Juneteenth in STEMM and the barriers to equitable science.

We are 52 Black scientists. Here, we establish the context of Juneteenth in STEMM and discuss the barriers Black scientists face, the struggles they endure, and the lack of recognition they receive. We review racism's history in science and provide institutional-level solutions to reduce the burdens on Black scientists.

Understanding the biological basis of psychiatric disease: What's next?

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?

Revising the a Priori Hypothesis: Systemic Racism Has Penetrated Scientific Funding.

To manifest our sincerest aspirations to "enhance health, lengthen life, and reduce illness and disability," the US biomedical research enterprise must directly confront the reality of structural racism in scientific funding and the widespread denial of its existence. I believe that moment in American history has, at long last, arrived.

For Black Scientists, the Sorrow Is Also Personal.

I have tried to live in a world that does not see color but have only succeeded in living in a world that does not see me.

Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability.

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.

Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

A Shared Vision for Machine Learning in Neuroscience.

With ever-increasing advancements in technology, neuroscientists are able to collect data in greater volumes and with finer resolution. The bottleneck in understanding how the brain works is consequently shifting away from the amount and type of data we can collect and toward what we actually do with the data. There has been a growing interest in leveraging this vast volume of data across levels of analysis, measurement techniques, and experimental paradigms to gain more insight into brain function. Such efforts are visible at an international scale, with the emergence of big data neuroscience initiatives, such as the BRAIN initiative (Bargmann et al., 2014), the Human Brain Project, the Human Connectome Project, and the National Institute of Mental Health's Research Domain Criteria initiative. With these large-scale projects, much thought has been given to data-sharing across groups (Poldrack and Gorgolewski, 2014; Sejnowski et al., 2014); however, even with such data-sharing initiatives, funding mechanisms, and infrastructure, there still exists the challenge of how to cohesively integrate all the data. At multiple stages and levels of neuroscience investigation, machine learning holds great promise as an addition to the arsenal of analysis tools for discovering how the brain works.

Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency.

Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood. Here we use chronic multicircuit neurophysiological recordings to characterize functional interactions across cortical and limbic circuits in mice engineered to express a human loss-of-function depression allele Tph2-(R441H) [Tph2 knockin (Tph2KI)]. Our results show that Tph2KI mice exhibit increased intra-network synchrony within medial prefrontal cortex (mPFC) and basal amygdala (AMY) and increased inter-network synchrony between these two brain networks. Moreover, we demonstrate that chronic treatment with fluoxetine reverses several of the circuit alterations observed within Tph2KI mice. Together, our findings establish a functional link between functional hyposerotonergia and altered mPFC-AMY network dynamics.

Cortical control of affective networks.

Transcranial magnetic stimulation and deep brain stimulation have emerged as therapeutic modalities for treatment refractory depression; however, little remains known regarding the circuitry that mediates the therapeutic effect of these approaches. Here we show that direct optogenetic stimulation of prefrontal cortex (PFC) descending projection neurons in mice engineered to express Chr2 in layer V pyramidal neurons (Thy1-Chr2 mice) models an antidepressant-like effect in mice subjected to a forced-swim test. Furthermore, we show that this PFC stimulation induces a long-lasting suppression of anxiety-like behavior (but not conditioned social avoidance) in socially stressed Thy1-Chr2 mice: an effect that is observed >10 d after the last stimulation. Finally, we use optogenetic stimulation and multicircuit recording techniques concurrently in Thy1-Chr2 mice to demonstrate that activation of cortical projection neurons entrains neural oscillatory activity and drives synchrony across limbic brain areas that regulate affect. Importantly, these neural oscillatory changes directly correlate with the temporally precise activation and suppression of limbic unit activity. Together, our findings show that the direct activation of cortical projection systems is sufficient to modulate activity across networks underlying affective regulation. They also suggest that optogenetic stimulation of cortical projection systems may serve as a viable therapeutic strategy for treating affective disorders.

Microglial MyD88-dependent pathways are regulated in a sex-specific manner in the context of HMGB1-induced anxiety.

Chronic stress is a significant risk factor for the development and recurrence of anxiety disorders. Chronic stress impacts the immune system, causing microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is an established modulator of neuronal firing and a potent pro-inflammatory stimulus released from neuronal and non-neuronal cells following stress. HMGB1, in the context of stress, acts as a danger-associated molecular pattern (DAMP), instigating robust proinflammatory responses throughout the brain, so much so that localized drug delivery of HMGB1 alters behavior in the absence of any other forms of stress, i.e., social isolation, or behavioral stress models. Few studies have investigated the molecular mechanisms that underlie HMGB1-associated behavioral effects in a cell-specific manner. The aim of this study is to investigate cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction with regard to cell-type specificity and potential sex differences. Here, we report that both male and female mice exhibited anxiety-like behavior following increased HMGB1 in the mPFC as well as changes in microglial morphology. Interestingly, our results demonstrate that HMGB1-induced anxiety may be mediated by distinct microglial MyD88-dependent mechanisms in females compared to males. This study supports the hypothesis that MyD88 signaling in microglia may be a crucial mediator of the stress response in adult female mice.

