Fear Inhibition Research Articles

Hippocampal activation during contextual fear inhibition related to resilience in the early aftermath of trauma

BackgroundImpaired contextual fear inhibition is often associated with posttraumatic stress disorder (PTSD). Our previous work has demonstrated that more hippocampal activation during a response inhibition task after trauma exposure was related to greater resilience and fewer future PTSD symptoms. In the current study, we sought to extend our previous findings by employing a contextual fear conditioning and extinction paradigm to further determine the role of the hippocampus in resilience and PTSD in the early aftermath of trauma. MethodsParticipants (N = 28) were recruited in the Emergency Department shortly after experiencing a traumatic event. A contextual fear inhibition task was conducted in a 3 T MRI scanner approximately two months post-trauma. Measures of resilience (CD-RISC) at time of scan and PTSD symptoms three months post-trauma were collected. The associations between hippocampal activation during fear conditioning and during the effect of context during extinction, and post-trauma resilience and PTSD symptoms at three-months were assessed. ResultsDuring fear conditioning, activation of the bilateral hippocampal region of interest (ROI) correlated positively with resilience (r = 0.48, p = 0.01). During the effect of context during extinction, greater bilateral hippocampal activation correlated with lower PTSD symptoms three months post-trauma after controlling for baseline PTSD symptoms, age and gender (r=-0.59, p=0.009). ConclusionsGreater hippocampal activation was related to post-trauma resilience and lower PTSD symptoms three months post-trauma. The current study supports and strengthens prior findings suggesting the importance of hippocampus-dependent context processing as a mechanism for resilience versus PTSD risk, which could be a potential mechanistic target for novel early interventions.

Manipulation of rapid eye movement sleep via orexin and GABAA receptor modulators differentially affects fear extinction in mice: effect of stable versus disrupted circadian rhythm.

Sleep disruption, and especially rapid eye movement (REM) sleep disruption, is associated with fear inhibition impairment in animals and humans. The REM sleep-fear inhibition relationship raises concern for individuals with posttraumatic stress disorder (PTSD), whose sleep disturbance is commonly treated with hypnotics that disrupt and/or decrease REM sleep, such as benzodiazepines or "Z-drugs." Here, we examined the effects of the Z-drug zolpidem, a gamma-aminobutyric acidA (GABAA) receptor positive allosteric modulator, as well as suvorexant, an orexin receptor antagonist (hypnotics which decrease and increase REM sleep, respectively) in the context of circadian disruption in murine models of fear inhibition-related processes (i.e. fear extinction and safety learning). Adult male C57Bl/6J mice completed fear and safety conditioning before undergoing shifts in the light-dark (LD) cycle or maintaining a consistent LD schedule. Fear extinction and recall of conditioned safety were thereafter tested daily. Immediately prior to the onset of the light phase between testing sessions, mice were treated with zolpidem, suvorexant, or vehicle (methylcellulose). Polysomnographic analyses showed the temporal distribution of REM sleep was misaligned during LD cycle-shifts, while REM sleep duration was preserved. Suvorexant increased REM sleep and improved fear extinction rate, relative to zolpidem, which decreased REM sleep. Survival analysis demonstrated LD shifted mice treated with suvorexant were faster to achieve complete extinction than vehicle and zolpidem-treated mice in the LD shifted condition. By contrast, retention of conditioned safety memory was not influenced by either treatment. This study thus provides preclinical evidence for the potential clinical utility of hypnotics which increase REM sleep for fear extinction after PTSD-relevant sleep disturbance.

Anti-PTSD Effects of Hypidone Hydrochloride (YL-0919): A Novel Combined Selective 5-HT Reuptake Inhibitor/5-HT1A Receptor Partial Agonist/5-HT6 Receptor Full Agonist.

