BACKGROUND:Dynamical systems theory (DST) has recently gained traction as a framework to describe and predict the progression of psychopathology. However, a number of challenges to the application of DST to psychopathology have arisen, including the heterogeneity of symptom measures and the lack of theoretical underpinnings to describe the temporal unfolding of psychiatric illnesses. SUMMARY:In this article, we aim to show how the integration of methods from phenomenology may strengthen the application of DST in psychopathology research. We explore how phenomenological psychopathology can improve DST-based investigations in two key ways: (1) by specifying the core symptoms of interest in psychopathological states in a more precise manner by focusing on subjective experiences, and (2) by deepening our theoretical understanding of how these symptoms evolve in severity over time. We show how incorporating phenomenologically informed measures of experience can complement DST using clinical high risk (CHR) for psychosis as a test case, and we demonstrate the utility of combining phenomenologically informed theory and DST by examining the ipseity-disturbance model (IDM) of psychosis development. We close by offering a vision for the broader integration of DST and phenomenological research methods within psychopathological research. KEY MESSAGES:Phenomenological investigations can synergize with and advance the use of DST to better understand and predict psychiatric disorders and transitions in states of mental health.

Current approaches for surveying whole brains for neurons activated during a particular state typically rely on immediate early gene (IEG) expression. However, IEG expression is variable across subjects and brain areas, demanding large sample sizes. Further, it cannot determine if the same or different neurons respond to two events. To overcome these issues, we present a whole-brain screening method utilizing transgenic mice to label neurons activated at two timepoints. An imaging and analysis pipeline surveys activity in ~500 brain areas in different conditions. Compared to IEG methods, this approach reduces required sample sizes and enhances sensitivity and specificity. Finally, graph theoretical analyses are utilized to identify key circuit nodes - brain areas whose activity correlates with activity in other areas in a state-dependent manner. We validate this method by surveying whole-brain activity during hunger and satiety, and by investigating neural circuits activated by the GLP1 agonist semaglutide used to treat obesity. ### Competing Interest Statement The authors have declared no competing interest.

Philosophy of mind has made substantial progress on biologically-rooted approaches to understanding the mind and subjectivity through the enactivist perspective, but research on subjectivity within neuroscience has not kept apace. Indeed, we possess no principled means of relating experiential phenomena to neurophysiological processes. Here, we present the Nested States Model as a framework to guide empirical investigation into the relationship between subjectivity and neurobiology. Building on recent work in phenomenology and philosophy of mind, we develop an account of experiential states as layered, or nested. We argue that this nested structure is also apparent in brain activity. The recognition of this structural homology — that both experiential and brain states can be characterized as systems of nested states — brings our views of subjective mental states into broad alignment with our understanding of general principles and properties of brain activity. This alignment enables a more systematic approach to formulating specific hypotheses and predictions about how the two domains relate to one another.

Background: Subjective experience is central to the nature of mental illness, yet it has not played a central role in most empirical approaches to psychopathology. While phenomenological perspectives in psychiatry have seen a recent resurgence, there remains a need for more detailed models of psychopathological processes based on explicit phenomenological and enactive foundations. Summary: We present a framework derived from the Nested States Model (NSM) through which such phenomenologically-grounded models might be constructed. The NSM describes the dynamic structure of subjective experience as a system of nested states that reciprocally influence one another across hierarchical layers. Here, we show how the NSM provides a scheme for characterizing patterns of experience that comprise various psychopathological processes. We demonstrate the utility of this scheme both for clinical practice and for building our knowledge of psychopathological processes more broadly. Key Messages: The NSM can advance three aims that we see as critical for the lasting integration of phenomenological approaches to psychopathology within psychiatry. First, we show that the NSM provides a means for constructing clinical formulations and treatment considerations that center squarely on an individual’s subjective experiences. Second, the NSM supplies a framework for organizing findings from clinical-phenomenological research that can guide the construction of broader phenomenologically-grounded models of psychopathological processes. Lastly, the NSM aligns our perspective on subjective experience with emerging perspectives on brain dynamics, helping to bridge phenomenological work with ongoing neurophysiological research.

