Scholarly Works, School of Neuroscience

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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.
Traditional Prostate Cancer Risk Assessment Scales Do Not Predict Outcomes from Brain Metastases: A Population-Based Predictive Nomogram
Ladner, Liliana R.; Adhikari, Srijan; Bhutada, Abhishek S.; Cuoco, Joshua A.; Patel, Vaibhav M.; Entwistle, John J.; Rogers, Cara M.; Marvin, Eric A. (MDPI, 2024-08-30)
Brain metastases are an uncommon yet life-limiting manifestation of prostate cancer. However, there is limited insight into the natural progression, therapeutics, and patient outcomes for prostate cancer once metastasized to the brain. This is a retrospective study of 461 patients with metastatic prostate cancer to the brain with a primary outcome of median overall survival (OS). The Surveillance, Epidemiology, and End Results (SEER) database was examined using Cox regression univariate and multivariable analyses, and a corresponding nomogram was developed. The median overall survival was 15 months. In the multivariable analysis, Hispanic patients had significantly increased OS (median OS 17 months, p = 0.005). Patients with tumor sizes greater than three centimeters exhibited significantly reduced OS (median OS 19 months, p = 0.014). Patients with additional metastases to the liver exhibited significantly reduced OS (median OS 3.5 months, p < 0.001). Increased survival was demonstrated in patients treated with chemotherapy or systemic treatment (median OS 19 months, p = 0.039), in addition to radiation and chemotherapy (median OS 25 months, p = 0.002). The nomogram had a C-index of 0.641. For patients with prostate metastases to the brain, median OS is influenced by race, tumor size, presence of additional metastases, and treatment. The lack of an association between traditional prostate cancer prognosis metrics, including Gleason and ISUP grading, and mortality highlights the need for individualized, metastasis-specific prognosis metrics. This prognostic nomogram for prostate metastases to the brain can be used to guide the management of affected patients.
T-DOpE probes reveal sensitivity of hippocampal oscillations to cannabinoids in behaving mice
Kim, Jongwoon; Huang, Hengji; Gilbert, Earl T.; Kaiser C., Arndt; English, Daniel Fine; Jia, Xiaoting (Nature Research, 2024-02-24)
Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. We developed a thermal tapering process enabling fabrication of low-cost, flexible probes combining ultrafine features: dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly. We demonstrate T-DOpE (Tapered Drug delivery, Optical stimulation, and Electrophysiology) probes achieve in single neuron-scale devices (1) highfidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. The device tip can beminiaturized (as small as 50 μm) tominimize tissue damage while the ~20 times larger backend allows for industrial-scale connectorization. T-DOpE probes implanted in mouse hippocampus revealed canonical neuronal activity at the level of local field potentials (LFP) and neural spiking. Taking advantage of the triple-functionality of these probes, we monitored LFP while manipulating cannabinoid receptors (CB1R; microfluidic agonist delivery) and CA1 neuronal activity (optogenetics). Focal infusion of CB1R agonist downregulated theta and sharp wave-ripple oscillations (SPWRs). Furthermore, we found that CB1R activation reduces sharp wave-ripples by impairing the innate SPW-R-generating ability of the CA1 circuit.
SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia
Joyce, Jonathan D.; Moore, Greyson A.; Goswami, Poorna; Harrell, Telvin L.; Taylor, Tina M.; Hawks, Seth A.; Green, Jillian C.; Jia, Mo; Irwin, Matthew D.; Leslie, Emma; Duggal, Nisha K.; Thompson, Christopher K.; Bertke, Andrea S. (MDPI, 2024-07-28)
Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.
Editorial: Effects of performing arts training on the brain, (socio)cognitive and motor functions across the lifespan
Kausel, Leonie; Basso, Julia C.; Grinspun, Noemí; Alain, Claude (Frontiers Media, 2023-12-06)
Performing arts are a cultural expression that is ubiquitous around the world and consists of arts that are performed for an audience, such as music, dance, and drama. In recent years, there has been a growing interest in understanding how this expressive, and in essence social activity, impacts brain development and plasticity. This topic aimed to collect evidence on how the brain and (socio)cognitive and motor functions are influenced by performing arts training along the lifespan, deepening the current knowledge on this subject and helping to unravel the neurobiological mechanisms that underlie these changes. The five articles presented in this Research Topic explore research on an acting intervention, cover matters related to dance training, identify variables related to music sophistication, and focus on performing arts and musical training.
