Inhibitory Learning Research Articles

A Proinflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol.

Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than Ch25h knock-out (KO) microglia with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo, LPS treatment also disrupts LTP and inhibits one-trial learning in wild-type mice, but not Ch25h KO mice. These results demonstrate that the oxysterol 25HC is a key modulator of synaptic plasticity and memory under proinflammatory stimuli.SIGNIFICANCE STATEMENT Neuroinflammation is thought to contribute to cognitive impairment in multiple neuropsychiatric illnesses. In this study, we found that a proinflammatory stimulus, LPS, disrupts hippocampal LTP via a metaplastic mechanism. The effects of LPS on LTP are mimicked by the oxysterol 25-hydroxycholesterol (25HC), an immune mediator synthesized in brain microglia. Effects of LPS on both synaptic plasticity and one-trial inhibitory avoidance learning are eliminated in mice deficient in Ch25h (cholesterol 25-hydroxylase), the primary enzyme responsible for endogenous 25HC synthesis. Thus, these results indicate that 25HC is a key mediator of the effects of an inflammatory stimulus on hippocampal function and open new potential avenues to overcome the effects of neuroinflammation on brain function.

Assessing the inhibitory properties of a latent inhibitor in flavor-aversion learning

In Experiment 1, rats received 16 nonreinforced trials of exposure to a flavor (A) that was subsequently used as the conditioned stimulus in flavor-aversion conditioning. In the critical condition, Flavor A was presented in compound with a different novel flavor on each of the eight daily trials. This treatment produced latent inhibition, in that this preexposure retarded conditioning just as did 16 trials with A alone. Rats in the control conditions, given no preexposure or exposure just to the sequence of novel flavors, learned readily. Experiment 2 examined the effects of these forms of preexposure on performance on a summation test, in which Flavor A was presented in compound with a separately conditioned flavor (X). The preexposure procedure in which A was presented along with novel flavors rendered A effective in inhibiting the response conditioned to X on that test. The conclusion, that this form of training can establish the target stimulus as a conditioned inhibitor, is predicted by the account of latent inhibition put forward by Hall and Rodríguez (2010) which proposes that the latent inhibition effect is a consequence both of a reduction in the associability of the stimulus and of a process of inhibitory associative learning that opposes the initial expectation that a novel event will be followed by some consequence.

Dynamics of Dendritic Spines in Dorsal Striatum after Retrieval of Moderate and Strong Inhibitory Avoidance Learning

In marked contrast to the ample literature showing that the dorsal striatum is engaged in memory consolidation, little is known about its involvement in memory retrieval. Recent findings demonstrated significant increments in dendritic spine density and mushroom spine counts in dorsal striatum after memory consolidation of moderate inhibitory avoidance (IA) training; further increments were found after strong training. Here, we provide evidence that in this region spine counts were also increased as a consequence of retrieval of moderate IA training, and even higher mushroom spine counts after retrieval of strong training; by contrast, there were fewer thin spines after retrieval. Similar changes in mushroom and thin spine populations were found in the ventral striatum (nucleus accumbens), but they were related to the aversive stimulation and not to memory retrieval. These results suggest that memory retrieval is a dynamic process which produces neuronal structural plasticity that might be necessary for maintaining or strengthening assemblies that encode stored information.

Examining the role of the supplementary motor area in motor imagery-based skill acquisition.

Motor imagery (MI) and physical practice (PP) have been seen as parallel processes that can drive acquisition of motor skills. Emerging evidence, however, suggests these two processes may be fundamentally different, whereby MI-based motor skill acquisition relies more on effector-independent encoding of movement relative to PP. This alternate view is supported by evidence where real and virtual lesions to brain areas involved in visuospatial processing impair MI-based skill acquisition, and via behavioural studies showing perceptual, but not motor, transfer impairs skill acquisition via MI whereas this effect is reversed in PP. This study further investigated the degree to which MI utilizes effector-independent encoding of movement by investigating the role of the supplementary motor area (SMA), an area involved in perceptual to motor transformations, in MI-based motor skill acquisition. Sixty-four participants completed a serial reaction time paradigm following assignment to one of four groups based on training modality (MI or PP) and stimulation type (sham stimulation or continuous theta burst stimulation to inhibit the SMA). Faster reaction times (RTs) to elements of a repeated sequence in comparison to randomly generated elements indicated that sequence-specific learning occurred. Learning occurred in both PP and MI, with the magnitude of learning significantly smaller in MI. Inhibitory stimulation impaired learning in both modalities. In the context of a framework that distinguishes effector-independent and -dependent components of learning, these findings indicate the SMA plays a role in developing motor chunks in both PP and MI facilitating effector-independent learning in both modalities.

