Trans-omic profiling uncovers molecular controls of early human cerebral organoid formation.

Defining the molecular networks orchestrating human brain formation is crucial for understanding neurodevelopment and neurological disorders. Challenges in acquiring early brain tissue have incentivized the use of three-dimensional human pluripotent stem cell (hPSC)-derived neural organoids to recapitulate neurodevelopment. To elucidate the molecular programs that drive this highly dynamic process, here, we generate a comprehensive trans-omic map of the phosphoproteome, proteome, and transcriptome of the exit of pluripotency and neural differentiation toward human cerebral organoids (hCOs). These data reveal key phospho-signaling events and their convergence on transcriptional factors to regulate hCO formation. Comparative analysis with developing human and mouse embryos demonstrates the fidelity of our hCOs in modeling embryonic brain development. Finally, we demonstrate that biochemical modulation of AKT signaling can control hCO differentiation. Together, our data provide a comprehensive resource to study molecular controls in human embryonic brain development and provide a guide for the future development of hCO differentiation protocols.

Training Psychology and Psychiatry Diversity Dialogue Facilitators.

This article describes a Diversity Dialogue Facilitator Training Program for Trainees, an innovative project that prepares psychology and psychiatry learners to facilitate diversity dialogues with healthcare professionals (i.e., clinical and research faculty, staff, and learners) in academic healthcare settings. Through participating in this program, trainees learn to facilitate discussions in which participants reflect upon oppression, discrimination, and disparities; explore their biases; connect and exchange views with colleagues regarding challenging societal events; and delineate action steps for advancing equity, inclusion, social responsivity, and justice in their professional and personal lives. After outlining contextual factors that informed project development, implementation, and dissemination, the iterative process of creating and implementing the training curriculum is detailed, with the aim of offering a model for other academic health center-based training programs interested in establishing a similar initiative. Lessons learned also are shared with the hope of contributing to future efforts to advance training in diversity dialogue facilitation and expand the role of psychologists in medical settings.

Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms.

BACKGROUND: The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. OBJECTIVES: Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. METHODS: Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. RESULTS: We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. CONCLUSIONS: Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

In situ proximity labeling identifies Lewy pathology molecular interactions in the human brain.

The intracellular misfolding and accumulation of alpha-synuclein into structures collectively called Lewy pathology (LP) is a central phenomenon for the pathogenesis of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Understanding the molecular architecture of LP is crucial for understanding synucleinopathy disease origins and progression. Here we used a technique called biotinylation by antibody recognition (BAR) to label total (BAR-SYN1) and pathological alpha-synuclein (BAR-PSER129) in situ for subsequent mass spectrometry analysis. Results showed superior immunohistochemical detection of LP following the BAR-PSER129 protocol, particularly for fibers and punctate pathology within the striatum and cortex. Mass spectrometry analysis of BAR-PSER129-labeled LP identified 261 significantly enriched proteins in the synucleinopathy brain when compared to nonsynucleinopathy brains. In contrast, BAR-SYN1 did not differentiate between disease and nonsynucleinopathy brains. Pathway analysis of BAR-PSER129-enriched proteins revealed enrichment for 718 pathways; notably, the most significant KEGG pathway was PD, and Gene Ontology (GO) cellular compartments were the vesicle, extracellular vesicle, extracellular exosome, and extracellular organelle. Pathway clustering revealed several superpathways, including metabolism, mitochondria, lysosome, and intracellular vesicle transport. Validation of the BAR-PSER129-identified protein hemoglobin beta (HBB) by immunohistochemistry confirmed the interaction of HBB with PSER129 Lewy neurites and Lewy bodies. In summary, BAR can be used to enrich for LP from formalin-fixed human primary tissues, which allowed the determination of molecular signatures of LP. This technique has broad potential to help understand the phenomenon of LP in primary human tissue and animal models.

Antiracist Practice in Psychiatry: Principles and Recommendations.

The COVID-19 pandemic has amplified mental health disparities among people of color, particularly for Black, Latinx, and American Indian populations. In addition to experiencing overt hostility and systemic injustice, people from marginalized racial-ethnic groups experience prejudice and bias from clinicians that has disrupted rapport and trust in mental health systems; these experiences, in turn, have deepened these health disparities. In this article, the authors describe factors that have served to perpetuate mental health disparities and outline key components of antiracist practice in psychiatry (and in mental health practice, more generally). With lessons learned in recent years, this article presents practical ways to incorporate antiracist practices into clinical care.

Promoting resilience in persons with serious mental health conditions during the Coronavirus pandemic.

This article highlights the profound and far-reaching impact of the Coronavirus disease 2019 (COVID-19) health crisis on persons with serious mental health conditions. To understand and mitigate against the negative effects of the crisis on this population, we offer a resilience intervention framework that attends to three key resilience processes, namely control, coherence, and connectedness (3Cs). We then detail interventions and associated evidence-informed intervention strategies at the individual, interpersonal, and systemic levels that behavioral health professionals can employ to bolster each of the 3Cs for persons with serious mental health conditions. These intervention strategies, which must be implemented in a flexible manner, are designed to enhance the biopsychosocial functioning of persons with serious mental health conditions during the COVID-19 pandemic and beyond and strengthen their interpersonal and systemic environments. We conclude with recommendations for future directions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Integrating Diversity, Equity, and Inclusion Into an Academic Department of Psychiatry and Behavioral Sciences.

This article highlights one department's efforts to bolster diversity, equity, and inclusion as an exemplar for other academic departments. It offers an approach for building an infrastructure and leadership group and details accomplishments associated with strategic plan priorities related to visibility, values, stakeholder education, recruitment, retention, promotion, and community engagement. It also delineates challenges encountered in transforming a departmental culture to one that is more diverse, equitable, and inclusive and strategies for overcoming these challenges. Finally, it discusses next steps and recommendations for other academic departments.