Granular retrosplenial cortex layer 2/3 generates high-frequency oscillations dynamically coupled with hippocampal rhythms across brain states
Arndt, Kaiser C.; Gilbert, Earl T.; Klaver, Lianne M.F.; Kim, Jongwoon; Buhler, Chelsea M.; Basso, Julia C.; McKenzie, Sam; English, Daniel Fine (CellPress, 2024-03-26)
The granular retrosplenial cortex (gRSC) exhibits high-frequency oscillations (HFOs; ~150 Hz), which can be driven by a hippocampus-subiculum pathway. How the cellular-synaptic and laminar organization of gRSC facilitates HFOs is unknown. Here, we probe gRSC HFO generation and coupling with hippocampal rhythms using focal optogenetics and silicon-probe recordings in behaving mice. ChR2-mediated excitation of CaMKII-expressing cells in L2/3 or L5 induces HFOs, but spontaneous HFOs are found only in L2/3, where HFO power is highest. HFOs couple to CA1 sharp wave-ripples (SPW-Rs) during rest and the descending phase of theta. gRSC HFO current sources and sinks are the same for events during both SPW-Rs and theta oscillations. Independent component analysis shows that high gamma (50–100 Hz) in CA1 stratum lacunosum moleculare is comodulated with HFO power. HFOs may thus facilitate interregional communication of a multisynaptic loop between the gRSC, hippocampus, and medial entorhinal cortex during distinct brain and behavioral states.
Examining the Effect of Increased Aerobic Exercise in Moderately Fit Adults on Psychological State and Cognitive Function
Basso, Julia C.; Oberlin, Douglas J.; Satyal, Medha K.; O’Brien, Catherine E.; Crosta, Christen; Psaras, Zach; Metpally, Anvitha; Suzuki, Wendy A. (Frontiers Media, 2022-07-12)
Regular physical exercise can decrease the risk for obesity, diabetes, and cardiovascular disease, increase life expectancy, and promote psychological health and neurocognitive functioning. Cross-sectional studies show that cardiorespiratory fitness level (VO₂ max) is associated with enhanced brain health, including improved mood state and heightened cognitive performance. Interventional studies are consistent with these cross-sectional studies, but most have focused on low-fit populations. Few such studies have asked if increasing levels of physical activity in moderately fit people can significantly enhance mood, motivation, and cognition. Therefore, the current study investigated the effects of increasing aerobic exercise in moderately fit individuals on psychological state and cognitive performance.We randomly assigned moderately fit healthy adults, 25–59 years of age, who were engaged in one or two aerobic exercise sessions per week to either maintain their exercise regimen (n = 41) or increase their exercise regimen (i.e., 4–7 aerobic workouts per week; n = 39) for a duration of 3 months. Both before and after the intervention, we assessed aerobic capacity using a modified cardiorespiratory fitness test, and hippocampal functioning via various neuropsychological assessments including a spatial navigation task and the Mnemonic Similarity Task as well as self-reported measures including the Positive and Negative Affect Scale, Beck Anxiety Inventory, State-Trait Anxiety Inventory, Perceived Stress Scale, Rumination Scale, Eating Disorders Examination, Eating Attitudes Test, Body Attitudes Test, and Behavioral Regulation of Exercise Questionnaire. Consistent with our initial working hypotheses, we found that increasing exercise significantly decreased measures of negative affect, including fear, sadness, guilt, and hostility, as well as improved body image. Further, we found that the total number of workouts was significantly associated with improved spatial navigation abilities and body image as well as reduced anxiety, general negative affect, fear, sadness, hostility, rumination, and disordered eating. In addition, increases in fitness levels were significantly associated with improved episodic memory and exercise motivation as well as decreased stress and disordered eating. Our findings are some of the first to indicate that in middle-aged moderately-fit adults, continuing to increase exercise levels in an already ongoing fitness regimen is associated with additional benefits for both psychological and cognitive health.
