The Basolateral Amygdala Is Essential for Rapid Escape: A Human and Rodent Study.

Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.

The Neural Basis of Escape Behavior in Vertebrates.

Escape is one of the most studied animal behaviors, and there is a rich normative theory that links threat properties to evasive actions and their timing. The behavioral principles of escape are evolutionarily conserved and rely on elementary computational steps such as classifying sensory stimuli and executing appropriate movements. These are common building blocks of general adaptive behaviors. Here we consider the computational challenges required for escape behaviors to be implemented, discuss possible algorithmic solutions, and review some of the underlying neural circuits and mechanisms. We outline shared neural principles that can be implemented by evolutionarily ancient neural systems to generate escape behavior, to which cortical encephalization has been added to allow for increased sophistication and flexibility in responding to threat.

Celebrating organizational history triggers social identity threat among Black Americans.

Many mainstream organizations celebrate their historical successes. In their history, however, they often marginalized racial minorities, women, and other underrepresented groups. We suggest that when organizations celebrate their histories, even without mentioning historical marginalization, they can undermine belonging and intentions to join the organization among historically marginalized groups. Four experiments demonstrate that Black participants who were exposed to an organization that celebrated their history versus the present showed reduced belonging and intentions to participate in the organization. These effects were mediated by expectations of biased treatment in the organization. Further, when organizations had a history of Black people in power, celebrating history was no longer threatening, highlighting that the negative effects of celebrating history are most likely when organizations are or are assumed to be majority-White and have treated Black Americans poorly. Taken together, these findings suggest that emphasizing organizational history can be a source of social identity threat among Black Americans.

Deportation threat predicts Latino US citizens and noncitizens' psychological distress, 2011 to 2018.

The national context of deportation threat, defined as the federal government's approach to deportation and/or deportation's salience to the US public, fluctuated between 2011 and 2018. US Latinos across citizenship statuses may have experienced growing psychological distress associated with these changes, given their disproportionate personal or proximal vulnerabilities to deportation. Drawing on 8 y of public- and restricted-access data from the National Health Interview Survey (2011 to 2018), this article examines trends in psychological distress among Latinos who are US-born citizens, naturalized citizens, and noncitizens. It then seeks to explain these trends by considering two theoretical pathways through which the national context of deportation threat could distress Latinos: 1) through discrete dramatic societal events that independently signal a change to the country's approach to deportation and/or that render deportation temporarily more salient to the public or 2) through more gradual changes to the country's everyday institutional (i.e., quotidian efforts to detain and deport noncitizens) and social (i.e., deportation's ongoing salience to a concerned public) environment of deportation threat. We find that, though both pathways matter to some degree, there is more consistent evidence that the gradual changes are associated with Latino US citizens and noncitizens' overall experiences of psychological distress. The article highlights how, even absent observable spillover effects of dramatic societal events bearing on deportation threat, the institutional and social environment in which they occur implicates Latinos' well-being.

Anxiety, Depression, and Decision Making: A Computational Perspective.

In everyday life, the outcomes of our actions are rarely certain. Further, we often lack the information needed to precisely estimate the probability and value of potential outcomes as well as how much effort will be required by the courses of action under consideration. Under such conditions of uncertainty, individual differences in the estimation and weighting of these variables, and in reliance on model-free versus model-based decision making, have the potential to strongly influence our behavior. Both anxiety and depression are associated with difficulties in decision making. Further, anxiety is linked to increased engagement in threat-avoidance behaviors and depression is linked to reduced engagement in reward-seeking behaviors. The precise deficits, or biases, in decision making associated with these common forms of psychopathology remain to be fully specified. In this article, we review evidence for which of the computations supporting decision making are altered in anxiety and depression and consider the potential consequences for action selection. In addition, we provide a schematic framework that integrates the findings reviewed and will hopefully be of value to future studies.

Cultural threat perceptions predict violent extremism via need for cognitive closure.

