Domain-selective and sex-dependent regulation of learning and memory in mice by GIRK channel activity in CA1 pyramidal neurons of the dorsal hippocampus.

G protein-gated inwardly rectifying K+ (GIRK) channels mediate the postsynaptic inhibitory effect of many neurotransmitters in the hippocampus and are implicated in neurological disorders characterized by cognitive deficits. Here, we show that enhancement or suppression of GIRK channel activity in dorsal CA1 pyramidal neurons disrupted novel object recognition in mice, without impacting open field activity or avoidance behavior. Contextual fear learning was also unaffected, but extinction of contextual fear was disrupted by suppression of GIRK channel activity in male mice. Thus, the strength of GIRK channel activity in dorsal CA1 pyramidal neurons regulates select cognitive task performance in mice.

Beyond reconsolidation: The need for a broad theoretical approach in clinical translations of research on retrieval-induced plasticity.

Experimental findings showing that retrieved memories are labile and vulnerable to disruption have led to important theoretical ideas at a basic science level that have been applied to the clinic at a translational level. At a theoretical level, these findings suggest that retrieved memories can be modulated by behavioral or pharmacological treatments as they are reconsolidated and returned to storage. At a clinical level, these findings suggest that treatments that target reconsolidation may help dampen or even erase especially problematic memories, such as those associated with trauma. However, there are many caveats to these effects and issues that need to be considered when thinking broadly about retrieval-induced plasticity and extensions into the clinic. First, performance during a memory test often does not reflect the entirety of the animal's knowledge about a situation; asking questions in different ways may reveal the presence of a memory that was thought to be eliminated. Second, although reconsolidation and extinction are often treated as competing processes, there is abundant evidence that extinction can progress through associative and nonassociative changes in the original memory that are often described in terms of reconsolidation effects. Third, targeting a reconsolidation process as a therapeutic may not be helpful in disorders like posttraumatic stress disorder, in which traumatic experiences induce a cascade of symptoms that are self-perpetuating and may ultimately maintain themselves long after trauma. Underlying all of these challenges is the need for a rich theoretical framework focused on retrieval-induced plasticity that is informed by developments in associative learning theory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Systemic corticosterone enhances fear memory extinction in rats: Involvement of the infralimbic medial prefrontal cortex GABAA and GABAB receptors.

PURPOSE: The infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) regulates the extinction of conditioned fear memory. Glucocorticoid and gamma-aminobutyric acid (GABA) receptors are expressed in the mPFC and are also critical in fear extinction. This study investigated the possible interactive effects of the glucocorticoids and GABAergic system in the IL on the regulation of fear extinction. METHOD: The rats were trained using an auditory fear conditioning task during which they received three conditioned stimuli (tones, 30 s, 4 kHz, 80 dB), co-terminated with the three unconditioned stimuli (footshock, 0.8 mA, 1 s). Extinction testing was conducted over 3 days (Ext 1-3). Thirty minutes before the first extinction trial (Ext 1), the rats received bicuculline (BIC, 1 mg/kg/2 mL, intraperitoneal [i.p.]) as a GABAA receptor antagonist or CGP55845 (CGP, 0.1 mg/kg/2 ML, i.p.) as a GABAB receptor antagonist followed by systemic injection of corticosterone (CORT, 3 mg/kg/2 ML, i.p.). Furthermore, separate groups of rats received a bilateral intra-IL injection of BIC (100 ng/0.3 µL/side) or CGP (10 ng/0.3 µL/side) followed by a systemic injection of CORT (3 mg/kg/2 ML, i.p.) before the first extinction trial (Ext 1). The extracellular signal-regulated kinase (ERK1) and cAMP response element-binding (CREB) activity in the IL was examined by Western blot analysis after Ext 1. FINDING: The results indicated that systemic CORT injection facilitated fear extinction and increased the expression of ERK1 but not CREB in the IL. Both systemic and intra-IL co-injection of BIC or CGP blocked the effects of CORT on fear extinction and ERK1 expression. CONCLUSION: These findings suggest that glucocorticoids and the GABAergic system may modulate fear extinction through the ERK pathway in the IL.