Posttraumatic stress disorder (PTSD) is a debilitating trauma and stressor-related disorder that has become a major neuropsychiatric problem, leading to substantial disruptions in individual health and societal costs. Our previous studies have demonstrated that hypidone hydrochloride (YL-0919), a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist, exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 exerts anti-PTSD effects and its underlying mechanisms are still unclear. In the present study, we showed that repeated treatment with YL-0919 caused significant suppression of contextual fear, enhanced anxiety and cognitive dysfunction induced by the time-dependent sensitization (TDS) procedure in rats and by inescapable electric foot-shock in a mouse model of PTSD. Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC.

An analysis of fear inhibition and fear extinction in a sample of veterans with obstructive sleep apnea (OSA): Implications for co-morbidity with post-traumatic stress disorder (PTSD)

Obstructive sleep apnea (OSA) is a respiratory condition characterized by interrupted sleep due to repeated, temporary collapse of the soft tissue of the upper airway that can lead to a cascade of physiological and psychological adverse health outcomes. The most common therapeutic interventions for OSA patients include the application of continuous positive airway pressure (CPAP) which acts to keep the airway open and, as such, provides less interrupted and more restorative sleep. Improved sleep has been linked to more efficacious treatments for psychiatric conditions most notably those that include cognitive-behavioral elements, new learning, and memory consolidation. In the current study, we investigated the acquisition, inhibition, and extinction of conditioned fear in OSA patients, before and after CPAP therapy, using an established fear-potentiated startle paradigm. Patients with OSA displayed an intact ability to acquire, inhibit, and extinguish fear prior to CPAP treatment and this ability was significantly enhanced following CPAP usage. In addition, those patients with more severe OSA, as measured by apnea-hypopnea index (AHI), were more likely to show improved fear inhibition and extinction. Lastly, we observed impairments in discrimination between reinforced and nonreinforced conditioned stimuli, in the inhibition of fear, and in fear extinction in a subset of patients with OSA and co-morbid posttraumatic stress disorder (PTSD). These data suggest that evolving treatment algorithms for PTSD should address disrupted sleep problems prior to initiation of inhibition/extinction-based exposure therapies.

Late gestational exposure to dexamethasone and fetal programming of abnormal behavior in Wistar Kyoto rats.

IntroductionFetal programming was characterized a few decades ago, explaining the correlation of physiological phenotypes of offspring exposed to early‐life stress. High acute or chronic prenatal stress can overwhelm the enzymatic placental barrier, inducing transcriptional changes in the fetus that can result in different adverse behavioral and physiological phenotypes. The current study investigates the impact of exposure to the synthetic glucocorticoid, dexamethasone, during late gestation on behavioral outcomes.MethodsPregnant Wistar Kyoto rats were given daily subcutaneous injections from gestational days 15–21 of either dexamethasone (0.9% NaCl, 4% EtOH, 100 µg kg−1 day−1) or were physically manipulated as naïve controls. Pups were raised normally until 17 weeks of age and underwent the Porsolt swim task and elevated plus maze for depressive and anxiety‐like behaviors, respectively. Neural tissue was preserved for genetic analysis using quantitative real‐time polymerase chain reaction.ResultsStatistical analyses show significant disruption of behavior and genetic profiles of offspring exposed to dexamethasone in‐utero. Exposed animals spent more time immobile on the swim task and entered open arms of the elevated plus maze more often than their naïve counterparts. In the prefrontal cortex, there was a sex by treatment interaction on gene expression relevant to neural transmission in ryanodine receptor 2, as well as increased gene expression in SNAP25, COMT, and LSAMP in males prenatally exposed to dexamethasone compared with controls. Both dysregulated genes and behavior are linked to decreased anxiety and fear inhibition.ConclusionOur results indicate adult offspring exposed to dexamethasone in‐utero have a tendency toward passive stress‐coping strategies and an inhibition of anxiety on behavioral tasks. Methyltransferase activity, synaptic activity, and cellular processes were disrupted in the prefrontal cortices of these animals. Specifically, genes involved in emotional response pathways were overexpressed, supporting the link between the behavioral and genetic profiles. Combined, we determine that dexamethasone offspring have adaptive predispositions when faced with novel situations, with increased immobility in the swim task and increased exploration on the elevated plus maze.

