Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

We describe the close correspondence between predatory imminence continuum theory (PICT) and the National Institute of Mental Health's Research Domain Criteria (RDoC) for negative valence. RDoC's negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. PICT divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat. While there is a close correspondence between PICT modes and negative valence threat constructs, based on PICT, we describe some potential elaborations of RDoC constructs. Both have consonant views of fear and anxiety and provide explicit distinctions between these emotional states, relating them to specific defensive behaviors and functions. We describe recent data that causally implicate human subjective emotional states with amygdala activity, which is also critical for defensive behavior. We conclude that attention to neuroethological views of defense can advance our understanding of the etiology and treatment of anxiety and stress disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adaptation of Threat Responses Within the Negative Valence Framework.

External threats are a major source of our experience of negatively valanced emotion. As a threat becomes closer and more real, our specific behavior patterns and our experiences of negative affect change in response to the perceived imminence of threat. Recognizing this, the National Institute of Mental Health's Research Domain Criteria (RDoC) Negative Valence system is largely based around different levels of threat imminence. This perspective describes the correspondence between the RDoC Negative Valence System and a particular neurobiological/neuroecological model of reactions to threat, the Predatory Imminence Continuum (PIC) Theory. Using the COVID-19 pandemic as an illustration, we describe both adaptive and maladaptive behavior patterns from this perspective to illustrate how behavior in response to a crisis may get shaped. We end with suggestions on how further consideration of the PIC suggests potential modifications of the negative valence systems RDoC.

Increased Fear Generalization and Amygdala AMPA Receptor Proteins in Chronic Traumatic Brain Injury.

Cognitive impairments and emotional lability are common long-term consequences of traumatic brain injury (TBI). How TBI affects interactions between sensory, cognitive, and emotional systems may reveal mechanisms that underlie chronic mental health comorbidities. Previously, we reported changes in auditory-emotional network activity and enhanced fear learning early after TBI. In the current study, we asked whether TBI has long-term effects on fear learning and responses to novel stimuli. Four weeks following lateral fluid percussion injury (FPI) or sham surgery, adult male rats were fear conditioned to either white noise-shock or tone-shock pairing, or shock-only control and subsequently were tested for freezing to context and to the trained or novel auditory cues in a new context. FPI groups showed greater freezing to their trained auditory cue, indicating long-term TBI enhanced fear. Interestingly, FPI-Noise Shock animals displayed robust fear to the novel, untrained tone compared with Sham-Noise Shock across both experiments. Shock Only groups did not differ in freezing to either auditory stimulus. These findings suggest that TBI precipitates maladaptive associative fear generalization rather than non-associative sensitization. Basolateral amygdala (BLA) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr) subunits GluA1 and GluA2 levels were analyzed and the FPI-Noise Shock group had increased GluA1 (but not GluA2) levels that correlated with the level of tone fear generalization. This study illustrates a unique chronic TBI phenotype with both a cognitive impairment and increased fear and possibly altered synaptic transmission in the amygdala long after TBI, where stimulus generalization may underlie maladaptive fear and hyperarousal.

Conditional and unconditional components of aversively motivated freezing, flight and darting in mice.

Fear conditioning is one of the most frequently used laboratory procedures for modeling learning and memory generally, and anxiety disorders in particular. The conditional response (CR) used in the majority of fear conditioning studies in rodents is freezing. Recently, it has been reported that under certain conditions, running, jumping, or darting replaces freezing as the dominant CR. These findings raise both a critical methodological problem and an important theoretical issue. If only freezing is measured but rodents express their learning with a different response, then significant instances of learning, memory, or fear may be missed. In terms of theory, whatever conditions lead to these different behaviors may be a key to how animals transition between different defensive responses and different emotional states. In mice, we replicated these past results but along with several novel control conditions. Contrary to the prior conclusions, running and darting were primarily a result of nonassociative processes and were actually suppressed by associative learning. Darting and flight were taken to be analogous to nonassociative startle or alpha responses that are potentiated by fear. Additionally, associative processes had some impact on the topography of flight behavior. On the other hand, freezing was the purest reflection of associative learning. We also uncovered a rule that describes when these movements replace freezing: when afraid, freeze until there is a sudden novel change in stimulation, then burst into vigorous flight attempts. This rule may also govern the change from fear to panic.

Anxiety, fear, panic: An approach to assessing the defensive behavior system across the predatory imminence continuum.

