Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder.

Introduction: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been investigated in PTSD. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analyses), and EC (secondary) using Neurite Orientation Dispersion and Density Imaging.Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion-weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure.Results: Higher PACAP levels were associated with greater EC NDI (ß = 0.0099, q = 0.032) and lower EC ODI (ß = -0.0073, q = 0.047), and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures.Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not the hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal-associated memory circuits in PTSD.

PACAP was associated with altered entorhinal cortex neurite density in PTSD.PACAP was not associated with altered neurite density in amygdala or hippocampus.PACAP may impact arousal-associated memory circuits.

Genetic risk for hospitalization of African American patients with severe mental illness reveals HLA loci.

Background: Mood disorders such as major depressive and bipolar disorders, along with posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and other psychotic disorders, constitute serious mental illnesses (SMI) and often lead to inpatient psychiatric care for adults. Risk factors associated with increased hospitalization rate in SMI (H-SMI) are largely unknown but likely involve a combination of genetic, environmental, and socio-behavioral factors. We performed a genome-wide association study in an African American cohort to identify possible genes associated with hospitalization due to SMI (H-SMI). Methods: Patients hospitalized for psychiatric disorders (H-SMI; n=690) were compared with demographically matched controls (n=4467). Quality control and imputation of genome-wide data were performed following the Psychiatric Genetic Consortium (PGC)-PTSD guidelines. Imputation of the Human Leukocyte Antigen (HLA) locus was performed using the HIBAG package. Results: Genome-wide association analysis revealed a genome-wide significant association at 6p22.1 locus in the ubiquitin D (UBD/FAT10) gene (rs362514, p=9.43x10-9) and around the HLA locus. Heritability of H-SMI (14.6%) was comparable to other psychiatric disorders (4% to 45%). We observed a nominally significant association with 2 HLA alleles: HLA-A*23:01 (OR=1.04, p=2.3x10-3) and HLA-C*06:02 (OR=1.04, p=1.5x10-3). Two other genes (VSP13D and TSPAN9), possibly associated with immune response, were found to be associated with H-SMI using gene-based analyses. Conclusion: We observed a strong association between H-SMI and a locus that has been consistently and strongly associated with SCZ in multiple studies (6p21.32-p22.1), possibly indicating an involvement of the immune system and the immune response in the development of severe transdiagnostic SMI.

The neurophysiological consequences of racism-related stressors in Black Americans.

Racism-related stressors, from experiences of both implicit and explicit racial discrimination to systemic socioeconomic disadvantage, have a cumulative impact on Black Americans' health. The present narrative review synthesizes peripheral (neuroendocrine and inflammation markers), psychophysiological (heart-rate variability, skin conductance), and neuroimaging (structural and functional) findings that demonstrate unique associations with racism-related stress. Emerging evidence reveals how racism-related stressors contribute to differential physiological and neural responses and may have distinct impacts on regions involved with threat and social processing. Ultimately, the neurophysiological effects of racism-related stress may confer biological susceptibility to stress and trauma-related disorders. We note critical gaps in the literature on the neurophysiological impact of racism-related stress and outline additional research that is needed on the multifactorial interactions between racism and mental health. A clearer understanding of the interactions between racism-related stress, neurophysiology, and stress- and trauma-related disorders is critical for preventative efforts, biomarker discovery, and selection of effective clinical treatments for Black Americans.

Children of trauma survivors: Influences of parental posttraumatic stress and child-perceived parenting.

BACKGROUND: Research has established a negative association between parental posttraumatic stress symptoms (PTSS), including subthreshold symptoms, and child physical and behavioral health outcomes. Such intergenerational transmission of risk has multiple possible mechanisms, including lack of positive parenting, increased negative parenting, shared environmental and contextual risks, and potential biological components such as shared genetics or even transmission of epigenetic risk. METHOD: This study examined 93 parent-child dyads (n = 171 participants total) from a mixed Urban-Suburban US metropolitan area to investigate the relations between parental PTSS and child-perceived parenting and child PTSS. We sought to examine interactions between parental PTSS and parenting on child PTSS. RESULTS: We found an association between parent and child PTSS, consistent with prior literature showing increased risk for children of trauma survivors. Interestingly, we found effects of positive parenting on diminished child PTSS symptoms only in parents without PTSS, whereas the effect of positive parenting on buffering child symptoms was absent in parents with PTSS. LIMITATIONS: The present findings are tempered by the use of self-report data to assess parent and child PTSS, which is not as reliable as clinician assessment of symptoms. Further, the use of survey data limits what is known about the extent of trauma exposure in parents and children, and different measures were used to assess PTSS in parents and kids, which limits comparability of these reported symptoms. DISCUSSION: Limitations notwithstanding, findings suggest joint attention paid to parenting practices and to a parent's recovery, even from subthreshold symptoms of PTSS, as two different but important ways to support trauma survivor parents in their efforts to most optimally parent and protect their children from intergenerational risk.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.

