Neurosciences Commons^™

Labeling Piezo2 Activity In The Peripheral Nervous System, Nicholas W Villarino, Yasmeen M F Hamed, Britya Ghosh, Adrienne E Dubin, Amanda H Lewis, Max A Odem, Meaghan C Loud, Yu Wang, M Rocio Servin-Vences, Ardem Patapoutian, Kara L Marshall

Duncan NRI Faculty and Staff Publications

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the …

A Multiparameter Molecular Classifier To Predict Response To Neoadjuvant Lapatinib Plus Trastuzumab Without Chemotherapy In Her2+ Breast Cancer, Jamunarani Veeraraghavan, Carolina Gutierrez, Carmine De Angelis, Robert Davis, Tao Wang, Tomas Pascual, Pier Selenica, Katherine Sanchez, Hiroaki Nitta, Monesh Kapadia, Anne C Pavlick, Patricia Galvan, Brent Rexer, Andres Forero-Torres, Rita Nanda, Anna M Storniolo, Ian E Krop, Matthew P Goetz, Julie R Nangia, Antonio C Wolff, Britta Weigelt, Jorge S Reis-Filho, Susan G Hilsenbeck, Aleix Prat, C Kent Osborne, Rachel Schiff, Mothaffar F Rimawi

Faculty, Staff and Student Publications

PURPOSE: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy.

EXPERIMENTAL DESIGN: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based …

In Situ Characterization Of 17-4ph Stainless Steel By Small-Angle Neutron Scattering, Shibo Yan, Zijun Wang, Tianfu Li, Zhong Chen, Xiaoming Du, Yuntao Liu, Dongfeng Chen, Kai Sun, Rongdeng Liu, Bing Bai, Xinfu He, Kaitai Liu, Shuanzhu Wang

Faculty, Staff and Student Publications

17-4PH martensitic steel is usually used as valve stems in nuclear power plants and it suffers from thermal aging embrittlement due to long-time service in a high-temperature and high-pressure environment. Here, we characterized the evolution of microstructures at the nano-scale in 17-4PH steel by in situ small-angle neutron scattering (SANS) with a thermo-mechanically coupled loading device. The device could set different temperatures and tensile so that an in situ SANS experiment could dynamically characterize the process of nanoscale structural changes. The results showed that with increasing thermal aging time, the ε-Cu phase precipitates and grows as the temperature is 475 …

The Nurosleeve, A User-Centered 3d Printed Hybrid Orthosis For Individuals With Upper Extremity Impairment, Mehdi Khantan, Mikael Avery, Phyo Thuta Aung, Rachel M. Zarin, Emma Hammelef, Nabila Shawki, Mijail Demian Serruya, Alessandro Naopli

Farber Institute for Neuroscience Faculty Papers

BACKGROUND: Active upper extremity (UE) assistive devices have the potential to restore independent functional movement in individuals with UE impairment due to neuromuscular diseases or injury-induced chronic weakness. Academically fabricated UE assistive devices are not usually optimized for activities of daily living (ADLs), whereas commercially available alternatives tend to lack flexibility in control and activation methods. Both options are typically difficult to don and doff and may be uncomfortable for extensive daily use due to their lack of personalization. To overcome these limitations, we have designed, developed, and clinically evaluated the NuroSleeve, an innovative user-centered UE hybrid orthosis.

METHODS: This …

Novel Murine Glioblastoma Models That Reflect The Immunotherapy Resistance Profile Of A Human Disease, Chao-Hsien Chen, Renee L Chin, Genevieve P Hartley, Spencer T Lea, Brian J Engel, Cheng-En Hsieh, Rishika Prasad, Jason Roszik, Takashi Shingu, Gregory A Lizee, Amy B Heimberger, Steven W Millward, Jian Hu, David S Hong, Michael A Curran

Faculty, Staff and Student Publications

BACKGROUND: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms.

METHODS: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through …

Two Structurally Defined Aβ Polymorphs Promote Different Pathological Changes In Susceptible Mice, Ruben Gomez-Gutierrez, Ujjayini Ghosh, Wai-Ming Yau, Nazaret Gamez, Katherine Do, Carlos Kramm, Hamid Shirani, Laura Vegas-Gomez, Jonathan Schulz, Ines Moreno-Gonzalez, Antonia Gutierrez, K Peter R Nilsson, Robert Tycko, Claudio Soto, Rodrigo Morales

Faculty, Staff and Student Publications

Misfolded Aβ is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aβ strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain-specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, …

Piezo2 In Somatosensory Neurons Controls Gastrointestinal Transit, M Rocio Servin-Vences, Ruby M Lam, Alize Koolen, Yu Wang, Dimah N Saade, Meaghan Loud, Halil Kacmaz, Suzanne Frausto, Yunxiao Zhang, Arthur Beyder, Kara L Marshall, Carsten G Bönnemann, Alexander T Chesler, Ardem Patapoutian

Duncan NRI Faculty and Staff Publications

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in …

The Role Of Occupational Therapy In Duchenne Muscular Dystrophy, Mina Salinas, Mary Greer, Rudy Seward

Summer 2023 Virtual OTD Capstone Symposium

Duchenne muscular dystrophy (DMD) is a progressive inherited type of muscular dystrophy that results in progressive muscle weakness and requires a multidisciplinary approach for disease management. Occupational Therapy (OT) services are extremely valuable to this population as individuals diagnosed with this condition face significant difficulty in areas of occupational performance. Research shows occupational therapy services are not being received consistently and there are disparities in services received leaving a gap in the literature about the referral process and the understanding of OT's role.