In order to effectively thwart predation, antipredator defensive behaviors must be matched to the current spatio-temporal relationship to the predator. We have proposed a model where different defensive responses are organized along a predatory imminence continuum (PIC). The PIC is a behavior system organized as a sequence of innately programmed behavioral modes, each representing a different interaction with the predator or threat. Ranging from low threat to predator contact, the PIC categorizes defense modes as pre-encounter, post-encounter, and circa-strike, corresponding to states of anxiety, fear, and panic, respectively. This experiment examined if the same significant stressor caused overexpression of all defensive responses along the PIC, including anxiety-like behavior, freezing, and panic-like responses. Female and male mice were exposed to acute stress that consisted of a series of ten pseudorandomly presented unsignaled footshocks (or no shocks). Mice were subsequently tested on a battery of tasks to assess stress effects on pre-encounter (anxiety-like), post-encounter (fear), and circa-strike (panic-like) behaviors. Results revealed that following stress, mice exhibited increased anxiety-like behavior shown through reduced average velocity within a modified open field. Furthermore, stressed mice showed increased fear following a single footshock in a new context as well as an increase in reactivity to white noise in the original stress context, with stressed mice exhibiting a more robust circa-strike-like response than controls. Therefore, significant stress exposure influenced the defensive states of anxiety, fear, and panic across the predatory imminence continuum. This research could therefore reveal how such responses become maladaptive following traumatic stress in humans.

Frontoamygdala hyperconnectivity predicts affective dysregulation in adolescent moderate-severe TBI.

In survivors of moderate to severe traumatic brain injury (msTBI), affective disruptions often remain underdetected and undertreated, in part due to poor understanding of the underlying neural mechanisms. We hypothesized that limbic circuits are integral to affective dysregulation in msTBI. To test this, we studied 19 adolescents with msTBI 17 months post-injury (TBI: M age 15.6, 5 females) as well as 44 matched healthy controls (HC: M age 16.4, 21 females). We leveraged two previously identified, large-scale resting-state (rsfMRI) networks of the amygdala to determine whether connectivity strength correlated with affective problems in the adolescents with msTBI. We found that distinct amygdala networks differentially predicted externalizing and internalizing behavioral problems in patients with msTBI. Specifically, patients with the highest medial amygdala connectivity were rated by parents as having greater externalizing behavioral problems measured on the BRIEF and CBCL, but not cognitive problems. The most correlated voxels in that network localize to the rostral anterior cingulate (rACC) and posterior cingulate (PCC) cortices, predicting 48% of the variance in externalizing problems. Alternatively, patients with the highest ventrolateral amygdala connectivity were rated by parents as having greater internalizing behavioral problems measured on the CBCL, but not cognitive problems. The most correlated voxels in that network localize to the ventromedial prefrontal cortex (vmPFC), predicting 57% of the variance in internalizing problems. Both findings were independent of potential confounds including ratings of TBI severity, time since injury, lesion burden based on acute imaging, demographic variables, and other non-amygdalar rsfMRI metrics (e.g., rACC to PCC connectivity), as well as macro- and microstructural measures of limbic circuitry (e.g., amygdala volume and uncinate fasciculus fractional anisotropy). Supporting the clinical significance of these findings, patients with msTBI had significantly greater externalizing problem ratings than healthy control participants and all the brain-behavior findings were specific to the msTBI group in that no similar correlations were found in the healthy control participants. Taken together, frontoamygdala pathways may underlie chronic dysregulation of behavior and mood in patients with msTBI. Future work will focus on neuromodulation techniques to directly affect frontoamygdala pathways with the aim to mitigate such dysregulation problems.

Region-Dependent Modulation of Neural Plasticity in Limbic Structures Early after Traumatic Brain Injury.

