Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements.

Neuronal stimulation induced by the brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences affect BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and the heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal stimulation.

Effects of Mindfulness-Based Interventions on Cardiometabolic-Related Adverse Pregnancy Outcomes: A Systematic Review.

BACKGROUND: Growing evidence suggests maternal stress contributes to the development of adverse pregnancy outcomes that are associated with cardiovascular and cardiometabolic risk in birthing persons. Mindfulness-based interventions may positively affect psychological stress in pregnancy and, in turn, reduce stress. However, few study authors have examined the effects of mindfulness-based interventions on adverse pregnancy outcomes that heighten cardiovascular risk. OBJECTIVE: The aim of this study was to appraise available literature examining the effects of mindfulness-based interventions delivered during pregnancy on adverse pregnancy outcomes associated with future cardiovascular and cardiometabolic disease risk. METHODS: In this systematic review, multiple electronic databases were searched using major keywords, including "mindfulness-based intervention," "pregnancy," "preterm delivery," "gestational diabetes," "small for gestational age," "preeclampsia," and "hypertension in pregnancy" during February 2023. RESULTS: Six studies using mindfulness-based interventions during pregnancy were included. The review indicated that these interventions were largely effective at reducing prenatal stress; however, the overall effects of interventions were mixed concerning their impact on pregnancy complications. Study authors examining the effects on gestational diabetes-related outcomes reported significant improvements in blood glucose levels, hemoglobin A1c, and oral glucose tolerance. Outcomes were mixed or inconclusive related to the effects of interventions on the incidence of preterm birth, birth of a small-for-gestational-age newborn, and preeclampsia. CONCLUSIONS: Mitigating cardiovascular and cardiometabolic risk-associated adverse pregnancy outcomes through mindfulness-based approaches may represent an emerging field of study. The few studies and limited, mixed findings synthesized in this review indicate that high-validity studies are warranted to examine the effects of mindfulness-based interventions on pregnancy complications that contribute to cardiovascular-related maternal morbidity and suboptimal life course health for diverse birthing persons.

Auxiliary α2δ1 and α2δ3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development.

VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct α2δ subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that α2δ1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of α2δ3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that α2δ1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on α2δ1 knockdown. Overexpression of α2δ3 increases the excitatory synaptic density as well but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonaloutgrowth in immature interneurons. Together, our findings demonstrate that α2δ1 and α2δ3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in α2δ surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity.SIGNIFICANCE STATEMENT The computational capacity of neuronal networks is determined by their connectivity. Chemical synapses are the main interface for transfer of information between individual neurons. The initial formation of network connectivity requires spontaneous electrical activity and the calcium channel-mediated signaling. We found that, in early development, auxiliary α2δ3 subunits of calcium channels foster presynaptic release of GABA, trigger formation of inhibitory synapses, and promote axonal outgrowth in inhibitory interneurons. In contrast, later in development, α2δ1 subunits promote the glutamatergic neurotransmission and synaptogenesis, as well as strongly enhance neuronal network activity. We propose that formation of connectivity in neuronal networks is associated with a concerted interplay of α2δ1 and α2δ3 subunits of calcium channels.

Collaboration With Tribal Stakeholders to Explore Care for Postpartum Depression in the Chickasaw Nation.

OBJECTIVE: To describe and interpret Indigenous women's experiences of postpartum depression (PPD) from the perspectives of community advisory board members. DESIGN: Qualitative, descriptive design with a community-engagement approach. SETTING: Virtual group interviews. PARTICIPANTS: Community advisory board members (N = 8) who were tribal employees, citizens of the tribe, and/or family members of citizens who had detailed knowledge of PPD among Indigenous women and issues surrounding their care. METHODS: In video- and audio-recorded virtual group interviews, we asked participants questions using a semistructured interview guide. We used qualitative content analysis to generate results. RESULTS: Major themes included The "Who, What, and Where" of PPD in Indigenous Women; Meanings Attributed to PPD in Indigenous Women; Realities of PPD Care in the Chickasaw Nation; and Feasibility, Acceptability, Perceived Barriers, and Facilitators of a Future Collaboration. CONCLUSION: The participants identified next steps for addressing PPD in the Chickasaw Nation: raise awareness of PPD among providers, patients, and families; improve messaging about PPD to decrease stigma and normalize mental health care; and develop or adapt a culturally appropriate and relevant tool to screen for PPD in Indigenous women.