Understanding the psychological processes that drive violent extremism is a pressing global issue. Across six studies, we demonstrate that perceived cultural threats lead to violent extremism because they increase people's need for cognitive closure (NFC). In general population samples (from Denmark, Afghanistan, Pakistan, France, and an international sample) and a sample of former Mujahideen in Afghanistan, single-level and multilevel mediation analyses revealed that NFC mediated the association between perceived cultural threats and violent extremist outcomes. Further, in comparisons between the sample of former Afghan Mujahideen and the general population sample from Afghanistan following the known-group paradigm, the former Mujahideen scored significantly higher on cultural threat, NFC, and violent extremist outcomes. Moreover, the proposed model successfully differentiated former Afghan Mujahideen participants from the general Afghan participants. Next, two preregistered experiments provided causal support for the model. Experimentally manipulating the predictor (cultural threat) in Pakistan led to higher scores on the mediator (NFC) and dependent variables (violent extremist outcomes). Finally, an experiment conducted in France demonstrated the causal effect of the mediator (NFC) on violent extremist outcomes. Two internal meta-analyses using state-of-the-art methods (i.e., meta-analytic structural equation modeling and pooled indirect effects analyses) further demonstrated the robustness of our results across the different extremist outcomes, designs, populations, and settings. Cultural threat perceptions seem to drive violent extremism by eliciting a need for cognitive closure.

Rats respond to aversive emotional arousal of human handlers with the activation of the basolateral and central amygdala.

Reading danger signals may save an animal's life, and learning about threats from others allows avoiding first-hand aversive and often fatal experiences. Fear expressed by other individuals, including those belonging to other species, may indicate the presence of a threat in the environment and is an important social cue. Humans and other animals respond to conspecifics' fear with increased activity of the amygdala, the brain structure crucial for detecting threats and mounting an appropriate response to them. It is unclear, however, whether the cross-species transmission of threat information involves similar mechanisms, e.g., whether animals respond to the aversively induced emotional arousal of humans with activation of fear-processing circuits in the brain. Here, we report that when rats interact with a human caregiver who had recently undergone fear conditioning, they show risk assessment behavior and enhanced amygdala activation. The amygdala response involves its two major parts, the basolateral and central, which detect a threat and orchestrate defensive responses. Further, we show that humans who learn about a threat by observing another aversively aroused human, similar to rats, activate the basolateral and centromedial parts of the amygdala. Our results demonstrate that rats detect the emotional arousal of recently aversively stimulated caregivers and suggest that cross-species social transmission of threat information may involve similar neural circuits in the amygdala as the within-species transmission.

Fear circuit-based neurobehavioral signatures mirror resilience to chronic social stress in mouse.

Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.

Threat Expectation Does Not Improve Perceptual Discrimination despite Causing Heightened Priority Processing in the Frontoparietal Network.

Threat cues have been widely shown to elicit increased sensory and attentional neural processing. However, whether this enhanced recruitment leads to measurable behavioral improvements in perception is still in question. Here, we adjudicate between two opposing theories: that threat cues do or do not enhance perceptual sensitivity. We created threat stimuli by pairing one direction of motion in a random dot kinematogram with an aversive sound. While in the MRI scanner, 46 subjects (both men and women) completed a cued (threat/safe/neutral) perceptual decision-making task where they indicated the perceived motion direction of each moving dot stimulus. We found strong evidence that threat cues did not increase perceptual sensitivity compared with safe and neutral cues. This lack of improvement in perceptual decision-making ability occurred despite the threat cue resulting in widespread increases in frontoparietal BOLD activity, as well as increased connectivity between the right insula and the frontoparietal network. These results call into question the intuitive claim that expectation automatically enhances our perception of threat and highlight the role of the frontoparietal network in prioritizing the processing of threat-related environmental cues.

Auditory aversive generalization learning prompts threat-specific changes in alpha-band activity.

Pairing a neutral stimulus with aversive outcomes prompts neurophysiological and autonomic changes in response to the conditioned stimulus (CS+), compared to cues that signal safety (CS-). One of these changes-selective amplitude reduction of parietal alpha-band oscillations-has been reliably linked to processing of visual CS+. It is, however, unclear to what extent auditory conditioned cues prompt similar changes, how these changes evolve as learning progresses, and how alpha reduction in the auditory domain generalizes to similar stimuli. To address these questions, 55 participants listened to three sine wave tones, with either the highest or lowest pitch (CS+) being associated with a noxious white noise burst. A threat-specific (CS+) reduction in occipital-parietal alpha-band power was observed similar to changes expected for visual stimuli. No evidence for aversive generalization to the tone most similar to the CS+ was observed in terms of alpha-band power changes, aversiveness ratings, or pupil dilation. By-trial analyses found that selective alpha-band changes continued to increase as aversive conditioning continued, beyond when participants reported awareness of the contingencies. The results support a theoretical model in which selective alpha power represents a cross-modal index of continuous aversive learning, accompanied by sustained sensory discrimination of conditioned threat from safety cues.

Cognitive stimulation as a mechanism linking socioeconomic status and neural function supporting working memory: a longitudinal fMRI study.

