An analysis of reinstatement after extinction of a conditioned taste aversion.

Taste aversion learning has sometimes been considered a specialized form of learning. In several other conditioning preparations, after a conditioned stimulus (CS) is conditioned and extinguished, reexposure to the unconditioned stimulus (US) by itself can reinstate the extinguished conditioned response. Reinstatement has been widely studied in fear and appetitive Pavlovian conditioning, as well as operant conditioning, but its status in taste aversion learning is more controversial. Six taste-aversion experiments with rats therefore sought to discover conditions that might encourage it there. The results often yielded little to no evidence of reinstatement, and we also found no evidence of concurrent recovery, a related phenomenon in which responding to a CS that has been conditioned and extinguished is restored if a second CS is separately conditioned. However, a key result was that reinstatement occurred when the conditioning procedure involved multiple closely spaced conditioning trials that could have allowed the animal to learn that a US presentation signaled or set the occasion for another trial with a US. Such a mechanism is precluded in many taste aversion experiments because they often use very few conditioning trials. Overall, the results suggest that taste aversion learning is experimentally unique, though not necessarily biologically or evolutionarily unique. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Enhancing fear extinction.

Gradually reducing a source of fear during extinction treatments may weaken negative memories in the long term.

The impact of extinction timing on pre-extinction arousal and subsequent return of fear.

Exposure-based therapy is effective in treating anxiety, but a return of fear in the form of relapse is common. Exposure is based on the extinction of Pavlovian fear conditioning. Both animal and human studies point to increased arousal during immediate compared to delayed extinction (>+24 h), which presumably impairs extinction learning and increases the subsequent return of fear. Impaired extinction learning under arousal might interfere with psychotherapeutic interventions. The aim of the present study was to investigate whether arousal before extinction differs between extinction groups and whether arousal before extinction predicts the return of fear in a later (retention) test. As a highlight, both the time between fear acquisition and extinction (immediate vs. delayed) and the time between extinction and test (early vs. late test) were systematically varied. We performed follow-up analyses on data from 103 young, healthy participants to test the above hypotheses. Subjective arousal ratings and physiological arousal measures of sympathetic and hypothalamic pituitary adrenal axis activation (tonic skin conductance and salivary cortisol) were collected. Increased pre-extinction arousal in the immediate extinction group was only confirmed for subjective arousal. In linear regression analyses, none of the arousal measures predicted a significant return of fear in the different experimental groups. Only when we aggregated across the two test groups, tonic skin conductance at the onset of extinction predicted the return of fear in skin conductance responses. The overall results provide little evidence that pre-extinction arousal affects subsequent extinction learning and memory. In terms of clinical relevance, there is no clear evidence that exposure could be improved by reducing subjective or physiological arousal.

Replication study on the role of dopamine-dependent prefrontal reactivations in human extinction memory retrieval.

Even after successful extinction, conditioned fear can return. Strengthening the consolidation of the fear-inhibitory safety memory formed during extinction is one way to counteract return of fear. In a previous study, we found that post-extinction L-DOPA administration improved extinction memory retrieval 24 h later. Furthermore, spontaneous post-extinction reactivations of a neural activation pattern evoked in the ventromedial prefrontal cortex (vmPFC) during extinction predicted extinction memory retrieval, L-DOPA increased the number of these reactivations, and this mediated the effect of L-DOPA on extinction memory retrieval. Here, we conducted a preregistered replication study of this work in healthy male participants. We confirm that spontaneous post-extinction vmPFC reactivations predict extinction memory retrieval. This predictive effect, however, was only observed 90 min after extinction, and was not statistically significant at 45 min as in the discovery study. In contrast to our previous study, we find no evidence that L-DOPA administration significantly enhances retrieval and that this is mediated by enhancement of the number of vmPFC reactivations. However, additional non-preregistered analyses reveal a beneficial effect of L-DOPA on extinction retrieval when controlling for the trait-like stable baseline levels of salivary alpha-amylase enzymatic activity. Further, trait salivary alpha-amylase negatively predicts retrieval, and this effect is reduced by L-DOPA treatment. Importantly, the latter findings result from non-preregistered analyses and thus further investigation is needed.

A retrospective analysis of the relation between resurgence and renewal of behavior targeted for reduction.