A legacy of fear: Physiological evidence for intergenerational effects of trauma exposure on fear and safety signal learning among African Americans

ObjectiveTo determine the influence of maternal trauma and posttraumatic stress disorder (PTSD) symptoms on children’s physiological response to threat and safety signals during a fear conditioning task in trauma-exposed mothers and children. MethodParticipants were African American mother-child dyads (N = 137; children aged 8–13 years). Mothers’ trauma history and PTSD symptoms were assessed; Latent Class Analysis (LCA) was conducted from these measures to identify distinct classes. Children reported violence exposure and completed a differential fear conditioning task using fear-potentiated startle (FPS) responses to conditioned danger (CS+) and safety (CS-) signals. ResultsFour classes of maternal trauma history and PTSD symptoms emerged: 1) Lower Trauma, 2) Moderate Trauma, 3) High Sexual Abuse, and 4) High Trauma and PTSD Symptoms. Children’s FPS to CS + and CS- were tested with maternal class as the between-subjects factor. FPS to the danger signal was not significantly different across maternal classes, but FPS to safety (CS-) was significantly higher for the Lower Trauma and High Trauma and PTSD Symptoms classes than either the Moderate Trauma or the High Sexual Abuse classes. ConclusionsResults indicate that maternal trauma impacts children’s ability to modulate fear responses in the presence of a safety signal, independent of the children’s own trauma exposure. To our knowledge, this is the first study to demonstrate that children’s fear inhibition is impacted by maternal trauma exposure. Prior studies have linked fear inhibition to mental health outcomes, highlighting the need to understand intergenerational modulation of fear learning and physiology.

Learning About Safety: Conditioned Inhibition as a Novel Approach to Fear Reduction Targeting the Developing Brain.

Adolescence is a peak time for the onset of psychiatric disorders, with anxiety disorders being the most common and affecting as many as 30% of youths. A core feature of anxiety disorders is difficulty regulating fear, with evidence suggesting deficits in extinction learning and corresponding alterations in frontolimbic circuitry. Despite marked changes in this neural circuitry and extinction learning throughout development, interventions for anxious youths are largely based on principles of extinction learning studied in adulthood. Safety signal learning, based on conditioned inhibition of fear in the presence of a cue that indicates safety, has been shown to effectively reduce anxiety-like behavior in animal models and attenuate fear responses in healthy adults. Cross-species evidence suggests that safety signal learning involves connections between the ventral hippocampus and the prelimbic cortex in rodents or the dorsal anterior cingulate cortex in humans. Particularly because this pathway follows a different developmental trajectory than fronto-amygdala circuitry involved in traditional extinction learning, safety cues may provide a novel approach to reducing fear in youths. In this review, the authors leverage a translational framework to bring together findings from studies in animal models and humans and to bridge the gap between research on basic neuroscience and clinical treatment. The authors consider the potential application of safety signal learning for optimizing interventions for anxious youths by targeting the biological state of the developing brain. Based on the existing cross-species literature on safety signal learning, they propose that the judicious use of safety cues may be an effective and neurodevelopmentally optimized approach to enhancing treatment outcomes for youths with anxiety disorders.

