Scholarly Works, School of Neuroscience

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Research articles, presentations, and other scholarship

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Systematic evaluation of parameters in RNA bisulfite sequencing data generation and analysis
Johnson, Zachary; Xu, Xiguang; Pacholec, Christina; Xie, Hehuang (Oxford University Press, 2022-03-31)
The presence of 5-methylcytosine (m5C) in RNA molecules has been known for decades and its importance in regulating RNA metabolism has gradually become appreciated. Despite recent advances made in the functional and mechanistic understanding of RNA m5C modifications, the detection and quantification of methylated RNA remains a challenge. In this study, we compared four library construction procedures for RNA bisulfite sequencing and implemented an analytical pipeline to assess the key parameters in the process of m5C calling. We found that RNA fragmentation after bisulfite conversion increased the yield significantly, and an additional high temperature treatment improved bisulfite conversion efficiency especially for sequence reads mapped to the mitochondrial transcriptome. Using Unique Molecular Identifiers (UMIs), we observed that PCR favors the amplification of unmethylated templates. The low sequencing quality of bisulfite-converted bases is a major contributor to the methylation artifacts. In addition, we found that mitochondrial transcripts are frequently resistant to bisulfite conversion and no p-m5C sites with high confidence could be identified on mitochondrial mRNAs. Taken together, this study reveals the various sources of artifacts in RNA bisulfite sequencing data and provides an improved experimental procedure together with analytical methodology.
Dynamics of RNA m⁵C modification during brain development
Johnson, Zachary; Xu, Xiguang; Lin, Yu; Xie, Hehuang (Elsevier, 2023-05)
Post-transcriptional RNA modifications have been recognized as key regulators of neuronal differentiation and synapse development in the mammalian brain. While distinct sets of 5-methylcytosine (m5C) modified mRNAs have been detected in neuronal cells and brain tissues, no study has been performed to characterize methylated mRNA profiles in the developing brain. Here, together with regular RNA-seq, we performed transcriptome-wide bisulfite sequencing to compare RNA cytosine methylation patterns in neural stem cells (NSCs), cortical neuronal cultures, and brain tissues at three postnatal stages. Among 501 m5C sites identified, approximately 6% are consistently methylated across all five conditions. Compared to m5C sites identified in NSCs, 96% of them were hypermethylated in neurons and enriched for genes involved in positive transcriptional regulation and axon extension. In addition, brains at the early postnatal stage demonstrated substantial changes in both RNA cytosine methylation and gene expression of RNA cytosine methylation readers, writers, and erasers. Furthermore, differentially methylated transcripts were significantly enriched for genes regulating synaptic plasticity. Altogether, this study provides a brain epitranscriptomic dataset as a new resource and lays the foundation for further investigations into the role of RNA cytosine methylation during brain development.
Monoubiquitination of histone H2B is a crucial regulator of the transcriptome during memory formation
Navabpour, Shaghayegh; Farrell, Kayla; Kincaid, Shannon E.; Omar, Nour; Musaus, Madeline; Lin, Yu; Xie, Hehuang; Jarome, Timothy J. (Cold Spring Harbor Laboratory Press, 2024-03)
Posttranslational modification of histone proteins is critical for memory formation. Recently, we showed that monoubiquitination of histone H2B at lysine 120 (H2Bub) is critical for memory formation in the hippocampus. However, the transcriptome controlled by H2Bub remains unknown. Here, we found that fear conditioning in male rats increased or decreased the expression of 86 genes in the hippocampus but, surprisingly, siRNA-mediated knockdown of the H2Bub ligase, Rnf20, abolished changes in all but one of these genes. These findings suggest that monoubiquitination of histone H2B is a crucial regulator of the transcriptome during memory formation.
Increasing H2B Monoubiquitination Improves the Transcriptome and Memory in the Aged Hippocampus
Kincaid, Shannon; Setenet, Gueladouan; Preveza, Natalie J.; Arndt, Kaiser C.; Gwin, Phillip; Lin, Yu; Xie, Hehuang; Jarome, Timothy J. (Society for Neuroscience, 2025-04)
A decline in cognitive abilities is associated with the aging process, affecting nearly 33% of US adults over the age of 70, and is a risk factor for the development of dementia and Alzheimer's disease. Several studies have reported age-related alterations in the transcriptome in the hippocampus, a major site of memory storage that is among the first regions impacted with age, dementia, and Alzheimer's disease. However, much remains unknown about why these transcriptional changes exist in the aged hippocampus and how this impacts memory late in life. Here, we show that monoubiquitination of histone H2B (H2Bubi), an epigenetic mechanism recently reported to be major regulator of the epigenome and transcriptome during memory formation in the young adult brain, decreases with age in the hippocampus of male rats. In vivo CRISPR-dCas9-mediated upregulation of Rnf20, the only ubiquitin E3 ligase for H2B, in the hippocampus significantly improved memory retention in aged rats. Remarkably, RNA-seq analysis revealed that in addition to the 18 genes typically upregulated in the aged rat hippocampus following contextual fear conditioning, Rnf20 upregulation caused learning-related increases and decreases in 40 and 11 unique genes, respectively, suggesting that these 51 genes may be among those most critical for improving memory in advanced age. Together, these data suggest that H2B monoubiquitination is a significant regulator of age-related dysregulation of the transcriptome and impairments in memory.