Examining Differences in Fear Learning in Patients With Obsessive-Compulsive Disorder With Pupillometry, Startle Electromyography and Skin Conductance Responses.

Obsessive-compulsive disorder (OCD) is characterized by recurrent, persistent thoughts and repetitive behaviors causing stress and anxiety. In the associative learning model of OCD, mechanisms of fear extinction are supposed to partly underlie symptom development, maintenance and treatment of OCD, proposing that OCD patients suffer from rigid memory associations and inhibitory learning deficits. To test these assumptions, previous studies have used skin conductance and subjective ratings as readouts in fear conditioning paradigms, finding impaired fear extinction learning, impaired fear extinction recall or no differences between individuals with OCD and healthy controls. Against this heterogeneous background, we tested fear acquisition and extinction in 37 OCD patients and 56 healthy controls, employing skin conductance as well as pupillometry and startle electromyography. Extinction recall was also included in a subsample. We did not observe differences between groups in any of the task phases, except a trend toward higher startle amplitudes during extinction for OCD. Overall, sensitive readouts such as pupillometry and startle responses did not provide evidence for moderate-to-large inhibitory learning deficits using classical fear conditioning, challenging the assumption of generically impaired extinction learning and memory in OCD.

Strain comparisons in inhibitory discrimination learning and novel object recognition procedures

Strain differences in visual abilities and exploratory tendencies can confound rats’ performance in cognitive tests of learning and memory. In the present study we compared the performance of albino Wistar and pigmented Lister Hooded rats in appetitive conditioning and recognition memory procedures, specifically within-subjects inhibitory learning (A+ /AX-) and novel object recognition (NOR) variants. The inhibition task included an excitatory training stage and summation and retardation tests. Difference scores were used to help control for individual variation in baseline nosepoke responding. NOR was tested after a 10 min delay, following 24hr delay and using a recency variant. Discrimination ratios were used to control for individual variation in exploratory activity. In the inhibitory learning procedure, Lister Hooded showed more magazine activity prior to stimulus presentations than Wistar rats but this was a transient effect restricted to day 1 of excitatory training. There was no strain difference in associative learning at the excitatory training stage. The Wistars went on to show some performance advantage at the inhibitory discrimination stage and marginally stronger retardation test performance. In the NOR tasks, there was no significant effect of strain on cognitive performance, but the Wistars showed some advantage in the 10 min delay variant, whereas in the 24hr delay and relative recency NOR variants, the Lister Hooded rats showed some advantage. Overall the results of the present study confirm the suitability of Wistar rats for use in associative learning and basic NOR procedures.

ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5

Gangliosides are glycosphingolipids, which are abundant in brain, are known to modulate ion channels and cell-to-cell communication. Deficiencies can result in aberrant myelination and altered immune responses, which can give rise to neurodevelopmental psychiatric disorders. However, to date, little mechanistic data is available on how ganglioside deficiencies contribute to the behavioural disorders. In humans, the loss of lactosylceramide-alpha-2,3-sialyltransferase (ST3Gal5) leads to a severe neuropathology, but in ST3Gal5 knock-out (St3gal5−/−) mice the absence of GM3 and associated a-, b- and c-series gangliosides is partially compensated by 0-series gangliosides and there is no overt behavioural phenotype. Here, we sought to examine the behavioural and molecular consequences of GM3 loss more closely. Mutants of both sexes exhibited impaired conditioned taste aversion in an inhibitory learning task and anxiety-like behaviours in the open field, moderate motor deficits, abnormal social interactions, excessive grooming and rearing behaviours. Taken together, the aberrant behaviours are suggestive of an autism spectrum disorder (ASD)-like syndrome. Molecular analysis showed decreased gene and protein expression of proteolipid protein-1 (Plp1) and over expression of proinflammatory cytokines, which has been associated with ASD-like syndromes. The inflammatory and behavioural responses to lipopolysaccharide (LPS) were also altered in the St3gal5−/− mice compared to wild-type, which is indicative of the importance of GM3 gangliosides in regulating immune responses. Together, the St3gal5−/− mice display ASD-like behavioural features, altered response to systemic inflammation, signs of hypomyelination and neuroinflammation, which suggests that deficiency in a- and b-series gangliosides could contribute to the development of an ASD-like pathology in humans.

Anti-Amnesic Effect of Curculigo orchioides Plant Extract and Its Function on Acetylcholinesterase Enzyme

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and one of the most predominant causes of dementia in older people. Preventing acetylcholine from breakdown by an excess amount of acetylcholinesterase is a proven therapy for AD. Traditionally Curculigo orchioides is known for its antioxidant activity, enzyme inhibition activity, and other medicinal uses. In this study, in vitro acetylcholinesterase, inhibitory activity was investigated, and methanolic extract of the plant showed significant activity. This study aims to investigate cholinesterase inhibitory activity, learning, and memory-enhancing activity of Curculigo orchioides.
 Materials and Methods: The crude methanol extract of the dried powder was prepared by the cold extraction method. In-vitro acetylcholinesterase (AChE) inhibitory activities were determined by the modified Ellman’s method. To confirm learning and memory-enhancing effects, the scopolamine-induced memory impairment Swiss-albino mice were used, and to find the anti-amnesic effect of the extract, a passive shock avoidance task was applied.
 Results: Results proved that scopolamine-induced cognitive dysfunction decreased significantly by administration of the plant extract solution in the passive avoidance task, and inhibited brain acetylcholinesterase activity. While running an in-vitro AChE inhibitory test the IC50 was 0.782±0.067μg/ml.
 Conclusion: The results suggested that methanolic extract of Curculigo orchioides can inhibit AChE in-vitro. Besides this, it provides data that proves its ability to improve whole brain AChE activity and enhance memory.

Family-Based Cognitive Behavioral Therapy for Youth With Misophonia: A Case Report

Misophonia is a common condition that causes significant distress and impairment for patients and families. Despite the growing body of literature, most treatment descriptions do not incorporate objective assessment measures or detail techniques to involve family members in addressing misophonia. This case report provides a step-by-step family-based cognitive-behavioral approach to treat youth with misophonia, uses objective rating scales to monitor therapeutic improvement, and elicits feedback on the therapeutic skills used between therapy sessions. It also provides guidance on implementing inhibitory learning exposures for youth with misophonia.

Learning biases to angry and happy faces during Pavlovian aversive conditioning.

Learning biases in Pavlovian aversive conditioning have been found in response to specific categories of threat-relevant stimuli, such as snakes or angry faces. This has been suggested to reflect a selective predisposition to preferentially learn to associate stimuli that provided threats to survival across evolution with aversive outcomes. Here, we contrast with this perspective by highlighting that both threatening (angry faces) and rewarding (happy faces) social stimuli can produce learning biases during Pavlovian aversive conditioning. Using a differential aversive conditioning paradigm, the present study (N = 107) showed that the conditioned response to angry and happy faces was more readily acquired and more resistant to extinction than the conditioned response to neutral faces. Strikingly, whereas the effects for angry faces were of moderate size, the conditioned response persistence to happy faces was of relatively small size and influenced by interindividual differences in their affective evaluation, as indexed by a Go/No-Go Association Task. Computational reinforcement learning analyses further suggested that angry faces were associated with a lower inhibitory learning rate than happy faces, thereby inducing a greater decrease in the impact of negative prediction error signals that contributed to weakening extinction learning. Altogether, these findings provide further evidence that the occurrence of learning biases in Pavlovian aversive conditioning is not specific to threat-related stimuli and depends on the stimulus' affective relevance to the organism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Avoidance in Anorexia Nervosa: Towards a research agenda