Inhibiting presynaptic calcium channel motility in the auditory cortex suppresses synchronized input processing.

Introduction: The emergent coherent population activity from thousands of stochastic neurons in the brain is believed to constitute a key neuronal mechanism for salient processing of external stimuli and its link to internal states like attention and perception. In the sensory cortex, functional cell assemblies are formed by recurrent excitation and inhibitory influences. The stochastic dynamics of each cell involved is largely orchestrated by presynaptic CAV2.1 voltage-gated calcium channels (VGCCs). Cav2.1 VGCCs initiate the release of neurotransmitters from the presynaptic compartment and are therefore able to add variability into synaptic transmission which can be partly explained by their mobile organization around docked vesicles. Methods: To investigate the relevance of Cav2.1 channel surface motility for the input processing in the primary auditory cortex (A1) in vivo, we make use of a new optogenetic system which allows for acute, reversable cross-linking Cav2.1 VGCCs via a photo-cross-linkable cryptochrome mutant, CRY2olig. In order to map neuronal activity across all cortical layers of the A1, we performed laminar current-source density (CSD) recordings with varying auditory stimulus sets in transgenic mice with a citrine tag on the N-terminus of the VGCCs. Results: Clustering VGCCs suppresses overall sensory-evoked population activity, particularly when stimuli lead to a highly synchronized distribution of synaptic inputs. Discussion: Our findings reveal the importance of membrane dynamics of presynaptic calcium channels for sensory encoding by dynamically adjusting network activity across a wide range of synaptic input strength.

Establishment of a Community Advisory Board to Address Postpartum Depression Among Indigenous Women.

In this article, we describe the process of establishing an academically and tribally supported community advisory board (CAB) to guide and inform community-engaged research about postpartum depression (PPD) among Indigenous women. Using a community-based participatory research framework, we created a CAB with stakeholders from the Chickasaw Nation because they are well situated to inform a research agenda about PPD in Indigenous women. We developed CAB roles, goals, and responsibilities; established processes for compensation and recognition; identified and recruited potential members; and conducted meetings to build rapport, brainstorm, receive feedback, and invite discussion of topics related to PPD that have been deemed important by the tribe (October 2021 through June 2022). The CAB defined specific roles, goals, and responsibilities for the academic-community partnership, including assumptions, expectations, and confidentiality. We used a standing agenda item to recognize member achievements. Members of the CAB represented many tribal departments and professional disciplines. We use a CAB framework to evaluate our process and to provide recommendations for future research and policymaking.

Direct observation of motor protein stepping in living cells using MINFLUX.

Dynamic measurements of molecular machines can provide invaluable insights into their mechanism, but these measurements have been challenging in living cells. Here, we developed live-cell tracking of single fluorophores with nanometer spatial and millisecond temporal resolution in two and three dimensions using the recently introduced super-resolution technique MINFLUX. Using this approach, we resolved the precise stepping motion of the motor protein kinesin-1 as it walked on microtubules in living cells. Nanoscopic tracking of motors walking on the microtubules of fixed cells also enabled us to resolve the architecture of the microtubule cytoskeleton with protofilament resolution.