Childhood experiences of low socioeconomic status are associated with alterations in neural function in the frontoparietal network and ventral visual stream, which may drive differences in working memory. However, the specific features of low socioeconomic status environments that contribute to these disparities remain poorly understood. Here, we examined experiences of cognitive deprivation (i.e. decreased variety and complexity of experience), as opposed to experiences of threat (i.e. violence exposure), as a potential mechanism through which family income contributes to alterations in neural activation during working memory. As part of a longitudinal study, 148 youth between aged 10 and 13 years completed a visuospatial working memory fMRI task. Early childhood low income, chronicity of low income in early childhood, and current income-to-needs were associated with task-related activation in the ventral visual stream and frontoparietal network. The association of family income with decreased activation in the lateral occipital cortex and intraparietal sulcus during working memory was mediated by experiences of cognitive deprivation. Surprisingly, however, family income and deprivation were not significantly related to working memory performance, and only deprivation was associated with academic achievement in this sample. Taken together, these findings suggest that early life low income and associated cognitive deprivation are important factors in neural function supporting working memory.

Temporally and anatomically specific contributions of the human amygdala to threat and safety learning.

Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Phenotype-Based Threat Assessment.

Bacterial pathogen identification, which is critical for human health, has historically relied on culturing organisms from clinical specimens. More recently, the application of machine learning (ML) to whole-genome sequences (WGSs) has facilitated pathogen identification. However, relying solely on genetic information to identify emerging or new pathogens is fundamentally constrained, especially if novel virulence factors exist. In addition, even WGSs with ML pipelines are unable to discern phenotypes associated with cryptic genetic loci linked to virulence. Here, we set out to determine if ML using phenotypic hallmarks of pathogenesis could assess potential pathogenic threat without using any sequence-based analysis. This approach successfully classified potential pathogenetic threat associated with previously machine-observed and unobserved bacteria with 99% and 85% accuracy, respectively. This work establishes a phenotype-based pipeline for potential pathogenic threat assessment, which we term PathEngine, and offers strategies for the identification of bacterial pathogens.

Threat and Reward Imminence Processing in the Human Brain.

In the human brain, aversive and appetitive processing have been studied with controlled stimuli in rather static settings. In addition, the extent to which aversive-related and appetitive-related processing engage distinct or overlapping circuits remains poorly understood. Here, we sought to investigate the dynamics of aversive and appetitive processing while male and female participants engaged in comparable trials involving threat avoidance or reward seeking. A central goal was to characterize the temporal evolution of responses during periods of threat or reward imminence. For example, in the aversive domain, we predicted that the bed nucleus of the stria terminalis (BST), but not the amygdala, would exhibit anticipatory responses given the role of the former in anxious apprehension. We also predicted that the periaqueductal gray (PAG) would exhibit threat-proximity responses based on its involvement in proximal-threat processes, and that the ventral striatum would exhibit threat-imminence responses given its role in threat escape in rodents. Overall, we uncovered imminence-related temporally increasing ("ramping") responses in multiple brain regions, including the BST, PAG, and ventral striatum, subcortically, and dorsal anterior insula and anterior midcingulate, cortically. Whereas the ventral striatum generated anticipatory responses in the proximity of reward as expected, it also exhibited threat-related imminence responses. In fact, across multiple brain regions, we observed a main effect of arousal. In other words, we uncovered extensive temporally evolving, imminence-related processing in both the aversive and appetitive domain, suggesting that distributed brain circuits are dynamically engaged during the processing of biologically relevant information regardless of valence, findings further supported by network analysis.SIGNIFICANCE STATEMENT In the human brain, aversive and appetitive processing have been studied with controlled stimuli in rather static settings. Here, we sought to investigate the dynamics of aversive/appetitive processing while participants engaged in trials involving threat avoidance or reward seeking. A central goal was to characterize the temporal evolution of responses during periods of threat or reward imminence. We uncovered imminence-related temporally increasing ("ramping") responses in multiple brain regions, including the bed nucleus of the stria terminalis, periaqueductal gray, and ventral striatum, subcortically, and dorsal anterior insula and anterior midcingulate, cortically. Overall, we uncovered extensive temporally evolving, imminence-related processing in both the aversive and appetitive domain, suggesting that distributed brain circuits are dynamically engaged during the processing of biologically relevant information regardless of valence.

Brain-Wide Projections and Differential Encoding of Prefrontal Neuronal Classes Underlying Learned and Innate Threat Avoidance.