Anorexia Nervosa is a severe and disabling mental disorder and a huge challenge to treat. Intense fears of e.g., food, eating, weight gain and social evaluation are core features of anorexia nervosa and obstacles during treatment. The perceived threats trigger avoidance and safety behaviors like highly restrictive eating, strict eating rules, vomiting and body checking, to minimize feared outcomes. The role of avoidance in anorexia nervosa is however hardly studied experimentally. In the present article, the focus is on a new transdiagnostic research agenda featuring both basic and clinical experimental research into avoidance as a most important mechanism maintaining the eating disorder. Avoidance learning and the generalization of learned avoidance behaviors are discussed, as well as safety behaviors and the need for inhibitory learning as a treatment target during exposure therapy.

Optimizing Long-term Outcomes of Exposure for Chronic Primary Pain from the Lens of Learning Theory

Exposure in vivo is a theory-driven and widely used treatment to tackle functional disability in people with chronic primary pain. Exposure is quite effective; yet, in line with exposure outcomes for anxiety disorders, a number of patients may not profit from it, or relapse. In this focus article, we critically reflect on the current exposure protocols in chronic primary pain, and provide recommendations on how to optimize them. We propose several adaptations that are expected to strengthen inhibitory learning and/or retrieval of the extinction memory, thus likely decreasing relapse. We summarize the limited, but emerging experimental data in the pain domain, and draw parallels with experimental evidence in the anxiety literature. Our reflections and suggestions pertain to the use of the fear hierarchy, reassurance, positive psychology interventions, exposure with a range of stimuli and within different contexts, and the use of safety behaviors during treatment, as well as associating the fear-inducing stimuli with novel outcomes. In addition, we reflect on the importance of specifically tackling (the return of) pain-related avoidance behavior with techniques such as disentangling fear from avoidance and reinforcing approach behaviors. Finally, we discuss challenges in the clinical application of exposure to improve functioning in chronic primary pain and possible avenues for future research. PerspectiveInspired by recent advances in learning theory and its applications on the treatment of anxiety disorders, we reflect on the delivery of exposure treatment for chronic primary pain and propose strategies to improve its long-term outcomes.

The Role of the Lateral Habenula in Inhibitory Learning from Reward Omission.

The lateral habenula (LHb) is a phylogenetically primitive brain structure that plays a key role in learning to inhibit distinct responses to specific stimuli. This structure is activated by primary aversive stimuli, cues predicting an imminent aversive event, unexpected reward omissions, and cues associated with the omission of an expected reward. The most widely described physiological effect of LHb activation is acutely suppressing midbrain dopaminergic signaling. However, recent studies have identified multiple means by which the LHb promotes this effect as well as other mechanisms of action. These findings reveal the complex nature of LHb circuitry. The present paper reviews the role of this structure in learning from reward omission. We approach this topic from the perspective of computational models of behavioral change that account for inhibitory learning to frame key findings. Such findings are drawn from recent behavioral neuroscience studies that use novel brain imaging, stimulation, ablation, and reversible inactivation techniques. Further research and conceptual work are needed to clarify the nature of the mechanisms related to updating motivated behavior in which the LHb is involved. As yet, there is little understanding of whether such mechanisms are parallel or complementary to the well-known modulatory function of the more recently evolved prefrontal cortex.

Merging Our Understanding of Anxiety and Exposure: Using Inhibitory Learning to Target Anxiety Sensitivity in Exposure Therapy.