Assessing Human Spatial Navigation in a Virtual Space and its Sensitivity to Exercise
Smith, Alana J.; Tasnim, Noor; Psaras, Zach; Gyamfi, Daphne; Makani, Krishna; Suzuki, Wendy A.; Basso, Julia C. (MyJove Corporation, 2024-01-26)
Spatial navigation (SN) is the ability to locomote through the environment, which requires an understanding of where one is located in time and space. This capacity is known to rely on the sequential firing of place cells within the hippocampus. SN is an important behavior to investigate as this process deteriorates with age, especially in neurodegenerative disorders. However, the investigation of SN is limited by the lack of sophisticated behavioral techniques to assess this hippocampal-dependent task. Therefore, the goal of this protocol was to develop a novel, real-world approach to studying SN in humans. Specifically, an active virtual SN task was developed using a cross-platform game engine. During the encoding phase, participants navigated their way through a virtual city to locate landmarks. During the remembering phase, participants remembered where these reward locations were and delivered items to these locations. Time to find each location was captured and episodic memory was assessed by a free recall phase, including aspects of place, order, item, and association. Movement behavior (x, y, and z coordinates) was assessed through an asset available in the game engine. Importantly, results from this task demonstrate that it accurately captures both spatial learning and memory abilities as well as episodic memory. Further, findings indicate that this task is sensitive to exercise, which improves hippocampal functioning. Overall, the findings suggest a novel way to track human hippocampal functioning over the course of time, with this behavior being sensitive to physical activity training paradigms.
Effects of a Neuroscience-Based Mindfulness Meditation Program on Psychological Health: Pilot Randomized Controlled Trial
Lynn, Sarah; Basso, Julia C. (JMIR Publications, 2023)
Background: Mindfulness and meditation have a rich historical tradition, and a growing scientific base of evidence supports their use in creating positive psychological and neuroplastic changes for practitioners. Although meditation can be taught in various ways, the scientific community has yet to systematically study the impact of different types of meditation on neuropsychological outcomes, especially as it pertains to digital implementation. Therefore, it is critical that the instruction of mindfulness be evidence based because meditation is being used in both scientific and clinical settings. Objective: This study investigated the use of teacher cueing and the integration of neuroscience education into a meditation program. Compassion cueing was chosen as the element of experimental manipulation because traditional lineages of Buddhist meditation teach compassion for self and others as one of the primary outcomes of meditation. We hypothesized that participants receiving compassion cueing would have enhanced neuropsychological outcomes compared with those receiving functional cueing and that gains in neuroscience knowledge would relate to positive neuropsychological outcomes. Methods: Participants (n=89) were randomized to receive either functional cueing (control group) or compassion cueing (experimental group) and engaged with five 10-minute meditation sessions a week for 4 weeks. All intervention sessions were administered through digital presentation. All participants completed ecological momentary assessments before and after the daily intervention, as well as pre- and postintervention questionnaires. Results: Participants demonstrated significant benefits over time, including increased mindfulness and self-compassion, decreased depression, and gains in neuroscience content (all P<.001); however, no significant between-group differences were found. Daily scores from each day of the intervention showed a statistically significant shift from active toward settled. Importantly, long-term increases in mindfulness were positively correlated to changes in compassion (r=0.326; P=.009) and self-compassion (r=0.424; P<.001) and negatively correlated to changes in anxiety (r=–0.266; P=.03) and depression (r=–0.271; P=.03). Finally, the acute effects of meditation were significantly correlated to the longitudinal outcomes (with a small-to-medium effect size), especially those relevant to mindfulness. Conclusions: We developed a novel neuroscience-based education–meditation program that enhanced self-regulation as evidenced by improved mindfulness, self-compassion, and mood state. Our findings demonstrate the behavioral importance of engaging with mindfulness meditation and reinforce the idea that the benefits of meditation are independent of teacher cueing behavior. Future studies will need to investigate the brain-based changes underlying these meditation-induced outcomes.
Clinical Theranostics in Recurrent Gliomas: A Review
Hoggarth, Austin R.; Muthukumar, Sankar; Thomas, Steven M.; Crowley, James; Kiser, Jackson; Witcher, Mark R. (MDPI, 2024-04-28)
Gliomas represent the most commonly occurring tumors in the central nervous system and account for approximately 80% of all malignant primary brain tumors. With a high malignancy and recurrence risk, the prognosis of high-grade gliomas is poor, with a mean survival time of 12–18 months. While contrast-enhanced MRI serves as the standard diagnostic imaging modality for gliomas, it faces limitations in the evaluation of recurrent gliomas, failing to distinguish between treatment-related changes and tumor progression, and offers no direct therapeutic options. Recent advances in imaging modalities have attempted to address some of these limitations, including positron emission tomography (PET), which has demonstrated success in delineating tumor margins and guiding the treatment of recurrent gliomas. Additionally, with the advent of theranostics in nuclear medicine, PET tracers, when combined with therapeutic agents, have also evolved beyond a purely diagnostic modality, serving both diagnostic and therapeutic roles. This review will discuss the growing involvement of theranostics in diagnosing and treating recurrent gliomas and address the associated impact on quality of life and functional recovery.