Functional communication training (FCT) is an evidence-based treatment for behavior targeted for reduction that often combines extinction for target responses and arranges functionally equivalent reinforcement for alternative behavior. Long-term effectiveness of FCT can become compromised when transitioning from clinic to nonclinic contexts or thinning reinforcement schedules for appropriate behavior. Such increases in targeted behavior have been conceptualized as renewal and resurgence, respectively. The relation between resurgence and renewal has yet to be reported. Therefore, the present report retrospectively analyzed the relation between renewal and resurgence in data collected when implementing FCT with children diagnosed with developmental disabilities. We found no relation when evaluating all 34 individuals assessed for resurgence and renewal or a subset of individuals exhibiting both resurgence and renewal. These findings suggest that one form of relapse may not be predictive of another form of relapse.

KIF5B plays important roles in dendritic spine plasticity and dendritic localization of PSD95 and FMRP in the mouse cortex in vivo.

Kinesin 1 (KIF5) is one major type of motor protein in neurons, but its members' function in the intact brain remains less studied. Using in vivo two-photon imaging, we find that conditional knockout of Kif5b (KIF5B cKO) in CaMKIIα-Cre-expressing neurons shows heightened turnover and lower stability of dendritic spines in layer 2/3 pyramidal neurons with reduced spine postsynaptic density protein 95 acquisition in the mouse cortex. Furthermore, the RNA-binding protein fragile X mental retardation protein (FMRP) is translocated to the proximity of newly formed spines several hours before the spine formation events in vivo in control mice, but this preceding transport of FMRP is abolished in KIF5B cKO mice. We further find that FMRP is localized closer to newly formed spines after fear extinction, but this learning-dependent localization is disrupted in KIF5B cKO mice. Our findings provide the crucial in vivo evidence that KIF5B is involved in the dendritic targeting of synaptic proteins that underlies dendritic spine plasticity.

Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats.

BACKGROUND: Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N-methyl-D-aspartate (NMDA) receptors or metabotropic receptors' type 5 (mGlu5) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. METHODS: In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N-ω-propyl-L-arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. RESULTS: Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5-5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. CONCLUSIONS: Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats.

Novelty-retrieval-extinction paradigm to decrease high-intensity fear memory recurrence.

BACKGROUND: The retrieval-extinction paradigm based on memory reconsolidation can prevent fear memory recurrence more effectively than the extinction paradigm. High-intensity fear memories tend to resist reconsolidation. Novelty-retrieval-extinction can promote the reconsolidation of fear memory lacking neuroplasticity in rodents; however, whether it could effectively promote high-intensity fear memory reconsolidation in humans remains unclear. METHODS: Using 120 human participants, we implemented the use of the environment (novel vs. familiar) with the help of virtual reality technology. Novelty environment exploration was combined with retrieval-extinction in fear memory of two intensity levels (normal vs. high) to examine whether novelty facilitates the reconsolidation of high-intensity fear memory and prevents recurrence. Skin conductance responses were used to clarify novelty-retrieval-extinction effects at the behavioral level across three experiments. RESULTS: Retrieval-extinction could prevent the reinstatement of normal-intensity fear memory; however, for high-intensity fear memory, only the novelty-retrieval-extinction could prevent recurrence; we further validated that novelty-retrieval-extinction may be effective only when the environment is novel. LIMITATIONS: Although the high-intensity fear memory is higher than normal-intensity in this study, it may be insufficient relative to fear experienced in real-world contexts or by individuals with mental disorders. CONCLUSIONS: To some extent, these findings indicate that the novelty-retrieval-extinction paradigm could prevent the recurrence of high-intensity fear memory, and we infer that novelty of environment may play an important role in novelty-retrieval-extinction paradigm. The results of this study have positive implications for the existing retrieval extinction paradigm and the clinical treatment of phobia.

D-Pinitol mitigates post-traumatic stress disorder-like behaviors induced by single prolonged stress in mice through mineralocorticoid receptor antagonism.

Post-traumatic stress disorder (PTSD) is a mental illness that can occur in individuals who have experienced trauma. Current treatments for PTSD, typically serotonin reuptake inhibitors, have limited effectiveness for patients and often cause serious adverse effects. Therefore, a novel class of treatment with better pharmacological profile is necessary. D-Pinitol has been reported to be effective for depression and anxiety disorders, but there are no reports associated with PTSD. In the present study, we investigated the effects of D-pinitol in a mouse model of PTSD induced by a single prolonged stress (SPS) protocol. We examined the therapeutic effects of D-pinitol on emotional and cognitive impairments in the SPS mouse model. We also investigated the effects of D-pinitol on fear memory formation. Mineralocorticoid receptor transactivation assay, Western blot, and quantitative PCR were employed to investigate how D-pinitol exerts its pharmacological activities. D-Pinitol ameliorated PTSD-like behaviors in a SPS mouse model. D-Pinitol also normalized the increased mRNA expression levels and protein levels of the mineralocorticoid receptor in the amygdala. A mineralocorticoid receptor agonist reversed the effects of D-pinitol on fear extinction and recall, and the antagonistic property of D-pinitol against the mineralocorticoid receptor was confirmed in vitro. Our findings suggest that D-pinitol could serve as a potential therapeutic agent for PTSD due to its antagonistic effect on the mineralocorticoid receptor.

