RESUMEN

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).

Asunto(s)

Consolidación de la Memoria , Plasticidad Neuronal , Animales , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de los fármacos , Humanos , Consolidación de la Memoria/fisiología , Consolidación de la Memoria/efectos de los fármacos , Extinción Psicológica/fisiología , Extinción Psicológica/efectos de los fármacos , Trastornos por Estrés Postraumático/psicología , Recuerdo Mental/fisiología , Recuerdo Mental/efectos de los fármacos , Investigación Biomédica Traslacional , Memoria/fisiología , Memoria/efectos de los fármacos

RESUMEN

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.

Asunto(s)

Reacción de Prevención , Condicionamiento Operante , Refuerzo en Psicología , Humanos , Reacción de Prevención/fisiología , Masculino , Femenino , Adulto Joven , Adulto , Condicionamiento Operante/fisiología , Extinción Psicológica/fisiología , Adolescente

RESUMEN

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.

Asunto(s)

Condicionamiento Clásico , Extinción Psicológica , Miedo , Respuesta Galvánica de la Piel , Extinción Psicológica/fisiología , Humanos , Miedo/fisiología , Masculino , Respuesta Galvánica de la Piel/fisiología , Condicionamiento Clásico/fisiología , Femenino , Adulto , Adulto Joven , Adolescente , Análisis de Varianza

RESUMEN

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.

Asunto(s)

Condicionamiento Clásico , Extinción Psicológica , Miedo , Respuesta Galvánica de la Piel , Imagen por Resonancia Magnética , Trauma Psicológico , Humanos , Extinción Psicológica/fisiología , Masculino , Miedo/fisiología , Femenino , Adulto , Respuesta Galvánica de la Piel/fisiología , Adulto Joven , Condicionamiento Clásico/fisiología , Trauma Psicológico/fisiopatología , Trauma Psicológico/diagnóstico por imagen , Red en Modo Predeterminado/fisiopatología , Red en Modo Predeterminado/diagnóstico por imagen , Exposición a la Violencia , Delitos Sexuales , Adolescente , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología

RESUMEN

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.

Asunto(s)

Extinción Psicológica , Miedo , Estrés Psicológico , Humanos , Extinción Psicológica/fisiología , Femenino , Masculino , Adulto , Miedo/fisiología , Miedo/psicología , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Adulto Joven , Estradiol/metabolismo , Estradiol/sangre , Estradiol/análisis , Caracteres Sexuales , Hormonas Esteroides Gonadales/metabolismo , Hormonas Esteroides Gonadales/análisis , Factores Sexuales , Adolescente , Saliva/química , Saliva/metabolismo , Fase Folicular/fisiología , Fase Folicular/psicología , Ciclo Menstrual/fisiología , Ciclo Menstrual/psicología , Condicionamiento Clásico/fisiología

RESUMEN

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.

Asunto(s)

Consumo de Bebidas Alcohólicas , Juicio , Optimismo , Animales , Masculino , Ratas , Consumo de Bebidas Alcohólicas/psicología , Consumo de Bebidas Alcohólicas/metabolismo , Optimismo/psicología , Juicio/fisiología , Comportamiento de Búsqueda de Drogas/fisiología , Motivación/fisiología , Alcoholismo/psicología , Alcoholismo/metabolismo , Etanol/administración & dosificación , Pesimismo/psicología , Encéfalo/metabolismo , Extinción Psicológica/fisiología

RESUMEN

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.

Asunto(s)

Trastornos de Ansiedad , Condicionamiento Clásico , Extinción Psicológica , Miedo , Terapia Implosiva , Recompensa , Humanos , Extinción Psicológica/fisiología , Terapia Implosiva/métodos , Miedo/fisiología , Trastornos de Ansiedad/terapia , Condicionamiento Clásico/fisiología

RESUMEN

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).

Asunto(s)

Reacción de Prevención , Condicionamiento Operante , Extinción Psicológica , Humanos , Masculino , Extinción Psicológica/fisiología , Femenino , Reacción de Prevención/fisiología , Adulto Joven , Adulto , Condicionamiento Operante/fisiología , Adolescente , Condicionamiento Clásico/fisiología

RESUMEN

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.

Asunto(s)

Miedo , Hipocampo , Proteínas de Unión a Tacrolimus , Animales , Masculino , Miedo/fisiología , Proteínas de Unión a Tacrolimus/metabolismo , Proteínas de Unión a Tacrolimus/genética , Hipocampo/metabolismo , Ratas , Corticosterona/metabolismo , Corticosterona/sangre , Ratas Sprague-Dawley , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Receptores de Glucocorticoides/metabolismo , Extinción Psicológica/fisiología

RESUMEN

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.

Asunto(s)

Extinción Psicológica , Metanfetamina , Ratones Endogámicos C57BL , Corteza Prefrontal , Animales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Metanfetamina/farmacología , Femenino , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Ratones , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Condroitina ABC Liasa/farmacología

RESUMEN

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.

Asunto(s)

Extinción Psicológica , Miedo , Corteza Prefrontal , Estimulación Transcraneal de Corriente Directa , Humanos , Miedo/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Extinción Psicológica/fisiología , Masculino , Femenino , Corteza Prefrontal/fisiología , Adulto , Adulto Joven , Respuesta Galvánica de la Piel/fisiología , Condicionamiento Clásico/fisiología

RESUMEN

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.

Asunto(s)

Astrocitos , Miedo , Hipocampo , Depresión Sináptica a Largo Plazo , Memoria , Receptor de Serotonina 5-HT1A , Animales , Receptor de Serotonina 5-HT1A/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiología , Miedo/fisiología , Masculino , Depresión Sináptica a Largo Plazo/fisiología , Ratones , Memoria/fisiología , Astrocitos/metabolismo , Ratones Noqueados , Envejecimiento/fisiología , Envejecimiento/metabolismo , Ratones Endogámicos C57BL , Extinción Psicológica/fisiología , Transmisión Sináptica

RESUMEN

Background: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown. Methods: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs. Results: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits. Conclusions: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.