Circadian Rhythms in Conditioned Threat Extinction Reflect Time-of-Day Differences in Ventromedial Prefrontal Cortex Neural Processing.

Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction.

Multimodal assessment of the role of intolerance of uncertainty in fear acquisition and extinction.

Personality traits linked to internalizing disorders influence the way we develop fears, but also how we regain a sense of safety. In the present study, we investigated the effect of intolerance of uncertainty (IU) on defensive responses using a differential fear conditioning protocol with an extinction phase. The conditioned stimulus was associated with an aversive sound (90 dB) in 75 % of the presentations during acquisition. A final sample of 176 participants completed the experiment. We measured self-reports of associative (expectancy of the unconditioned stimulus in acquisition) and evaluative learning (arousal and valence), and both physiological (skin conductance response) and electrocortical responses (steady-state visually evoked potentials, ssVEPs; late positive potentials, LPP) to the conditioned stimuli. Our results show that IU's impact is limited, with no effect in both acquisition and extinction. These findings emphasize the necessity of large samples in research on inter-individual differences and contribute to our understanding of how IU may or may not be involved in fear and safety learning processes considering multiple aspects of fear responding.

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.

Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status.

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention. A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples. Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group. These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

Impact of trauma type on neural mechanisms of threat conditioning and its extinction.

Trauma type moderates the impact of trauma exposure on clinical symptomatology; however, the impact of trauma type on the neural correlates of emotion regulation is not as well understood. This study examines how violent and nonviolent trauma differentially influence the neural correlates of conditioned fear and extinction. We aggregated psychophysiological and fMRI data from three studies; we categorized reported trauma as violent or nonviolent, and subdivided violent trauma as sexual or nonsexual. We examined skin conductance responses (SCR) during a fear conditioning and extinction paradigm. For fMRI data analyses, we conducted region-specific and whole-brain analyses. We examined associations between beta weights from specific brain regions and CAPS scores. The group exposed to violent trauma showed significantly higher SCR during extinction recall. Those exposed to nonviolent trauma showed significantly higher functional activation during late extinction learning. The group exposed to violent trauma showed higher functional connectivity within the default mode network (DMN) and between the DMN and frontoparietal control network. For secondary analyses of sexual vs nonsexual trauma, we did not observe any between-group differences in SCR. During late extinction learning, the group exposed to sexual trauma showed significantly higher activation in the prefrontal cortex and precuneus. During extinction recall, the group exposed to nonsexual trauma showed significantly higher activation in the insular cortex. Violent trauma significantly impacts functional brain activations and connectivity in brain areas important for perception and attention with no significant impact on brain areas that modulate emotion regulation. Sexual trauma impacts brain areas important for internal perception.

Signalling unpaired unconditional stimuli during extinction does not impair their effect to reduce renewal of conditional fear.

Presenting unpaired unconditional stimuli (US) during extinction training reduces the renewal of conditional fear due to context change and slows re-acquisition. The present study investigated whether this reduced return of fear is mediated by Pavlovian inhibitory conditioning to the conditional stimulus paired with the US during acquisition (CS+) that is acquired when this stimulus is presented without the US in an excitatory extinction context. Using an ABA renewal paradigm that trained extinction in a context different from acquisition and renewal test, participants either received no USs (Standard), five unsignalled US presentations (Unsignalled) or five presentations of the US preceded by a novel, third CS (Signalled) during extinction training. Extinction was followed by tests for renewal and re-acquisition. Replicating previous results, renewal of electrodermal conditional responses was observed in group Standard, but not in group Unsignalled. Signalling the additional USs, and thus reducing context conditioning and the potential for inhibitory conditioning, did not reduce their effect in that renewal was absent in group Signalled. These results are inconsistent with an inhibitory conditioning account of the effects of unpaired US presentations during extinction. A trial sequence learning account or an arousal account may explain the effects of unpaired presentations of the US during extinction.

