Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Preoperative Risk Factors and Postoperative Complications of COVID-Positive Children Requiring Urgent or Emergent Surgical Care.

BACKGROUND: Preoperative COVID-19 testing protocols were widely implemented for children requiring surgery, leading to increased resource consumption and many delayed or canceled operations or procedures. This study using multi-center data investigated the relationship between preoperative risk factors, COVID-positivity, and postoperative outcomes among children undergoing common urgent and emergent procedures. METHODS: Children (<18 years) who underwent common urgent and emergent procedures were identified in the 2021 National Surgical Quality Improvement Program Pediatric database. The outcomes of COVID-positive and non-COVID-positive (negative or untested) children were compared using simple and multivariable regression models. RESULTS: Among 40,628 children undergoing gastrointestinal surgery (appendectomy, cholecystectomy), long bone fracture fixation, cerebrospinal fluid shunt procedures, gonadal procedures (testicular detorsion, ovarian procedures), and pyloromyotomy, 576 (1.4%) were COVID-positive. COVID-positive children had higher American Society of Anesthesiologists scores (p ≤ 0.001) and more frequently had preoperative sepsis (p ≤ 0.016) compared to non-COVID-positive children; however, other preoperative risk factors, including comorbidities, were largely similar. COVID-positive children had a longer length of stay than non-COVID-positive children (median 1.0 [IQR 0.0-2.0] vs. 1.0 [IQR 0.0-1.0], p < 0.001). However, there were no associations between COVID-19 positivity and overall complications, pulmonary complications, infectious complications, or readmissions. CONCLUSIONS: Despite increased preoperative risk factors, COVID-positive children did not have an increased risk of postoperative complications after common urgent and emergent procedures. However, length of stay was greater for COVID-positive children, likely due to delays in surgery related to COVID-19 protocols. These findings may be applicable to future preoperative testing and surgical timing guidelines related to respiratory viral illnesses in children. LEVEL OF EVIDENCE: III.

Relationship between the COVID-19 pandemic and structural inequalities within the pediatric trauma population.

BACKGROUND: The COVID-19 pandemic disrupted social, political, and economic life across the world, shining a light on the vulnerability of many communities. The objective of this study was to assess injury patterns before and after implementation of stay-at-home orders (SHOs) between White children and children of color and across varying levels of vulnerability based upon children's home residence. METHODS: A multi-institutional retrospective study was conducted evaluating patients < 18 years with traumatic injuries. A "Control" cohort from an averaged March-September 2016-2019 time period was compared to patients injured after SHO initiation-September 2020 ("COVID" cohort). Interactions between race/ethnicity or social vulnerability index (SVI), a marker of neighborhood vulnerability and socioeconomic status, and the COVID-19 timeframe with regard to the outcomes of interest were assessed using likelihood ratio Chi-square tests. Differences in injury intent, type, and mechanism were then stratified and explored by race/ethnicity and SVI separately. RESULTS: A total of 47,385 patients met study inclusion. Significant interactions existed between race/ethnicity and the COVID-19 SHO period for intent (p < 0.001) and mechanism of injury (p < 0.001). There was also significant interaction between SVI and the COVID-19 SHO period for mechanism of injury (p = 0.01). Children of color experienced a significant increase in intentional (COVID 16.4% vs. Control 13.7%, p = 0.03) and firearm (COVID 9.0% vs. Control 5.2%, p < 0.001) injuries, but no change was seen among White children. Children from the most vulnerable neighborhoods suffered an increase in firearm injuries (COVID 11.1% vs. Control 6.1%, p = 0.001) with children from the least vulnerable neighborhoods having no change. All-terrain vehicle (ATV) and bicycle crashes increased for children of color (COVID 2.0% vs. Control 1.1%, p = 0.04 for ATV; COVID 6.7% vs. Control 4.8%, p = 0.02 for bicycle) and White children (COVID 9.6% vs. Control 6.2%, p < 0.001 for ATV; COVID 8.8% vs. Control 5.8%, p < 0.001 for bicycle). CONCLUSIONS: In contrast to White children and children from neighborhoods of lower vulnerability, children of color and children living in higher vulnerability neighborhoods experienced an increase in intentional and firearm-related injuries during the COVID-19 pandemic. Understanding inequities in trauma burden during times of stress is critical to directing resources and targeting intervention strategies.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Location of Treatment Among Infants Requiring Complex Surgical Care.

INTRODUCTION: Rural children have worse health outcomes compared to urban children. One mechanism for this finding may be decreased access to specialized care at children's hospitals. The objective of this study was to evaluate the hospital types where complex surgical care in infants is performed nationally. METHODS: This study examined infants (<1 y old) in the Kids' Inpatient Database from 2009 to 2019 who underwent surgery for one of the following conditions: esophageal atresia, gastroschisis, omphalocele, Hirschsprung disease, anorectal malformation, pyloric stenosis, small bowel atresia, congenital diaphragmatic hernia, and necrotizing enterocolitis. The relationship between patient residence (rural versus urban) and location of surgical care (children's hospital versus other) was compared in relation to other covariates using multivariable logistic regression models. RESULTS: Among 29,185 infants undergoing these operations, 16.0% lived in a rural area. Rural infants were more frequently White (64.8% versus 43.4% P < 0.001), from the lowest two income quartiles (86.5% versus 52.0%, P < 0.001), and from the South or Midwest regions (P < 0.001). Surgical care was predominantly (94.1%) provided at urban teaching hospitals but frequently not at children's hospitals, especially among rural infants. After adjusting for other covariates, rural infants were significantly less likely to undergo care at a children's hospital for both 2009 (adjusted odds ratio 0.66, P < 0.001) and 2012-2019 (adjusted odds ratio 0.78, P < 0.001). CONCLUSIONS: A sizable portion of complex surgical care in infants is performed outside children's hospitals, especially among those from rural areas. Further work is necessary to ensure adequate access to children's hospitals for rural children.

Characteristics and neighborhood-level opportunity of assault-injured children in Milwaukee.

BACKGROUND: Multiple studies have explored demographic characteristics and social determinants of health in relation to the risk of pediatric assault-related injuries and reinjury. However, few have explored protective factors. The Child Opportunity Index (COI) uses neighborhood-level indicators to measure 'opportunity' based on factors such as education, social environment, and economic resources. We hypothesized that higher 'opportunity' would be associated with less risk of reinjury in assault-injured youth. METHODS: This was a single-institution, retrospective study at a Level 1 Pediatric Trauma Center. Trauma registry and electronic medical record data were queried for children ≤ 18 years old with assault-related injuries from 1/1/2016 to 5/31/2021. Reinjured children, defined as any child who sustained more than one assault injury, were compared to non-reinjured children. Area Deprivation Index (ADI), a marker of socioeconomic status, and COI were determined through census block and tract data, respectively. A post-hoc analysis examined COI between all assault-injured children, unintentionally injured children, and a state-based normative cohort representative of non-injured children. RESULTS: There were 55,862 traumatic injury encounters during the study period. Of those, 1224 (2.3%) assault injured children were identified, with 52 (4.2%) reinjured children and 1172 (95.8%) non-reinjured children. Reinjured children were significantly more likely to be older (median age 15.0 [IQR 13.8-17.0] vs. median age 14.0 [IQR 8.8-16.0], p < 0.001) and female (55.8% vs. 37.5%, p = 0.01) than non-reinjured children. COI was not associated with reinjury. There were also no significant differences in race, ethnicity, insurance status, ADI, or mechanism and severity of injury between cohorts. Post-hoc analysis revealed that assault-injured children were more likely to live in areas of lower COI than the other cohorts. CONCLUSIONS: Compared to children who sustained only one assault during the study period, children who experienced more than one assault were more likely to be older and female. Furthermore, living in an area with more or less opportunity did not influence the risk of reinjury. However, all assault-injured children were more likely to live in areas of lower COI compared to unintentionally injured and a state-based normative cohort. Identification of factors on a social or environmental level that leads to assaultive injury warrants further exploration.

RESIDENTS AS INTERVIEWERS: A COMPARISON OF RESIDENT AND FACULTY EVALUATIONS OF EMERGENCY MEDICINE RESIDENCY APPLICANTS.