The effects of a retrieval cue on renewal of conditioned responses in human appetitive conditioning.

Contextual renewal of reward anticipation may be one potential mechanism underlying relapse in eating and substance use disorders. We therefore tested retrieval cues, a method derived from an inhibitory retrieval-based model of extinction learning to attenuate contextual renewal using an appetitive conditioning paradigm. A pilot study was carried out in Experiment 1 to validate a differential chocolate conditioning paradigm, in which a specific tray was set up as a conditioned stimulus (CS) for eating chocolate (unconditioned stimulus, US). Using an ABA renewal design in Experiment 2, half of the participants were presented with a retrieval cue in the acquisition phase (group AC) and the other half in the extinction phase (group EC). Presentation of the retrieval cue in the EC was associated with reduced renewal of US-expectancy, while there was a clear renewal effect for US-expectancy in the AC. One limitation was the difference in cue presentations between both groups due to the number of trials in acquisition and extinction. Experiment 3 therefore aimed at replicating the results of Experiment 2, but with fewer cue presentations for the EC to match the AC. No significant group differences were observed indicating no effect of the retrieval cue. Theoretical and clinical implications in light of the differing results are discussed.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilizes a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impairs cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict. Behavioral alterations are accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes are observed in human cytokines, including HIV-induced reductions in human TNFα, and cocaine and HIV interactions on GM-CSF levels. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

Extinct and extant termites reveal the fidelity of behavior fossilization in amber.

Fossils encompassing multiple individuals provide rare direct evidence of behavioral interactions among extinct organisms. However, the fossilization process can alter the spatial relationship between individuals and hinder behavioral reconstruction. Here, we report a Baltic amber inclusion preserving a female-male pair of the extinct termite species Electrotermes affinis. The head-to-abdomen contact in the fossilized pair resembles the tandem courtship behavior of extant termites, although their parallel body alignment differs from the linear alignment typical of tandem runs. To solve this inconsistency, we simulated the first stage of amber formation, the immobilization of captured organisms, by exposing living termite tandems to sticky surfaces. We found that the posture of the fossilized pair matches trapped tandems and differs from untrapped tandems. Thus, the fossilized pair likely is a tandem running pair, representing the direct evidence of the mating behavior of extinct termites. Furthermore, by comparing the postures of partners on a sticky surface and in the amber inclusion, we estimated that the male likely performed the leader role in the fossilized tandem. Our results demonstrate that past behavioral interactions can be reconstructed despite the spatial distortion of body poses during fossilization. Our taphonomic approach demonstrates how certain behaviors can be inferred from fossil occurrences.

Serotonin Signaling in Hippocampus during Initial Cocaine Abstinence Drives Persistent Drug Seeking.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT1B receptors and prevent consolidation of the updated nondrug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

Renewal in human fear conditioning: A systematic review and meta-analysis.

Renewal is a 'return of fear' manipulation in human fear conditioning to investigate learning processes underlying anxiety and trauma. Even though renewal paradigms are widely used, no study has compared the strength of different renewal paradigms. We conduct a systematic review (N = 80) and meta-analysis (N = 23) of human fear conditioning studies assessing renewal. Our analysis shows that the classic ABA design is the most effective paradigm, compared to ABC and ABBA designs. We present evidence that conducting extinction in multiple contexts and increasing the similarity between acquisition and extinction contexts reduce renewal. Furthermore, we show that additional cues can be used as safety and 'protection from extinction' cues. The review shows that alcohol weakens the extinction process and that older adults appear less sensitive to context changes and thus show less renewal. The large variability in approaches to study renewal in humans suggests that standardisation of fear conditioning procedures across laboratories would be of great benefit to the field.

CK2 negatively regulates the extinction of remote fear memory.

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer's disease and Parkinson's disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.

Resurgence Following Higher or Lower Quality Alternative Reinforcement.

