Neurosciences Commons^™

Multiple Guidance Mechanisms Control Axon Growth To Generate Precise T-Shaped Bifurcation During Dorsal Funiculus Development In The Spinal Cord, Bridget M. Curran, Kelsey R. Nickerson, Andrea R. Yung, Lisa V. Goodrich, Alexander Jaworski, Marc Tessier-Lavigne, Le Ma

Farber Institute for Neuroscience Faculty Papers

The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 had axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis …

A Single-Cell Transcriptomic Map Of The Developing Atoh1 Lineage Identifies Neural Fate Decisions And Neuronal Diversity In The Hindbrain, Jessica C Butts, Sih-Rong Wu, Mark A Durham, Ryan S Dhindsa, Jean-Pierre Revelli, M Cecilia Ljungberg, Olivier Saulnier, Madison E Mclaren, Michael D Taylor, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for …

Dysregulation Of Dopamine Dynamics Through Monoamine Transporters By The Hiv-1 Protein Transactivator Of Transcription, Sarah Davis

Theses and Dissertations

Prevalence of HIV-1 Associated Cognitive Disorders (HAND) persists in the era of combined antiretroviral therapies, causing impaired memory, motor function, and decreased quality of life. Evidence from clinical samples of persons with HAND has implicated dopamine, as well as the HIV-1 viral protein transactivator of transcription (Tat) as key molecules associated with disease progression. Through molecular modeling, in vitro and in vivo mutagenesis our lab has characterized Tat as a negative allosteric modulator for monoamine transporters, including the dopamine transporter (DAT), vesicular monoamine transporter (VMAT-2), and norepinephrine transporter. While this work has shed light on how Tat impacts the function …

Neural Mechanisms Of Estrogen And Inflammation In Female Stress Susceptibility, Samantha Jane Bouknight

Theses and Dissertations

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are highly debilitating psychiatric disorders that notably share stress as an etiological factor. Stress is a common occurrence experienced daily by virtually everyone and, while most people are resilient, a substantial portion of the population exhibit risk factors that yield them susceptible to developing stress-related psychiatric disorders. One prominent factor that has long been known to increase this risk is the female biological sex with women presenting at least twice as often with disorders like PTSD and MDD compared to men. Interestingly, this bias exists distinctly during the reproductive years and …

Tfeb Activation Hallmarks Antigenic Experience Of B Lymphocytes And Directs Germinal Center Fate Decisions, Matthias Münchhalfen, Richard Görg, Michael Haberl, Jens Löber, Jakob Willenbrink, Laura Schwarzt, Charlotte Höltermann, Christian Ickes, Leonard Hammermann, Jan Kus, Björn Chapuy, Andrea Ballabio, Sybille D Reichardt, Alexander Flügel, Niklas Engels, Jürgen Wienands

Duncan NRI Faculty and Staff Publications

Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation …

Loss Of Transient Receptor Potential Channel 5 Causes Obesity And Postpartum Depression, Yongxiang Li, Tessa M Cacciottolo, Na Yin, Yang He, Hesong Liu, Hailan Liu, Yuxue Yang, Elana Henning, Julia M Keogh, Katherine Lawler, Edson Mendes De Oliveira, Eugene J Gardner, Katherine A Kentistou, Panayiotis Laouris, Rebecca Bounds, Ken K Ong, John R B Perry, Inês Barroso, Longlong Tu, Jonathan C Bean, Meng Yu, Kristine M Conde, Mengjie Wang, Olivia Ginnard, Xing Fang, Lydia Tong, Junying Han, Tia Darwich, Kevin W Williams, Yongjie Yang, Chunmei Wang, Shelagh Joss, Helen V Firth, Yong Xu, I Sadaf Farooqi

Duncan NRI Faculty and Staff Publications

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of …

Pathophysiology In Brain Arteriovenous Malformations: Focus On Endothelial Dysfunctions And Endothelial-To-Mesenchymal Transition, Jae Yeong Jeong, Adrian E Bafor, Bridger H Freeman, Peng R Chen, Eun S Park, Eunhee Kim

Faculty, Staff and Student Publications

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to …

The Oncolytic Adenovirus Delta-24-Rgd In Combination With Onc201 Induces A Potent Antitumor Response In Pediatric High-Grade And Diffuse Midline Glioma Models, Daniel De La Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper Van Der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso

Faculty, Staff and Student Publications

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the …

Circuit-Specific Deep Brain Stimulation Provides Insights Into Movement Control., Aryn H Gittis, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Deep brain stimulation (DBS), a method in which electrical stimulation is delivered to specific areas of the brain, is an effective treatment for managing symptoms of a number of neurological and neuropsychiatric disorders. Clinical access to neural circuits during DBS provides an opportunity to study the functional link between neural circuits and behavior. This review discusses how the use of DBS in Parkinson's disease and dystonia has provided insights into the brain networks and physiological mechanisms that underlie motor control. In parallel, insights from basic science about how patterns of electrical stimulation impact plasticity and communication within neural circuits are …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …

In Vivo Examination Of Peripheral Drivers Of Alzheimer’S Disease, Celso Catumbela

Dissertations and Theses (Open Access)

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and predominantly affects elderly populations. This disease is well known for its effects on the brain, but a wealth of clinical reports show that dementia can also modify, or be modified by, various peripheral and systemic processes. Yet, the pathological contribution of peripheral comorbidities to AD remains to be fully understood. In an attempt to address some knowledge gaps, we characterized the cerebral and peripheral pathology in mice with history of either liver injury or sepsis. In the former subjects, we found that even in the absence of genetic risk …

Biological Sex Influences Daily Locomotor Rhythms In Mice Held Under Different Housing Conditions, Amanda Pastrick, Matthew Diaz, Griffin Adaya, Victoria Montinola, Madeline Arzbecker, Deborah A. M. Joye, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

Daily rhythms are programmed by a central circadian clock that is modulated by photoperiod. Here, we recorded locomotor activity rhythms in C57Bl/6 or mPer2^Luc mice of both sexes held under different housing conditions. First, we confirm that the structure of locomotor activity rhythms differs between male and female mice in both genetic backgrounds. Male mice exhibit a nightly “siesta,” whereas female mice fluctuate between nights with and without a nightly siesta, which corresponds with changes in locomotor activity levels, circadian period, and vaginal cytology. The nightly siesta is modulated by the presence of a running wheel in both sexes …

Simulation-Based Caregiving Skills Training For Family Members Of High-Grade Glioma Patients, Meagan Whisenant, Shiao-Pei Weathers, Yisheng Li, Ellen Aldrich, Kristin Ownby, Jessica Thomas, An Ngo-Huang, Eduardo Bruera, Kathrin Milbury

Faculty, Staff and Student Publications

BACKGROUND: Because family caregivers of patients with a high-grade glioma experience high levels of distress and feel unprepared to perform the complex caregiving tasks associated with the disease and its treatment, we pilot-tested a caregiving skills intervention that integrates hands-on caregiving with coping skill training.

METHODS: In this single-arm trial, caregivers participated in a 4-session research nurse-led intervention involving simulation-based caregiving skills training at the hospital and psychoeducation delivered via videoconference. We collected measures of patients' and caregivers' psychological symptoms; caregivers' caregiving self-efficacy and role adjustment; and patients' cancer-related symptoms (MDASI) at baseline and again postintervention. We tracked feasibility data. …

African American Patients Have A Higher Probability Of Cognitive Impairment After Incident Stroke: An Analysis Of National Electronic Health Record Data, Alicia Zha, Chenguang Zhang, Gen Zhu, Xinran Huang, Sahar Anjum, Yashar Talebi, Sean Savitz, Hulin Wu

Faculty, Staff and Student Publications

Background: Cognitive impairment (CI) and stroke are diseases with significant disparities in race and geography. Post stroke cognitive impairment (PSCI) can be as high as 15-70 % but few studies have utilized large administrative or electronic health records (EHR) to evaluate trends in PSCI. We utilized an EHR database to evaluate for disparities in PSCI in a large sample of patients after first recorded stroke to evaluate for disparities in race.