Traumatic brain injury (TBI)-induced disruptions in synaptic function within brain regions and across networks in the limbic system may underlie a vulnerability for maladaptive plasticity and contribute to behavioral comorbidities. In this study we measured how synaptic proteins respond to lateral fluid percussion injury (FPI) brain regions known to regulate emotion and memory, including the basolateral amygdala (BLA), dorsal and ventral hippocampus (DH, VH), and medial prefrontal cortex (PFC). We investigated proteins involved in regulating plasticity, including synaptic glutamatergic a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA; GluA1, GluA2) and N-methyl-D-aspartate (NMDA; NR1, NR2A, NR2B) receptor subunits as well as inhibitory gamma-aminobutyric acid (GABA) synthetic enzymes (GAD67, GAD65) via western blot. Adult male rats received a mild-moderate lateral FPI or sham surgery and ipsi- and contralateral BLA, DH, VH, and PFC were collected 6 h, 24 h, 48 h, and 7 days post-injury. In the ipsilateral BLA, there was a significant decrease in NR1 and GluA2 24 h after injury, whereas NR2A and NR2B were increased in the contralateral BLA at 48 h compared with sham. GAD67 was increased ipsilaterally at 24 h, but decreased contralaterally at 48 h in the BLA. In the DH, both NMDA (NR2A, NR2B) and GABA-synthetic (GAD65, GAD67) proteins were increased acutely at 6 h compared with sham. GAD67 was also robustly increased in the ipsilateral VH at 6 h. In the contralateral VH, NR2A significantly increased between 6 h and 24 h after FPI, whereas GAD65 was decreased across the same time-points in the contralateral VH. In the medial PFC at 24 h we saw bilateral increases in GAD67 and a contralateral decrease in GluA1. Later, there was a significant decrease in GAD67 in contralateral PFC from 48 h to 7 days post-injury. Collectively, these data suggest that lateral FPI causes a dynamic homeostatic response across limbic networks, leading to an imbalance of the proteins involved in plasticity in neural systems underlying cognitive and emotional regulation.

Associations of Self-Reported Oral Health Quality of Life with Actual Oral Health Status in Children.

Purpose: Quality of life is considered a component of patient centered care. The purpose of this study was to examine the relationship between self-reported oral health related quality of life (OHRQoL) and the actual oral health status of children.Methods: This retrospective cohort study consisted of pediatric dental chart reviews from three clinics. Demographic and dental visit data along with the child's OHRQoL utilizing the Pediatric Oral health-related Quality of Life (POQL) instrument, were collected. Associations with untreated decay, treated decay, or POQL score were tested, using Chi-square, Fisher's exact test, 2-sample t-tests, or ANOVA. Linear regression was used to evaluate the effect of statistical confounders in the relationship between untreated decay and POQL scores. Significance level was set to 0.05.Results: Two hundred ninety-seven out of 336 children had both POQL and caries data. White children and children with untreated decay had significantly more negative POQL scores. Children rating their oral health as "excellent" or "very good" and children with sealants on molars had significantly more positive POQLs. Associations between POQL scores were significant with untreated decay, but not sealants, when considering both variables in the same model. After adjusting for having sealants, POQL scores were on average 7.5 points higher (more negative) in children with untreated decay, than in children without decay (p<0.001).Conclusions: Collecting OHRQoL data allows oral health providers to easily incorporate patient perceptions in their assessment and care and would ensure that all oral health needs of the patients are being met. This is important for children, who may have difficulty expressing their concerns, particularly in clinical environments.

Sex Differences in Behavioral Sensitivities After Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with high rates of post-injury psychiatric and neurological comorbidities. TBI is more common in males than females despite females reporting more symptoms and longer recovery following TBI and concussion. Both pain and mental health conditions like anxiety and post-traumatic stress disorder (PTSD) are more common in women in the general population, however the dimorphic comorbidity in the TBI population is not well-understood. TBI may predispose the development of maladaptive anxiety or PTSD following a traumatic stressor, and the impact of sex on this interaction has not been investigated. We have shown that white noise is noxious to male rats following fluid percussion injury (FPI) and increases fear learning when used in auditory fear conditioning, but it is unclear whether females exhibit a similar phenotype. Adult female and male rats received either lateral FPI or sham surgery and 48 h later received behavioral training. We first investigated sex differences in response to 75 dB white noise followed by white noise-signaled fear conditioning. FPI groups exhibited defensive behavior to the white noise, which was significantly more robust in females, suggesting FPI increased auditory sensitivity. In another experiment, we asked how FPI affects contextual fear learning in females and males following unsignaled footshocks of either strong (0.9 mA) or weaker (0.5 mA) intensity. We saw that FPI led to rapid acquisition of contextual fear compared to sham. A consistent pattern of increased contextual fear after TBI was apparent in both sexes across experiments under differing conditioning protocols. Using a light gradient open field task we found that FPI females showed a defensive photophobia response to light, a novel finding supporting TBI enhanced sensory sensitivity across modalities in females. General behavioral differences among our measures were observed between sexes and discussed with respect to interpretations of TBI effects for each sex. Together our data support enhanced fear following a traumatic stressor after TBI in both sexes, where females show greater sensitivity to sensory stimuli across multiple modalities. These data demonstrate sex differences in emergent defensive phenotypes following TBI that may contribute to comorbid PTSD, anxiety, and other neurological comorbidities.