Pre-adolescent stress disrupts adult, but not adolescent, safety learning

Anxiety disorders are highly prevalent across the lifespan, although diagnoses peak early in adolescence. As a method for inhibiting fear, safety signals have the potential to augment conventional treatments for anxiety. However, the ability to acquire and use safety signals during adolescence remains unclear. Moreover, the impact of stress on safety learning has received surprisingly little attention given that stress is a major factor preceding anxiety onset. In this study, mice were trained in a discriminative conditioning protocol to facilitate safety learning and were tested for fear inhibition using a conditioned safety signal. Next, independent groups of mice were exposed to chronic unpredictable stress (CUS) conditions between postnatal day 22 and 28, followed by tests for anxiety-like phenotypes or fear inhibition using a safety signal, performed either 24 h or five weeks following CUS. Pre-adolescent CUS reduced weight in adolescence and this effect endured into adulthood. CUS also increased specific anxiety-like behaviors in adolescence that were unique from the increase in anxiety observed in adulthood. Despite increased anxiety-like behaviors, adolescents were able to learn about and effectively use safety signals to inhibit fear. In contrast, adults that experienced CUS showed a subtle increase in anxiety but had impaired safety signal learning and usage. Together, these findings indicate that pre-adolescent stress has immediate and enduring effects on anxiety-like behaviors but impairs the capacity for conditioned inhibition only following incubation.

Juvenile stress facilitates safety learning in male and female high alcohol preferring mice

Adversities during juvenility increase the risk for stress-related disorders, such as post-traumatic stress disorder (PTSD) and alcohol use disorder. However, stress can also induce coping mechanisms beneficial for later stressful experiences. We reported previously that mice selectively bred for high alcohol preference (HAP) exposed to stress during adolescence (but not during adulthood) showed enhanced fear-conditioned responses in adulthood, as measured by fear-potentiated startle (FPS). However, HAP mice also showed enhanced responding to safety cues predicting the absence of foot shocks in adulthood. Here, we pursue these findings in HAP mice by investigating in further detail how juvenile stress impacts the acquisition of safety and fear learning. HAP mice were subjected to three days of juvenile stress (postnatal days 25, 27, 28) and discriminative safety/fear conditioning in adulthood. FPS was used to assess safety versus fear cue discrimination, fear learning, and fear inhibition by the safety cue. Both stressed and unstressed HAP mice were able to discriminate between both cues as well as learn the fear cue-shock association. Interestingly, it was only the previously stressed mice that were able to inhibit their fear response when the fear cue was co-presented with the safety cue, thus demonstrating safety learning. We also report an incidental finding of alopecia in the juvenile stress groups, a phenotype seen in stress-related disorders. These results in HAP mice may be relevant to understanding the influence of juvenile trauma for individual risk and resilience toward developing PTSD and how individuals might benefit from safety cues in behavioral psychotherapy.

Effects of optogenetic photoexcitation of infralimbic cortex inputs to the basolateral amygdala on conditioned fear and extinction

Deficiencies in the ability to extinguish fear is a hallmark of Trauma- and stressor-related disorders, Anxiety disorders, and certain other neuropsychiatric conditions. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear is of significant translational relevance. Previous studies in rodents have shown that glutamatergic projections from the infralimbic prefrontal cortex (IL) to basolateral amygdala (BLA) play a crucial instructional role in the formation of extinction memories, and also indicate that variation in the strength of this input correlates with extinction efficacy. To further examine the relationship between the IL→BLA pathway and extinction we expressed three different titers of the excitatory opsin, channelrhodopsin (ChR2), in IL neurons and photostimulated their projections in the BLA during partial extinction training. The behavioral effects of photoexcitation differed across the titer groups: the low titer had no effect, the medium titer selectively facilitated extinction memory formation, and the high titer produced both an acute suppression of fear and a decrease in fear during (light-free) extinction retrieval. We discuss various possible explanations for these titer-specific effects, including the possibility of IL-mediated inhibition of BLA fear-encoding neurons under conditions of sufficiently strong photoexcitation. These findings further support the role of IL→BLA pathway in regulating fear and highlight the importance of methodological factors in optogenetic studies of neural circuits underling behavior.

The role of the ventromedial prefrontal cortex and context in regulating fear learning and extinction.