Opioid use disorder (OUD) and overdose deaths are a public health crisis. One contributing factor is stigma towards people who use opioids. We developed and conducted a public-facing, half-day educational event designed to challenge misperceptions about OUD from a contemporary neuroscience perspective. Participants engaged with three different resources on the neurobiology of addiction, and, at the end of the event, they rated its effectiveness. We also collected and compared pre- and post-event composite OUD stigma scales. Participants rated our approach and the overall event as highly effective. Additionally, OUD stigma scores were lower immediately following the event, and this decrease was primarily driven by decreased internalized stigma. Here, we demonstrate an effective proof-of-concept that an accessible, public-facing, neuroscience education event may reduce OUD stigma in the community.

For years, advocates had worked toward this moment. On November 30, 2021, the nation’s first medically supervised drug injection facility (officially “overdose prevention center”) opened in New York City. The public response—even in a bastion of progressive politics—was surprisingly negative. Opponents claimed that the centers would encourage drug use and moral decay. Why help people who are willfully making bad choices? Why waste public resources, especially when a much larger pandemic loomed?

Adolescent binge drinking is a major risk factor for psychiatric disorders later in life including alcohol use disorder. Adolescent alcohol exposure induces epigenetic reprogramming at the enhancer region of the activity-regulated cytoskeleton-associated protein (Arc) immediate-early gene, known as synaptic activity response element (SARE), and decreases Arc expression in the amygdala of both rodents and humans. The causal role of amygdalar epigenomic regulation at Arc SARE in adult anxiety and drinking after adolescent alcohol exposure is unknown. Here, we show that dCas9-P300 increases histone acetylation at the Arc SARE and normalizes deficits in Arc expression, leading to attenuation of adult anxiety and excessive alcohol drinking in a rat model of adolescent alcohol exposure. Conversely, dCas9-KRAB increases repressive histone methylation at the Arc SARE, decreases Arc expression, and produces anxiety and alcohol drinking in control rats. These results demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure.

Nearly all psychiatric diseases involve alterations in subjective, lived experience. The scientific study of the biological basis of mental illness has generally focused on objective measures and observable behaviors, limiting the potential for our understanding of brain mechanisms of disease states and possible treatments. However, applying methods designed principally to interpret objective behavioral measures to the measurement and extrapolation of subjective states presents a number of challenges. In order to help bridge this gap, we draw on the tradition of phenomenology, a philosophical movement concerned with elucidating the structure of lived experience, which emerged in the early 20th century and influenced philosophy of mind, cognitive science, and psychiatry. A number of early phenomenologically-oriented psychiatrists made influential contributions to the field, but this approach retreated to the background as psychiatry moved towards more operationalized disease classifications. Recently, clinical-phenomenological research and viewpoints have re-emerged in the field. We argue that the potential for phenomenological research and methods to generate productive hypotheses about the neurobiological basis of psychiatric diseases has thus far been underappreciated. Using specific examples drawing on the subjective experience of mania and psychosis, we demonstrate that phenomenologically-oriented clinical studies can generate novel and fruitful propositions for neuroscientific investigation. Additionally, we outline a proposal for more rigorously integrating phenomenological investigations of subjective experience with the methods of modern neuroscience research, advocating a cross-species approach with a key role for human subjects research. Collaborative interaction between phenomenology, psychiatry, and neuroscience has the potential to move these fields towards a unified understanding of the biological basis of mental illness.

Noncoding RNAs (ncRNAs) represent the majority of the transcriptome and play important roles in regulating neuronal functions. ncRNAs are exceptionally diverse in both structure and function and include enhancer RNAs, long ncRNAs, and microRNAs, all of which demonstrate specific temporal and regional expression in the brain. Here, we review recent studies demonstrating that ncRNAs modulate chromatin structure, act as chaperone molecules, and contribute to synaptic remodeling and behavior. In addition, we discuss ncRNA function within the context of neuropsychiatric diseases, particularly focusing on addiction and schizophrenia, and the recent methodological developments that allow for better understanding of ncRNA function in the brain. Overall, ncRNAs represent an underrecognized molecular contributor to complex neuronal processes underlying neuropsychiatric disorders.

The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.