Indirectly acquired fear memories have distinct, sex-specific molecular signatures from directly acquired fear memories
Navabpour, Shaghayegh; Patrick, Morgan B.; Omar, Nour A.; Kincaid, Shannon E.; Bae, Yeeun; Abraham, Jennifer; McGrew, Jacobi; Musaus, Madeline; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (PLOS, 2024-12-23)
Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects women more than men. About 30% of patients suffering from PTSD develop the disorder by witnessing a traumatic event happen to someone else. However, as the focus has remained on those directly experiencing the traumatic event, whether indirectly acquired fear memories that underlie PTSD have the same molecular signature as those that are directly acquired remains unknown. Here, using a rodent indirect fear learning paradigm where one rat (observer) watches another rat (demonstrator) associate an auditory cue with foot shock, we found that fear can be indirectly acquired by both males and females regardless of the sex or novelty (familiarity) of the demonstrator animal. However, behaviorally, indirectly acquired fear responses resemble those of pseudoconditioning, a behavioral response that is thought to not represent learning. Despite this, using unbiased proteomics, we found that indirectly acquired fear memories have distinct protein degradation profiles in the amygdala and anterior cingulate cortex (ACC) relative to directly acquired fear memories and pseudoconditioning, which further differed significantly by sex. Additionally, Egr2 and c-fos expression in the retrosplenial cortex of observer animals resembled that of demonstrator rats but was significantly different than that of pseudoconditioned rats. Together, these findings reveal that indirectly acquired fear memories have sex-specific molecular signatures that differ from those of directly acquired fear memories or pseudoconditioning. These data have important implications for understanding the neurobiology of indirectly acquired fear memories that may underlie bystander PTSD.
Neural Signatures of Cognitive Control Predict Future Adolescent Substance Use Onset and Frequency
Chen, Ya-Yun; Lindenmuth, Morgan; Lee, Tae-Ho; Lee, Jacob; Casas, Brooks; Kim-Spoon, Jungmeen (Elsevier, 2024-11-29)
BACKGROUND: Adolescent substance use is a significant predictor of future addiction and related disorders. Understanding neural mechanisms underlying substance use initiation and frequency during adolescence is critical for early prevention and intervention. METHODS: The current longitudinal study followed 91 substance-naïve adolescents annually for 7 years from ages 14 to 21 years to identify potential neural precursors that predict substance use initiation and frequency. Cognitive control processes were examined using the Multi-Source Interference Task to assess functional neural connectivity. A questionnaire was used to assess substance use frequency. RESULTS: Stronger connectivity between the dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (dlPFC) at time 1 predicted a delayed onset of substance use, indicative of a protective effect. A notable decline in this dACC–dlPFC connectivity was observed 1 year prior to substance use initiation. Conversely, lower connectivity of the dACC with the supplementary motor area and heightened connectivity of the anterior insula with the dorsal medial prefrontal cortex and angular gyrus were predictive of greater frequency of future substance use. These findings remained after controlling for demographic and socioeconomic covariates. CONCLUSIONS: This study highlights the critical role of cognitive control–related neural connectivity in predicting substance use initiation and frequency during adolescence. The results imply that efforts to strengthen and monitor the development of the top-down cognitive control system in the brain from early adolescence can be protective and deter progression into problematic substance use. Furthermore, for adolescents with heightened frequency of substance use, interventions may prove more effective by targeting interoceptive processes in cognitive control training.