BACKGROUND: Interviews are an integral component of the residency selection process. Many programs use current residents as interviewers in addition to faculty. Although the reliability of interview scores between faculty members has been examined, little is known about the reliability between resident and faculty interviewers. OBJECTIVE: This study evaluates the reliability of residents as interviewers compared with faculty. METHODS: A retrospective analysis of interview scores from the 2020-2021 application cycle was performed at an emergency medicine (EM) residency program. Each applicant participated in five separate one-on-one interviews led by four faculty members and one senior resident. Interviewers assigned applicants a score from 0 to 10. Consistency between interviewers was measured using the intraclass correlation coefficient (ICC). Generalizability theory was used to measure variance components including applicant, interviewer, and rater type (resident vs. faculty) and their impact on scoring. RESULTS: There were 250 applicants interviewed by 16 faculty members and 7 senior residents during the application cycle. The mean (SD) interview score given by resident interviewers was 7.10 (1.53) and the mean (SD) score given by faculty was 7.07 (1.69). There was no statistically significant difference between the pooled scores (p = 0.97). Reliability between interviewers was good to excellent (ICC = 0.90; 95% CI 0.88-0.92). The generalizability study showed most score variance was attributable to applicant characteristics and only 0.6% was attributable to interviewer or rater type (resident vs. faculty). CONCLUSIONS: There was strong concordance between faculty and resident interview scores indicating reliability of EM resident scoring compared to faculty.

Disparities in disposition from trauma centers to inpatient psychiatric treatment in a national sample of patients with self-inflicted injury.

BACKGROUND: Surgery providers are integral to the treatment of patients with self-inflicted injuries. Patient disposition (eg, home, inpatient psychiatric treatment, rehabilitation) is important to long-term outcomes, but little is known about factors influencing disposition after discharge following traumatic self-inflicted injury. We tested whether patient or injury characteristics were associated with disposition after treatment for self-inflicted injury. METHODS: National Trauma Data Bank query for self-inflicted injuries from 2010 to 2018. RESULTS: There were 77,731 patients treated for self-inflicted injuries during the study period. Discharge home was the most common disposition (45%), and those without insurance were less likely to discharge to inpatient psychiatric treatment than those with insurance. Racial minority patients were less likely to discharge to inpatient psychiatric treatment (18.9%) than nonminority patients (23.8%, P < .001). Additionally, patients discharged to inpatient psychiatric treatment had significantly lower injury severity score (7.24 ± 7.5) than those who did not (8.69 ± 9.1, P < .001). CONCLUSION: Racial/ethnic minority patients and those without insurance were significantly less likely to discharge to an inpatient psychiatric facility after treatment at a trauma center for self-inflicted injury. Future research is needed to evaluate the internal factors (eg, trauma center practices) and external factors (eg, inpatient psychiatric facilities not accepting patients with wound care needs) driving disposition variability.

Association of Gender, Race, Mechanism of Injury on Alcohol Use, Posttraumatic Stress Disorder, and Depression in Trauma.

BACKGROUND: There is a paucity of literature documenting whether trauma patients with different mechanisms of injury have different rates of hazardous alcohol use and/or risk for depression and posttraumatic stress disorder. OBJECTIVE: The purpose of this article is to determine whether there are associations between mechanism of injury, hazardous drinking, depression, and posttraumatic stress disorder. Secondary objectives were to examine associations prior to and after the onset of the COVID-19 pandemic. METHODS: This is a retrospective cohort study of 5 years of trauma registry data of adult trauma patients (older than 18 years) admitted to a Midwestern Level I trauma center conducted from January 2016 to November 2020. Multivariable logistic regression analyses were performed to explore the association of gender, race, and mechanism of injury on hazardous drinking and posttraumatic stress disorder and depression. RESULTS: A total of 9,392 trauma patients completed the Alcohol Use Disorders Identification Test-Consumption Items to identify hazardous drinking, and 5,012 completed the Injured Trauma Survivor Screen to identify risk for developing posttraumatic stress disorder and/or depression. The proportion of patients screening positive for hazardous drinking was higher for motor vehicle collisions (21.9%) than for gunshot wounds (17.6%) or falls (18.8%; χ2(2) = 14.311, p < .001). Those involved in motor vehicle collisions were also at a higher risk for the development of depression and posttraumatic stress disorder (54.5%) relative to falls (33.5%) but not gunshot wounds (50.7%; χ2(2) = 200.185, p < .001). The impact of COVID-19 revealed increased hazardous drinking, depression, and posttraumatic stress disorder in patients with falls and motor vehicle collisions but not gunshot wounds. CONCLUSIONS: Motor vehicle collision patients are at most risk for hazardous drinking concomitant with risk for depression and posttraumatic stress disorder. These results help focus future research efforts toward interventions that can reduce these risks.