To understand how the brain produces behavior, we must elucidate the relationships between neuronal connectivity and function. The medial prefrontal cortex (mPFC) is critical for complex functions including decision-making and mood. mPFC projection neurons collateralize extensively, but the relationships between mPFC neuronal activity and brain-wide connectivity are poorly understood. We performed whole-brain connectivity mapping and fiber photometry to better understand the mPFC circuits that control threat avoidance in male and female mice. Using tissue clearing and light sheet fluorescence microscopy (LSFM), we mapped the brain-wide axon collaterals of populations of mPFC neurons that project to nucleus accumbens (NAc), ventral tegmental area (VTA), or contralateral mPFC (cmPFC). We present DeepTraCE (deep learning-based tracing with combined enhancement), for quantifying bulk-labeled axonal projections in images of cleared tissue, and DeepCOUNT (deep-learning based counting of objects via 3D U-net pixel tagging), for quantifying cell bodies. Anatomical maps produced with DeepTraCE aligned with known axonal projection patterns and revealed class-specific topographic projections within regions. Using TRAP2 mice and DeepCOUNT, we analyzed whole-brain functional connectivity underlying threat avoidance. PL was the most highly connected node with functional connections to subsets of PL-cPL, PL-NAc, and PL-VTA target sites. Using fiber photometry, we found that during threat avoidance, cmPFC and NAc-projectors encoded conditioned stimuli, but only when action was required to avoid threats. mPFC-VTA neurons encoded learned but not innate avoidance behaviors. Together our results present new and optimized approaches for quantitative whole-brain analysis and indicate that anatomically defined classes of mPFC neurons have specialized roles in threat avoidance.SIGNIFICANCE STATEMENT Understanding how the brain produces complex behaviors requires detailed knowledge of the relationships between neuronal connectivity and function. The medial prefrontal cortex (mPFC) plays a key role in learning, mood, and decision-making, including evaluating and responding to threats. mPFC dysfunction is strongly linked to fear, anxiety and mood disorders. Although mPFC circuits are clear therapeutic targets, gaps in our understanding of how they produce cognitive and emotional behaviors prevent us from designing effective interventions. To address this, we developed a high-throughput analysis pipeline for quantifying bulk-labeled fluorescent axons [DeepTraCE (deep learning-based tracing with combined enhancement)] or cell bodies [DeepCOUNT (deep-learning based counting of objects via 3D U-net pixel tagging)] in intact cleared brains. Using DeepTraCE, DeepCOUNT, and fiber photometry, we performed detailed anatomic and functional mapping of mPFC neuronal classes, identifying specialized roles in threat avoidance.

Dynamic threat-reward neural processing under semi-naturalistic ecologically relevant scenarios.

Studies of affective neuroscience have typically employed highly controlled, static experimental paradigms to investigate the neural underpinnings of threat and reward processing in the brain. Yet our knowledge of affective processing in more naturalistic settings remains limited. Specifically, affective studies generally examine threat and reward features separately and under brief time periods, despite the fact that in nature organisms are often exposed to the simultaneous presence of threat and reward features for extended periods. To study the neural mechanisms of threat and reward processing under distinct temporal profiles, we created a modified version of the PACMAN game that included these environmental features. We also conducted two automated meta-analyses to compare the findings from our semi-naturalistic paradigm to those from more constrained experiments. Overall, our results revealed a distributed system of regions sensitive to threat imminence and a less distributed system related to reward imminence, both of which exhibited overlap yet neither of which involved the amygdala. Additionally, these systems broadly overlapped with corresponding meta-analyses, with the notable absence of the amygdala in our findings. Together, these findings suggest a shared system for salience processing that reveals a heightened sensitivity toward environmental threats compared to rewards when both are simultaneously present in an environment. The broad correspondence of our findings to meta-analyses, consisting of more tightly controlled paradigms, illustrates how semi-naturalistic studies can corroborate previous findings in the literature while also potentially uncovering novel mechanisms resulting from the nuances and contexts that manifest in such dynamic environments.

Strategies for describing myxozoan pathogens, dreadful fish diseases in aquaculture.