Fragile X protein controls neural stem cell proliferation in the Drosophila brain.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function for Fragile X protein (FMRP), an RNA-binding protein thought to regulate synaptic plasticity by controlling the localization and translation of specific mRNAs. We have recently shown that FMRP is required to control the proliferation of the germline in Drosophila. To determine whether FMRP is also required for proliferation during brain development, we examined the distribution of cell cycle markers in dFmr1 brains compared with wild-type throughout larval development. Our results indicate that the loss of dFmr1 leads to a significant increase in the number of mitotic neuroblasts (NB) and BrdU incorporation in the brain, consistent with the notion that FMRP controls proliferation during neurogenesis. Developmental studies suggest that FMRP also inhibits neuroblast exit from quiescence in early larval brains, as indicated by misexpression of Cyclin E. Live imaging experiments indicate that by the third instar larval stage, the length of the cell cycle is unaffected, although more cells are found in S and G2/M in dFmr1 brains compared with wild-type. To determine the role of FMRP in neuroblast division and differentiation, we used Mosaic Analysis with a Repressible Marker (MARCM) approaches in the developing larval brain and found that single dFmr1 NB generate significantly more neurons than controls. Our results demonstrate that FMRP is required during brain development to control the exit from quiescence and proliferative capacity of NB as well as neuron production, which may provide insights into the autistic component of FXS.

Perinatal Care of Childhood Sexual Abuse Survivors: Scoping Review.

BACKGROUND: An estimated one in nine women seeking perinatal care is a survivor of childhood sexual abuse (CSA), yet CSA may be unknown to nurses and other health care providers. Childhood sexual abuse can have adverse physical and psychological effects for survivors, and the intimacy of perinatal care can trigger distress like intrusive thoughts. PURPOSE: To explore available literature about CSA survivors and perinatal care. Specific aims were to 1) identify nursing actions that ease undesirable feelings during perinatal care for CSA survivors and 2) identify gaps in the literature on perinatal care for CSA survivors. STUDY DESIGN AND METHODS: Following the PRISMA-ScR Checklist, MEDLINE and CINAHL databases were searched using: "Child Abuse, Sexual," "Perinatal Care," and "Parturition." Initial yield was 109 records. RESULTS: Applying inclusion and exclusion criteria produced 14 full-text articles. Findings suggest that obtaining consent, promoting safety, trust, and control, fostering a healthy nurse-patient relationship, and inquiring about abuse may improve how CSA survivors experience perinatal care. Gaps in literature include nursing assessments for history of CSA with nonverbal cues. CLINICAL IMPLICATIONS: For all patients, nurses should foster security and trust. It is critical that CSA survivors be in control of their care. Procedures should be thoroughly explained, and most importantly, consent should be obtained prior to every physical touch. Nurses must ask about history of CSA because it is part of patient-centered care, which is central to nursing.

"It Took Away the Joy:" First American Mothers' Experiences with Postpartum Depression.

BACKGROUND: Postpartum depression (PPD) is a devastating mental illness associated with adverse health outcomes for mother, child, and family. Higher PPD prevalence in First American women suggests a racial/ethnic disparity, yet little is known about how PPD is experienced from their perspective. PURPOSE: To 1) describe First American women's PPD experiences and the meanings they ascribe to those experiences and 2) describe the cultural knowledge, influences, and practices during the perinatal period. STUDY DESIGN AND METHODS: This phenomenological study used a community-based participatory research approach. Criterion and snowball sampling captured First American women who had PPD now or in the past (N = 8). Interviews used a semistructured guide and thematic analysis followed. RESULTS: Mean age was 30.25 years. Most women were multigravidas (n = 7) and rated themselves as "very" (n = 4) or "mostly" (n = 3) Native American. Women were mostly of low socioeconomic status and had a history of depression (n = 7) and/or a history of prenatal depression (n = 6). Themes: 1) stressors that contributed to PPD; 2) how PPD made me feel; 3) what made my PPD better; 4) heritage-centered practices; 5) support through PPD; 6) how I felt after PPD; and 7) am I a good mother? CLINICAL IMPLICATIONS: This study provides a better understanding of some First American women's PPD experiences that facilitates judgment of the importance of PPD within a cultural context. Clinicians need to create culturally appropriate responses to First American women's PPD needs.

High-throughput super-resolution single-particle trajectory analysis reconstructs organelle dynamics and membrane reorganization.