Making an Effective Flipped Neuroscience Lab by Approaching Students from Their Limbic Brain
Fu, Zhuo (Faculty for Undergraduate Neuroscience, 2024-07-21)
During the pandemic, we filmed our neuroscience labs, and now the videos provide a great resource to flip the lab. Our lab, however, covers a wide range of complicated topics, ranging from gross anatomy, immunohistochemistry (IHC) staining, and fluorescence imaging to cockroach microscopic surgery and measuring nerve conduction velocity on worms and human subjects, and it is challenging to get students to finish watching these complicated experiments. The biggest challenge that students face while watching these experiment demonstrations is their own emotions. When we were editing the films of the labs, we did not reduce the complexity, but we explained concepts by using concepts and objects that students are already familiar with so we do not trigger anxiety. To reduce boredom, we employed three major methods: questioning, humor, and increasing the pace. To address potential anxiety or reluctance about the in-person part of the lab, we mention at the beginning of every lab session that making mistakes is completely acceptable and, as they make mistakes, we help them understand what went wrong and how to correct it. We also introduce additional activities in some lab sessions to pique their interest. For instance, we ask students to test the effects of Red Bull on crickets and investigate whether students who play more video games have higher conduction velocities in the median nerve. Thus far, our flipped lab has been quite successful in terms of maintaining video retention rates and in-person attendance rates. A notable example of the effectiveness of improved hands-on skills is the cockroach microscopic surgery. Before implementing the flipped lab, only 10% of students were able to successfully complete the surgery and acquire nerve activity recordings. With the flipped lab, 90% of students were able to obtain a recording independently.
The Predictive Value of Plasma Bioactive Lipids on Craving in Human Volunteers With Alcohol Use Disorder
Miliano, Cristina; Natividad, Luis A.; Quello, Susan; Stoolmiller, Mike; Gregus, Ann M.; Buczynski, Matthew W.; Mason, Barbara J. (Elsevier, 2024-07-26)
Background: Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by alcohol seeking and consumption despite negative consequences. Despite the availability of multiple treatments, patients continue to exhibit high relapse rates. Thus, biomarkers that can identify patients at risk for heightened craving are urgently needed. Mounting preclinical and clinical evidence implicates perturbations in bioactive lipid signaling in the neurobiology of craving in AUD. We hypothesize that these lipids are potential biomarkers for predicting alcohol craving in patients with AUD. Methods: This study used archival deidentified clinical data and corresponding plasma specimens from 157 participants in 3 clinical studies of AUD. We evaluated plasma levels of 8 lipid species as predictors of craving in response to in vivo alcohol and affective cues during abstinence. Results: Participants were 109 men and 48 women who met DSM-5 criteria for severe AUD. We found that plasma levels of 12- and 15-HETE, 12/15-lipoxygenase–produced proinflammatory lipids, and palmitoylethanolamide, an anti-inflammatory fatty acid amide hydrolase–regulated lipid metabolite, were differentially correlated with alcohol craving during abstinence, predicting higher craving independent of demographics, alcohol use history, and multiple therapeutic treatments. Conclusions: Our findings highlight the promise of these lipid metabolites as biomarkers of heightened alcohol craving. The results open a novel opportunity for further research and clinical evaluation of these biomarkers to optimize existing treatments and develop new therapeutics for AUD.
Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice
Murdaugh, Laura B.; Miliano, Cristina; Chen, Irene; Faunce, Christine L.; Natividad, Luis A.; Gregus, Ann M.; Buczynski, Matthew W. (Nature Portfolio, 2024-03-19)
Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.
Differential roles of diacylglycerol lipase (DAGL) enzymes in nicotine withdrawal
Buzzi, Belle; Koseli, Eda; Alkhlaif, Yasmin; Parker, Abigail; Mustafa, Mohammed A.; Lichtman, Aron H.; Buczynski, Matthew W.; Damaj, M. Imad (Elsevier, 2023-07-11)
Nicotine and tobacco-related deaths remains a leading cause of preventable death and disease in the United States. Several studies indicate that modulation of the endocannabinoid system, primarily of the endocannabinoid 2-Arachidonoylglycerol (2-AG), alters nicotinic dependence behaviors in rodents. This study, using transgenic knock-out (KO) mice, evaluated the role of the two 2-AG biosynthesis enzymes, (Diacylglycerol lipase-α) DAGL-α and DAGL-β in spontaneous nicotine withdrawal. DAGL-α deletion prevents somatic and affective signs of nicotine withdrawal, while DAGL-β deletion plays a role in hyperalgesia due to nicotine withdrawal. These results suggest a differential role of these enzymes in the various signs of nicotine withdrawal. Our behavioral findings relate to the distribution of these enzymes with DAGL-β being highly expressed in macrophages and DAGL-α in neurons. This study offers new potential targets for smoking cessation therapies.
Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception
Bustin, Katelyn A.; Shishikura, Kyosuke; Chen, Irene; Lin, Zongtao; McKnight, Nate; Chang, Yuxuan; Wang, Xie; Li, Jing Jing; Arellano, Eric; Pei, Liming; Morton, Paul D.; Gregus, Ann M.; Buczynski, Matthew W.; Matthews, Megan L. (Academic Press - Elsevier, 2023-03-15)
Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.
Enumerating rights: more is not always better
Ball, Sheryl B.; Dave, Chetan; Dodds, Stefan (Springer, 2023-05-11)
Contemporary political and policy debate rhetoric increasingly employs the language of ‘rights’: how they are assigned and what entitlements individuals in a society are due. While the obvious constitution design issues surround how rights enumeration affects the relationship between a government and its citizens, we instead analyze how rights framing impacts how citizens interact with each other. We design and implement a novel experiment to test whether social cooperation depends on the enumeration and positive or negative framing of the right of subjects to take a particular action. We find that when rights are framed positively, there exists an ‘entitlement effect’ that reduces social cooperation levels and crowds-out the tendency of individuals to act pro-socially.
Vaccine Hesitancy and Betrayal Aversion
Alsharawy, Abdelaziz; Dwibedi, Esha; Aimone, Jason; Ball, Sheryl B. (Springer, 2022-05-17)
The determinants of vaccine hesitancy remain complex and context specific. Betrayal aversion occurs when an individual is hesitant to risk being betrayed in an environment involving trust. In this pre-registered vignette experiment, we show that betrayal aversion is not captured by current vaccine hesitancy measures despite representing a significant source of unwillingness to be vaccinated. Our survey instrument was administered to 888 United States residents via Amazon Mechanical Turk in March 2021. We find that over a third of participants have betrayal averse preferences, resulting in an 8–26% decline in vaccine acceptance, depending on the betrayal source. Interestingly, attributing betrayal risk to scientists or government results in the greatest declines in vaccine acceptance. We explore an exogenous message intervention and show that an otherwise effective message acts narrowly and fails to reduce betrayal aversion. Our results demonstrate the importance of betrayal aversion as a preference construct in the decision to vaccinate.
Emotional words evoke region- and valence-specific patterns of concurrent neuromodulator release in human thalamus and cortex
Batten, Seth R.; Hartle, Alec E.; Barbosa, Leonardo S.; Hadj-Amar, Beniamino; Bang, Dan; Melville, Natalie; Twomey, Tom; White, Jason P.; Torres, Alexis; Celaya, Xavier; McClure, Samuel M.; Brewer, Gene A.; Lohrenz, Terry; Kishida, Kenneth T.; Bina, Robert W.; Witcher, Mark R.; Vannucci, Marina; Casas, Brooks; Chiu, Pearl; Montague, P. Read; Howe, William M. (Elsevier, 2025-01-28)
Words represent a uniquely human information channel—humans use words to express thoughts and feelings and to assign emotional valence to experience. Work from model organisms suggests that valence assignments are carried out in part by the neuromodulators dopamine, serotonin, and norepinephrine. Here, we ask whether valence signaling by these neuromodulators extends to word semantics in humans by measuring sub-second neuromodulator dynamics in the thalamus (N = 13) and anterior cingulate cortex (N = 6) of individuals evaluating positive, negative, and neutrally valenced words. Our combined results suggest that valenced words modulate neuromodulator release in both the thalamus and cortex, but with regionand valence-specific response patterns, as well as hemispheric dependence for dopamine release in the anterior cingulate. Overall, these experiments provide evidence that neuromodulator-dependent valence signaling extends to word semantics in humans, but not in a simple one-valence-per-transmitter fashion.
Molecular Basis of Oncogenic PI3K Proteins
Sheng, Zhi; Beck, Patrick; Gabby, Maegan; Habte-Mariam, Semhar; Mitkos, Katherine (MDPI, 2024-12-30)
The dysregulation of phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in driving neoplastic transformation by promoting uncontrolled cell survival and proliferation. This oncogenic activity is primarily caused by mutations that are frequently found in PI3K genes and constitutively activate the PI3K signaling pathway. However, tumorigenesis can also arise from nonmutated PI3K proteins adopting unique active conformations, further complicating the understanding of PI3K-driven cancers. Recent structural studies have illuminated the functional divergence among highly homologous PI3K proteins, revealing how subtle structural alterations significantly impact their activity and contribute to tumorigenesis. In this review, we summarize current knowledge of Class I PI3K proteins and aim to unravel the complex mechanism underlying their oncogenic traits. These insights will not only enhance our understanding of PI3K-mediated oncogenesis but also pave the way for the design of novel PI3K-based therapies to combat cancers driven by this signaling pathway.