Myxozoans are obligate endoparasites, cosmopolitan in distribution with both vertebrate and invertebrate hosts. Their myxospores consist of shell valves, polar capsules with coiled polar tubules that are extrudible, and infective amoeboid germs. Myxozoan parasites are most abundant, and due to their increasing number in recent years, they can pose an emerging threat to the fish industry worldwide. Hence, the immediate need is to devise a strategy to understand and detect parasites and parasitism. They may proliferate to different organs with the advancement of infection. This all warrants the development/devising of strategies and results of integrative studies in order to identify these dreadful parasites and resolve taxonomic issues. Different methods whether classical methods including gross morphology or advanced methods such as electron microscopy (SEM, TEM, STEM), Confocal laser scanning microscopy (CLSM), histopathological studies, site preference, host and tissue specificity, a molecular approach using new markers can be clubbed for identification because these parasites are hidden and are difficult to recognize. This group was earlier classified only on the basis of myxospores morphology, but due to the high structural variability of this group advanced methods and approaches have to be implied which can minimize the problems in assigning new species.

Devaluation by Omission: Limited Identity Options Elicit Anger and Increase Identification.

In the present research, we explored social-identity threat caused by subtle acts of omission, specifically situations in which social-identity information is requested but one's identity is not among the options provided. We predicted that being unable to identify with one's group-that is, in the demographics section of a survey-may signal social-identity devaluation, eliciting negative affect (e.g., anger) and increasing the importance of the omitted identity to group members' sense of self. Six preregistered experiments (N = 2,964 adults) sampling members of two minority-identity groups (i.e., gender minorities and members of a minority political party) support these predictions. Our findings document the existence of a subtle but likely pervasive form of social-identity threat.

Stereotype Threat and Gender Bias in Internal Medicine Residency: It is Still Hard to be in Charge.

BACKGROUND: Despite similar numbers of women and men in internal medicine (IM) residency, women face unique challenges. Stereotype threat is hypothesized to contribute to underrepresentation of women in academic leadership, and exploring how it manifests in residency may provide insight into forces that perpetuate gender disparities. OBJECTIVE: To quantify the prevalence of stereotype threat in IM residency and explore experiences contributing to that stereotype threat. DESIGN: We used a mixed methods study design. First, we surveyed IM residents using the Stereotype Vulnerability Scale (SVS) to screen for stereotype threat. Second, we conducted focus groups with women who scored high on the SVS to understand experiences that led to stereotype threat. PARTICIPANTS: The survey was sent to all IM residents at University of California, San Francisco (UCSF), in September-November 2019. Focus groups were conducted at UCSF in Spring 2020. APPROACH: The survey included an adapted version of the SVS. For focus groups, we developed a focus group guide informed by literature on stereotype threat. We used a thematic approach to data analysis. The mixed methods design enabled us to draw metainferences by integrating the two data sources. KEY RESULTS: Survey response rate was 61% (110/181). Women were significantly more likely than men to have a score indicating stereotype threat vulnerability (77% vs 0%, p < 0.001). Four themes from focus groups characterized women's experiences of gender bias and stereotype threat: gender norm tension, microaggressions and sexual harassment, authority questioned, and support and allyship. CONCLUSIONS: Gender-based stereotype threat is highly prevalent among women IM residents. This phenomenon poses a threat to confidence and ability to execute patient care responsibilities, detracting from well-being and professional development. These findings indicate that, despite robust representation of women in IM training, further attention is needed to address gendered experiences and contributors to women's vulnerability to stereotype threat.

Enhanced late positive potential to conditioned threat cue during delayed extinction in anxious youth.

BACKGROUND: Deficits in threat learning relate to anxiety symptoms. Since several anxiety disorders arise in adolescence, impaired adolescent threat learning could contribute to adolescent changes in risk for anxiety. This study compared threat learning among anxious and non-anxious youth using self-reports, peripheral psychophysiology measures, and event-related potentials. Because exposure therapy, the first-line treatment for anxiety disorders, is largely based on principles of extinction learning, the study also examined the link between extinction learning and treatment outcomes among anxious youth. METHODS: Clinically anxious (n = 28) and non-anxious (n = 33) youth completed differential threat acquisition and immediate extinction. They returned to the lab a week later to complete a threat generalization test and a delayed extinction task. Following these two experimental visits, anxious youth received exposure therapy for 12 weeks. RESULTS: Anxious as compared to non-anxious youth demonstrated elevated cognitive and physiological responses across acquisition and immediate extinction learning, as well as greater threat generalization. In addition, anxious youth showed enhanced late positive potential response to the conditioned threat cue compared to the safety cue during delayed extinction. Finally, aberrant neural response during delayed extinction was associated with poorer treatment outcomes. CONCLUSIONS: The study emphasizes differences between anxious and non-anxious youth in threat learning processes and provides preliminary support for a link between neural processing during delayed extinction and exposure-based treatment outcome in pediatric anxiety.