Sex differences in response inhibition-related neural predictors of PTSD in recent trauma-exposed civilians.

BACKGROUND: Females are more likely to develop posttraumatic stress disorder (PTSD) than males. Impaired inhibition has been identified as mechanism for PTSD development, but studies on the potential sex differences of this neurobiological mechanism and how it relates to PTSD severity and progression are sparse. Here we examined sex differences in neural activation during response inhibition and PTSD following recent trauma. METHODS: Participants (N= 205, 138 female sex assigned at birth) were recruited from emergency departments within 72 hours of a traumatic event. PTSD symptoms were assessed 2-weeks and 6-months post-trauma. A Go/NoGo task was performed 2-weeks post-trauma in a 3T MRI scanner to measure neural activity during response inhibition in the ventromedial prefrontal cortex (vmPFC), right inferior frontal gyrus (rIFG), and the bilateral hippocampus. General Linear models were used to examine the interaction effect of sex on the relationship between our regions of interest (ROIs) and the whole brain, and PTSD symptoms at 6-months, and symptom progression between 2-weeks and 6-months. RESULTS: Lower response-inhibition-related vmPFC activation 2-weeks post-trauma predicted more PTSD symptoms at 6-months in females but not in males, while greater response-inhibition-related rIFG activation predicted lower PTSD symptom progression in males but not females. Whole brain interaction effects were observed in the medial temporal gyrus and left precentral gyrus. CONCLUSIONS: There are sex differences in the relationship between inhibition-related brain activation and PTSD symptom severity and progression. These findings suggest that sex differences should be assessed in future PTSD studies and reveal potential targets for sex-specific interventions.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder.

In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Sensory alterations in post-traumatic stress disorder.

PTSD is characterized by difficulties in accurately evaluating the threat value of sensory stimuli. While the role of canonical fear and threat neural circuitry in this ability has been well studied, recent lines of evidence suggest a need to include more emphasis on sensory processing in the conceptualization of PTSD symptomology. Specifically, studies have demonstrated a strong association between variability in sensory processing regions and the severity of PTSD symptoms. In this review, we summarize recent findings that underscore the importance of sensory processing in PTSD, in addition to the structural and functional characteristics of associated sensory brain regions. First, we discuss the link between PTSD and various behavioral aspects of sensory processing. This is followed by a discussion of recent findings that link PTSD to variability in the structure of both gray and white matter in sensory brain regions. We then delve into how brain activity (measured with task-based and resting-state functional imaging) in sensory regions informs our understanding of PTSD symptomology.

Training for Lasting Change: Trauma-Informed Training Results in Improved and Sustained Individual and Organizational Knowledge, Attitudes, and Policies.

Objective: Trauma-informed care (TIC) trainings seek to improve individual and organizational recognition and care to individuals who have experienced trauma. However, whether TIC trainings result in long-term changes to an organization's policies and practices remains unclear. This article describes the effectiveness of a workshop designed to train professionals across disciplines in understanding and implementing TIC in their work and workplace.Methods: Between July 2021 and May 2022, participants completed a 2-day (approximately 12 hours) training in TIC that included didactics on cultural responsivity, the biological effects of trauma, the components of TIC, and how to deploy TIC within their organization. Prior to the training, participants completed a previously validated survey, the Survey for Trauma-Informed Systems Change, which evaluated their pre-training (T0) competency in TIC and the level of TIC within their organization. Within 48 hours following the training, participants completed a post-survey (T1). To evaluate the longer-term impact of the training, participants repeated the post-survey at 6 months post-training (T2).Results: Over a 1-year period, 598 individuals (78% women, 20% men; mean age = 45.5 years) received training in TIC. There was a significant increase between the T0 survey and the T1 post-survey in self-assessed knowledge and attitudes; systemwide knowledge and attitudes; training, support, interaction, and environment; and awareness of cultural background at work (P values < .001), but not safety and acceptance at work (P = .06). Open-ended qualitative responses on the T2 survey, which probed what specific policies and/or practices had been modified within the participant's organization, revealed improvement in several key themes (training, policy, and communication).Conclusions: This unique trauma-informed didactic training resulted isn persistent quantitative and qualitative change within individuals and organizations. Most notably, the training yielded greater confidence in utilizing TIC practices and systemic change at the organizational level. The results suggest that a 2-day training in TIC can transform organizational training, policy, and communications.

Prior Sexual Trauma Exposure Impacts Posttraumatic Dysfunction and Neural Circuitry Following a Recent Traumatic Event in the AURORA Study.