Machine learning prediction of posttraumatic stress disorder trajectories following traumatic injury: Identification and validation in two independent samples.

Due to its heterogeneity, the prediction of posttraumatic stress disorder (PTSD) development after traumtic injury is difficult. Recent machine learning approaches have yielded insight into predicting PTSD symptom trajectories. Using data collected within 1 month of traumatic injury, we applied eXtreme Gradient Boosting (XGB) to classify admitted and discharged patients (hospitalized, n = 192; nonhospitalized, n = 214), recruited from a Level 1 trauma center, according to PTSD symptom trajectories. Trajectories were identified using latent class mixed models on PCL-5 scores collected at baseline, 1-3 months posttrauma, and 6 months posttrauma. In both samples, nonremitting, remitting, and resilient PTSD symptom trajectories were identified. In the admitted patient sample, a unique delayed trajectory emerged. Machine learning classifiers (i.e., XGB) were developed and tested on the admitted patient sample and externally validated on the discharged sample with biological and clinical self-report baseline variables as predictors. For external validation sets, prediction was fair for nonremitting versus other trajectories, areas under the curve (AUC = .70); good for nonremitting versus resilient trajectories, AUCs = .73-.76; and prediction failed for nonremitting versus remitting trajectories, AUCs = .46-.48. However, poor precision (< .57) across all models suggests limited generalizability of nonremitting symptom trajectory prediction from admitted to discharged patient samples. Consistency in symptom trajectory identification across samples supports prior studies on the stability of PTSD symptom trajectories following trauma exposure; however, continued work and replication with larger samples are warranted to understand overlapping and unique predictive features of PTSD in different traumatic injury populations.

Predicting outcomes after traumatic brain injury: A novel hospital prediction model for a patient reported outcome.

BACKGROUND: Estimation of long-term quality of life in patients sustaining Traumatic brain injuries is a difficult but important task during the early hospitalization. There are very limited tools to assess these outcomes, therefore we aimed to develop a predictive model for quality-of-life that could be used in hospitalized adults with TBIs. METHODS: The TRACK-TBI dataset was used to identify adult patients with TBI from 2014 to 2018. Multiple variables were assessed to predict favorable versus unfavorable scores on the Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS). RESULTS: We included 1549 subjects. 57% had a favorable outcome, and were more likely to have private insurance, higher GCS scores, and fewer comorbidities. A model (TBI-PRO) for 3, 6, and 12-month QOLIBRI score was created. The AUROCs for predicting 3, 6 and 12-month favorable QOLIBRI scores were 0.81, 0.79, and 0.76, respectively. CONCLUSION: The TBI-PRO model adequately estimates long-term outcomes in patients with TBI.

Circulating endocannabinoids and genetic polymorphisms as predictors of posttraumatic stress disorder symptom severity: heterogeneity in a community-based cohort.

The endocannabinoid signaling system (ECSS) regulates fear and anxiety. While ECSS hypoactivity can contribute to symptoms of established post-traumatic stress disorder (PTSD), the role of the ECSS in PTSD development following trauma is unknown. A prospective, longitudinal cohort study of 170 individuals (47% non-Hispanic Caucasian and 70% male) treated at a level 1 trauma center for traumatic injury was carried out. PTSD symptom assessments and blood were obtained during hospitalization and at follow-up (6-8 months post injury). Serum concentrations of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) were determined at both time points and selected genetic polymorphisms in endocannabinoid genes, including rs324420 in fatty acid amide hydrolase, were assessed. For the entire sample, serum concentrations of AEA at hospitalization were significantly higher in those diagnosed with PTSD at follow-up (p = 0.030). Serum concentrations of 2-AG were significantly, positively correlated with PTSD symptom severity at follow-up only in minorities (p = 0.014). Minority participants (mostly Black/African American) also demonstrated significant, negative correlations between serum AEA concentrations and PTSD symptom severity both measured at hospitalization (p = 0.015). The A/A genotype at rs324420 was associated with significantly higher PTSD symptom severity (p = 0.025) and occurred exclusively in the Black participants. Collectively, these results are contrary to our hypothesis and find positive associations between circulating endocannabinoids and risk for PTSD. Minority status is an important modulator of the association between endocannabinoids and risk for PTSD, suggesting that the ECSS contributes to risk most significantly in these individuals and the contextual factors related to these findings should be further explored.