Electome network factors: Capturing emotional brain networks related to health and disease.

Therapeutic development for mental disorders has been slow despite the high worldwide prevalence of illness. Unfortunately, cellular and circuit insights into disease etiology have largely failed to generalize across individuals that carry the same diagnosis, reflecting an unmet need to identify convergent mechanisms that would facilitate optimal treatment. Here, we discuss how mesoscale networks can encode affect and other cognitive processes. These networks can be discovered through electrical functional connectome (electome) analysis, a method built upon explainable machine learning models for analyzing and interpreting mesoscale brain-wide signals in a behavioral context. We also outline best practices for identifying these generalizable, interpretable, and biologically relevant networks. Looking forward, translational electome analysis can span species and various moods, cognitive processes, or other brain states, supporting translational medicine. Thus, we argue that electome analysis provides potential translational biomarkers for developing next-generation therapeutics that exhibit high efficacy across heterogeneous disorders.

Ethical, legal, and policy challenges in field-based neuroimaging research using emerging portable MRI technologies: guidance for investigators and for oversight.

Researchers are rapidly developing and deploying highly portable MRI technology to conduct field-based research. The new technology will widen access to include new investigators in remote and unconventional settings and will facilitate greater inclusion of rural, economically disadvantaged, and historically underrepresented populations. To address the ethical, legal, and societal issues raised by highly accessible and portable MRI, an interdisciplinary Working Group (WG) engaged in a multi-year structured process of analysis and consensus building, informed by empirical research on the perspectives of experts and the general public. This article presents the WG's consensus recommendations. These recommendations address technology quality control, design and oversight of research, including safety of research participants and others in the scanning environment, engagement of diverse participants, therapeutic misconception, use of artificial intelligence algorithms to acquire and analyze MRI data, data privacy and security, return of results and managing incidental findings, and research participant data access and control.

A widespread electrical brain network encodes anxiety in health and depressive states.

In rodents, anxiety is charactered by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system are fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain-state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.

A novel cross-institutional college internship program to train future diverse leaders in clinical research with data-driven approaches to assess impact.

The field of Clinical Research, like many other scientific disciplines, has struggled to recruit and retain talented researchers from diverse communities. While there is a strong history of documenting the problem, having a diverse and inclusive workforce is hindered by the lack of data-driven approaches, cross-institutional partnerships, access to mentors, and positive immersive experiences for people from underrepresented groups. Here, we describe a novel initiative for North Carolina Central University Clinical Research Sciences Program (NCCU-CRSP) student interns to partner with Duke University to have immersive clinical and pre-clinical research training in a 15-week internship as the culminating experience towards their degree for a Bachelor of Science in Clinical Research. The goals of the internship are: 1) to give hands-on training to enhance the impact of classroom-based learning, 2) broaden their understanding of the wide swath of positions available to them, 3) promote their sense of self-efficacy, confidence, science identity, research identity, and connections to the pre-clinical and clinical community, and 4) prepare them to be workforce ready upon graduating. The students dedicate 75% of their time to clinical research with Duke University at Pickett Road and 25% to pre-clinical research in the Collective for Psychiatric Neuroengineering in the Duke Psychiatry Department of the School of Medicine. They will also receive eight 1-h professional development training sessions from the Duke-NCCU Clinical and Translational Science Initiative's Workforce Development Team and five 1-h sessions based on the Entering Research Curriculum developed by the Center for the Improvement of Mentored Experiences in Research (CIMER). Finally, they will be brought in as a cohort and coached on peer mentoring and mutual support frameworks to enhance their sense of community. These student-interns will perform pre- and post-internship self-assessment surveys to quantify their self-efficacy, feelings of belonging, access to research opportunities and mentors, and to give details of their future education and career goals. We will evaluate the impact of the internship using validated tools and apply these findings for future optimization of program design and tactical advice for other programs with shared missions. Furthermore, we will email them on an annual basis with follow-up surveys to assess the longitudinal impact of this internship program, their educational experiences at NCCU, what job titles they hold, how prepared they feel for their roles, and what they hope their future career trajectory will be. Collectively, these approaches will apply theoretical frameworks developed by social and cognitive psychology, vocational theory, and educational research to clinical research training with the goals of recruiting and training talented and diverse leaders within clinical research. We hope that by evaluating our successes, failures, strengths, and liabilities through empirically derived evidence we will also inspire future studies that use data-driven approaches to elevate our approaches as we work together to train and recruit talented researchers from diverse communities into our scientific enterprise and to launch them with more in-depth experiential learning that will empower them to succeed.

Estimating a brain network predictive of stress and genotype with supervised autoencoders.

Targeted brain stimulation has the potential to treat mental illnesses. We develop an approach to help design protocols by identifying relevant multi-region electrical dynamics. Our approach models these dynamics as a superposition of latent networks, where the latent variables predict a relevant outcome. We use supervised autoencoders (SAEs) to improve predictive performance in this context, describe the conditions where SAEs improve predictions, and provide modelling constraints to ensure biological relevance. We experimentally validate our approach by finding a network associated with stress that aligns with a previous stimulation protocol and characterizing a genotype associated with bipolar disorder.