Super-resolution imaging can generate thousands of single-particle trajectories. These data can potentially reconstruct subcellular organization and dynamics, as well as measure disease-linked changes. However, computational methods that can derive quantitative information from such massive datasets are currently lacking. We present data analysis and algorithms that are broadly applicable to reveal local binding and trafficking interactions and organization of dynamic subcellular sites. We applied this analysis to the endoplasmic reticulum and neuronal membrane. The method is based on spatiotemporal segmentation that explores data at multiple levels and detects the architecture and boundaries of high-density regions in areas measuring hundreds of nanometers. By connecting dense regions, we reconstructed the network topology of the endoplasmic reticulum (ER), as well as molecular flow redistribution and the local space explored by trajectories. The presented methods are available as an ImageJ plugin that can be applied to large datasets of overlapping trajectories offering a standard of single-particle trajectory (SPT) metrics.

Postpartum Depression in American Indian/Alaska Native Women: A Scoping Review.

BACKGROUND: Postpartum depression (PPD) is the most common complication of childbirth and affects one in nine new mothers in the United States. OBJECTIVE: The purpose of this review was to synthesize PPD research in American Indian/Alaska Native (AI/AN) women. Specific aims were to 1) explore the extent to which PPD literature includes AI/AN women measured by the proportion of study samples that were AI/AN women and 2) identify and analyze gaps in the PPD literature for AI/AN women. DESIGN: Databases were searched using: "postpartum depression" and "American Indian," "Native American," "Alaska Native," "Inuit," and "Indigenous." "Postpartum depressive symptoms" and "puerperal mood disorder" were each paired with race/ethnicity search terms, yielding a final sample of nine articles. RESULTS: The proportion of study samples that were AI/AN women ranged from 0.8% to 100%. Compared with all women in the United States (11%), AI/AN women have higher PPD prevalence (14%-29.7%), suggesting a disparity among the different groups of women. Screening instruments were inconsistent among studies, and not all studies used a screening instrument specific to PPD. No cultural influences, risk, or protective factors were reported for AI/AN women. In the only intervention study, no significant differences in PPD symptoms between groups were found after the intervention. CONCLUSIONS: This review uncovered significant gaps in the literature and suggested ways to advance the PPD science for AI/AN women. Clinical implications were described.

More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation.

Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction. However, studies on molecular interaction partners and recent progress in omics technologies have extended the actual concept of these molecules. With this review, we want to illustrate some new perspectives of VGCCs reaching beyond their function as calcium-permeable pores in the plasma membrane. Therefore, we will discuss the relevance of VGCCs as voltage sensors in functional complexes with ryanodine receptors, channel-independent actions of auxiliary VGCC subunits, and provide an insight into how VGCCs even directly participate in gene regulation. Furthermore, we will illustrate how structural changes in the intracellular C-terminus of VGCCs generated by alternative splicing events might not only affect the biophysical channel characteristics but rather determine their molecular environment and downstream signaling pathways.

Maternal Mortality Among American Indian/Alaska Native Women: A Scoping Review.

Background: Maternal mortality decreased globally by about 38% between 2000 and 2017, yet, it continues to climb in the United States. Gaping disparities exist in U.S. maternal mortality between white (referent group) and minority women. Despite important and appropriate attention to disparities for black women, almost no attention has been given to American Indian/Alaska Native (AI/AN) women. The purpose of this scoping review is to synthesize available literature concerning AI/AN maternal mortality. Methods: Databases were searched using the terms maternal mortality and pregnancy-related death, each paired with American Indian, Native American, Alaska Native, Inuit, and Indigenous. Criteria (e.g., hemorrhage) were paired with initial search terms. Next, pregnancy-associated death was paired with American Indian, Native American, Alaska Native, Inuit, and Indigenous. Criteria in this category were homicide, suicide, and substance use. Results: The three leading causes of AI/AN pregnancy-related maternal mortality are hemorrhage, cardiomyopathies, and hypertensive disorders of pregnancy. AI/AN maternal mortality data for homicide and suicide consistently include small samples and often categorize AI/AN maternal deaths in an "Other" race/ethnicity, which precludes targeted AI/AN data analysis. No studies that reported AI/AN maternal mortality as a result of substance use were found. Health care characteristics such as quality, access, and location also may influence maternal outcomes and maternal mortality. Conclusions: Despite AI/AN maternal mortality being disproportionately high compared to other racial/ethnic groups, relatively little is known about root causes.