Lost in Follow-Up: Predictors of Patient No-Shows to Clinic Follow-Up After Abdominal Injury.

BACKGROUND: The aim of this study is to evaluate risk factors for non-attendance to post-discharge, hospital follow-up appointments for traumatically injured patients who underwent exploratory laparotomy. METHODS: This is a retrospective chart review of patients who underwent exploratory laparotomy for traumatic abdominal injury at an urban, Midwestern, level I trauma center with clinic follow-up scheduled after discharge. Clinically, relevant demographic characteristics, patients' distance from hospital, and the presence of staples, sutures, and drains requiring removal were collected. Descriptive statistics of categorical variables were calculated as totals and percentages and compared with a chi-squared test or Fisher's exact when appropriate. RESULTS: The sample included 183 patients who were largely assaultive trauma survivors (68%), male (80%), and black (53%) with a mean age of 35.4 ± 14.9 years. Overall, 18.5% no-showed for their follow-up appointment. On multivariate analysis for clinic no-show; length of stay (odds ratio = 0.92 [0.84-0.99], P = 0.04) and the need for suture, staple, or drain removal were protective for clinic attendance (odds ratio = 5.59 [1.07-7.01], P = 0.04). Overall, 12 patients (6.4%) were readmitted. Forty patients (18.3%) had their follow-up in the emergency department (ED). On multivariate regression of risk factors for ED visits, the only statistically significant factors (P < 0.05) were clinic appointment no-show (OR = 2.81) and self-pay insurance (OR = 4.78). CONCLUSIONS: Abdominal trauma patients are at high risk of no-show for follow-up appointments and no-show visits are associated with ED visits. Future work is needed evaluating interventions to improve follow-up.

Validation of the Injured Trauma Survivor Screen: An American Association for the Surgery of Trauma multi-institutional trial.

BACKGROUND: Psychological distress is common following a traumatic injury event. The Injured Trauma Survivor Screen (ITSS) was developed at a level 1 trauma center to assess for posttraumatic stress disorder (PTSD) and major depressive episode (MDE) following admission for a traumatic injury. The ITSS sensitivity and specificity were analyzed 1 to 3 and 6 to 9 months postinjury to test the validity across trauma centers. METHOD: Four level 1 trauma centers from the East, Midwest, South, and West in the United States recruited 375 eligible adult inpatients (excluded participants included those with moderate or severe traumatic brain injury, whose injury was self-inflicted, were noncommunicative, or were non-English speaking). Baseline sample (White/Caucasian, 63.2%; male, 62.4%; mean (SD) age, 45 (17.11) years; injured by motor vehicle collision, 42.4%) measurements were conducted during index hospitalization. At first follow-up, 69.6% (n = 261) were retained; at second follow-up, 61.3% (n = 230) were retained. Measurements included the ITSS, PTSD Checklist for DSM-5, Center for Epidemiologic Studies Depression Scale-Revised, and Clinician-Administered PTSD Scaled for DSM 5. RESULTS: At follow-up 1, the ITSS PTSD subscale had a sensitivity of 75% and specificity of 78.8%, and the MDE subscale had a sensitivity of 80.4% and specificity of 65.6%. At follow-up 2, the PTSD subscale had a sensitivity of 72.7% and specificity of 83.1%, and the MDE subscale had a sensitivity of 76.1% and specificity of 68.3%. A combined risk group using two symptom based measures administered at baseline produced increased specificity. CONCLUSION: The nine-item ITSS continues to be an efficient and effective risk screen for PTSD and MDE following traumatic injury requiring hospitalization. This multi-institutional validation study creates a solid foundation for further exploration of the generalizability of this screen's psychometric properties in distinct populations. LEVEL OF EVIDENCE: Prognostic study, level III.

A Randomized Trial of Modified Prolonged Exposure to Prevent the Development of Posttraumatic Stress Disorder in Patients Hospitalized With Traumatic Injuries.

