Greater stress and trauma mediate race-related differences in epigenetic age between Black and White young adults in a community sample.

Black Americans suffer lower life expectancy and show signs of accelerated aging compared to other Americans. While previous studies observe these differences in children and populations with chronic illness, whether these pathologic processes exist or how these pathologic processes progress has yet to be explored prior to the onset of significant chronic illness, within a young adult population. Therefore, we investigated race-related differences in epigenetic age in a cross-sectional sample of young putatively healthy adults and assessed whether lifetime stress and/or trauma mediate those differences. Biological and psychological data were collected from self-reported healthy adult volunteers within the local New Haven area (399 volunteers, 19.8% Black, mean age: 29.28). Stress and trauma data was collected using the Cumulative Adversity Inventory (CAI) interview, which assessed specific types of stressors, including major life events, traumatic events, work, financial, relationship and chronic stressors cumulatively over time. GrimAge Acceleration (GAA), determined from whole blood collected from participants, measured epigenetic age. In order to understand the impact of stress and trauma on GAA, exploratory mediation analyses were then used. We found cumulative stressors across all types of events (mean difference of 6.9 p = 2.14e-4) and GAA (ß = 2.29 years [1.57-3.01, p = 9.70e-10] for race, partial η2 = 0.091, model adjusted R2 = 0.242) were significantly greater in Black compared to White participants. Critically, CAI total score (proportion mediated: 0.185 [0.073-0.34, p = 6e-4]) significantly mediated the relationship between race and GAA. Further analysis attributed this difference to more traumatic events, particularly assaultive traumas and death of loved ones. Our results suggest that, prior to development of significant chronic disease, Black individuals have increased epigenetic age compared to White participants and that increased cumulative stress and traumatic events may contribute significantly to this epigenetic aging difference.

Racial and Ethnic Differences in Psychiatry Resident Prescribing: a Quality Improvement Education Intervention to Address Health Equity.

OBJECTIVE: Quality improvement (QI) tools can identify and address health disparities. This paper describes the use of resident prescriber profiles in a novel QI curriculum to identify racial and ethnic differences in antidepressant and antipsychotic prescribing. METHODS: The authors extracted medication orders written by 111 psychiatry residents over an 18-month period from an electronic medical record and reformatted these into 6133 unique patient encounters. Binomial logistic models adjusted for covariates assessed racial and ethnic differences in antipsychotic or antidepressant prescribing in both emergency and inpatient psychiatric encounters. A multinomial model adjusted for covariates then assessed racial and ethnic differences in primary diagnosis. Models also examined interactions between gender and race/ethnicity. RESULTS: Black (adjusted OR 0.66; 95% CI, 0.50-0.87; p < 0.01) and Latinx (adjusted OR, 0.65; 95% CI, 0.49-0.86; p < 0.01) patients had lower odds of receiving antidepressants relative to White patients despite diagnosis. Black and Latinx patients were no more likely to receive antipsychotics than White patients when adjusted for diagnosis. Black (adjusted OR 3.85; 95% CI, 2.9-5.2) and Latinx (adjusted OR 1.60; 95% CI, 1.1-2.3) patients were more likely to receive a psychosis than a depression diagnosis when compared to White patients. Gender interactions with race/ethnicity did not significantly change results. CONCLUSIONS: Our findings suggest that racial/ethnic differences in antidepressant prescription likely result from alternatively higher diagnosis of psychotic disorders and prescription of antipsychotics in Black and Latinx patients. Prescriber profiles can serve as a powerful tool to promote resident QI learning around the effects of structural racism on clinical care.

Suspending Student Selections to Alpha Omega Alpha Honor Medical Society: How One School Is Navigating the Intersection of Equity and Wellness.

Medical education must provide students with a delicate balance of academic rigor, equity, and wellness. While the medical education community espouses all these values, the authors believe the way medical students are evaluated and rewarded undermines equity and wellness. Alpha Omega Alpha Honor Medical Society (AΩA) membership is arguably the highest honor that a medical student can achieve. In the short term, it opens doors to the most selective training opportunities, and in the long term, ushers students into an elite group of future physician leaders. Yet recent data have demonstrated that AΩA is disproportionately awarded to white students.At Icahn School of Medicine at Mount Sinai (ISMMS), the authors observed that students underrepresented in science and medicine were persistently underrepresented among those selected for AΩA. They describe efforts at ISMMS to reduce bias in the selection process and the ultimate decision to suspend medical student selection for AΩA altogether. The authors argue that selection to AΩA reinforces the structural biases and social privilege that are embedded in medical education and undermines the ability to deliver an educational experience that has as its core tenets equity and wellness. Suspending participation in student selection for AΩA is an important step toward recognizing that medical school learning environments continue to privilege white students over students who are underrepresented in medicine.

HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice.

Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. This underlines the need of new therapeutic approaches to improve cognition in treated schizophrenia patients. Our previous findings suggested that upregulation of histone deacetylase 2 (HDAC2) expression upon chronic antipsychotic treatment may lead to negative effects on cognition and cortical synaptic structure. Here we tested different phenotypes of psychosis, synaptic plasticity, cognition and antipsychotic drug action in HDAC2 conditional knockout (HDAC2-cKO) mice and controls. Conditional depletion of HDAC2 function in glutamatergic pyramidal neurons led to a protective phenotype against behavior models induced by psychedelic and dissociative drugs, such as DOI and MK801, respectively. Immunoreactivity toward synaptophysin, which labels presynaptic terminals of functional synapses, was decreased in the frontal cortex of control mice chronically treated with clozapine - an opposite effect occurred in HDAC2-cKO mice. Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients.

Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.

Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice.

The heteromeric receptor complex between 5-HT2A and mGlu2 has been implicated in some of the behavioral phenotypes in mouse models of psychosis(1,2). Consequently, investigation of structural details of the interaction between 5-HT2A and mGlu2 affecting schizophrenia-related behaviors represents a powerful translational tool. As previously shown, the head-twitch response (HTR) in mice is elicited by hallucinogenic drugs and this behavioral response is absent in 5-HT2A knockout (KO) mice(3,4). Additionally, by conditionally expressing the 5-HT2A receptor only in cortex, it was demonstrated that 5-HT2A receptor-dependent signaling pathways on cortical pyramidal neurons are sufficient to elicit head-twitch behavior in response to hallucinogenic drugs(3). Finally, it has been shown that the head-twitch behavioral response induced by the hallucinogens DOI and lysergic acid diethylamide (LSD) is significantly decreased in mGlu2-KO mice(5). These findings suggest that mGlu2 is at least in part necessary for the 5-HT2A receptor-dependent psychosis-like behavioral effects induced by LSD-like drugs. However, this does not provide evidence as to whether the 5-HT2A-mGlu2 receptor complex is necessary for this behavioral phenotype. To address this question, herpes simplex virus (HSV) constructs to express either mGlu2 or mGlu2ΔTM4N (mGlu2/mGlu3 chimeric construct that does not form the 5-HT2A-mGlu2 receptor complex) in the frontal cortex of mGlu2-KO mice were used to examine whether this GPCR heteromeric complex is needed for the behavioral effects induced by LSD-like drugs(6).

Neurosurgical Skills Assessment: Measuring Technical Proficiency in Neurosurgery Residents Through Intraoperative Video Evaluations.

OBJECTIVES: Although technical skills are fundamental in neurosurgery, there is little agreement on how to describe, measure, or compare skills among surgeons. The primary goal of this study was to develop a quantitative grading scale for technical surgical performance that distinguishes operator skill when graded by domain experts (residents, attendings, and nonsurgeons). Scores provided by raters should be highly reliable with respect to scores from other observers. METHODS: Neurosurgery residents were fitted with a head-mounted video camera while performing craniotomies under attending supervision. Seven videos, 1 from each postgraduate year (PGY) level (1-7), were anonymized and scored by 16 attendings, 8 residents, and 7 nonsurgeons using a grading scale. Seven skills were graded: incision, efficiency of instrument use, cauterization, tissue handling, drilling/craniotomy, confidence, and training level. RESULTS: A strong correlation was found between skills score and PGY year (P < 0.001, analysis of variance). Junior residents (PGY 1-3) had significantly lower scores than did senior residents (PGY 4-7, P < 0.001, t test). Significant variation among junior residents was observed, and senior residents' scores were not significantly different from one another. Interrater reliability, measured against other observers, was high (r = 0.581 ± 0.245, Spearman), as was assessment of resident training level (r = 0.583 ± 0.278, Spearman). Both variables were strongly correlated (r = 0.90, Pearson). Attendings, residents, and nonsurgeons did not score differently (P = 0.46, analysis of variance). CONCLUSIONS: Technical skills of neurosurgery residents recorded during craniotomy can be measured with high interrater reliability. Surgeons and nonsurgeons alike readily distinguish different skill levels. This type of assessment could be used to coach residents, to track performance over time, and potentially to compare skill levels. Developing an objective tool to evaluate surgical performance would be useful in several areas of neurosurgery education.

Operator experience determines performance in a simulated computer-based brain tumor resection task.

PURPOSE: Develop measures to differentiate between experienced and inexperienced neurosurgeons in a virtual reality brain surgery simulator environment. METHODS: Medical students (n = 71) and neurosurgery residents (n = 12) completed four simulated Glioblastoma multiforme resections. Simulated surgeries took place over four days with intermittent spacing in between (average time between surgeries of 4.77 ± 0.73 days). The volume of tumor removed (cc), volume of healthy brain removed (cc), and instrument path length (mm) were recorded. Additionally, surgical effectiveness (% tumor removed divided by % healthy brain removed) and efficiency (% tumor removed divided by instrument movement in mm) were calculated. Performance was compared (1) between groups, and (2) for each participant over time to assess the learning curve. In addition, the effect of real-time instruction ("coaching") was assessed with a randomly selected group of medical students. RESULTS: Neurosurgery residents removed less healthy brain, were more effective in removing tumor and sparing healthy brain tissue, required less instrument movement, and were more efficient in removing tumor tissue than medical students. Medical students approached the resident level of performance over serial sessions. Coached medical students showed more conservative surgical behavior, removing both less tumor and less healthy brain. In sum, neurosurgery residents removed more tumor, removed less healthy brain, and required less instrument movement than medical students. Coaching modified medical student performance. CONCLUSIONS: Virtual Reality brain surgery can differentiate operators based on both recent and long-term experience and may be useful in the acquisition and assessment of neurosurgical skills. Coaching alters the learning curve of naïve inexperienced individuals.