An organism's ability to learn about and respond to stimuli in its environment is crucial for survival, which can involve learning simple associations such as learning what stimuli predict danger. However, individuals must also be able to use contextual information to adapt to changing environmental demands. While the circuitry that supports fear conditioning has been extensively studied, the circuitry that allows individuals to regulate fear under different circumstance is less well understood. A view of ventromedial prefrontal cortex (vmPFC) function has emerged wherein the prelimbic region of the vmPFC supports fear expression, while the infralimbic region supports fear inhibition. However, despite a rich literature exploring the role of these regions in appetitive learning and memory suggesting a more nuanced function, there has been little integration of this literature with studies of the vmPFC in fear learning. In this review, we argue that the function of the vmPFC in fear learning is not restricted to fear inhibition versus expression per se. Instead, the vmPFC uses contextual information to guide behavior, particularly in situations of ambiguity or conflict.

Interaction of Fear Conditioning with Eyeblink Conditioning Supports the Sensory Gating Hypothesis of the Amygdala in Men.

Inhibition of the amygdala slows down acquisition of conditioned eyeblink responses (CRs). Based on the two-stage or two-factor theory of aversive conditioning, amygdala-dependent conditioned fear is a necessary prerequisite to acquire eyeblink CRs but is no longer needed after eyeblink CRs are attained. According to the sensory gating hypothesis of the amygdala, on the other hand, the amygdala modulates the salience of unconditioned stimuli (USs) and conditioned stimuli (CSs) in eyeblink conditioning. We tested these two opposing assumptions in five groups of 20 young and healthy men. On day 1, three groups underwent fear acquisition training followed by acquisition of eyeblink CRs. On the next day (day 2), extinction was tested. In group 1, fear and eyeblink extinction trials overlapped; in group 2, fear and eyeblink extinction trials alternated; and in group 3, fear extinction trials were followed by eyeblink extinction trials. Groups 4 and 5 were control conditions testing fear and eyeblink conditioning only. Preceding fear acquisition training facilitated acquisition of conditioned eyeblinks. Concomitant fear extinction impeded extinction of eyeblink CRs, which was accompanied by increased autonomic responses. Fear extinction, however, was not significantly altered by concomitant eyeblink extinction. Recall of fear CRs on day 2 was facilitated in group 1, suggesting additive response summation. Findings are difficult to explain with the two-stage theory of aversive conditioning, which predicts the suppression of conditioned fear once conditioned eyeblinks are acquired. Facilitated acquisition and impeded extinction of eyeblink CRs, however, are in accordance with the sensory-gating hypothesis of the amygdala.

Control of fear extinction by hypothalamic melanin-concentrating hormone–expressing neurons

Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone-expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.

Circadian disruption impairs fear extinction and memory of conditioned safety in mice

Animal models of fear conditioning and fear inhibition are frequently employed in the study of associative learning and commonly derive important human implications. Animal and human studies have demonstrated fear processing abilities are moderated by circadian rhythms, however, the influence of circadian disruption on fear inhibition is not well understood. Here, we examined the effects of circadian disruption on fear inhibition processes (i.e., fear extinction and safety learning) in a pre-clinical model. Adult male C57Bl/6 J mice completed cued fear and safety conditioning in the active phase before undergoing acute shifts in the Light-Dark (LD) cycle. Specifically, the light-phase was advanced by eight-hours across a one-day period (Experiment 1) or a two-day period (Experiment 2), before returning to original timing. Fear and safety recall were assessed over two days following LD shifts. Control groups maintained one LD cycle throughout both experiments. In both experiments, mice allocated to LD shifted groups revealed misaligned patterns of previously circadian locomotor activity. In the second recall session of Experiment 1, LD shifted mice demonstrated reduced retention of conditioned safety memory. However, in Experiment 2, LD shifted mice displayed heightened fear across conditioned fear cues in both recall sessions, therefore demonstrating consistent fear extinction impairment. Moreover, in recall session two, these mice revealed impaired ability to suppress fear during initial presentations of fear and safety cues. Overall, our data suggest maintaining a consistent LD cycle may be crucially important to individuals at high-risk of trauma-exposure and subsequent development of posttraumatic stress disorder.