Individuals who require hospitalization after traumatic injuries are at increased risk for developing posttraumatic stress disorder (PTSD); however, few early behavioral interventions have been effective at preventing PTSD within this population. The aim of this pilot study was to assess the feasibility and effectiveness of modified prolonged exposure therapy (mPE) to prevent PTSD and depression symptoms among patients hospitalized after a DSM-5 single-incident trauma. Hospitalized patients were eligible if they screened positive for PTSD risk. Participants (N = 74) were randomly assigned in a parallel-groups design to receive mPE (n = 38) or standard of care treatment (SoC; n = 36) while admitted to the hospital after a traumatic injury. Individuals randomized to the intervention condition received one (42.1%), two (36.8%), or three sessions (15.8%) of mPE, mainly depending on length of stay. There were no significant differences between groups regarding PTSD or depression severity at 1- or 3-months posttrauma, except for more PTSD diagnoses in the intervention group after 1 month, ϕ = -.326. Intervention differences were nonsignificant when we took baseline PTSD symptoms and the nonindependence of the repeated measurements within the data into account. No adverse events were reported. Overall, mPE was no more effective than SoC for hospitalized, traumatic injury survivors with a high PTSD risk. The results may point to a need for a stepped-care approach, where intervention protocols focus on first briefly treating individuals who are actively exhibiting acute stress reactions, then extensively treating those whose symptoms do not decrease over time.

Mouse Models for Studying Depression-Like States and Antidepressant Drugs.

Depression is a common psychiatric disorder, with diverse symptoms and high comorbidity with other brain dysfunctions. Due to this complexity, little is known about the neural and genetic mechanisms involved in depression pathogenesis. In a large proportion of patients, current antidepressant treatments are often ineffective and/or have undesirable side effects, fueling the search for more effective drugs. Animal models mimicking various symptoms of depression are indispensable in studying the biological mechanisms of this disease. Here, we summarize several popular methods for assessing depression-like symptoms in mice, and their utility in screening antidepressant drugs.

Experimental Models of Anxiety for Drug Discovery and Brain Research.

Animal models have been vital to recent advances in experimental neuroscience, including the modeling of common human brain disorders such as anxiety, depression, and schizophrenia. As mice express robust anxiety-like behaviors when exposed to stressors (e.g., novelty, bright light, or social confrontation), these phenotypes have clear utility in testing the effects of psychotropic drugs. Of specific interest is the extent to which mouse models can be used for the screening of new anxiolytic drugs and verification of their possible applications in humans. To address this problem, the present chapter will review different experimental models of mouse anxiety and discuss their utility for testing anxiolytic and anxiogenic drugs. Detailed protocols will be provided for these paradigms, and possible confounds will be addressed accordingly.

Modeling withdrawal syndrome in zebrafish.

The zebrafish (Danio rerio) is rapidly becoming a popular model species in behavioral neuroscience research. Zebrafish behavior is robustly affected by environmental and pharmacological manipulations, and can be examined using exploration-based paradigms, paralleled by analysis of endocrine (cortisol) stress responses. Discontinuation of various psychotropic drugs evokes withdrawal in both humans and rodents, characterized by increased anxiety. Sensitivity of zebrafish to drugs of abuse has been recently reported in the literature. Here we examine the effects of ethanol, diazepam, morphine and caffeine withdrawal on zebrafish behavior. Overall, discontinuation of ethanol, diazepam and morphine produced anxiogenic-like behavioral or endocrine responses, demonstrating the utility of zebrafish in translational research of withdrawal syndrome.

Mouse models for studying depression-like states and antidepressant drugs.

Depression is a common psychiatric disorder, with diverse symptoms and high comorbidity with other brain dysfunctions. Due to this complexity, little is known about the neural and genetic mechanisms involved in depression pathogenesis. In a large proportion of patients, current antidepressant treatments are often ineffective and/or have undesirable side effects, fueling the search for more effective drugs. Animal models mimicking various symptoms of depression are indispensable in studying the biological mechanisms of this disease. Here, we summarize several popular methods for assessing depression-like symptoms in mice and their utility in screening antidepressant drugs.

Experimental models of anxiety for drug discovery and brain research.

Animal models have been vital to recent advances in experimental neuroscience, including the modeling of common human brain disorders such as anxiety, depression, and schizophrenia. As mice express robust anxiety-like behaviors when exposed to stressors (e.g., novelty, bright light, or social confrontation), these phenotypes have clear utility in testing the effects of psychotropic drugs. Of specific interest is the extent to which mouse models can be used for the screening of new anxiolytic drugs and verification of their possible applications in humans. To address this problem, the present chapter will review different experimental models of mouse anxiety and discuss their utility for testing anxiolytic and anxiogenic drugs. Detailed protocols will be provided for these paradigms, and possible confounds will be addressed accordingly.