Inhibition of IRF5 cellular activity with cell-penetrating peptides that target homodimerization.

The transcription factor interferon regulatory factor 5 (IRF5) plays essential roles in pathogen-induced immunity downstream of Toll-, nucleotide-binding oligomerization domain-, and retinoic acid-inducible gene I-like receptors and is an autoimmune susceptibility gene. Normally, inactive in the cytoplasm, upon stimulation, IRF5 undergoes posttranslational modification(s), homodimerization, and nuclear translocation, where dimers mediate proinflammatory gene transcription. Here, we report the rational design of cell-penetrating peptides (CPPs) that disrupt IRF5 homodimerization. Biochemical and imaging analysis shows that IRF5-CPPs are cell permeable, noncytotoxic, and directly bind to endogenous IRF5. IRF5-CPPs were selective and afforded cell type- and species-specific inhibition. In plasmacytoid dendritic cells, inhibition of IRF5-mediated interferon-α production corresponded to a dose-dependent reduction in nuclear phosphorylated IRF5 [p(Ser462)IRF5], with no effect on pIRF5 levels. These data support that IRF5-CPPs function downstream of phosphorylation. Together, data support the utility of IRF5-CPPs as novel tools to probe IRF5 activation and function in disease.

Sensory sensitivity as a link between concussive traumatic brain injury and PTSD.

Traumatic brain injury (TBI) is one of the most common injuries to military personnel, a population often exposed to stressful stimuli and emotional trauma. Changes in sensory processing after TBI might contribute to TBI-post traumatic stress disorder (PTSD) comorbidity. Combining an animal model of TBI with an animal model of emotional trauma, we reveal an interaction between auditory sensitivity after TBI and fear conditioning where 75 dB white noise alone evokes a phonophobia-like phenotype and when paired with footshocks, fear is robustly enhanced. TBI reduced neuronal activity in the hippocampus but increased activity in the ipsilateral lateral amygdala (LA) when exposed to white noise. The white noise effect in LA was driven by increased activity in neurons projecting from ipsilateral auditory thalamus (medial geniculate nucleus). These data suggest that altered sensory processing within subcortical sensory-emotional circuitry after TBI results in neutral stimuli adopting aversive properties with a corresponding impact on facilitating trauma memories and may contribute to TBI-PTSD comorbidity.

Timing and the transition between modes in the defensive behavior system.

Antipredator defense is organized in a way that mirrors Timberlake's feeding behavior system because the goal of defense is to thwart predatory behavior. Each predatory mode has a corresponding antipredator mode. Like appetitive behavior systems, the defensive behavior system is organized around distinct modes along a spatiotemporal continuum we call the predatory imminence continuum. Behavior systems theory directs investigation toward the factors that lead to transitions between modes. In the feeding and sex systems the time between Conditional Stimulus (CS) and Unconditional Stimulus (US; e.g., CS-US interval or CS duration) is an important factor. Short CSs elicit conditional responses (CR) characteristic of more terminal modes and long CSs provoke CRs belonging to initial modes. Therefore, we asked if short CSs (10 s) would provoke CRs like the vigorous activity bursts and escape-like responses characteristic of the terminal mode of the predatory imminence continuum (Circa-Strike Behavior). Also, via analogy to appetitive systems, long CSs (3 min) were predicted to favor the intermediate mode, post-encounter behavior, which is characterized by freezing. Instead we found that both CSs produced freezing but not activity burst CRs and that freezing was actually greater with the short CS. We suggest that this difference between behavior systems flows from selection pressure that favors moving toward terminal modes in appetitive systems but away from terminal modes in the antipredator system. In addition, since appetitive reinforcers are more likely to be repeatedly experienced than predators, the learning of timing may be less relevant to defense. We also found that shock produced activity bursts and argue that when you are in the post-encounter mode (freezing) a sudden change in stimulation causes an immediate transition to circa-strike (terminal) behavior.

Educating Healthcare Students: Strategies to Teach Systems Thinking to Prepare New Healthcare Graduates.