Background: Prior sexual trauma (ST) is associated with greater risk for posttraumatic stress disorder after a subsequent traumatic event; however, the underlying neurobiological mechanisms remain opaque. We investigated longitudinal posttraumatic dysfunction and amygdala functional dynamics following admission to an emergency department for new primarily nonsexual trauma in participants with and without previous ST. Methods: Participants (N = 2178) were recruited following acute trauma exposure (primarily motor vehicle collision). A subset (n = 242) completed magnetic resonance imaging that included a fearful faces task and a resting-state scan 2 weeks after the trauma. We investigated associations between prior ST and several dimensions of posttraumatic symptoms over 6 months. We further assessed amygdala activation and connectivity differences between groups with or without prior ST. Results: Prior ST was associated with greater posttraumatic depression (F1,1120 = 28.35, p = 1.22 × 10-7, ηp2 = 0.06), anxiety (F1,1113 = 17.43, p = 3.21 × 10-5, ηp2 = 0.05), and posttraumatic stress disorder (F1,1027 = 11.34, p = 7.85 × 10-4, ηp2 = 0.04) severity and more maladaptive beliefs about pain (F1,1113 = 8.51, p = .004, ηp2 = 0.02) but was not related to amygdala reactivity to fearful versus neutral faces (all ps > .05). A secondary analysis revealed an interaction between ST and lifetime trauma load on the left amygdala to visual cortex connectivity (peak Z value: -4.41, corrected p < .02). Conclusions: Findings suggest that prior ST is associated with heightened posttraumatic dysfunction following a new trauma exposure but not increased amygdala activity. In addition, ST may interact with lifetime trauma load to alter neural circuitry in visual processing regions following acute trauma exposure. Further research should probe the relationship between trauma type and visual circuitry in the acute aftermath of trauma.

Digital Collateral Information Through Electronic and Social Media in Psychotherapy: Comparing Clinician-reported Trends Before and During the COVID-19 Pandemic.

BACKGROUND: Patient clinical collateral information is critical for providing psychiatric and psychotherapeutic care. With the shift to primarily virtual care triggered by the COVID-19 pandemic, psychotherapists may have received less clinical information than they did when they were providing in-person care. This study assesses whether the shift to virtual care had an impact on therapists' use of patients' electronic and social media to augment clinical information that may inform psychotherapy. METHODS: In 2018, we conducted a survey of a cohort of psychotherapists affiliated with McLean Hospital. We then reapproached the same cohort of providers for the current study, gathering survey responses from August 10, 2020, to September 1, 2020, for this analysis. We asked clinicians whether they viewed patients' electronic and social media in the context of their psychotherapeutic relationship, what they viewed, how much they viewed it, and their attitudes about doing so. RESULTS: Of the 99 respondents, 64 (64.6%) had viewed at least 1 patient's social media and 8 (8.1%) had viewed a patient's electronic media. Of those who reported viewing patients' media, 70 (97.2%) indicated they believed this information helped them provide more effective treatment. Compared with the 2018 prepandemic data, there were significantly more clinicians with>10 years of experience reporting media use in therapy. There was also a significant increase during the pandemic in the viewing of media of adult patients and a trend toward an increase in viewing of media of older adult patients. CONCLUSIONS: Review of patients' electronic and social media in therapy became more common among clinicians at a large psychiatric teaching hospital during the COVID-19 pandemic. These findings support continuing research about how reviewing patients' media can inform and improve clinical care.

The emerging role of the gut microbiome in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) occurs in some people following exposure to a terrifying or catastrophic event involving actual/threatened death, serious injury, or sexual violence. PTSD is a common and debilitating mental disorder that imposes a significant burden on individuals, their families, health services, and society. Moreover, PTSD is a risk factor for chronic diseases such as coronary heart disease, stroke, diabetes, as well as premature mortality. Furthermore, PTSD is associated with dysregulated immune function. Despite the high prevalence of PTSD, the mechanisms underlying its etiology and manifestations remain poorly understood. Compelling evidence indicates that the human gut microbiome, a complex community of microorganisms living in the gastrointestinal tract, plays a crucial role in the development and function of the host nervous system, complex behaviors, and brain circuits. The gut microbiome may contribute to PTSD by influencing inflammation, stress responses, and neurotransmitter signaling, while bidirectional communication between the gut and brain involves mechanisms such as microbial metabolites, immune system activation, and the vagus nerve. In this literature review, we summarize recent findings on the role of the gut microbiome in PTSD in both human and animal studies. We discuss the methodological limitations of existing studies and suggest future research directions to further understand the role of the gut microbiome in PTSD.

Neighborhood Disadvantage and Neural Correlates of Threat and Reward Processing in Survivors of Recent Trauma.

