Extinction Of Conditioned Fear Research Articles

Different genetic factors underlie fear conditioning and episodic memory.

Fear conditioning seems to account for the acquisition of post-traumatic stress disorder, whereas conscious recall of events in aftermath of trauma reflects episodic memory. Studies show that both fear conditioning and episodic memory are heritable, but no study has evaluated whether they reflect common or separate genetic factors. To this end, we studied episodic memory and fear conditioning in 173 healthy twin pairs using visual stimuli predicting unconditioned electric shocks. Fear conditioning acquisition and extinction was determined using conditioned visual stimuli predicting unconditioned mild electric shocks, whereas electrodermal activity served as the fear learning index. Episodic memory was evaluated using cued recall of pictorial stimuli unrelated to conditioning. We used multivariate structural equation modeling to jointly analyze memory performance and acquisition as well as extinction of fear conditioning. Best-fit twin models estimated moderate genetic loadings for conditioning and memory measures, with no genetic covariation between them. Individual differences in fear conditioning and episodic memory reflect distinct genetically influenced processes, suggesting that the genetic risk for learning-induced anxiety disorders includes at least two memory-related genetic factors. These findings are consistent with the facts that the two separate learning forms are distant in their evolutionary development, involve different brain mechanisms, and support that genetically independent memory systems are pivotal in the development and maintenance of syndromes related to fear learning.

The Impact of Unconditioned Stimulus Devaluation on Conditional Fear Extinction

Unconditioned stimulus(US) devaluation has been put forward as an effective measure to decrease fear response. Previous studies mostly focused on investigating the impact of US devaluation in the test phase after fear acquisition. As widely recognized, exposure therapy based on the theory of extinction training is a frequently used method for the treatment of mental disorders. Hence, we made an attempt to implement this program in the extinction training to examine if it could improve the therapeutic effect. In addition, to further understand the mechanisms of US devaluation, evaluative conditioning was explored.An experiment was designed to test the impact of reduction in US intensity on conditioned fear extinction.All participants were subjected to a fear conditioning experiment consisted of acquisition, US devaluation and extinction phases while subjective US-expectancy and skin conductance response(SCR)were rated online. In the experiment, the intensity of US was decreased after acquisition for one group(devaluation) and held constant for another group(control). Two simple geometrical figures served as CS+ and CS?, and a 1-sec female vocal stimulus(i.e., scream) as US. Each CS+ was paired with a US during the acquisition phase, and in the subsequent devaluation phrase, subjects were only exposed to the intensity-changed US for three times. To measure evaluative conditioning, participants were required to rate CS-valence at the end of each conditioning phase.The results show that US-expectancy to CS+ was not significantly different between two groups, which seemed to reflect a similar mode of fear extinction. However, the SCR to CS+ of devaluation groupwas significantly lower than that of control group, suggesting an efficient promoted process of fear extinction by US revaluation. The effect of US devaluation was also found in evaluative conditioning. Compared to control group,devaluation group showed more positive valence ratings for CS+.The results suggest that US devaluation did promote the extinction according to the SCR. Through the US devaluation, the explicit awareness of CS-US bond did not change; but the SCR, representing a procedural fear memory formed by implicit learning, had been influenced, which declared a separation between different fear response indexes. From the evaluating conditioning results, we inferred that US might have served as a transporter, to transform the negative valence to CS. After devaluation, individuals might restate the cognition of CS fear valence, leading to the promotion of extinction. The results suggest that the modulation of US intensity may provide a new perspective for exposure therapy. Based on relevant literature review, the knowledge of the internal mechanisms of US devaluation that influence the conditioned fear extinction has acquired great advance. In the future, the treatment on mental disorders should be more focused on the behavioral therapy based on extinction training.