Methods: This is a retrospective cohort analysis of Cerner Health Facts® EHR database, which is comprised of EHR data from hundreds of hospitals/clinics in the US from 2009-2018. We …

Apolipoprotein Ε4 Is Associated With Increased Risk Of Fall- And Fracture-Related Hospitalization: The Perth Longitudinal Study Of Ageing Women, Jedd Pratt, Jack Dalla Via, Craig Sale, Abadi K. Gebre, Blossom C.M. Stephan, Simon Laws, Kun Zhu, Wai H. Lim, Richard L. Prince, Joshua R. Lewis, Marc Sim

Research outputs 2022 to 2026

Apolipoprotein ε4 (APOE ε4) may be a genetic risk factor for reduced bone mineral density (BMD) and muscle function, which could have implications for fall and fracture risk. We examined the association between APOE ε4 status and long-term fall- and fracture-related hospitalization risk in older women. A total of 1 276 community-dwelling women from the Perth Longitudinal Study of Aging Women (mean age ± SD = 75.2 ± 2.7 years) were included. At baseline, women underwent APOE genotyping and detailed phenotyping for covariates including prevalent falls and fractures, as well as health and lifestyle factors. The association between APOE ε4 …

The Effects Of Non-Invasive Brain Stimulation On Excitability Of The Primary Motor Cortices And Complex Motor Task Learning, Erik Woodruff Wilkins

UNLV Theses, Dissertations, Professional Papers, and Capstones

Transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) are promising non-invasive brain stimulation techniques, particularly for clinical applications involving altered or impaired motor function, such as in stroke and Parkinson’s disease. Although tDCS and tACS are different modalities, both forms of stimulation operate on the same principle - weak electrical currents are delivered through electrodes placed on the scalp in specific configurations known as “montages”. The most commonly used montage for targeting the primary motor cortex (M1) is the M1-SO configuration. This montage leverages the established observation that cortical regions directly beneath the anode generally increase in …

Regulation And Mechanisms Of Ocular Dominance Plasticity At Cellular Resolution., Thomas Christopher Brown

Electronic Theses and Dissertations

Sensory systems throughout the brain require experience to aid in proper wiring during development. While forming, many sensory systems have periods of heightened sensitivity where alterations in the quality of experience can have a profound impact on cortical responses throughout life. These periods of heightened sensitivity have been coined critical periods. In the visual system of mice a critical period for ocular dominance has been well studied and defined between postnatal days nineteen and thirty-six. During this critical period, altering visual experience by suturing one eye closed called monocular deprivation (MD) shifts responses in cortex towards the non-deprived eye. Similar …

Epidural Stimulation For Urogenital Dysfunction In The Spinal Cord Injured Rat., Natasha Lorraine Wilkins

Electronic Theses and Dissertations

Spinal cord injury (SCI) is a devastating, life changing event that greatly impacts quality of life. SCI can have body-wide, multi-system consequences including dysfunction within the urogenital system. Challenges with the urinary system include urinary incontinence, urine retention, and detrusor-sphincter dyssynergia all of which require maintenance through the regular use of catheters. Sexual dysfunction in men, who comprise nearly 80% of the SCI population, includes erectile dysfunction, anejaculation, retrograde ejaculation, poor expulsive force during ejaculation, and poor sperm quality. The treatment for sexual function in SCI men is focused more on fertility through the collection of sperm for insemination procedures …

Neural Interactions In Bottom-Up Communication, Prashant Chama Raju

Graduate Theses and Dissertations

The visual system’s remarkable ability to process vast amounts of sensory information rapidly and accurately is fundamental to cognitive neuroscience. This study investigates a key aspect of this capability: the compartmentalization of information into feature-specific subspaces during bottom-up communication. My primary question was: does Canonical Correlation Analysis (CCA) reveal a subspace that encodes color and direction of moving dot stimuli? I found that the first canonical component (CC1) does an excellent job decoding the stimuli, despite being one-dimensional while the stimuli were drawn from a two-dimensional space (red-green and up-down plane). I demonstrate that motion features are processed within distinct …

Investigating Genetic Overlap Between Alzheimer’S Disease, Lipids, And Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis, Artika Kirby, Tenielle Porter, Emmanuel O. Adewuyi, Simon M. Laws

Research outputs 2022 to 2026

There is evidence to support a link between abnormal lipid metabolism and Alzheimer’s disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its relationship with lipids and CAD traits remains unresolved. Conflicting evidence further underscores the ongoing investigation into this research area. Here, we systematically assess the cross-trait genetic overlap of AD with 13 representative lipids (from eight classes) and seven CAD traits, leveraging robust analytical methods, well-powered large-scale genetic data, and rigorous replication testing. Our main analysis demonstrates a significant …