Gender, Racial, and Ethnic and Inequities in Receipt of Multiple National Institutes of Health Research Project Grants.

Importance: Diversity in the biomedical research workforce is essential for addressing complex health problems. Female investigators and investigators from underrepresented ethnic and racial groups generate novel, impactful, and innovative research, yet they are significantly underrepresented among National Institutes of Health (NIH) investigators. Objective: To examine the gender, ethnic, and racial distribution of super NIH investigators who received 3 or more concurrent NIH grants. Design, Setting, and Participants: This cross-sectional study included a national cohort of NIH-funded principal investigators (PIs) from the NIH Information for Management, Planning, Analysis, and Coordination (IMPAC II) database from 1991 to 2020. Exposures: Self-identified gender, race and ethnicity, annual number of NIH grant receipt, career stage, and highest degree. Main Outcomes and Measures: Distribution of investigators receiving 3 or more research project grants, referred to as super principal investigators (SPIs), by gender, race, and ethnicity. Results: Among 33 896 investigators in fiscal year 2020, 7478 (22.01%) identified as Asian, 623 (1.8%) as Black, 1624 (4.8%) as Hispanic, and 22 107 (65.2%) as White; 21 936 (61.7%) identified as men; and 8695 (35.3%) were early-stage investigators. Between 1991 and 2020, the proportion of SPIs increased 3-fold from 704 (3.7%) to 3942 (11.3%). However, SPI status was unequal across gender, ethnic, and racial groups. Women and Black PIs were significantly underrepresented among SPIs, even after adjusting for career stage and degree, and were 34% and 40% less likely than their male and White colleagues, respectively, to be an SPI. Black women PIs were the least likely to be represented among SPIs and were 71% less likely to attain SPI status than White men PIs (adjusted odds ratio, 0.29; 95% CI, 0.21-0.41). Conclusions and Relevance: In this cross-sectional study of a national cohort of NIH-funded investigators, the gender, ethnic, and racial gaps in receipt of multiple research project grants among NIH investigators was clearly apparent and warrants further investigation and interventions.

Advancing workforce diversity by leveraging the Clinical and Translational Science Awards (CTSA) program.

Clinical trials continue to disproportionately underrepresent people of color. Increasing representation of diverse backgrounds among clinical research personnel has the potential to yield greater representation in clinical trials and more efficacious medical interventions by addressing medical mistrust. In 2019, North Carolina Central University (NCCU), a Historically Black College and University with a more than 80% underrepresented student population, established the Clinical Research Sciences Program with support from the Clinical and Translational Science Awards (CTSA) program at neighboring Duke University. This program was designed to increase exposure of students from diverse educational, racial, and ethnic backgrounds to the field of clinical research, with a special focus on health equity education. In the first year, the program graduated 11 students from the two-semester certificate program, eight of whom now hold positions as clinical research professionals. This article describes how leveraging the CTSA program helped NCCU build a framework for producing a highly trained, competent, and diverse workforce in clinical research responsive to the call for increased diversity in clinical trial participation.

Structural Racism in Psychiatric Research Careers: Eradicating Barriers to a More Diverse Workforce.

Investigators from minoritized backgrounds are underrepresented in psychiatric research. That underrepresentation contributes to disparities in outcomes of access to mental health care. Drawing on lived experience, scholarly qualitative reports, and empirical data, the authors review how the underrepresentation of minoritized researchers arises from interlocking, self-reinforcing effects of structural biases in our research training and funding institutions. Minoritized researchers experience diminished early access to advanced training and opportunities, stereotype threats and microaggressions, isolation due to lack of peers and senior mentors, decreased access to early funding, and unique community and personal financial pressures. These represent structural racism-a system of institutional assumptions and practices that perpetuates race-based disparities, in spite of those institutions' efforts to increase diversity and in contradiction to the values that academic leaders outwardly espouse. The authors further review potential approaches to reversing these structural biases, including undergraduate-focused research experiences, financial support for faculty who lead training/mentoring programs, targeted mentoring through scholarly societies, better use of federal diversity supplement funding, support for scientific reentry, cohort building, diversity efforts targeting senior leadership, and rigorous examination of hiring, compensation, and promotion practices. Several of these approaches have empirically proven best practices and models for dissemination. If implemented alongside outcome measurement, they have the potential to reverse decades of structural bias in psychiatry and psychiatric research.

An aging-susceptible circadian rhythm controls cutaneous antiviral immunity.

Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced levels of antiviral proteins (AVPs) and circadian regulators, including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin, and such circadian control of AVPs was diminished by disruption of immune cell IL-27 signaling and deletion of Bmal1/Clock genes in mouse skin, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment with the circadian-enhancing agents nobiletin and SR8278 reduced infection of herpes simplex virus 1 in epidermal explants and human keratinocytes in a BMAL1/CLOCK-dependent manner. Circadian-enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.

An Aging-Susceptible Circadian Rhythm Controls Cutaneous Antiviral Immunity.

Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a Bmal1/Clock-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.