Infralimbic cortex activity is required for the expression but not the acquisition of conditioned safety

The ability to discriminate between danger and safety is crucial for survival across species. Whereas danger signals predict the onset of a potentially threatening event, safety signals indicate the non-occurrence of an aversive event, thereby reducing fear and stress responses. While the neural basis of conditioned safety remains to be elucidated, fear extinction studies provide evidence that the infralimbic cortex (IL) modulates fear inhibition. In the current study, the IL was temporarily inactivated with local muscimol injections in male and female rats. The effect of IL inactivation on the acquisition and expression of conditioned safety was investigated utilizing the startle response. Temporary inactivation of the IL prior to conditioning did not affect the acquisition of conditioned safety, whereas IL inactivation during the expression test completely blocked the expression of conditioned safety in male and female rats. Inactivation of the neighboring prelimbic (PL) cortex during the expression test did not affect the expression of safety memory. Our findings suggest that the IL is a critical brain region for the expression of safety memory. Because patients suffering from anxiety disorders are often unable to make use of safety cues to inhibit fear, the present findings are of clinical relevance and could potentially contribute to therapy optimization of anxiety-related psychiatric disorders.

Safety Learning Augments Fear Regulation During Adolescence via Ventral Hippocampus

A peak in diagnoses for anxiety disorders occurs during adolescence and earlier onset has been associated with increased symptom severity and comorbidities on a long-term scale. This highlights the necessity of research investigating the mechanisms underlying fear inhibition specifically as it manifests during adolescence, which can be used to inform the translation of novel methods for threat response inhibition to developmental populations.

Public Mental Health as One of the Key Factors in Dealing with COVID-19

Zusammenfassung Ziel Das Ziel des Beitrages besteht darin, auf die bedeutsame Rolle der Prävention und Reduktion der psychischen Belastungen in der Allgemeinbevölkerung und in sensiblen Gruppen im Rahmen der Coronavirus-Krankheit-2019 (COVID-19) -Pandemie hinzuweisen. Methodik Der vorliegende Beitrag umfasst die Analyse und Bewertung von Studien und Empfehlungen von Organisationen wie der Weltgesundheitsorganisation (WHO), die die bevölkerungsbezogenen psychischen Auswirkungen von Epi-/Pandemien und deren Einfluss auf den weiteren Verlauf untersucht haben. Ergebnisse Angstbedingte Verhaltensweisen können sich negativ auf den Verlauf von Epidemien auswirken. Im Rahmen vergangener Ausbrüche von Infektionskrankheiten (Ebola- und Zika-Virus) konnte ermittelt werden, dass maladaptive Verhaltensweisen, bedingt durch erhöhte psychische Belastungen und Ängste, die Implementierung von Behandlungsstrategien und -maßnahmen beeinträchtigen und zu einer stärkeren Ausbreitung beitragen können. Hierbei können Strategien im Umgang mit Infektionskrankheiten, die Verdrängung und Unterdrückung von Ängsten beinhalten, einen Teufelskreis auslösen, wobei Ängste und Verdrängung sich gegenseitig verstärken. Schlussfolgerungen Die COVID-19-Pandemie stellt eine immense Herausforderung mit noch ungewissem Ausgang für Regierungen, Gesundheitssysteme und Menschen dar, die mit erheblichen Beeinträchtigungen der psychischen Gesundheit in der Bevölkerung verbunden ist. Im Einklang mit Empfehlungen der WHO sollten nationale Leitlinien und präventive Maßnahmen die psychischen Auswirkungen, die Akzeptanz und Normalisierung von Ängsten und die Förderung von Resilienz in der Bevölkerung im Umgang mit COVID-19 umfassen, um einer weiteren Ausbreitung entgegenwirken zu können.