Resurgence is a temporary increase in a previously suppressed target behavior following a worsening in reinforcement conditions. Previous studies have examined how higher rates or magnitudes of alternative reinforcement affect suppression of the target behavior and subsequent resurgence. However, there has been no investigation of the effects of higher versus lower qualities of alternative reinforcement on resurgence. Using a three-phase resurgence preparation with rats, the present experiments examined the effects of an alternative reinforcer that was of higher (Experiment 1) or lower (Experiment 2) quality than the reinforcer that had previously maintained the target behavior. The results of both experiments showed greater reductions in target behavior with a higher quality alternative reinforcer and larger increases in target responding when a higher quality alternative reinforcer was removed. Along with prior findings with higher rates and magnitudes of alternative reinforcement, these findings suggest that variations in reinforcer dimensions that increase the efficacy of alternative reinforcement also tend to increase resurgence when alternative reinforcement is removed. The results are discussed in terms of the resurgence as choice in context model and in terms of potential clinical implications.

Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice.

Adenylyl cyclase 1 (AC1) is a selective subtype of ACs, which is selectively expressed in neurons. The activation of AC1 is activity-dependent, and AC1 plays an important role in cortical excitation that contributes to chronic pain and related emotional disorders. Previous studies have reported that human-used NB001 (hNB001, a selective AC1 inhibitor) produced analgesic effects in different animal models of chronic pain. However, the potential effects of hNB001 on learning and memory have been less investigated. In the present study, we found that hNB001 affected neither the induction nor the expression of trace fear, but selectively enhanced the relearning ability during the extinction in aged mice. By contrast, the same application of hNB001 did not affect recent, remote auditory fear memory, or remote fear extinction in either adult or aged mice. Furthermore, a single or consecutive 30-day oral administration of hNB001 did not affect acute nociceptive response, motor function, or anxiety-like behavior in either adult or aged mice. Our results are consistent with previous findings that inhibition of AC1 did not affect general sensory, emotional, and motor functions in adult mice, and provide strong evidence that inhibiting the activity of AC1 may be beneficial for certain forms of learning and memory in aged mice.

The role of stimulus combinations in the repeated assessment of resurgence.

The current study examined the role of stimulus combinations on the repeated assessment of resurgence. Using a within-session resurgence procedure, rats were exposed to different conditions, each with distinct stimulus combinations (AAA, ABA, ABB, ABC and AAB). Two arrangements of stimulus changes were compared: Experiment 1 involved changes in stimulus combinations every five sessions, while Experiment 2 implemented changes every session. Resurgence was observed in both experiments; however, Experiment 2 demonstrated more consistent and repeated resurgence when stimulus combinations changed every session. Notably, the ABA, ABB and ABC conditions showed the highest percentage of sessions in which resurgence was observed. Lastly, the current study extends the application of the within-session resurgence procedure to rats and auditory stimuli, providing a reliable method for assessing resurgence in single subjects under different variable conditions.

Line- and sex-dependent effects of juvenile stress on contextual fear- and anxiety-related behavior in high- and low-alcohol-preferring mouse lines.

Juvenile stress (JS) is a known risk factor for the development of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD), both of which are frequently co-morbid. Data suggest there may be common, genetically-influenced biological responses to stress that contribute to the development of both AUD and PTSD. The present study investigated the impact of JS on contextual fear learning and extinction, as well as corticosterone (CORT) responses before and after JS, before and after contextual fear conditioning (CFC), and after fear extinction in male and female high-alcohol-preferring (HAP2) and low-alcohol-preferring (LAP2) mouse lines. We also measured unconditioned anxiety-related behavior in the light-dark-transition test before CFC. HAP2 and LAP2 mice did not differ in fear acquisition, but HAP2 mice showed faster fear extinction compared to LAP2 mice. No effects of JS were seen in HAP2 mice, whereas in LAP2 mice, JS reduced fear acquisition in males and facilitated fear extinction in females. Females showed greater fear-related behavior relative to males, regardless of subgroup. HAP2 males demonstrated more anxiolytic-like responses than LAP2 males and LAP2 females demonstrated more anxiolytic-like responses than LAP2 males in the light-dark transition test. HAP2 and LAP2 mice did not differ in CORT during the juvenile stage; however, adult LAP2 mice showed greater CORT levels than HAP2 mice at baseline and after CFC and extinction testing. These findings build upon prior work in these unique mouse lines that differ in genetic propensity toward alcohol preference and provide new information regarding contextual fear learning and extinction mechanisms theorized to contribute to co-morbid AUD and PTSD.