Embryonic Thermal Programming and Dietary Baicalein Supplementation Post-Hatch: Effects on Broiler Adipose Tissue Deposition
Sulaiman, Usman; Vaughan, Reagan; Siegel, Paul; Liu, Dongmin; Gilbert, Elizabeth; Cline, Mark (MDPI, 2024-12-10)
Optimization of growth performance and fat metabolism in broilers are critical for meat quality and overall production efficiency. This experiment investigated the effects of dietary baicalein supplementation and embryonic heat conditioning (EHC) on the growth performance and adipose tissue metabolism of 10-day old broilers. Fertile eggs were divided into control and EHC groups, with EHC eggs exposed to intermittent heating (39.5 °C) from day 7 to day 16 of incubation. Hatched chicks were further divided into four groups: CC (control control), CT (control treatment with baicalein), EC (embryonic heat control), and ET (embryonic heat treatment with baicalein), and were fed ad libitum. On day 10 post-hatch, blood and adipose tissue samples were collected for analysis. C/EBPα mRNA was lower in the ET group compared to the EC group and higher in the CT group compared to the CC group. PPARγ and HSL mRNAs were elevated in both the ET and CT groups relative to their controls. Additionally, plasma non-esterified fatty acid (NEFA) levels were significantly higher in the CT group compared to the CC group. These results indicate that baicalein supplementation, particularly when combined with embryonic heat conditioning, can modulate fat metabolism and potentially improve the growth performance of broilers, thereby offering insights into strategies for enhancing poultry production.
Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor
van der Heijden, Meike E.; Brown, Amanda M.; Kizek, Dominic J.; Sillitoe, Roy (eLife, 2024-07-29)
The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.
Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice
van der Heijden, Meike E. (Springer, 2024-05-23)
Evidence from clinical and preclinical studies has shown that the cerebellum contributes to cognitive functions, including social behaviors. Now that the cerebellum’s role in a wider range of behaviors has been confirmed, the question arises whether the cerebellum contributes to social behaviors via the same mechanisms with which it modulates movements. This review seeks to answer whether the cerebellum guides motor and social behaviors through identical pathways. It focuses on studies in which cerebellar cells, synapses, or genes are manipulated in a cell-type specific manner followed by testing of the effects on social and motor behaviors. These studies show that both anatomically restricted and cerebellar cortex-wide manipulations can lead to social impairments without abnormal motor control, and vice versa. These studies suggest that the cerebellum employs different cellular, synaptic, and molecular pathways for social and motor behaviors. Future studies warrant a focus on the diverging mechanisms by which the cerebellum contributes to a wide range of neural functions.
More Than a Small Brain: The Importance of Studying Neural Function during Development
Dooley, James C.; van der Heijden, Meike E. (Society for Neuroscience, 2024-11-27)
The nervous system contains complex circuits comprising thousands of cell types and trillions of connections. Here, we discuss how the field of "developmental systems neuroscience" combines the molecular and genetic perspectives of developmental neuroscience with the (typically adult-focused) functional perspective of systems neuroscience. This combination of approaches is critical to understanding how a handful of cells eventually produce the wide range of behaviors necessary for survival. Functional circuit development typically lags behind neural connectivity, leading to intermediate stages of neural activity that are either not seen in adults or, if present, are considered pathophysiological. Developmental systems neuroscience examines these intermediate stages of neural activity, mapping out the critical phases and inflection points of neural circuit function to understand how neural activity and behavior emerge across development. Beyond understanding typical development, this approach provides invaluable insight into the pathophysiology of neurodevelopmental disorders by identifying when and how functional development diverges between health and disease. We argue that developmental systems neuroscience will identify important periods of neural development, reveal novel therapeutic windows for treatment, and set the stage to answer fundamental questions about the brain in health and disease.
Spatial Transcriptomics and Single-Nucleus Multi-Omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development
Xu, Xiguang; Lin, Yu; Yin, Liduo; Serpa, Priscila da Silva; Conacher, Benjamin; Pacholec, Christina; Carvallo, Francisco; Hrubec, Terry; Farris, Shannon; Zimmerman, Kurt; Wang, Xiaobin; Xie, Hehuang (MDPI, 2024-11-07)
Background: Folate, an essential vitamin B9, is crucial for diverse biological processes, including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Objectives/Methods: Here, we employed a mouse model and spatial transcriptomic and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Results: Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Conclusions: Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.

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