Exposure-based therapies are the gold standard treatment for anxiety disorders, and recent advancements in basic and clinical research point to the need to update the implementation of exposure. Recent research has highlighted the importance of transdiagnostic factors such as anxiety sensitivity (AS), or fear of anxiety-related sensations. Elevated AS is common among all anxiety disorders and contains three dimensions, or expectancies, that can be used to guide treatment. Recently, treatments directly targeting AS have shown potential in reducing symptoms of anxiety. In addition, inhibitory learning theory (ILT) provides an alternative explanation of exposure processes based on basic learning research. ILT extends the current framework by accounting for renewal of fear, which is important given the substantial number of individuals who experience a return of symptoms following treatment. The current paper will provide an overview of ILT and discuss several ILT techniques that can be used to target AS. These two converging bodies of research hold strong potential for optimizing treatment for anxiety.

Intranasal oxytocin compensates for estrus cycle-specific reduction of conditioned safety memory in rats: Implications for psychiatric disorders

Stress and anxiety disorder patients frequently fail to benefit from psychotherapies which often consist of inhibitory fear learning paradigms. One option to improve the therapy outcome is medication-enhanced psychotherapy. Research in humans and laboratory rodents has demonstrated that oxytocin (OT) reduces fear and facilitates fear extinction. However, the role of OT in conditioned safety learning, an understudied but highly suitable type of inhibitory fear learning, remains to be investigated. The present study aimed at investigating the effect of intranasal OT on conditioned safety. To test this, Sprague Dawley rats (♂n = 57; ♀n = 72) were safety conditioned. The effects of pre-training or pre-testing intranasal OT on conditioned safety and contextual fear, both measured by the acoustic startle response, and on corticosterone plasma levels were assessed. Furthermore, the involvement of the estrous cycle was analyzed. The present data show that intranasal OT administration before the acquisition or recall sessions enhanced conditioned safety memory in female rats while OT had no effects in male rats. Further analysis of the estrus cycle revealed that vehicle-treated female rats in the metestrus showed reduced safety memory which was compensated by OT-treatment. Moreover, all vehicle-treated rats, regardless of sex, expressed robust contextual fear following conditioning. Intranasal OT-treated rats showed a decrease in contextual fear, along with reduced plasma corticosterone levels. The present data demonstrate that intranasal OT has the capacity to compensate deficits in safety learning, along with a reduction in contextual fear and corticosterone levels. Therefore, add-on treatment with intranasal OT could optimize the therapy of anxiety disorders.

Psychotherapy of anxiety disorders: state of the art

Alongside depression, anxiety disorders are the most frequent reason for consulting apsychotherapist. This article describes the recent progress in understanding basic learning processes in anxiety treatment, the resulting therapeutic procedures, the current state of knowledge on the efficacy of the various psychotherapeutic procedures and on the moderators of the success of treatment. The English and German language literature was reviewed and compiled, with an emphasis on the last 10years. Cognitive-behavioral therapy (CBT) achieves the best and broadest level of evidence across all anxiety disorders. Initial studies have also provided emerging evidence for the efficacy of manualized short-term psychodynamic treatment. The most discussed mechanism of action is that of inhibitory learning. Augmentation strategies and personalized treatment approaches are gaining in relevance. Current models of inhibitory learning are rooted in basic research and foster adeeper understanding of the underlying neurobiological mechanisms. In order to optimize success of exposure treatment in vulnerable subgroups of patients, many procedural, device-based and pharmacological augmentation strategies are currently under investigation, whereby the latter are mostly still in the stage of (pre)clinical testing.

Traffic noise inhibits cognitive performance in a songbird.

Noise pollution is commonly associated with human environments and mounting evidence indicates that noise has a variety of negative effects on wildlife. Noise has also been linked to cognitive impairment in humans and because many animals use cognitively intensive processes to overcome environmental challenges, noise pollution has the potential to interfere with cognitive function in animals living in urban areas or near roads. We experimentally examined how road traffic noise impacts avian cognitive performance by testing adult zebra finches (Taeniopygia guttata) on a battery of foraging tasks in the presence or absence of traffic noise playback. Here, we show that traffic noise reduces cognitive performance, including inhibitory control, motor learning, spatial memory and social learning, but not associative colour learning. This study demonstrates a novel mechanism through which anthropogenic noise can impact animals, namely through cognitive interference, and suggests that noise pollution may have previously unconsidered consequences for animals.