Importance: Differences in neighborhood socioeconomic characteristics are important considerations in understanding differences in risk vs resilience in mental health. Neighborhood disadvantage is associated with alterations in the function and structure of threat neurocircuitry. Objective: To investigate associations of neighborhood disadvantage with white and gray matter and neural reactivity to positive and negative stimuli in the context of trauma exposure. Design, Setting, and Participants: In this cross-sectional study, survivors of trauma who completed sociodemographic and posttraumatic symptom assessments and neuroimaging were recruited as part of the Advancing Understanding of Recovery After Trauma (AURORA) study between September 2017 and June 2021. Data analysis was performed from October 25, 2022, to February 15, 2023. Exposure: Neighborhood disadvantage was measured with the Area Deprivation Index (ADI) for each participant home address. Main Outcomes and Measures: Participants completed separate threat and reward tasks during functional magnetic resonance imaging. Diffusion-weighted and high-resolution structural images were also collected. Linear models assessed the association of ADI with reactivity, microstructure, and macrostructure of a priori regions of interest after adjusting for income, lifetime trauma, sex at birth, and age. A moderated-mediation model tested whether ADI was associated with neural activity via microstructural changes and if this was modulated by PTSD symptoms. Results: A total of 280 participants (183 females [65.4%]; mean [SD] age, 35.39 [13.29] years) completed the threat task and 244 participants (156 females [63.9%]; mean [SD] age, 35.10 [13.26] years) completed the reward task. Higher ADI (per 1-unit increase) was associated with greater insula (t274 = 3.20; ß = 0.20; corrected P = .008) and anterior cingulate cortex (ACC; t274 = 2.56; ß = 0.16; corrected P = .04) threat-related activity after considering covariates, but ADI was not associated with reward reactivity. Greater disadvantage was also associated with altered microstructure of the cingulum bundle (t274 = 3.48; ß = 0.21; corrected P = .001) and gray matter morphology of the ACC (cortical thickness: t273 = -2.29; ß = -0.13; corrected P = .02; surface area: t273 = 2.53; ß = 0.13; corrected P = .02). The moderated-mediation model revealed that ADI was associated with ACC threat reactivity via cingulum microstructural changes (index of moderated mediation = -0.02). However, this mediation was only present in individuals with greater PTSD symptom severity (at the mean: ß = -0.17; standard error = 0.06, t= -2.28; P = .007; at 1 SD above the mean: ß = -0.28; standard error = 0.08; t = -3.35; P < .001). Conclusions and Relevance: In this study, neighborhood disadvantage was associated with neurobiology that supports threat processing, revealing associations of neighborhood disadvantage with neural susceptibility for PTSD and suggesting how altered structure-function associations may complicate symptoms. Future work should investigate specific components of neighborhood disadvantage that may be associated with these outcomes.

Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been reported. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analysis), and EC (secondary analysis) using Neurite Orientation Dispersion and Density Imaging. Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion- weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure. Results: Higher PACAP levels in blood were associated with greater EC NDI (ß=0.31, q=0.034) and lower EC ODI (ß=-0.30, q=0.042) and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures. Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal- associated memory circuits.

Enhancing Fear Extinction: Pharmacological Approaches.

Extinction is the process by which the memory of a learned conditioned association decreases over time and with introduction of new associations. It is a vital part of fear learning, and it is critical to recovery in multiple fear-related disorders, including Specific and Social Phobias, Panic Disorder, Obsessive Compulsive Disorder (OCD), and Posttraumatic Stress Disorder (PTSD). The process of extinction is also the underlying mechanism for recovery in gold-standard therapies for PTSD, including prolonged exposure, cognitive processing therapy, eye movement desensitization and procession, as well as other empirically-based paradigms. Pharmacological modulators of extinction are thus promising targets for treatment of fear-related disorders. We focus here on emerging psychopharmacological treatments to facilitate extinction: D-cycloserine, scopolamine, losartan, ketamine, and 3,4-methylenedioxymethamphetamine. We also provide an overview of recent advances in molecular pathways that show promise as targets for extincion and inhibitory learning, including pathways related to cannabinoid, brain-derived neurotrophic factor, hypothalamic-pituitary-adrenal signaling, and promising work in neurosteroid compounds.

Automatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress.

Severe stress exposure increases the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and behavioral changes. Current markerless pose estimation tools allow for more complex and naturalistic behavioral tests. Here, we introduce the open-source tool DeepOF to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut-annotated pose estimation data. Applying this tool to chronic social defeat in male mice, the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter and fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. Moreover, DeepOF aims to facilitate reproducibility and unification of behavioral classification by providing an open-source tool, which can advance the study of rodent individual and social behavior, thereby enabling biological insights and, for example, subsequent drug development for psychiatric disorders.