Epigenetic Mechanisms of Serotonin Signaling.

Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression.

G protein-coupled receptor heterocomplexes in neuropsychiatric disorders.

G protein-coupled receptors (or GPCRs) represent the largest family of membrane proteins in the human genome and are the target of approximately half of all therapeutic drugs. GPCRs contain a conserved structure of seven transmembrane domains. Their amino terminus is located extracellularly, whereas the carboxy terminus extends into the cytoplasm. Accumulating evidence suggests that GPCRs exist and function as monomeric entities. Nevertheless, more recent findings indicate that GPCRs can also form dimers or even higher order oligomers. The differential pharmacological and signaling properties of GPCR heteromeric complexes hint that their physiological effects may be different as compared to those obtained in tissue cultures that express a particular GPCR. In this chapter, we review current data on the role of GPCR heteromerization in receptor signaling, as well as its potential implication in neuropsychiatric disorders such as schizophrenia, depression, and Parkinson's disease.

Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice.

Serotonin 5-HT(2A) and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT(2A)-KO mice. Disruption of 5-HT(2A) receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT(2A) receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT(2A)-KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT(2A) receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.

Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice.

Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD.

Prenatal stress induces schizophrenia-like alterations of serotonin 2A and metabotropic glutamate 2 receptors in the adult offspring: role of maternal immune system.

It has been suggested that severe adverse life events during pregnancy increase the risk of schizophrenia in the offspring. The serotonin 5-HT(2A) and the metabotropic glutamate 2 (mGlu2) receptors both have been the target of considerable attention regarding schizophrenia and antipsychotic drug development. We tested the effects of maternal variable stress during pregnancy on expression and behavioral function of these two receptors in mice. Prenatal stress increased 5-HT(2A) and decreased mGlu2 expression in frontal cortex, a brain region involved in perception, cognition, and mood. This pattern of expression of 5-HT(2A) and mGlu2 receptors was consistent with behavioral alterations, including increased head-twitch response to the hallucinogenic 5-HT(2A) agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] and decreased mGlu2-dependent antipsychotic-like effect of the mGlu2/3 agonist LY379268 (1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate) in adult, but not prepubertal, mice born to stressed mothers during pregnancy. Cross-fostering studies determined that these alterations were not attributable to effects of prenatal stress on maternal care. Additionally, a similar pattern of biochemical and behavioral changes were observed in mice born to mothers injected with polyinosinic:polycytidylic acid [poly(I:C)] during pregnancy as a model of prenatal immune activation. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for schizophrenia and other psychiatric disorders.

Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice.

RATIONALE: In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. OBJECTIVE: This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. METHOD: Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. RESULTS: Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). CONCLUSION: Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects.

Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function.

Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here, we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-hydroxytryptamine 2A (5-HT(2A)) receptor in the mouse frontal cortex. Substitution of these residues (Ala-677(4.40), Ala-681(4.44), and Ala-685(4.48)) leads to absence of 5-HT(2A)·mGlu2 receptor complex formation, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT(2A) agonists. Furthermore, the ligand binding interaction between the components of the 5-HT(2A)·mGlu2 receptor heterocomplex is up-regulated in the frontal cortex of schizophrenic subjects as compared with controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer.

HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity.

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT(2A) receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.

Different dorsal striatum circuits mediate action discrimination and action generalization.

Generalization is an important process that allows animals to extract rules from regularities of past experience and apply them to analogous situations. In particular, the generalization of previously learned actions to novel instruments allows animals to use past experience to act faster and more efficiently in an ever-changing environment. However, generalization of actions to a dissimilar instrument or situation may also be detrimental. In this study, we investigated the neural bases of action generalization and discrimination in mice trained on a lever-pressing task. Using specific schedules of reinforcement known to bias animals towards habitual or goal-directed behaviors, we confirmed that action generalization is more prominent in animals using habitual rather than goal-directed strategies. We discovered that selective excitotoxic lesions of the dorsolateral and dorsomedial striatum have opposite effects on the generalization of a previously learned action to a novel lever. Whereas lesions of the dorsolateral striatum impair action generalization, dorsomedial striatum lesions affect action discrimination and bias subjects towards action generalization. Importantly, these lesions do not affect the ability of animals to explore or match their lever-pressing rate to the reinforcement rate, or the ability to distinguish between different levers. The data presented here reveal that dorsolateral and dorsomedial striatal circuits have opposing roles in the generalization of previously learned actions to novel instruments, and suggest that these circuits compete for the expression of generalization in novel situations.