Distinct Transcriptomic Profiles in the Dorsal Hippocampus and Prelimbic Cortex Are Transiently Regulated following Episodic Learning

A fundamental, evolutionarily conserved biological mechanism required for long-term memory formation is rapid induction of gene transcription upon learning in relevant brain areas. For episodic types of memories, two regions undergoing this transcription are the dorsal hippocampus (dHC) and prelimbic (PL) cortex. Whether and to what extent these regions regulate similar or distinct transcriptomic profiles upon learning remain to be understood. Here, we used RNA sequencing in the dHC and PL cortex of male rats to profile their transcriptomes in untrained conditions (baseline) and at 1 h and 6 d after inhibitory avoidance learning. We found that, of 33,713 transcripts, >14,000 were significantly expressed at baseline in both regions and ∼3000 were selectively enriched in each region. Gene Ontology biological pathway analyses indicated that commonly expressed pathways included synapse organization, regulation of membrane potential, and vesicle localization. The enriched pathways in the dHC were gliogenesis, axon development, and lipid modification, while in the PL cortex included vesicle localization and synaptic vesicle cycle. At 1 h after learning, 135 transcripts changed significantly in the dHC and 478 in the PL cortex; of these, only 34 were shared. Biological pathways most significantly regulated by learning in the dHC were protein dephosphorylation, glycogen and glucan metabolism, while in the PL cortex were axon development and axonogenesis. The transcriptome profiles returned to baseline by 6 d after training. Thus, a significant portion of dHC and PL cortex transcriptomic profiles is divergent, and their regulation upon learning is largely distinct and transient.SIGNIFICANCE STATEMENT Long-term episodic memory formation requires gene transcription in several brain regions, including the hippocampus and PFC. The comprehensive profiles of the dynamic mRNA changes that occur in these regions following learning are not well understood. Here, we performed RNA sequencing in the dorsal hippocampus and prelimbic cortex, a PFC subregion, at baseline, 1 h, and 6 d after episodic learning in rats. We found that, at baseline, dorsal hippocampus and prelimbic cortex differentially express a significant portion of mRNAs. Moreover, learning produces a transient regulation of region-specific profiles of mRNA, indicating that unique biological programs in different brain regions underlie memory formation.

Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning.

Ethanol is a noncompetitive inhibitor of N-methyl-d-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo. We found that 24S-hydroxycholesterol and a synthetic oxysterol analog, SGE-301, overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent effects of ethanol on LTP in vitro, and the synthetic analog reversed defects in one-trial inhibitory avoidance learning in vivo. These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMS may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition.SIGNIFICANCE STATEMENTEthanol acutely inhibits hippocampal NMDARs, LTP, and learning. This study found that certain oxysterols that are NMDAR-positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP, and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses.

Lessons Learned From a Randomized Controlled Pilot Trial Testing an Inhibitory Learning Approach to Exposure in Anxious Youth

Accumulating evidence from basic and translational research indicates that fear extinction may be best explained by principles of “inhibitory learning,” by which prefrontal cortical structures inhibit activity in the amygdala. New guidelines for the clinical practice of exposure therapy have arisen from research on inhibitory learning, but these guidelines have received little empirical testing in clinical samples of youth receiving treatment for anxiety disorders. We investigated the acceptability, feasibility, and initial efficacy of conducting exposure therapy for anxiety disorders in youth according to clinical guidelines developed from basic research on inhibitory learning principles, using a pilot randomized controlled trial design. Thirteen youths (ages 7 to 16) were recruited from a university hospital-based pediatric outpatient clinic to participate in a 9-week treatment study and were randomized to either an inhibitory learning-based exposure condition or a standard exposure condition. Results supported the feasibility and acceptability of an inhibitory learning-based approach to exposure therapy in youth and, despite the small sample size, effect sizes were in favor of the inhibitory learning approach on several measures. Differences between the standard exposure and inhibitory learning conditions are discussed using two case examples. Discussion of results and lessons learned may contribute to changes in clinical guidelines for optimally effective practice of exposure.