Unveiling the power of optimism: Exploring behavioral and neuromolecular correlates of alcohol seeking and drinking in rats with biased judgement.

Alcohol use disorder (AUD) is a common psychiatric condition with substantial global mortality. Despite extensive research into its pathophysiology, the cognitive predispositions driving alcohol dependence are less understood. This study explores whether biased cognition, specifically traits of optimism and pessimism, predicts susceptibility to alcohol-seeking behaviors using an animal model. Rats were initially tested for judgement bias through Ambiguous Cue Interpretation tests. Those identified as 'optimistic' or 'pessimistic' were further examined for their tendency to escalate alcohol intake using the intermittent access 2-bottle choice (2BC) paradigm. Additionally, we assessed how judgement bias influenced the development of compulsive alcohol-seeking behavior in a Seeking-Taking (ST) and Seeking-Taking Punishment tasks, alcohol-seeking motivation in the Progressive Ratio Schedule of Reinforcement paradigm, the speed of extinction, and reinstatement after abstinence. Neurochemical analyses were conducted to investigate trait-specific differences in neurotransmitter-related gene expression and receptor densities in the brain. We used TaqMan Gene Expression Array Cards to analyze expression levels of genes linked to serotonergic, dopaminergic, glutamatergic, and GABAergic pathways, and alcohol metabolism in various brain regions. Receptor densities for 5-HT1A, 5-HT2A, and D2 were measured using autoradiography analysis. Behaviorally, 'optimistic' rats showed significantly lower alcohol consumption in the 2BC paradigm compared to 'pessimistic' rats. This lowered intake correlated with decreased monoamine oxidase-A (Maoa) expression in the medial prefrontal cortex (mPFC) and increased metabotropic glutamate receptor 2 (Grm2) expression in the amygdala (Amy). Additionally, we observed significant interactions between judgement bias and alcohol intake in the expression of several genes in the mPFC, nucleus accumbens (Nacc), orbitofrontal cortex (OFC), and Amy, as well as in 5-HT2A receptor binding in the Nacc. Overall, these results suggest that optimism is linked to lower alcohol consumption and related neurochemical changes, indicating a potential cognitive mechanism in AUD risk.

"All we have to fear is fear itself": Paradigms for reducing fear by preventing awareness of it.

Research on unconscious fear responses has recently been translated into experimental paradigms for reducing fear that bypass conscious awareness of the phobic stimulus and thus do not induce distress. These paradigms stand in contrast to exposure therapies for anxiety disorders, which require direct confrontation of feared situations and thus are distressing. We systematically review these unconscious exposure paradigms. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-based search yielded 39 controlled experiments based on 10 paradigms that tested whether exposure without awareness can reduce fear-related responses. In randomized controlled trials of phobic participants, unconscious exposure interventions: (a) reduced behavioral avoidance (weighted mean d = 0.77, N = 469) and self-reported fear (d = 0.78, N = 329) during in vivo exposure to feared situations; (b) reduced neurobiological indicators of fear and enhanced such indicators of fear regulation (d = 0.81, N = 205); (c) had significantly stronger effects on reducing symptomatic behaviors and enhancing neurobiological indicators of fear regulation than did conscious exposure (d = 0.78, N = 342); and (d) produced these effects without inducing subjective fear. In fear-conditioned participants, unconscious exposureinduced extinction learning (d = 0.80, N = 420), even during sleep, and yielded somewhat stronger extinction learning than conscious exposure did (d = 0.44, N = 438). We organize these findings within a neuroscientific framework and evaluate alternative mechanisms for unconscious exposure. The use of incommensurate outcome measures across exposure paradigms and nonreporting of relevant statistics limited meta-analyses. Despite steps taken to address publication bias, 25.6% of included studies came from a single laboratory. We propose potential clinical applications of these findings. Future research should clarify underlying mechanisms, use common outcome measures, and explore effects on other anxiety disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reward processes in extinction learning and applications to exposure therapy.