Asunto(s)

Modelos Animales de Enfermedad , Extinción Psicológica , Miedo , Ratones Noqueados , Neuronas , Oxitocina , Síndrome de Prader-Willi , Somatostatina , Vasopresinas , Animales , Oxitocina/farmacología , Somatostatina/farmacología , Somatostatina/metabolismo , Miedo/efectos de los fármacos , Miedo/fisiología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratones , Síndrome de Prader-Willi/fisiopatología , Síndrome de Prader-Willi/tratamiento farmacológico , Vasopresinas/metabolismo , Agresión/efectos de los fármacos , Agresión/fisiología , Masculino , Conducta Social , Núcleos Septales/efectos de los fármacos , Núcleos Septales/metabolismo , Optogenética , Ratones Endogámicos C57BL , Péptidos y Proteínas de Señalización Intracelular , Proteínas Intrínsecamente Desordenadas

RESUMEN

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

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This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Asunto(s)

Extinción Psicológica , Glucocorticoides , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Glucocorticoides/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hidrocortisona , Masculino , Adulto , Femenino , Imagen por Resonancia Magnética

RESUMEN

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.

Asunto(s)

Señales (Psicología) , Receptor beta de Estrógeno , Extinción Psicológica , Heroína , Recuerdo Mental , Animales , Masculino , Femenino , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/metabolismo , Heroína/farmacología , Ratas , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Recuerdo Mental/efectos de los fármacos , Recuerdo Mental/fisiología , Nitrilos/farmacología , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/efectos de los fármacos , Propionatos/farmacología , Factores Sexuales , Autoadministración , Ratas Sprague-Dawley , Dependencia de Heroína/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administered after the acquisition (consolidation) and retrieval (reconsolidation) of fear memory attenuates it persistently in rats and mice. CBD also reduces fear expression and enhances fear extinction. These effects involve the activation of cannabinoid type-1 (CB1) receptors in the dorsal hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, comprising the anterior cingulate, prelimbic, and infralimbic subregions. Serotonin type-1A (5-HT1A) receptors also mediate some CBD effects on fear memory. CBD effects on fear memory acquisition vary, depending on the aversiveness of the conditioning procedure. While rodent findings are relatively consistent and encouraging, human studies investigating CBD's efficacy in modulating aversive/traumatic memories are still limited. More studies are needed to investigate CBD's effects on maladaptive, traumatic memories, particularly in post-traumatic stress disorder patients.

Asunto(s)

Cannabidiol , Miedo , Trastornos por Estrés Postraumático , Animales , Cannabidiol/farmacología , Miedo/efectos de los fármacos , Miedo/fisiología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/fisiopatología , Humanos , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología

RESUMEN

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.

Asunto(s)

Encéfalo , Miedo , Memoria , Animales , Ratas , Memoria/fisiología , Miedo/fisiología , Encéfalo/fisiología , Masculino , Extinción Psicológica/fisiología , Condicionamiento Clásico/fisiología

RESUMEN

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.

Asunto(s)

Condicionamiento Operante , Extinción Psicológica , Esquema de Refuerzo , Refuerzo en Psicología , Animales , Extinción Psicológica/fisiología , Condicionamiento Operante/fisiología , Ratas , Masculino , Conducta Animal/fisiología , Ratas Sprague-Dawley , Ratas Long-Evans

RESUMEN

There is a growing number of studies investigating discriminatory fear conditioning and conditioned inhibition of fear to assess safety learning, in addition to extinction of cued fear. Despite all of these paradigms resulting in a reduction in fear expression, there are nuanced differences among them, which could be mediated through distinct behavioral and neural mechanisms. These differences could impact how we approach potential treatment options in clinical disorders with dysregulated fear responses. The objective of this review is to give an overview of the conditional discrimination and inhibition findings reported in both animal models and human neuropsychiatric disorders. Both behavioral and neural findings are reviewed among human and rodent studies that include conditional fear discrimination via conditional stimuli with and without reinforcement (CS+ vs. CS-, respectively) and/or conditional inhibition of fear through assessment of the fear response to a compound CS-/CS+ cue versus CS+. There are several parallels across species in behavioral fear expression as well as neural circuits promoting fear reduction in response to a CS- and/or CS-/CS+ compound cue. Continued and increased efforts to compare similar behavioral fear inhibition paradigms across species are needed to make breakthrough advances in our understanding and treatment approaches to individuals with fear disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Asunto(s)

Condicionamiento Clásico , Miedo , Trastornos Mentales , Humanos , Animales , Miedo/fisiología , Trastornos Mentales/terapia , Trastornos Mentales/psicología , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Inhibición Psicológica , Investigación Biomédica Traslacional , Discriminación en Psicología/fisiología , Señales (Psicología) , Encéfalo/fisiología

RESUMEN

Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues' influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment's potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.

Asunto(s)

Comportamiento de Búsqueda de Drogas , Etanol , Extinción Psicológica , Núcleo Accumbens , Ratas Long-Evans , Animales , Núcleo Accumbens/efectos de los fármacos , Masculino , Etanol/administración & dosificación , Etanol/farmacología , Comportamiento de Búsqueda de Drogas/fisiología , Ratas , Extinción Psicológica/fisiología , Extinción Psicológica/efectos de los fármacos , Autoadministración , Vías Nerviosas/fisiología , Alcoholismo , Señales (Psicología) , Corteza Prefrontal/fisiología , Corteza Prefrontal/efectos de los fármacos , Baclofeno/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Muscimol/farmacología