toad carcasses with toxin removed and containing a nausea-inducing chemical) across four gorge systems in north-western Australia and monitored bait uptake with remote cameras. Crocodile abundance was quantified with surveys. Free-ranging crocodiles rapidly learned to avoid toad baits but continued to consume control (chicken) baits. Toad invasion at our sites was followed by high rates of crocodile mortality (especially for small individuals) at a control site but not at nearby treatment sites. In areas with high connectivity to other waterbodies, repeated baiting over successive years had continuing positive impacts on crocodile survival. In summary, we succeeded in buffering the often-catastrophic impact of invasive cane toads on apex predators.

Risk avoidance and social anxiety in adolescence: Examination of event-related potentials and theta-dynamics on the Balloon Risk Avoidance Task.

Adolescents are at relatively high-risk for developing anxiety, particularly social anxiety. A primary hallmark of social anxiety is the impulse to avoid situations that introduce risk. Here, we examined the neural and behavioral correlates of risk avoidance in adolescents (N=59) 11 to 19 years of age. The Balloon Risk Avoidance Task was used with concurrent electroencephalography to measure event-related potentials (frontal P2; late slow-wave; N2, feedback-related negativity, FRN; posterior P3) and oscillatory dynamics (midfrontal theta, 4-7 Hz) in response to unsuccessful and successful risk avoidance conditions. Social anxiety was measured using the Social Phobia and Anxiety Inventory for Children. Results indicated that, across the whole sample, youth exhibited smaller P3, larger FRN, and larger theta responses to unsuccessful risk avoidance. Youth reporting high (compared to low) levels of social anxiety exhibited larger P2, slow-wave, and FRN responses to unsuccessful, compared to successful, risk avoidance. Further, greater social anxiety was associated with reduced theta responses to successful avoidance. Youth with higher levels of social anxiety showed smaller theta responses to both conditions compared to those with low levels of social anxiety. Taken together, the ERP-component differences and weakened theta power in socially anxious youth following unsuccessful avoidance are informative neural correlates for socially anxious youth during risk avoidance.