Inhibition of Cav2.2-mediated signaling disrupts conditioned fear extinction

Inhibition of Cav2.2-mediated signaling disrupts conditioned fear extinction

Differential roles of medial prefrontal subregions in the regulation of drug seeking

The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction. This dichotomy of mPFC function may be a general attribute, as similar dorsal–ventral distinctions exist for expression vs. extinction of fear conditioning. However, other results indicate that the role of mPFC neurons in reward processing is more complex than a simple PL-seek vs. IL-extinguish dichotomy. Both PL and IL have been shown to drive and inhibit drug seeking (and other types of behaviors) depending on a range of factors including the behavioral context, the drug-history of the animal, and the type of drug investigated. This heterogeneity of findings may reflect multiple subcircuits within each of these PFC areas supporting unique functions. It may also reflect the fact that the mPFC plays a multifaceted role in shaping cognition and behavior, including those overlapping with cocaine seeking and extinction. Here we discuss research leading to the hypothesis that dorsal and ventral mPFC differentially control drug seeking and extinction. We also present recent results calling the absolute nature of a PL vs. IL dichotomy into question. Finally, we consider alternate functions for mPFC that correspond less to response execution and inhibition and instead incorporate the complex cognitive behavior for which the mPFC is broadly appreciated.This article is part of a Special Issue entitled Addiction circuits.

Fear extinction in 17 day old rats is dependent on metabotropic glutamate receptor 5 signaling

We used pharmacological modulation of the mGlu5 receptor to investigate its role in the extinction of conditioned fear throughout development. In postnatal day (P) 17 rats, the positive allosteric modulator CDPPB facilitated, while the negative allosteric modulator MTEP impaired extinction. These drugs had no such effects on P24 or adult rats. These results establish a changing importance of mGlu5 in extinction of conditioned fear at distinct stages of development.

Sex-Specific Neuroanatomical Correlates of Fear Expression in Prefrontal-Amygdala Circuits

BackgroundThe neural projections from the infralimbic region of the prefrontal cortex to the amygdala are important for the maintenance of conditioned fear extinction. Neurons in this pathway exhibit a unique pattern of structural plasticity that is sex-dependent, but the relationship between the morphologic characteristics of these neurons and successful extinction in male and female subjects is unknown. MethodsUsing classic cued fear conditioning and an extinction paradigm in large cohorts of male and female rats, we identified subpopulations of both sexes that exhibited high (HF) or low (LF) levels of freezing on an extinction retrieval test, representing failed or successful extinction maintenance, respectively. We combined retrograde tracing with fluorescent intracellular microinjections to perform three-dimensional reconstructions of infralimbic neurons that project to the basolateral amygdala in these groups. ResultsThe HF and LF male rats exhibited neuroanatomical distinctions that were not observed in HF or LF female rats. A retrospective analysis of behavior during fear conditioning and extinction revealed that despite no overall sex differences in freezing behavior, HF and LF phenotypes emerged in male rats during extinction and in female rats during fear conditioning, which does not involve infralimbic–basolateral amygdala neurons. ConclusionsOur results suggest that the neural processes underlying successful or failed extinction maintenance may be sex-specific. These findings are relevant not only to future basic research on sex differences in fear conditioning and extinction but also to exposure-based clinical therapies, which are similar in premise to fear extinction and which are primarily used to treat disorders that are more common in women than in men.

The prelimbic cortex uses contextual cues to modulate responding towards predictive stimuli during fear renewal

Previous research suggests the prelimbic (PL) cortex is involved in expression of conditioned fear (Burgos-Robles, Vidal-Gonzalez, & Quirk, 2009; Corcoran & Quirk, 2007). However, there is a long history of research in the appetitive domain which implicates this region in using higher-order cues to modulate a behavioural response (Birrell & Brown, 2000; Floresco, Block, & Tse, 2008; Marquis, Killcross, & Haddon, 2007; Sharpe & Killcross, 2014). For example, the PL cortex is necessary to allow animals to use contextual cues to disambiguate response conflict in ambiguous circumstances (Marquis et al., 2007). Using an ABA fear renewal procedure, we assessed the role of the PL cortex in using contextual cues to modulate a response towards a conditioned stimulus (CS) in an aversive setting. We found that pre-training lesions of the PL cortex did not impact on the expression or extinction of conditioned fear. Rather, they selectively abolished renewal. Functional inactivation of the PL cortex during extinction did not disrupt the subsequent renewal of conditioned fear or the ability of animals to exhibit fear towards a CS during the extinction session. However, PL inactivation during the renewal test session disrupted the ability of animals to demonstrate a reinstatement of responding in the renewal context. An analysis of orienting responses showed that renewal deficits were accompanied by a lack of change in attentional responding towards the CS. These data suggest the PL cortex uses contextual cues to modulate both a behavioural and an attentional response during aversive procedures. We argue that the role of the PL cortex in the expression of conditioned fear is to use higher-order information to modulate responding towards predictive cues in ambiguous circumstance.