A developing finding from the novel coronavirus 2019 (COVID-19) pandemic is the burden of neuropsychiatric symptoms seen in COVID-19 survivors. While studies have shown clinically significant rates of depression, anxiety, insomnia, and trauma-related symptoms such as post-traumatic stress disorder (PTSD) after COVID-19, little is known about how these symptoms evolve over time. Here, we report findings from a cohort study of 52 participants recruited from the greater New York City area following acute COVID-19 infection. Participants completed the Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms, the Generalized Anxiety Disorder-7 (GAD-7) for anxiety-related symptoms, the Insomnia Severity Scale (ISS) for sleep-related symp-toms, and the PTSD Checklist-Civilian version (PCL-C) for trauma-related symptoms both at baseline and at long-term (24-60 weeks post-infection) follow-up. We found a high degree of correlation between psychiatric symptom scales within participants. More participants met established cutoffs for clinically significant insomnia and post-traumatic stress at follow-up compared to baseline. Symptom scales for depression, insomnia, and PTSD were increased at long-term follow-up, with only increased PCL-C scores surviving correction for multiple comparisons (Z = 2.92, W = 434, p = 0.004). Our results present evidence from a small cohort that neuropsychiatric symptoms, particularly those related to PTSD, may worsen over time in COVID-19 survivors. Future studies should continue to investigate these questions in broader populations, while addi-tionally exploring the potential biological and sociological mechanisms that may contribute to neuropsychi-atric pathology after COVID-19 infection.