Antibiotic exposure is associated with decreased risk of psychiatric disorders
Kerman, Ilan A.; Glover, Matthew E.; Lin, Yezhe; West, Jennifer L.; Hanlon, Alexandra L.; Kablinger, Anita S.; Clinton, Sarah M. (Frontiers, 2024-01-08)
Objective: This study sought to investigate the relationship between antibiotic exposure and subsequent risk of psychiatric disorders. Methods: This retrospective cohort study used a national database of 69 million patients from 54 large healthcare organizations. We identified a cohort of 20,214 (42.5% male; 57.9 ± 15.1 years old [mean ± SD]) adults without prior neuropsychiatric diagnoses who received antibiotics during hospitalization. Matched controls included 41,555 (39.6% male; 57.3 ± 15.5 years old) hospitalized adults without antibiotic exposure. The two cohorts were balanced for potential confounders, including demographics and variables with potential to affect: the microbiome, mental health, medical comorbidity, and overall health status. Data were stratified by age and by sex, and outcome measures were assessed starting 6 months after hospital discharge. Results: Antibiotic exposure was consistently associated with a significant decrease in the risk of novel mood disorders and anxiety and stressor-related disorders in: men (mood (OR 0.84, 95% CI 0.77, 0.91), anxiety (OR 0.88, 95% CI 0.82, 0.95), women (mood (OR 0.94, 95% CI 0.89,1.00), anxiety (OR 0.93, 95% CI 0.88, 0.98), those who are 26–49 years old (mood (OR 0.87, 95% CI 0.80, 0.94), anxiety (OR 0.90, 95% CI 0.84, 0.97)), and in those ≥50 years old (mood (OR 0.91, 95% CI 0.86, 0.97), anxiety (OR 0.92, 95% CI 0.87, 0.97). Risk of intentional harm and suicidality was decreased in men (OR 0.73, 95% CI 0.55, 0.98) and in those ≥50 years old (OR 0.67, 95% CI 0.49, 0.92). Risk of psychotic disorders was also decreased in subjects ≥50 years old (OR 0.83, 95 CI: 0.69, 0.99). Conclusion: Use of antibiotics in the inpatient setting is associated with protective effects against multiple psychiatric outcomes in an age- and sex-dependent manner.
Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy
Browning, Jack L.; Wilson, Kelsey A.; Shandra, Oleksii; Wei, Xiaoran; Mahmutovic, Dzenis; Maharathi, Biswajit; Robel, Stefanie; VandeVord, Pamela J.; Olsen, Michelle L. (MDPI, 2024-03-01)
Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE⁺), those without epilepsy (PTE⁻), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE⁺ and PTE⁻ relative to sham. Focusing on protein pathways unique to PTE⁺, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE⁻. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.
Risk of Excess Maternal Folic Acid Supplementation in Offspring
Xu, Xiguang; Zhang, Ziyu; Lin, Yu; Xie, Hehuang (MDPI, 2024-03-06)
Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.
NAPE-PLD regulates specific baseline affective behaviors but is dispensable for inflammatory hyperalgesia
Chen, Irene; Murdaugh, Laura B.; Miliano, Cristina; Dong, Yuyang; Gregus, Ann M.; Buczynski, Matthew W. (Elsevier, 2023-06-14)
N-acyl-ethanolamine (NAEs) serve as key endogenous lipid mediators as revealed by manipulation of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for metabolizing NAEs. Preclinical studies focused on FAAH or NAE receptors indicate an important role for NAE signaling in nociception and affective behaviors. However, there is limited information on the role of NAE biosynthesis in these same behavioral paradigms. Biosynthesis of NAEs has been attributed largely to the enzyme N-acylphosphatidylethanolamine Phospholipase D (NAPE-PLD), one of three pathways capable of producing these bioactive lipids in the brain. In this report, we demonstrate that Nape-pld knockout (KO) mice displayed reduced sucrose preference and consumption, but other baseline anxiety-like or depression-like behaviors were unaltered. Additionally, we observed sex-dependent responses in thermal nociception and other baseline measures in wildtype (WT) mice that were absent in Nape-pld KO mice. In the Complete Freund's Adjuvant (CFA) model of inflammatory arthritis, WT mice exhibited sex-dependent changes in paw edema that were lost in Nape-pld KO mice. However, there was no effect of Nape-pld deletion on arthritic pain-like behaviors (grip force deficit and tactile allodynia) in either sex, indicating that while NAPE-PLD may alter local inflammation, it does not contribute to pain-like behaviors associated with inflammatory arthritis. Collectively, these findings indicate that chronic and systemic NAPE-PLD inactivation will likely be well-tolerated, warranting further pharmacological evaluation of this target in other disease indications.