Anxiety disorders are common and highly distressing mental health conditions. Exposure therapy is a gold-standard treatment for anxiety disorders. Mechanisms of Pavlovian fear learning, and particularly fear extinction, are central to exposure therapy. A growing body of evidence suggests an important role of reward processes during Pavlovian fear extinction. Nonetheless, predominant models of exposure therapy do not currently incorporate reward processes. Herein, we present a theoretical model of reward processes in relation to Pavlovian mechanisms of exposure therapy, including a focus on dopaminergic prediction error signaling, coinciding positive emotional experiences (i.e., relief), and unexpected positive outcomes. We then highlight avenues for further research and discuss potential strategies to leverage reward processes to maximize exposure therapy response, such as pre-exposure interventions to increase reward sensitivity or post-exposure rehearsal (e.g., savoring, imaginal recounting strategies) to enhance retrieval and retention of learned associations.

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).

Degradation of perineuronal nets in the medial prefrontal cortex promotes extinction and reduces reinstatement of methamphetamine-induced conditioned place preference in female mice.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.

Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice.

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders.

Reducing FKBP51 Expression in the Ventral Hippocampus Decreases Auditory Fear Conditioning in Male Rats.

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.

Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

The impact of the left inferior frontal gyrus on fear extinction: A transcranial direct current stimulation study.

INTRODUCTION: Fear extinction is a fundamental component of exposure-based therapies for anxiety-related disorders. The renewal of fear in a different context after extinction highlights the importance of contextual factors. In this study, we aimed to investigate the causal role of the left inferior frontal gyrus (LiFG) in the context-dependency of fear extinction learning via administration of transcranial direct current stimulation (tDCS) over this area. METHODS: 180 healthy subjects were assigned to 9 groups: 3 tDCS conditions (anodal, cathodal, and sham) × 3 context combinations (AAA, ABA, and ABB). The fear conditioning/extinction task was conducted over three consecutive days: acquisition, extinction learning, and extinction recall. tDCS (2 mA, 10min) was administered during the extinction learning phase over the LiFG via a 4-electrode montage. Skin conductance response (SCR) data and self-report assessments were collected. RESULTS: During the extinction learning phase, groups with excitability-enhancing anodal tDCS showed a significantly higher fear response to the threat cues compared to cathodal and sham stimulation conditions, irrespective of contextual factors. This effect was stable until the extinction recall phase. Additionally, excitability-reducing cathodal tDCS caused a significant decrease of the response difference between the threat and safety cues during the extinction recall phase. The self-report assessments showed no significant differences between the conditions throughout the experiment. CONCLUSION: Independent of the context, excitability enhancement of the LiFG did impair fear extinction, and led to preservation of fear memory. In contrast, excitability reduction of this area enhanced fear extinction retention. These findings imply that the LiFG plays a role in the fear extinction network, which seems to be however context-independent.

Resurgence mitigation across extended extinction following four and eight cycles of on/off alternative reinforcement.

Resurgence is an increase in an extinguished operant response resulting from a worsening of conditions (e.g., extinction) for a more recently reinforced alternative behavior. Previous research has shown that exposure to cycles of alternative reinforcement available versus unavailable (i.e., on/off alternative reinforcement) across sessions can reduce subsequent resurgence. Most previous assessments of the procedure have examined target operant responding during only single-session resurgence tests, and it remains unclear if exposure to relatively few cycles of on/off alternative reinforcement can maintain low rates of target behavior across extended exposure to extinction. This experiment with rats examined the effects of 4 or 8 cycles of on/off alternative reinforcement on subsequent resurgence during a 10-session extinction test. The results show that exposure to 4 cycles of on/off alternative reinforcement is as effective as 8 cycles in producing low rates of target behavior during treatment and across extended extinction. This result is consistent with extant theories of resurgence and suggests that on/off alternative reinforcement could have translational utility following relatively few cycles of exposure.

Prediction error determines how memories are organized in the brain.

How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.