Fear Dysregulation Research Articles

Starting the pill during adolescence: Age of onset and duration of use influence morphology of the hippocampus and ventromedial prefrontal cortex.

From adolescence, women become more likely to experience fear dysregulation. Oral contraceptives (OCs) can modulate the brain regions involved in fear processes. OCs are generally used for years and often initiated during adolescence, a sensitive period where certain brain regions involved in the fear circuitry are still undergoing important reorganization. It remains unknown whether OC use during adolescence may induce long-lasting changes in the fear circuitry. This study aimed to examine whether age of onset moderated the relationship between duration of use and fear-related brain structures. We collected structural MRI data in 98 healthy adult women (61 current users, 37 past users) and extracted grey matter volumes (GMV) and cortical thickness (CT) of key regions of the fear circuitry. Non-linear multiple regressions revealed interaction effects between age of onset and quadratic duration of use on GMV of the right hippocampus and right ventromedial prefrontal cortex (vmPFC). Among women who initiated OCs earlier in adolescence, a short duration of use was associated with smaller hippocampal GMV and thicker vmPFC compared to a longer duration of use. For both GMV and CT of the right vmPFC, women with an early OC onset had more grey matter at a short duration of use than those with a later onset. Our results suggest that OC use earlier in adolescence may induce lasting effects on structural correlates of fear learning and its regulation. These findings support further investigation into the timing of OC use to better comprehend how OCs could disrupt normal brain development processes.

GABA and Executive functions in ASD

Gamma-aminobutyric acid (GABA) is a neurotransmitter critically involved in various psychological and behavioral processes. This review highlights the impact of GABAergic dysfunction within specific brain regions on a range of mental disorders, executive processes, self-control, and behavioral regulation.Reductions in GABAergic neurotransmission within distinct brain regions have been consistently associated with several mental health conditions. Within the context of anxiety disorders, depression, and post-traumatic stress disorder (PTSD), alterations in GABAergic function contribute to symptomatology. GABA plays a pivotal role in anxiety and mood regulation, with its impairment linked to symptoms of depression and mood disorders. Dysfunctional GABAergic transmission also contributes to fear dysregulation and features of PTSD. In terms of executive functions, GABAergic neurotransmission affects working memory, attentional control, and inhibitory regulation. Changes in GABA levels have been linked to decision-making abilities, impulsivity, and attention deficits, especially in conditions like attention deficit hyperactivity disorder (ADHD). GABA further plays a crucial role in self-control mechanisms by regulating impulsivity and prefrontal cortex functionality. Substance use disorders, often accompanied by impaired self-control, are significantly influenced by GABAergic system changes. Additionally, GABA's involvement in anxiety and emotional management affects the control of emotional responses. Behavioral control is modulated by GABAergic action in motor circuitry, where GABA provides inhibitory control for motor actions. Spontaneity, aggression, and stress are influenced by GABAergic dysfunction, impacting behavioral control. In the realm of attentional control, GABAergic neurotransmission influences selective attention and sensory salience, maintaining a balance between neural stimulation and inhibition. The study also explores executive function deficits in individuals with Autism Spectrum Disorder (ASD) in relation to GABA levels within specific brain regions. Moreover, GABA and its network connectivity contribute to individual variations in sensory responsiveness, emphasizing the dynamic role of GABA in the phenotypic heterogeneity of ASD. In summary, this research underscores the critical role of GABAergic neurotransmission within specific brain regions in various psychological disorders, executive functions, self-control, behavioral regulation, and attentional processes. Understanding the directional influence of GABAergic changes on behavior and mental health conditions can pave the way for more targeted interventions in neuropsychiatric disorders.

The neural circuits and molecular mechanisms underlying fear dysregulation in posttraumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD.

Network-level changes in the brain underlie fear memory strength.

The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using c-fos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.

Network-level changes in the brain underlie fear memory strength

The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using c-fos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.

Are fearful boys at higher risk for anxiety? Person-centered profiles of toddler fearful behavior predict anxious behaviors at age 6.

Dysregulated fear (DF), the presence of fearful behaviors in both low-threat and high-threat contexts, is associated with child anxiety symptoms during early childhood (e.g., Buss et al., 2013). However, not all children with DF go on to develop an anxiety disorder (Buss and McDoniel, 2016). This study leveraged the data from two longitudinal cohorts (N = 261) to (1) use person-centered methods to identify profiles of fearful temperament, (2) replicate the findings linking DF to anxiety behaviors in kindergarten, (3) test if child sex moderates associations between DF and anxiety behaviors, and (4) examine the consistency of findings across multiple informants of child anxiety behaviors. We identified a normative fear profile (low fear in low-threat contexts; high fear in high-threat contexts), a low fear profile (low fear across both low- and high-threat contexts) and a DF profile (high fear across both low- and high-threat contexts). Results showed that probability of DF profile membership was significantly associated with child self-reported overanxiousness, but not with parent-reported overanxiousness. Associations between DF profile membership and overanxiousness was moderated by child sex such that these associations were significant for boys only. Additionally, results showed that probability of DF profile membership was associated with both parent-reported social withdrawal and observations of social reticence, but there were no significant associations with child self-report of social withdrawal. Results highlight the importance of considering person-centered profiles of fearful temperament across different emotion-eliciting contexts, and the importance of using multiple informants to understand associations with temperamental risk for child anxiety.

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.

Maternal Worry Socialization and Toddler Inhibited Temperament: Transactional Associations and Stability across Time.

Caregiver socialization of child emotions has consequences for both typical development and anxiety risk, with caregivers’ non-supportive responses to worry perhaps especially salient to children’s anxiety development. Children, in turn, impact the caregiving environment they receive through their temperament. We investigated transactional relations between maternal non-supportive responses to child worry (mother-reported) and two differently-measured child inhibited temperament indices (i.e., mother-perceived child inhibition to novelty, laboratory-observed child dysregulated fear) in a sample of 136 predominantly non-Hispanic, White mother-toddler dyads. Worry socialization and mother-reported inhibition to novelty were measured at each of three time points (toddler age 2, 3, 4 years), and dysregulated fear was measured at ages 2 and 3. Constructs showed stability across time, with effect sizes ranging from medium to large. Child inhibited temperament measures positively correlated within time point at ages 2 and 3, and laboratory-observed child dysregulated fear predicted mothers’ later perceptions of their children’s inhibition to novelty. At toddler age 2, mothers of children showing more dysregulated fear reported responding more non-supportively to worry. However, when controlling for one another, more mother-perceived child inhibition to novelty and less laboratory-observed child dysregulated fear at age 3 predicted mothers’ greater non-supportive worry responses at child age 4. There was an indirect effect across time, such that children’s greater laboratory-observed dysregulated fear predicted their mothers’ heightened perceptions of inhibited temperament, which in turn predicted mothers’ greater non-supportive worry responses. Findings lend support to anxiety-relevant construct stability in toddlerhood, as well as child-elicited, rather than parent-elicited, associations across time.Supplementary informationThe online version contains supplementary material available at 10.1007/s10802-022-00938-w.

Enhanced contextual fear memory in peroxiredoxin 6 knockout mice is associated with hyperactivation of MAPK signaling pathway

Fear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemic Prdx6 knockout (Prdx6−/−) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mouse Prdx6 into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus of Prdx6−/− mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD.

Intranasal oxytocin decreases fear generalization in males, but does not modulate discrimination threshold.

A previously acquired fear response often spreads to perceptually or conceptually close stimuli or contexts. This process, known as fear generalization, facilitates the avoidance of danger, and dysregulations in this process play an important role in anxiety disorders. Oxytocin (OT) has been shown to modulate fear learning, yet effects on fear generalization remain unknown. We employed a randomized, placebo-controlled, double-blind, between-subject design during which healthy male participants received either intranasal OT or placebo (PLC) following fear acquisition and before fear generalization with concomitant acquisition of skin conductance responses (SCRs). Twenty-four to 72h before the fear learning and immediately after the fear generalization task, participants additionally complete a discrimination threshold task. Relative to PLC, OT significantly reduced perceived risk and SCRs towards the CS+ and GS1 (the generalization stimulus that is most similar to CS+) during fear generalization, whereas the discrimination threshold was not affected. Together, the results suggest that OT can attenuate fear generalization in the absence of effects on discrimination threshold. This study provides the first evidence for effects of OT on fear generalization in humans and suggests that OT may have therapeutic potential in anxiety disorders characterized by dysregulated fear generalization.

In or out: Response slowing across housing conditions as a measure of affect in three Western lowland gorillas (Gorilla gorilla gorilla).

BackgroundIndividuals experiencing negative affect have shown response slowing, a longer latency to respond in relation to baseline, when presented with aversive stimuli. We assessed response slowing in three male gorillas housed in a bachelor group as a function of daytime and nighttime housing arrangements.MethodsIn both experiments, three gorillas were rewarded for touching a single image (baseline, non-threatening gorilla or threatening gorilla) on a touchscreen. In Experiment One, they completed 48 50-trial sessions across combinations of three nested daytime and three nighttime conditions. In Experiment Two, they completed eight 50-trial sessions with novel stimuli across two daytime conditions, which were nested within two nighttime conditions. Housing conditions represented different amounts of space and degree of choice. We predicted that the gorillas would show response slowing to threatening stimuli when space and choice were restricted.ResultsWe did not observe response slowing in Experiment One, although daytime and nighttime conditions interacted to predict response latencies. The gorillas responded more slowly when they had access to indoors and outdoors overnight compared to when they were in their stalls or together in an indoor habitat, but only if they had been given access to both indoors and outdoors or locked in the indoor habitat the day before. In Experiment Two, the gorillas did show response slowing to threatening stimuli, but this pattern did not interact with housing conditions. Our results, although limited by a small sample, are somewhat consistent with those of a previous study that did not find significant response slowing for apes as a function of aversive testing conditions, although the procedure has been effective in identifying dysregulated fear (high fear in low threat conditions) in macaques. The utility of this paradigm for testing affect in apes awaits further evaluation.

Do Maternal Parenting Behaviors Indirectly Link Toddler Dysregulated Fear and Child Anxiety Symptoms?

Dysregulated fear (DF), display of high-fear in low-threat contexts, has been shown to predict child anxiety development. Maternal protective, comforting, and intrusive behaviors have also been linked to child anxiety development and may be candidate mechanisms linking DF to anxiety. First, the relation between DF (age 2) and child separation anxiety (age 4) as indirectly linked by maternal protective, comforting, and intrusive behaviors was investigated. Second, the relation between DF and social anxiety (age 4) through parenting behaviors was investigated. Results suggested DF significantly predicted child separation anxiety through maternal intrusive behaviors, above and beyond protective and comforting behaviors. Neither protective nor comforting parenting behavior served as indirect effects between DF and separation anxiety. No parenting behaviors were found to indirectly link the relation between DF and social anxiety. Results suggest that multiple parenting behaviors are involved as environmental mechanisms by which DF predicts separation anxiety.

Toddler dysregulated fear predicts continued risk for social anxiety symptoms in early adolescence.

Identifying early risk factors for the development of social anxiety symptoms has important translational implications. Accurately identifying which children are at the highest risk is of critical importance, especially if we can identify risk early in development. We examined continued risk for social anxiety symptoms at the transition to adolescence in a community sample of children (n = 112) that had been observed for high fearfulness at age 2 and tracked for social anxiety symptoms from preschool through age 6. In our previous studies, we found that a pattern of dysregulated fear (DF), characterized by high fear in low threat contexts, predicted social anxiety symptoms at ages 3, 4, 5, and 6 years across two samples. In the current study, we re-evaluated these children at 11-13 years of age by using parent and child reports of social anxiety symptoms, parental monitoring, and peer relationship quality. The scores for DF uniquely predicted adolescents' social anxiety symptoms beyond the prediction that was made by more proximal measures of behavioral (e.g., kindergarten social withdrawal) and concurrent environmental risk factors (e.g., parental monitoring, peer relationships). Implications for early detection, prevention, and intervention are discussed.

Multimodal Categorical and Dimensional Approaches to Understanding Threat Conditioning and Its Extinction in Individuals With Anxiety Disorders

The Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested. To use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders. This cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019. A 2-day threat conditioning and extinction protocol. Skin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning. This cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (ηp2 = 0.15; P = .004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, ηp2 = 0.21; P = .01 and in functional magnetic resonance imaging results, ηp2 = 0.12; P = .02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (ηp2 values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches. The data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms.

Role of the Bed Nucleus of the Stria Terminalis in PTSD: Insights From Preclinical Models.

Post-traumatic stress disorder (PTSD) afflicts approximately 8% of the United States population and represents a significant public health burden, but the underlying neural mechanisms of this and other anxiety- and stressor-related disorders are largely unknown. Within the last few decades, several preclinical models of PSTD have been developed to help elucidate the mechanisms underlying dysregulated fear states. One brain area that has emerged as a critical mediator of stress-related behavioral processing in both clinical and laboratory settings is the bed nucleus of the stria terminalis (BNST). The BNST is interconnected with essential emotional processing regions, including prefrontal cortex, hippocampus and amygdala. It is activated by stressor exposure and undergoes neurochemical and morphological alterations as a result of stressor exposure. Stress-related neuro-peptides including corticotropin-releasing factor (CRF) and pituitary adenylate cyclase activating peptide (PACAP) are also abundant in the BNST, further implicating an involvement of BNST in stress responses. Behaviorally, the BNST is critical for acquisition and expression of fear and is well positioned to regulate fear relapse after periods of extinction. Here, we consider the role of the BNST in stress and memory processes in the context of preclinical models of PTSD.

Maternal sensitivity during infancy and the regulation of startle in preschoolers

ABSTRACTCaregiving insensitivity and fear dysregulation predict anxiety symptoms in children. It is unclear, however, whether sensitive parental care during infancy predicts fear regulation later in childhood. To address this question, we asked whether observed maternal sensitivity, measured at 6 months, predicts 42-month-old children’s laboratory-induced fear responses (n=213) during a fear-eliciting episode. We predicted that higher levels of maternal sensitivity would be associated with greater fear regulation. We operationalized fear regulation as decreases in fear over repeated trials of a novel, potentially frightening, stimulus. Two aspects of fear responses were considered: expressed fear and startle. Expressed fear scores did not decrease over time but children exhibited less startle behavior in the second half of the task. Maternal sensitivity predicted this startle attenuation across trials. These findings highlight the contribution of maternal sensitivity during infancy to the development of fear regulation in early childhood, further suggesting its influence on offspring anxiety problems.

Stress-Enhanced Fear Learning, a Robust Rodent Model of Post-Traumatic Stress Disorder

Fear behaviors are important for survival, but disproportionately high levels of fear can increase the vulnerability for developing psychiatric disorders such as post-traumatic stress disorder (PTSD). To understand the biological mechanisms of fear dysregulation in PTSD, it is important to start with a valid animal model of the disorder. This protocol describes the methodology required to conduct stress-enhanced fear learning (SEFL) experiments, a preclinical model of PTSD, in both rats and mice. SEFL was developed to recapitulate critical aspects of PTSD, including long-term sensitization of fear learning caused by an acute stressor. SEFL uses aspects of Pavlovian fear conditioning but produces a distinct and robust sensitized fear response far greater than normal conditional fear responses. The trauma procedure involves placing a rodent in a conditioning chamber and administering 15 unsignaled shocks randomly distributed over 90 minutes (for rat experiments; for mouse experiments, 10 unsignaled shocks randomly distributed over 60 minutes are used). On day 2, rodents are placed in a novel conditioning context where they receive a single shock; then, on day 3 they are placed back in the same context as on day 2 and tested for changes in freezing levels. Rodents that previously received the trauma display enhanced levels of freezing on the test day compared to those that received no shocks on the first day. Thus, with this model, a single highly stressful experience (the trauma) produces extreme fear of the stimuli associated with the traumatic event.

Dysregulated Fear, Social Inhibition, and Respiratory Sinus Arrhythmia: AReplication and Extension.

Behavioral inhibition indicates increased risk for development of social anxiety. Recent work has identified a pattern of dysregulated fear (DF), characterized by high fear in low-threat situations, that provides a more precise marker of developmental risk through early childhood. This study tested a new longitudinal sample of children (n=124) from ages 24 to 48months. Replicating prior findings, at 24months, we identified a pattern of fearful behavior across contexts marked by higher fear to putatively low-threat situations. DF was associated with higher parental report of social inhibition at 24, 36, and 48months. Extending prior findings, we observed differences in cardiac physiology during fear-eliciting situations, suggesting that the neurobiological underpinnings of DF relate to difficulty with regulation.

Minocycline attenuates interferon-α-induced impairments in rat fear extinction.

BackgroundExtinction of conditioned fear is an important brain function for animals to adapt to a new environment. Accumulating evidence suggests that innate immune cytokines are involved in the pathology of psychotic disorders. However, the involvement of cytokines in fear dysregulation remains less investigated. In the present study, we investigated how interferon (IFN)-α disrupts the extinction of conditioned fear and propose an approach to rescue IFN-α-induced neurologic impairment.MethodsWe used a rat model of auditory fear conditioning to study the effect of IFN-α on the fear memory process. IFN-α was infused directly into the amygdala of rats and examined the rats’ behavioral response (freezing) to fear-conditioned stimuli. Immunohistochemical staining was used to examine the glia activity status of glia in the amygdala. The levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the amygdala were measured by enzyme-linked immunosorbent assay. We also administrated minocycline, a microglial activation inhibitor, before the IFN-α infusion to testify the possibility to reverse the IFN-α-induced effects.ResultsInfusing the amygdala with IFN-α impaired the extinction of conditioned fear in rats and activated microglia and astrocytes in the amygdala. Administering minocycline prevented IFN-α from impairing fear extinction. The immunohistochemical and biochemical results show that minocycline inhibited IFN-α-induced microglial activation and reduced IL-1β and TNF-α production.ConclusionsOur findings suggest that IFN-α disrupts the extinction of auditory fear by activating glia in the amygdala and provides direction for clinical studies of novel treatments to modulate the innate immune system in patients with psychotic disorders.

Toddlers’ dysregulated fear predicts delta–beta coupling during preschool

Dysregulated fear, or the persistence of high levels of fear in low-threat contexts, is an early risk factor for the development of anxiety symptoms. Previous work has suggested both propensities for over-control and under-control of fearfulness as risk factors for anxiety problems, each of which may be relevant to observations of dysregulated fear. Given difficulty disentangling over-control and under-control through traditional behavioral measures, we used delta–beta coupling to begin to understand the degree to which dysregulated fear may reflect propensities for over- or under-control. We found that toddlers who showed high levels of dysregulated fear evidenced greater delta–beta coupling at frontal and central electrode sites as preschoolers relative to children who were low in dysregulated fear. Importantly, these differences were not observed when comparisons were made based on fear levels in high threat contexts. Results suggest dysregulated fear may involve tendencies toward over-control at the neural level.