Prognostic Factors and Nomogram for Choroid Plexus Tumors: A Population-Based Retrospective Surveillance, Epidemiology, and End Results Database Analysis
Bhutada, Abhishek S.; Adhikari, Srijan; Cuoco, Joshua A.; In, Alexander; Rogers, Cara M.; Jane, John A.; Marvin, Eric A. (MDPI, 2024-01-31)
Background: Choroid plexus tumors (CPTs) are rare neoplasms found in the central nervous system, comprising 1% of all brain tumors. These tumors include choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Although gross total resection for choroid plexus papillomas (CPPs) is associated with long-term survival, there is a scarcity of prospective data concerning the role and sequence of neoadjuvant therapy in treating aCPP and CPC. Methods: From the years 2000 to 2019, 679 patients with CPT were identified from the Surveillance, Epidemiology, and End Result (SEER) database. Among these patients, 456 patients had CPP, 75 patients had aCPP, and 142 patients had CPC. Univariate and multivariable Cox proportional hazard models were run to identify variables that had a significant impact on the primary endpoint of overall survival (OS). A predictive nomogram was built for patients with CPC to predict 5-year and 10-year survival probability. Results: Histology was a significant predictor of OS, with 5-year OS rates of 90, 79, and 61% for CPP, aCPP, and CPC, respectively. Older age and African American race were prognostic for worse OS for patients with CPP. Older age was also associated with reduced OS for patients with aCPP. American Indian/Alaskan Native race was linked to poorer OS for patients with CPC. Overall, treatment with gross total resection or subtotal resection had no difference in OS in patients with CPP or aCPP. Meanwhile, in patients with CPC, gross total resection (GTR) was associated with significantly better OS than subtotal resection (STR) only. However, there is no difference in OS between patients that receive GTR and patients that receive STR with adjuvant therapy. The nomogram for CPC considers types of treatments received. It demonstrates acceptable accuracy in estimating survival probability at 5-year and 10-year intervals, with a C-index of 0.608 (95% CI of 0.446 to 0.77). Conclusions: This is the largest study on CPT to date and highlights the optimal treatment strategies for these rare tumors. Overall, there is no difference in OS with GTR vs. STR in CPP or aCPP. Furthermore, OS is equivalent for CPC with GTR and STR plus adjuvant therapy.
Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial
Legon, Wynn; Strohman, Andrew; In, Alexander; Payne, Brighton (Wolters Kluwer Health, Inc., 2024-02-01)
The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat–evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.
Using Drosophila Two-Choice Assay to Study Optogenetics in Hands-On Neurobiology Laboratory Activities
Fu, Zhuo; Huda, Ainul; Kimbrough, Ian F.; Ni, Lina (Faculty for Undergraduate Neuroscience, 2023)
Optogenetics has made a significant impact on neuroscience, allowing activation and inhibition of neural activity with exquisite spatiotemporal precision in response to light. In this lab session, we use fruit flies to help students understand the fundamentals of optogenetics through hands-on activities. The CsChrimson channelrhodopsin, a light-activated cation channel, is expressed in sweet and bitter sensory neurons. Sweet sensory neurons guide animals to identify nutrient-rich food and drive appetitive behaviors, while bitter sensory neurons direct animals to avoid potentially toxic substances and guide aversive behavior. Students use two-choice assays to explore the causality between the stimulation activation of these neurons and the appetitive and avoidance behaviors of the fruit flies. To quantify their observations, students calculate preference indices and use the Student’s t-test to analyze their data. After this lab session, students are expected to have a basic understanding of optogenetics, fly genetics, sensory perception, and how these relate to sensory-guided behaviors. They will also learn to conduct, quantify, and analyze two-choice behavioral assays.

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