Epigenetic inactivation of the autophagy-lysosomal system in appendix in Parkinson's disease.

The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson's disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD.

Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology.

Tau pathology in Alzheimer's disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The 'early' AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

Implementing Coordinated Specialty Care for First Episode Psychosis: A Review of Barriers and Solutions.

Specialized early interventions (SEI) for individuals diagnosed with a first episode of psychosis (FEP) are effective treatment modalities (Azrin et al. in Psychiatr Ann 45(11):548, https://doi.org/10.3928/00485713-20151103-05 , 2015). SEI offered immediately or shortly following a first episode improves functional and clinical outcomes for those individuals with, and at risk for, serious mental illness (SMI; Correll et al. in JAMA Psychiatry 75(6):555-565, https://doi.org/10.1001/jamapsychiatry.2018.0623 , 2018). In the United States, SEI programs referred to as Coordinated Specialty Care (CSC), have been utilized to provide a beneficial, team-based, multi-component method of treating FEP. However, despite the success, CSC programming is still met with considerable challenges. This article reviews existing CSC literature to identify and explore relevant barriers to successful implementation of CSC. Identified barriers include stigma, cultural competence, disengagement, measurement and evaluation, workforce development, implementation in rural areas, and financial stability. The ongoing efforts to address these barriers are described and areas for continued improvements are discussed.

Epigenomic analysis of Parkinson's disease neurons identifies Tet2 loss as neuroprotective.

Parkinson's disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover, Tet2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. Tet2 loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.

Flattening the emotional distress curve: A behavioral health pandemic response strategy for COVID-19.

This article proposes a framework for managing the behavioral health impacts of the COVID-19 global pandemic. This framework aligns and should be integrated with an existing public health pandemic intervals model. It includes six phases of a behavioral health pandemic response strategy: preplanning, response readiness, response mobilization, intervention, continuation, and amelioration. The ways behavioral health specialists can capitalize on their competence in the leadership, prevention, education, service, research, and advocacy domains within each behavioral health pandemic response phase are articulated. Behavioral health expertise can help ensure a more comprehensive, effective pandemic response that facilitates the flattening of the curve of disease spread, along with the corresponding emotional distress curve. A case illustration, the Caring Communities (CC) initiative, is offered as an exemplar of action steps in the leadership, prevention, education, service, research, and advocacy domains that behavioral health professionals can take within each of the behavioral health pandemic response phases. Key CC action steps include providing support groups, offering virtual wellness breaks, participating in educational outreach, creating and disseminating wellness guides, launching and leading a virtual behavioral health clinic for health care staff, participating in behavioral health research and program evaluation, and engaging in advocacy initiatives aimed at improving behavioral health care and addressing and reducing health disparities. Finally, recommendations for optimizing behavioral health contributions to future pandemic responses are proffered. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Hemispheric asymmetry in the human brain and in Parkinson's disease is linked to divergent epigenetic patterns in neurons.

BACKGROUND: Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson's disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. RESULTS: We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. CONCLUSIONS: Hemispheric differences in DNA methylation patterns are prevalent in neurons and may affect the progression and symptoms of PD.

Social justice advocacy in mental health services: Consumer, community, training, and policy perspectives.

This article addresses important aspects of and strategies for social justice advocacy in mental health care across consumer, community, educational, and policy domains. Social justice advocacy is intentional and sustained action intended to influence public policy outcomes, with and/or on behalf of a vulnerable individual, group, community, or the public at large. The paper presents a series of policy and advocacy levels of change, which may be used to promote social justice among individuals with mental health disorders with an emphasis on how psychologists can be valuable in these efforts. These social justice advocacy approaches are presented in a 3-level bio/socioecological framework at the micro, meso, and macro levels based on Bronfenbrenner's theoretical model. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.

Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.

Epigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer's disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.

Parkinson's disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration.

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein-positive neuropathology in aged VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossing VPS35 KI and null mice, our data demonstrate that a single D620N VPS35 allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.

Reluctant entrepreneurs: musicians and entrepreneurship in the 'new' music industry.

Changing labour conditions in the creative industries - with celebrations of autonomy and entrepreneurialism intertwined with increasing job insecurity, portfolio careers and short-term, project-based contracts - are often interpreted as heralding changes to employment relations more broadly. The position of musicians' labour in relation to these changes is unclear, however, given that these kinds of conditions have defined musicians' working practices over much longer periods of time (though they may have intensified due to well-documented changes to the music industry brought about by digitization and disintermediation). Musicians may thus be something of a barometer of current trends, as implied in the way that the musically derived label 'gig economy' is being used to describe the spread of precarious working conditions to broader sections of the population. This article, drawing on original qualitative research that investigated the working practices of musicians, explores one specific aspect of these conditions: whether musicians are self-consciously entrepreneurial towards their work and audience. We found that, while the musicians in our study are routinely involved in activities that could be construed as entrepreneurial, generally they were reluctant to label themselves as entrepreneurs. In part this reflected understandings of entrepreneurialism as driven by profit-seeking but it also reflected awareness that being a popular musician has always involved business and commercial dimensions. Drawing on theoretical conceptions of entrepreneurship developed by Joseph Schumpeter we highlight how the figure of the entrepreneur and the artist/musician share much in common and reflect various aspects of romantic individualism. Despite this, there are also some notable differences and we conclude that framing musicians' labour as entrepreneurial misrepresents their activities through an overemphasis on the economic dimensions of their work at the expense of the cultural.