EpigenomicsVol. 12, No. 11 EditorialOpen AccessEpigenetic regulation of enhancer RNAs in neuropsychiatric disease and addictionEvan J Kyzar & Subhash C PandeyEvan J Kyzar https://orcid.org/0000-0002-7688-0281Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USAJesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA & Subhash C Pandey *Author for correspondence: Tel.: 312 413 1310; Fax: 312 996 7658; E-mail Address: scpandey@uic.eduhttps://orcid.org/0000-0001-7139-8464Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USAJesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USADepartment of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USAPublished Online:13 Aug 2020https://doi.org/10.2217/epi-2020-0135AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Keywords: addictionalcoholenhancer RNAepigeneticsnon-coding RNAGenomic regulation is extremely complex and is regulated by both intracellular signaling mechanisms and the extracellular environment. Cis-regulatory elements known as enhancers regulate the expression of specific target genes and are crucial for normal development and cellular functions [1]. Interestingly, some enhancers are actively transcribed, producing non-coding RNAs (ncRNA) known as enhancer RNAs (eRNAs) [1,2]. These eRNAs are regulated by epigenetic mechanisms and have been shown to interact with other regulatory proteins including transcriptional machinery at promoters and to promote chromatin looping to refine robust control of gene expression mechanisms [1,3].In 2010, Kim et al. [2] made the groundbreaking discovery that eRNAs are transcribed bidirectionally from cis-regulatory enhancer regions. Enhancer sites are crucial regulators of gene expression in development and in adult tissue, coordinating cell-type specificity and transcriptional programs [4]. Many of these eRNAs are transcribed in response to neuronal depolarization, indicating that they might play a role in crucial activity-dependent regulatory activities. Further analysis showed that active enhancers enriched in H3K27ac are much more likely to be transcribed by RNA Pol II than inactive or poised enhancers enriched in H3K27me3 [2]. Most eRNAs are uncapped and therefore subject to rapid turnover within the nucleus [5]. Additionally, members of the CREB protein family including CBP and p300 appear to coordinate cellular transcriptional responses at eRNA sites [2,4,6].Early work on eRNA biogenesis and function has revealed that eRNAs are regionally specific within the brain in a manner that likely also extends to cell-type specificity [7]. Interestingly, many eRNAs are located near or within IEGs including Arc, Fos (which encodes the cFos protein), Gadd45b and neuronal Npas4 and are rapidly transcribed in response to neuronal activity [2,8–10]. These genes coordinate the activity-dependent epigenetic changes via their actions as chromatin modifiers and transcription factors, thus facilitating activity-dependent synaptic plasticity and behaviors including learning and complex emotional expression. Notably, eRNA transcription precedes mRNA transcription at activity-dependent IEGs [2,8,9], suggesting that eRNAs may play a role in activating and/or maintaining IEG expression in response to environmental stimuli.Upon their discovery, many questions arose regarding eRNA function. Among the most pressing was whether eRNAs are functional molecular entities or simply byproducts of promiscuous Pol II binding in response to increased levels of cellular or neuronal activity. Mechanistic studies began to shed light in this direction by showing that some eRNAs interact with the local chromatin environment to facilitate expression of target mRNAs. For example, the Arc eRNA is encoded from a SARE site located approximately 7 kilobases upstream of the Arc mRNA transcription start site and robustly responds to neuronal depolarization via a CREB response element [9]. Arc eRNA transcriptional activity is associated with enhancer–promoter looping, bringing the SARE site in closer proximity to the Arc transcription start site. Arc eRNA binds to a nonspecific RNA recognition motif within the NELF protein, which normally serves to inhibit elongation of Pol II [9]. The eRNA-bound NELF undergoes a conformational change, leading to the disinhibition of Pol II and subsequent transcription of Arc mRNA [9]. This work was critical, as it showed that the Arc eRNA indeed has a functional role apart from merely being a byproduct of widespread transcription.Recent work from the Pandey lab aimed to determine the contribution of the Arc eRNA to the lasting deficits seen in the amygdala of adult rats after adolescent alcohol exposure, representing one of the first explorations of eRNAs in animal models of neuropsychiatric disease [11]. Adolescence is a critical period in the development of addiction and other psychiatric conditions, as gene expression programs in the brain continue to change and inform adolescent-typical behaviors such as binge drinking. Repeated binge alcohol exposure leads to increased risk for alcohol use disorder (AUD) and negative affective states including anxiety disorders in adulthood, and animal models have recapitulated these behavioral phenotypes and repeatedly shown that chromatin architecture in the amygdala is altered by adolescent alcohol exposure [11,12].This work has demonstrated that adolescent alcohol exposure leads to decreased expression of Arc eRNA in the adult amygdala. The decrease in Arc eRNA transcription is mediated by decreased KDM6B occupancy of the SARE site and subsequent increased H3K27me3 deposition and decreased H3K27ac occupancy [11]. Importantly, it was shown that the NELF disinhibition of Arc mRNA transcription by Arc eRNA originally shown in neuronal culture [9] appears to also be operative in the rat amygdala [11]. Studies in the human postmortem amygdala found that increased H3K27me3 and enhancer of EZH2, and decreased H3K27ac at the SARE site of the ARC gene, are associated with decreased ARC mRNA expression in early-onset AUD patients [13]. Additionally, inhibition of Kdm6b or direct knockdown of the negative strand of Arc eRNA in the central nucleus of amygdala leads to anxiety-like behaviors, thus mimicking the phenotype observed in adult rats previously exposed to adolescent alcohol [11]. This was the first study that successfully modified behavioral phenotypes by direct inhibition of an eRNA transcript in vivo in brain [11].Aside from Arc eRNA, the eRNAs surrounding the Fos gene are some of the most well-studied, particularly