BACKGROUND: Educating undergraduate healthcare students is challenging due to the complexity of the healthcare environment today. Healthcare education systems focus mainly on discipline specific thinking using linear frameworks and reductionist approaches. Education of nurses, pharmacists, physicians, social workers, respiratory therapists takes place in a siloed environment with minimal interprofessional interaction. Yet, organizations expect new graduates to have skills and understanding of collaborative care with knowledge of healthcare systems thinking, IPP, TeamSTEPPS®, methods of group dynamics, and a knowledge of Informatics when they enter the workforce. PURPOSE: The purpose of this article is to 1) discuss and describe challenges in a high-tech complex healthcare environment that necessitate teaching systems thinking to future healthcare students, and 2) describe the use of interprofessional education (IPE), interprofessional practice (IPP), Team STEPPS®, curricular content, and other teaching methods as strategies for teaching systems thinking. CONCLUSION: Systems thinking in healthcare supports a holistic approach to care, inclusive of high-tech in the complex environment. With the rapid changes it is necessary to modify our teaching theories we use to educate new healthcare providers. Educating and practicing the key concepts/principles of IPE, IPP, and TeamSTEPPS®, and group dynamics, along with the important integration of technology, can provide the foundation to develop systems thinking and critical thinking in our complex healthcare environment.

Cholinergic Signaling Alters Stress-Induced Sensitization of Hippocampal Contextual Learning.

Post-traumatic stress disorder (PTSD) has a profound contextual component, and has been demonstrated to alter future contextual learning. However, the mechanism by which a single traumatic event affects subsequent contextual experiences has not been isolated. Acetylcholine (ACh) is an important modulator of hippocampus-dependent learning such as contextual memory strength. Using Stress-Enhanced Fear Learning (SEFL), which models aspects of PTSD in rats, we tested whether muscarinic acetylcholine receptors (mAChR) in dorsal hippocampus (DH) are required during trauma for the effect of trauma on subsequent contextual fear learning. We infused scopolamine or vehicle into DH immediately before stress, and tested fear in both the trauma context and a novel context after a mild stressor. The results show that during learning, ACh acting on mAChR within the DH is required for sensitization of future contextual fear learning. However, this effect is selective for contextual learning, as this blockade leaves discrete cue sensitization intact. Rather than simply sensitizing the BLA, as previous studies have suggested, SEFL requires cholinergic signaling in DH for contextual sensitization.

Stress reactivity after traumatic brain injury: implications for comorbid post-traumatic stress disorder.

Most people have or will experience traumatic stress at some time over the lifespan, but only a subset of traumatized individuals develop post-traumatic stress disorder (PTSD). Clinical research supports high rates of traumatic brain injury (TBI)-PTSD comorbidity and demonstrates TBI as a significant predictor of the development of PTSD. Biological factors impacted following brain injury that may contribute to increased PTSD risk are unknown. Heightened stress reactivity and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function are common to both TBI and PTSD, and affect amygdalar structure and function, which is implicated in PTSD. In this review, we summarize a growing body of literature that shows HPA axis dysregulation, as well as enhanced fear and amygdalar function after TBI. We present the hypothesis that altered stress reactivity as a result of brain injury impacts the amygdala and defense systems to be vulnerable to increased fear and PTSD development from traumatic stress. Identifying biological mechanisms that underlie this vulnerability, such as dysregulated HPA axis function, may lead to better targeted treatments and preventive measures to support psychological health after TBI.

Staff Nurses' Perspectives of Resources Needed During Floating.

OBJECTIVE: The aim of this study was to examine nurses' perceptions regarding the resources needed during floating. BACKGROUND: Most studies report on patterns of floating and the characteristics of float pool nurses. No studies exist regarding staff nurses' views of the types of resources needed to support floating. METHODS: Staff nurses in a pediatric hospital (N = 220) completed an electronic survey of both open- and close-ended questions. Close-ended data were analyzed with frequencies and percentages. Open-ended data were content-analyzed and then frequencies and percentages of categories of responses were performed. χ Analyses were used to examine relationships between the variables. RESULTS: There were no significant relationships between resources and years at the institution and number of times floated in past year. The top 3 categories of resources needed to float by nurse participants included having an assigned a resource/buddy, mini-orientation, and electronic updates about the units they are floating to. CONCLUSIONS: These findings underscore common frustrations nurses experience during floating and ways that nurse executives can create a more satisfactory floating environment and increase nursing satisfaction.

Development of a high-content imaging assay for screening compound aggregation.

Aggregated compounds can promiscuously and nonspecifically associate with proteins resulting in either false inhibition or activation of many different protein target classes. We developed a high-content imaging assay in a 384-well format using fluorescently labeled target proteins and an Operetta cell imager to screen for compound aggregates that interact with target proteins. The high-throughput assay can not only directly detect the interaction between compound aggregators and the target of interest, but also determine the critical aggregation concentration (CAC) of a given promiscuous small molecule.