Oxytocin Facilitates the Extinction of Conditioned Fear in Humans

BackgroundCurrent neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala–medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear. MethodsKey among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo. ResultsOxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases. ConclusionsCollectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.

Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment

Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin involved in neurodevelopment, neuroprotection and synaptic plasticity. It is also implicated in a range of psychiatric disorders such as schizophrenia, depression and post-traumatic stress disorder. Stress during adolescence/young adulthood can have long-term psychiatric and cognitive consequences, however it is unknown how altered BDNF signaling is involved in such effects. Here we investigated whether a congenital deficit in BDNF availability in rats increases vulnerability to the long-term effects of the stress hormone, corticosterone (CORT).Compared to wildtype (WT) littermates, BDNF heterozygous (HET) rats showed higher body weights and minor developmental changes, such as reduced relative brain and pituitary weight. These animals furthermore showed deficits in short-term spatial memory in the Y-maze and in prepulse inhibition and startle, but not in object-recognition memory. CORT treatment induced impairments in novel-object recognition memory in both genotypes but disrupted fear conditioning extinction learning in BDNF HET rats only.These results show selective behavioral changes in BDNF HET rats, at baseline or after chronic CORT treatment and add to our understanding of the role of BDNF and its interaction with stress. Importantly, this study demonstrates the utility of the BDNF HET rat in investigations into the pathophysiology of various psychiatric disorders.

Benzodiazepine administration prevents the use of error-correction mechanisms during fear extinction.

Three experiments examined the effect of systemic administration of the benzodiazepine midazolam on extinction and re-extinction of conditioned fear. Experiment 1 demonstrated that midazolam administration prior to extinction of a conditioned stimulus (CS) impaired that extinction when rats were subsequently tested drug free; however, extinction was spared if rats were extinguished, reconditioned, and re-extinguished under midazolam. Experiment 2 provided a replication of this effect within-subjects; rats were conditioned to two CSs (A and B), extinguished to one (A-), reconditioned to both, and then extinguished/re-extinguished to both stimuli in compound (AB-), under either vehicle or midazolam. On the drug-free test, rats given midazolam froze more to the CS that had been extinguished (B) than the one that been re-extinguished (A). The final experiment examined whether extinction under midazolam was regulated by prediction error. Rats were trained with three CSs (A, B, C) and extinguished to two (A-, C-). These stimuli then underwent additional extinction under midazolam or vehicle, with one CS now presented in compound with the non-extinguished CS (AB-, C-). Rats were then tested for fear of A relative to C. Rats given vehicle showed a deepening of extinction to A relative to C, as is predicted from error-correction models; however, rats given midazolam failed to show any such discrepancy in responding. The results are interpreted to indicate that the drug reduced prediction error during extinction by reducing fear, and rats were able to re-extinguish fear via a retrieval mechanism that is independent of prediction error.

Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines

Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. The "Marine Resiliency Study II" (MRS-II; October 2011-October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n=923, PTSD symptoms: n=42, anxiety symptoms: n=37, and depression symptoms: n=12). Results suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS-), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom group showed normal safety signal discrimination and extinction of conditioned fear, but exhibited increased baseline startle reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The depression symptom group showed similar physiological and self-report measures as the healthy group. These data are consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD symptoms compared to general anxiety and depression symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological "domains" across anxiety disorders that may predict differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will examine whether poor learning of safety signals provides a marker of vulnerability to develop PTSD or is specific to symptom state.

Modulation of survival circuits in extinction of conditioned fear

Modulation of survival circuits in extinction of conditioned fear

Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala.

Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear, which is associated with decreased ventromedial prefrontal cortex (vmPFC) control over amygdala activity. Vagus nerve stimulation (VNS) enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here we investigated whether pairing VNS with extinction learning facilitates plasticity between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA). Rats were trained on an auditory fear conditioning task, which was followed by a retention test and 1 day of extinction training. Vagus nerve stimulation or sham-stimulation was administered concurrently with exposure to the fear-conditioned stimulus and retention of fear conditioning was tested again 24 h later. Vagus nerve stimulation-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5× the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials (EFPs) in the BLA in anesthetized animals 24 h after retention testing. Brief burst stimulation in the IL produced LTD in the BLA field response in fear-conditioned and sham-treated animals. In contrast, the same stimulation resulted in potentiation of the IL-BLA pathway in the VNS-treated group. The present findings suggest that VNS promotes plasticity in the IL-BLA pathway to facilitate extinction of conditioned fear responses (CFRs).

Intra-amygdala microinfusion of IL-6 impairs the auditory fear conditioning of rats via JAK/STAT activation

Though accumulating literature implicates that cytokines are involved in the pathophysiology of mental disorders, the role of interleukin-6 (IL-6) in learning and memory functions remains unresolved. The present study was undertaken to investigate the effect of IL-6 on amygdala-dependent fear learning. Adult Wistar rats were used along with the auditory fear conditioning test and pharmacological techniques. The data showed that infusions of IL-6, aimed at the amygdala, dose-dependently impaired the acquisition and extinction of conditioned fear. In addition, the results in the Western blot analysis confirmed that JAK/STAT was temporally activated–phosphorylated by the IL-6 treatment. Moreover, the rats were treated with JSI-124, a JAK/STAT3 inhibitor, prior to the IL-6 treatment showed a significant decrease in the IL-6 induced impairments of fear conditioning. Taken together, our results demonstrate that the learning behavior of rats in the auditory fear conditioning could be modulated by IL-6 via the amygdala. Furthermore, the JAK/STAT3 activation in the amygdala seemed to play a role in the IL-6 mediated behavioral alterations of rats in auditory fear learning.

Flavones from Erythrina falcata are modulators of fear memory.

BackgroundFlavonoids, which have been identified in a variety of plants, have been demonstrated to elicit beneficial effects on memory. Some studies have reported that flavonoids derived from Erythrina plants can provide such beneficial effects on memory. The aim of this study was to identify the flavonoids present in the stem bark crude extract of Erythrina falcata (CE) and to perform a bioactivity-guided study on conditioned fear memory.MethodsThe secondary metabolites of CE were identified by high performance liquid chromatography combined with a diode array detector, electrospray ionization tandem mass spectrometry (HPLC-DAD-ESI/MSn) and nuclear magnetic resonance (NMR). The buthanolic fraction (BuF) was obtained by partitioning. Subfractions from BuF (BuF1 – BuF6) and fraction flavonoidic (FfA and FfB) were obtained by flash chromatography. The BuF3 and BuF4 fractions were used for the isolation of flavonoids, which was performed using HPLC-PAD. The isolated substances were quantified by HPLC-DAD and their structures were confirmed by nuclear magnetic resonance (NMR). The activities of CE and the subfractions were monitored using a one-trial, step-down inhibitory avoidance (IA) task to identify the effects of these substances on the acquisition and extinction of conditioned fear in rats.ResultsSix subclasses of flavonoids were identified for the first time in CE. According to our behavioral data, CE, BuF, BuF3 and BuF4, the flavonoidic fractions, vitexin, isovitexin and 6-C-glycoside-diosmetin improved the acquisition of fear memory. Rats treated with BuF, BuF3 and BuF4 were particularly resistant to extinction. Nevertheless, rats treated with FfA and FfB, vitexin, isovitexin and 6-C-glycoside-diosmetin exhibited gradual reduction in conditioned fear response during the extinction retest session, which was measured at 48 to 480 h after conditioning.ConclusionsOur results demonstrate that vitexin, isovitexin and diosmetin-6-C-glucoside and flavonoidic fractions resulted in a significant retention of fear memory but did not prevent the extinction of fear memory. These results further substantiate that the treatment with pure flavonoids or flavanoid-rich fractions might represent potential therapeutic approaches for the treatment of neurocognitive disorders, improvement of memory acquisition and spontaneous recovery of fear.

Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology.

Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear. Knowledge gained on the biological basis of Pavlovian conditioning has led to the general acceptance that fear extinction may be a useful model in understanding the underlying mechanisms in the pathophysiology of anxiety disorders and may also be a good model for current therapies treating these disorders. Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction. It is also unclear how the neural correlates of fear extinction may mediate sex differences in the etiology, maintenance, and prevalence of psychiatric disorders. In this review, we begin by highlighting the epidemiological differences in incidence rate. We then discuss how estradiol (E2), a primary gonadal hormone, may modulate the mechanisms of fear extinction and mediate some of the sex differences observed in psychiatric disorders.

Unconditioned stimulus revaluation to promote conditioned fear extinction in the memory reconsolidation window.

The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window.

Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning.

BackgroundThe gamma-amino-butyric acid (GABA) system is a critical mediator of fear extinction process. GABA can induce “phasic” or “tonic” inhibition in neurons through synaptic or extrasynaptic GABAA receptors, respectively. However, role of the thalamic “tonic GABA inhibition” in cognition has not been explored. We addressed this issue in extinction of conditioned fear in mice.ResultsHere, we show that GABAA receptors in the mediodorsal thalamic nucleus (MD) modulate fear extinction. Microinjection of gabazine, a GABAA receptor antagonist, into the MD decreased freezing behavior in response to the conditioned stimulus and thus facilitated fear extinction. Interestingly, microinjection of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a preferential agonist for the δ-subunit of extrasynaptic GABAA receptors, into the MD attenuated fear extinction. In the opposite direction, an MD-specific knock-out of the extrasynaptic GABAA receptors facilitated fear extinction.ConclusionsOur results suggest that “tonic GABA inhibition” mediated by extrasynaptic GABAA receptors in MD neurons, suppresses fear extinction learning. These results raise a possibility that pharmacological control of tonic mode of GABAA receptor activation may be a target for treatment of anxiety disorders like post-traumatic stress disorder.

Delay and trace fear conditioning in a complex virtual learning environment-neural substrates of extinction.

Extinction is an important mechanism to inhibit initially acquired fear responses. There is growing evidence that the ventromedial prefrontal cortex (vmPFC) inhibits the amygdala and therefore plays an important role in the extinction of delay fear conditioning. To our knowledge, there is no evidence on the role of the prefrontal cortex in the extinction of trace conditioning up to now. Thus, we compared brain structures involved in the extinction of human delay and trace fear conditioning in a between-subjects-design in an fMRI study. Participants were passively guided through a virtual environment during learning and extinction of conditioned fear. Two different lights served as conditioned stimuli (CS); as unconditioned stimulus (US) a mildly painful electric stimulus was delivered. In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), whereas in the trace conditioning group (TCG) the US was presented 4 s after CS+ offset. Both groups showed insular and striatal activation during early extinction, but differed in their prefrontal activation. The vmPFC was mainly activated in the DCG, whereas the TCG showed activation of the dorsolateral prefrontal cortex (dlPFC) during extinction. These results point to different extinction processes in delay and trace conditioning. VmPFC activation during extinction of delay conditioning might reflect the inhibition of the fear response. In contrast, dlPFC activation during extinction of trace conditioning may reflect modulation of working memory processes which are involved in bridging the trace interval and hold information in short term memory.

Gut vagal afferents differentially modulate innate anxiety and learned fear.

Vagal afferents are an important neuronal component of the gut-brain axis allowing bottom-up information flow from the viscera to the CNS. In addition to its role in ingestive behavior, vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear. Here, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on innate anxiety, conditioned fear, and neurochemical parameters in the limbic system. We found that compared with Sham controls, SDA rats consistently displayed reduced innate anxiety-like behavior in three procedures commonly used in preclinical rodent models of anxiety, namely the elevated plus maze test, open field test, and food neophobia test. On the other hand, SDA rats exhibited increased expression of auditory-cued fear conditioning, which specifically emerged as attenuated extinction of conditioned fear during the tone re-exposure test. The behavioral manifestations in SDA rats were associated with region-dependent changes in noradrenaline and GABA levels in key areas of the limbic system, but not with functional alterations in the hypothalamus-pituitary-adrenal grand stress. Our study demonstrates that innate anxiety and learned fear are both subjected to visceral modulation through abdominal vagal afferents, possibly via changing limbic neurotransmitter systems. These data add further weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior.