Prenatal Exposure to Ketamine Leads to Anxiety-Like Behaviors and Dysfunction in Bed Nucleus of Stria Terminalis.
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ABSTRACT:
SUBMITTER: Sun J
PROVIDER: S-EPMC7171933 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:While learning to fear stimuli that predict danger promotes survival, the inability to inhibit fear to inappropriate cues leads to a pernicious cycle of avoidance behaviors. Previous studies have revealed large inter-individual variations in fear responding with clinically anxious humans exhibiting a tendency to generalize learned fear to safe stimuli or situations. To shed light on the origin of these inter-individual variations, we subjected rats to a differential auditory fear conditioning paradigm in which one conditioned auditory stimulus (CS+) was paired to footshocks whereas a second (CS-) was not. We compared the behavior of rats that received pretraining excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) to that of sham rats. Sham rats exhibit a continuum of anxious/fearful behaviors. At one end of the continuum were rats that displayed a poor ability to discriminate between the CS+ and CS-, high contextual freezing, and an anxiety-like trait in the elevated plus maze (EPM). At the other end were rats that display less fear generalization to the CS-, lower freezing to context, and a nonanxious trait in the EPM. Although BNST-lesioned rats acquired similarly high levels of conditioned fear to the CS+, they froze less than sham rats to the CS-. In fact, BNST-lesioned rats behaved like sham rats with high discriminative abilities in that they exhibited low contextual fear and a nonanxious phenotype in the EPM. Overall, this suggests that inter-individual variations in fear generalization and anxiety phenotype are determined by BNST influences on the amygdala and/or its targets.
| S-EPMC2741739 | biostudies-literature
Project description:In children, behavioral inhibition (BI) in response to potential threat predicts the development of anxiety and affective disorders, and primate lesion studies suggest involvement of the orbitofrontal cortex (OFC) in mediating BI. Lesion studies are essential for establishing causality in brain-behavior relationships, but should be interpreted cautiously because the impact of a discrete lesion on a complex neural circuit extends beyond the lesion location. Complementary functional imaging methods assessing how lesions influence other parts of the circuit can aid in precisely understanding how lesions affect behavior. Using this combination of approaches in monkeys, we found that OFC lesions concomitantly alter BI and metabolism in the bed nucleus of stria terminalis (BNST) region and that individual differences in BNST activity predict BI. Thus it appears that an important function of the OFC in response to threat is to modulate the BNST, which may more directly influence the expression of BI.
| S-EPMC2915894 | biostudies-literature
Project description:In a previous study, we investigated the resting-state fMRI effective connectivity (EC) between the bed nucleus of the stria terminalis (BNST) and the laterobasal (LB), centromedial (CM), and superficial (SF) amygdala. We found strong negative EC from all amygdala nuclei to the BNST, while the BNST showed positive EC to the amygdala. However, the validity of these findings remains unclear, since a reproduction in different samples has not been done. Moreover, the association of EC with measures of anxiety offers deeper insight, due to the known role of the BNST and amygdala in fear and anxiety. Here, we aimed to reproduce our previous results in three additional samples. We used spectral Dynamic Causal Modeling to estimate the EC between the BNST, the LB, CM, and SF, and its association with two measures of self-reported anxiety. Our results revealed consistency over samples with regard to the negative EC from the amygdala nuclei to the BNST, while the positive EC from BNST to the amygdala was also found, but weaker and more heterogenic. Moreover, we found the BNST-BNST EC showing a positive and the CM-BNST EC, showing a negative association with anxiety. Our study suggests a reproducible pattern of negative EC from the amygdala to the BNST along with weaker positive EC from the BNST to the amygdala. Moreover, less BNST self-inhibition and more inhibitory influence from the CM to the BNST seems to be a pattern of EC that is related to higher anxiety.
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Project description:BackgroundThough a key symptom underlying many anxiety disorders is hypervigilant threat monitoring, its biological bases in humans remain poorly understood. Animal models suggest that anxious processes such as hypervigilant threat monitoring are distinct from cued fear-like responses and mediated by the bed nucleus of the stria terminalis (BNST). Here, we applied psychophysiological and neuroimaging methodologies sensitive to sustained arousal-based responses to test the role of the human BNST in mediating environmental threat monitoring, a potential experimental model for sustained anxiety symptoms.MethodsHealthy participants (n = 50) with varying trait anxiety performed an environmental threat-monitoring task during functional magnetic resonance imaging where a stimulus line continuously fluctuated in height, providing information relevant to subsequent risk for electric shocks. Skin conductance was collected in a separate cohort (n = 47) to validate task-evoked modulation of physiological arousal.ResultsA forebrain region consistent with the BNST showed greater overall recruitment and exaggerated tracking of threat proximity in individuals with greater anxiety. The insular cortex tracked threat proximity across all participants, showed exaggerated threat proximity responding with greater anxiety, and showed enhanced recruitment when threat proximity was ostensibly controllable.ConclusionsActivity in the BNST and insula continuously monitored changes in environmental threat level and also subserved hypervigilant threat-monitoring processes in more highly trait anxious individuals. These findings bridge human and animal research informing the role of the BNST in anxious-related processes. In addition, these findings suggest that continuous functional magnetic resonance imaging paradigms offer promise in further elucidating the neural circuitries supporting sustained anticipatory features of anxiety.
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Project description:The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.
| S-EPMC6456295 | biostudies-literature
Project description:Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD.
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Project description:Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These studies suggest novel mechanisms involved in the development of affective disorders, and highlight the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological anxiety and addiction.
| S-EPMC3717545 | biostudies-literature
Project description:Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala. Previous studies have established a role for the BNST in cue-induced cocaine seeking. However, it is unclear if the BNST underlies cue-induced seeking of other abused drugs such as ethanol. In the present set of experiments, BNST involvement in ethanol-seeking behavior was assessed in male DBA/2J mice using the conditioned place preference procedure (CPP). The BNST was inhibited during CPP expression using electrolytic lesions (Experiment 1), co-infusion of GABAA and GABAB receptor agonists muscimol and baclofen (M+B; Experiment 2), and activation of inhibitory designer receptors exclusively activated by designer drugs (hM4Di-DREADD) with clozapine-N-oxide (CNO; Experiment 3). The magnitude of ethanol CPP was reduced significantly by each of these techniques. Notably, infusion of M+B (Exp. 2) abolished CPP altogether. Follow-up studies to Exp. 3 showed that ethanol cue-induced c-Fos immunoreactivity in the BNST was reduced by hM4Di activation (Experiment 4) and in the absence of hM4Di, CNO did not affect ethanol CPP (Experiment 5). Combined, these findings demonstrate that the BNST is involved in the modulation of cue-induced ethanol-seeking behavior.
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Project description:Everyday prosociality includes helping behaviors such as holding doors or giving directions that are spontaneous and low-cost and are performed frequently by the average person. Such behaviors promote a wide array of positive outcomes that include increased well-being, trust, and social capital, but the cognitive and neural mechanisms that support these behaviors are not yet well understood. Whereas costly altruistic responding to others' distress is associated with elevated reactivity in the amygdala, we hypothesized that everyday prosociality would be more closely associated with activation in the bed nucleus of the stria terminalis (BNST), a region of the extended amygdala known for its roles in maintaining vigilance for relevant socio-affective environmental cues and in supporting parental care. One previous study of the neural correlates of everyday prosociality highlighted a functional cluster identified as the septal area but which overlapped with established coordinates of BNST. We used an anatomical mask of BNST (Torrisi et al., 2015) to evaluate the association of BNST activation and daily helping in a sample of 25 adults recruited from the community as well as 23 adults who had engaged in acts of extraordinary altruism. Results found that activation in left BNST during an empathy task predicted everyday helping over a subsequent 14-day period in both samples. BNST activation most strongly predicted helping strangers and proactive helping. We conclude that beyond facilitating care for offspring, activation in BNST may provide a basis for the motivation to engage in a broad array of everyday helping behaviors.
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Project description:Loss of appetite or anorexia associated with inflammation impairs quality of life and increases morbidity in many diseases. However, the exact neural mechanism that mediates inflammation-associated anorexia is still poorly understood. Here we identified a population of neurons, marked by the expression of protein kinase C-delta, in the oval region of the bed nucleus of the stria terminalis (BNST), which are activated by various inflammatory signals. Silencing of these neurons attenuates the anorexia caused by these inflammatory signals. Our results demonstrate that these neurons mediate bidirectional control of general feeding behaviors. These neurons inhibit the lateral hypothalamus-projecting neurons in the ventrolateral part of BNST to regulate feeding, receive inputs from the canonical feeding regions of arcuate nucleus and parabrachial nucleus. Our data therefore define a BNST microcircuit that might coordinate canonical feeding centers to regulate food intake, which could offer therapeutic targets for feeding-related diseases such as anorexia and obesity.
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