Dynamic compartmentalization of calcium channel signalling in neurons.

Calcium fluxes through the neuronal membrane are strictly limited in time due to biophysical properties of voltage-gated and ligand-activated ion channels and receptors. Being embedded into the crowded dynamic environment of biological membranes, Ca2+-permeable receptors and channels undergo perpetual spatial rearrangement, which enables their temporary association and formation of transient signalling complexes. Thus, efficient calcium-mediated signal transduction requires mechanisms to support very precise spatiotemporal alignment of the calcium source and Ca2+-binding lipids and proteins in a highly dynamic environment. The mobility of calcium channels and calcium-sensing proteins themselves can be considered as a physiologically meaningful variable that affects calcium-mediated signalling in neurons. In this review, we will focus on voltage-gated calcium channels (VGCCs) and activity-induced relocation of stromal interaction molecules (STIMs) in the endoplasmic reticulum (ER) to show that particularly in time ranges between milliseconds to minutes, dynamic rearrangement of calcium conducting channels and sensor molecules is of physiological relevance. This article is part of the special issue entitled 'Mobility and trafficking of neuronal membrane proteins'.

Transient Confinement of CaV2.1 Ca2+-Channel Splice Variants Shapes Synaptic Short-Term Plasticity.

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1+47 persistently displayed higher mobility within nanodomains. Synaptic accumulation of CaV2.1 was accomplished by optogenetic clustering, but only CaV2.1+47 increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of CaV2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.

Screening for Postpartum Depression in American Indian/Alaska Native Women: A Comparison of Two Instruments.

This review examined validation studies of the Edinburgh Postnatal Depression Scale (EPDS) and the Patient Health Questionnaire-9 (PHQ-9) to identify an appropriate postpartum depression (PPD) screening tool for American Indian and Alaska Native (AI/AN) women in the U.S. Databases were searched using: EPDS paired with psychometric properties or validation and PHQ-9 paired with PPD and psychometric properties or validation, yielding a final sample of 58 articles. Both tools have good internal consistency, but discriminative validity for detecting PPD in women from non-Western cultures is low. Positive predictive values in these women are low and diverse (EPDS [n = 21] median 67%, range 21.1-90%; PHQ-9 [n = 1] median 26%). The low predictive accuracy of both tools suggests the tools may be culturally biased.

Surface dynamics of voltage-gated ion channels.

Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks.

Dynamic association of calcium channel subunits at the cellular membrane.

High voltage gated calcium channels (VGCCs) are composed of at least three subunits, one pore forming [Formula: see text]-subunit, an intracellular [Formula: see text]-variant, and a mostly extracellular [Formula: see text]-variant. Interactions between these subunits determine the kinetic properties of VGCCs. It is unclear whether these interactions are stable over time or rather transient. Here, we used single-molecule tracking to investigate the surface diffusion of [Formula: see text]- and [Formula: see text]-subunits at the cell surface. We found that [Formula: see text]-subunits show higher surface mobility than [Formula: see text]-subunits, and that they are only transiently confined together, suggesting a weak association between [Formula: see text]- and [Formula: see text]-subunits. Moreover, we observed that different [Formula: see text]-subunits engage in different degrees of association with the [Formula: see text]-subunit, revealing the tighter interaction of [Formula: see text] with [Formula: see text]. These data indicate a distinct regulation of the [Formula: see text] interaction in VGCC subtypes. We modeled their membrane dynamics in a Monte Carlo simulation using experimentally determined diffusion constants. Our modeling predicts that the ratio of associated [Formula: see text]- and [Formula: see text]-subunits mainly depends on their expression density and confinement in the membrane. Based on the different motilities of particular [Formula: see text]-subunit combinations, we propose that their dynamic assembly and disassembly represent an important mechanism to regulate the signaling properties of VGCC.