Chronic inhibition of GABA synthesis in the infralimbic cortex facilitates conditioned safety memory and reduces contextual fear

Accurate discrimination between danger and safety cues is essential for survival. Recent findings in humans indicate that patients suffering from anxiety disorders cannot reliably use safety cues in order to inhibit fear responses. However, the neuroanatomical pathways of conditioned safety are still unclear. Aim of the present study was to investigate whether chronic inhibition of GABA synthesis in the infralimbic (IL) cortex, a critical region for fear inhibition, would lead to enhanced conditioned safety memory. Male Sprague Dawley rats were equipped with osmotic mini-pumps attached to an infusion cannula aimed at the IL. Mini-pumps were either filled with the glutamate decarboxylase (GAD) inhibitor l-allylglycine (l-AG) or the inactive enantiomer d-allylglycine (d-AG). Previous studies demonstrated that chronic infusions of l-AG lead to lower GABA levels and overall enhanced neural activity. The effect of IL disinhibition on conditioned safety was investigated utilizing the acoustic startle response. Chronic disinhibition of the IL facilitated conditioned safety memory, along with reduced contextual fear and lower corticosterone levels. The present findings suggest that the IL is a key brain region for conditioned safety memory. Because anxiety disorder patients are often not capable to use safety cues to inhibit unnecessary fear responses, the present findings are of clinical relevance and could potentially contribute to therapy optimization.

Sex differences in auditory fear discrimination are associated with altered medial prefrontal cortex function

The increased prevalence of post-traumatic stress disorder (PTSD) that is observed in women may involve sex differences in learned fear inhibition and medial prefrontal cortex (mPFC) function. PTSD is characterized by fear overgeneralization involving impaired fear regulation by safety signals. We recently found that males show fear discrimination and females show fear generalization involving reduced safety signalling after extended fear discrimination training. Here we determined if these sex differences involve altered mPFC function. Male and female rats underwent three days of auditory fear discrimination training, where one tone (CS+) was paired with footshock and another tone (CS−) was presented alone. Local field potentials were recorded from prelimbic (PL) and infralimbic (IL) mPFC during retrieval. We found that males discriminated and females generalized based on cue-induced freezing at retrieval. This was accompanied by sex differences in basal theta and gamma oscillations in PL and IL. Importantly, males also showed PL/IL theta activation during safety signalling by the CS− and IL gamma activation in response to the threat-related CS+, both of which were absent in females. These results add to growing evidence indicating that sex differences in learned fear inhibition are associated with altered mPFC function.

Neurobiology of Anxiety Disorders

In recent years, advances in the fields of neuroimaging and experimental psychology increased our understanding of the basic mechanisms of classical conditioning and learning, contributing to our knowledge of the neurobiology of anxiety disorders. Research has shown that the amygdala is the cornerstone of fear circuitry and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Activation of the amygdala in response to disorder-relevant stimuli has been observed in anxiety disorders. The roles of the hippocampus, nucleus accumbens, periaqueductal gray, and insular and medial prefrontal cortices in response to fear have been identified as well. Neurotransmitters such as serotonin, dopamine, γ-aminobutyric acid, glutamate, and some neurosteroids play an important part in the neurobiology of anxiety disorders. Neuropeptides such as oxytocin, neuropeptide Y, galanin, and cholecystokinin have been shown to modulate stress response. Drugs such as N-methyl-d-aspartate (NMDA) antagonists and blockers of voltage-gated calcium channels in the amygdala are anxiolytic. Fear extinction, which entails new learning of fear inhibition, is the mechanism of effective antianxiety treatments such as d-cycloserine, a partial NMDA agonist. Extinction is thought to occur by the medial prefrontal cortex, which inhibits the lateral amygdala under hippocampal modulation. Harnessing extinction to delink neutral stimuli from aversive responses is an important goal of the psychotherapy and pharmacotherapy of anxiety disorders. Discovery of the role of microRNAs in the etiology of anxiety disorders and their possible utility as targets to treat these disorders is fascinating. In this review, we discuss the neurobiology of anxiety disorders, which will help us better manage them clinically. This review contains 5 figures, 6 tables, and 39 references. Key words: Amygdala, anxiety disorders, neurobiology, fear conditioning, neurocircuitry, neurotransmitters, neuropeptides, neurosteroids, endogenous opioids.