in the brain. The Fos locus contains five distinct eRNAs that are stimulus-specific, meaning that distinct subsets of eRNAs are transcribed in response to neuronal depolarization, BDNF treatment and cAMP induction via forskolin [8]. Similar to Arc, the Fos eRNAs show an association between expression levels and enhancer–promoter proximity. Additionally, the stimulus-specificity of Fos eRNAs is at least partially dependent on transcription factors including CREB and NPAS4 [8]. A more recent study showed that bidirectional epigenetic regulation by CRISPR activation (dCas9-p300) or inhibition (dCas9-HDAC8) altered H3K27ac-associated chromatin dynamics at the Fos e2 eRNA locus, also known as Fos enhancer 2. Increased H3K27ac at this enhancer site facilitated Fos mRNA expression and neuronal burst-firing dynamics [10]. Increased activity at Fos e2 eRNA recruits BRD4 to the chromatin leading to Pol II-mediated transcriptional elongation of Fos mRNA [10]. Aside from furthering the knowledge of eRNA-mediated transcriptional mechanisms in neurons, this work involving well-studied IEGs evokes interesting questions regarding the role of eRNAs and their interaction with chromatin dynamics in the brain in both baseline and diseased states.Recent studies in animal models have confirmed that many of the in vitro findings translate into brain tissue while additionally linking eRNAs to behavior. First, induction of widespread neuronal activity in the hippocampus via kainic acid leads to marked activity-dependent eRNA transcription and alteration of enhancer–promoter looping [14]. Some of these alterations to chromatin architecture, particularly those involving the cFos-containing AP-1 transcription factor, persist long after induction of neuronal activity [14]. Secondly, response to a conditioned stimulus in motor learning tasks activates eRNA transcription and enhancer–promoter interactions in the cerebellar vermis [15]. Conditional CRISPR-mediated knockout of a core cohesin subunit, which serves to anchor enhancer–promoter loops, leads to loss of enhancer–promoter interactions and motor learning deficits [15].The perturbation of eRNAs in animal models begs the question of whether eRNAs are also involved in addiction and other neuropsychiatric disorders in humans. This is particularly relevant as the integration of genome-wide Hi-C data showing enhancer–promoter interactions with available Genome-Wide Association Studies data improves the predictive capacity for both psychiatric and neurodegenerative disorders [16]. For example, allelic variation at a conserved enhancer of the GAL gene is associated with increased alcohol intake and anxiety in humans, and CRISPR-mediated knockout of the Gal enhancer decreases alcohol consumption and anxiety-like behavior in male mice [17]. Analysis of differential DNA methylation at enhancer sites in the prefrontal cortex of Alzheimer disease patients revealed a hypomethylated enhancer cluster that appears to activate the BACE1 gene [18]. eRNAs transcribed in dopaminergic neurons in the human brain show an enrichment of genetic variants involved in schizophrenia, addiction and Parkinson's disease and this study further identified an eRNA on chromosome 17 regulated by Parkinson's disease-associated gene variation [19]. Lastly, a genome-wide study of prefrontal cortex from schizophrenia patients compared with controls revealed 118 differentially expressed eRNAs and allele-specific regulation of eRNA expression by known schizophrenia risk variants [20].Taken together, these studies demonstrate the importance of eRNAs in brain health and disease. However, the relative youth of these investigations mean that many questions remain to be answered [5]. What percentage of eRNAs are functional entities compared with those that may be transcriptional noise? Do eRNAs physically activate target gene transcription by chromatin looping, transcription factor binding, homotypic attraction, phase separation or some other unknown mechanism? What role does evolutionary selection play in tissue- and brain region-specific eRNA expression and function? Are eRNAs viable treatment targets or prognostic markers in neuropsychiatric diseases including AUD and other addictive disorders? The interactive role of chromatin dynamics with eRNAs [1,10,11] will likely be the subject of intense investigation in the coming years, as eRNA biology and its effects on brain function and behavior remain ripe for discovery.Financial & competing interest disclosureThis work was supported by National Institute on Alcohol Abuse and Alcoholism Grants UO1AA-019971, U24AA-024605 (Neurobiology of Adolescent Drinking in Adulthood [NADIA] project), RO1AA-010005, P50AA-022538 (Center for Alcohol Research in Epigenetics) and by the Department of Veterans Affairs (Merit Grant- I01 BX004517 and Senior Research Career Scientist Award) to SC Pandey, as well as a fellowship F30AA-024948 grant to EJ Kyzar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Calo E, Wysocka J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49(5), 825–837 (2013).Crossref, Medline, CAS, Google Scholar2. Kim TK, Hemberg M, Gray JM et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465(7295), 182–187 (2010).Crossref, Medline, CAS, Google Scholar3. Carullo NVN, Day JJ. Genomic enhancers in brain health and disease. Genes (Basel) 10(1), pii:E43 (2019).Crossref, Google Scholar4. 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Psychiatry 24(11), 1685–1695 (2019).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByEpigenetic regulations in neurological disordersCurrent and Future Perspectives of Noncoding RNAs in Brain Function and Neuropsychiatric DiseaseBiological Psychiatry, Vol. 91, No. 2 Vol. 12, No. 11 Follow us on social media for the latest updates Metrics History Received 5 April 2020 Accepted 16 April 2020 Published online 13 August 2020 Published in print June 2020 Information© 2020 Subhash C PandeyKeywordsaddictionalcoholenhancer RNAepigeneticsnon-coding RNAFinancial & competing interest disclosureThis work was supported by National Institute on Alcohol Abuse and Alcoholism Grants UO1AA-019971, U24AA-024605 (Neurobiology of Adolescent Drinking in Adulthood [NADIA] project), RO1AA-010005, P50AA-022538 (Center for Alcohol Research in Epigenetics) and by the Department of Veterans Affairs (Merit Grant- I01 BX004517 and Senior Research Career Scientist Award) to SC Pandey, as well as a fellowship F30AA-024948 grant to EJ Kyzar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download