Contrast Detection Is Enhanced By Deterministic, High-Frequency Transcranial Alternating Current Stimulation With Triangle And Sine Waveform, Weronika Potok, Onno Van Der Groen, Sahana Sivachelvam, Marc Bächinger, Flavio Fröhlich, Laszlo B. Kish, Nicole Wenderoth

Research outputs 2022 to 2026

Stochastic resonance (SR) describes a phenomenon where an additive noise (stochastic carrier-wave) enhances the signal transmission in a nonlinear system. In the nervous system, nonlinear properties are present from the level of single ion channels all the way to perception and appear to support the emergence of SR. For example, SR has been repeatedly demonstrated for visual detection tasks, also by adding noise directly to cortical areas via transcranial random noise stimulation (tRNS). When dealing with nonlinear physical systems, it has been suggested that resonance can be induced not only by adding stochastic signals (i.e., noise) but also by adding …

A Comparison Of Pm-Nato3’S Influence On Neural Progenitors And Mature Dopamine Neurons, Mary E. West

Masters Theses

This thesis presents significant findings regarding the role of PM-Nato3 in its interaction with developing neurons in the context of Parkinson's disease (PD) and regenerative medicine. We investigated the effects of PM-Nato3 on dopamine (DA) neurogenesis under different culture conditions, both in vitro and in vivo. In the standard dopaminergic culture condition, PM-Nato3 potentially increased the speed of DA neuron production but did not significantly increase the yield of DA neurons. In a minimal culture condition, there was no notable difference between the control and PM-Nato3 conditions, suggesting minimal impact on DA neurogenesis. In vivo studies using a mouse model …

Epileptic Seizure Classification Using Image-Based Data Representation, Amber Surles

Graduate Theses and Dissertations (2019 - present)

Epilepsy is a recurrence of seizures caused by a disorder of the brain in over 3.4 million people nationwide. Some people are able to predict their seizures based off prodrome, which is an early sign or symptom that usually resembles mood changes or a euphoric feeling even days to an hour before occurrence. Consequently, the natural instincts of the body to react to an upcoming attack lends credence to the existence of a pre-ictal state that precedes seizure episodes. Physicians and researchers have thus sought for an automated approach for predicting or detecting seizures.

In this research, we evaluate the …

Eosinophils Promote Effector Functions Of Lung Group 2 Innate Lymphoid Cells In Allergic Airway Inflammation In Mice, William E Lesuer, Melanie Kienzl, Sergei I Ochkur, Rudolf Schicho, Alfred D Doyle, Benjamin L Wright, Matthew A Rank, Alexander S Krupnick, Hirohito Kita, Elizabeth A Jacobsen

Faculty, Staff and Student Publications

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined.

OBJECTIVE: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro.

METHODS: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of …

Primary Balloon Angioplasty Of Venous Sinus Stenosis In Idiopathic Intracranial Hypertension, Juan Carlos Martinez-Gutierrez, Matthew J Kole, Victor Lopez-Rivera, Mehmet Enes Inam, Rosa Tang, Nagham Al-Zubidi, Ore-Ofeoluwatomi Adesina, Elvira Lekka, Allison C Engstrom, Sunil Sheth, Claudia Pedroza, Arthur L Day, Peng Roc Chen

Faculty, Staff and Student Publications

Background: Venous sinus stenosis (VSS) stenting has emerged as an effective treatment for patients with Idiopathic Intracranial Hypertension (IIH). However, stenting carries risk of in-stent stenosis/thrombosis and cumulative bleeding risk from long-term dual antiplatelet (DAPT) use. Thus, we investigated the potential safety and efficacy of primary balloon angioplasty as an alternative to stenting in IIH.

Methods: A prospectively maintained single-center registry of IIH patients undergoing endovascular procedures was queried. Inclusion criteria included patients with confirmed IIH and angiographically demonstrable VSS who underwent interventions from 2012- 2021. Patients were dichotomized into primary balloon angioplasty (Group A) and primary stenting (Group S), …

The Genetic Relationship Between Peripheral Inflammation And Alzheimer’S Disease, Davis Cammann

UNLV Theses, Dissertations, Professional Papers, and Capstones

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and has become an ever-present problem in aging populations. An increasing body of evidence suggests that neuroinflammation is one of the key drivers of AD pathology. One overlooked contributor to this burden is peripheral inflammation throughout the body. Due to increased permeability of the blood-brain-barrier (BBB) in older age, inflammatory plasma proteins and immune cells infiltrate the CNS and drive neuroinflammation through interactions with neurons and glia. In addition, age-related changes in the composition of gut microbiome taxa lead to increased gut permeability and inflammatory burden. Because inflammatory factors are …

Injury Induced Neuroplasticity And Cell Specific Targeting Of The Lumbar Enlargement For Gene Therapy., Brandon Lee Brown

Electronic Theses and Dissertations

This dissertation is an examination of spinal cord injury induced neuroplasticity and tests whether noninvasive gene therapy can successfully target neurons in the lumbar spinal cord. It begins with an overview of neural control of locomotion and a brief summary of therapeutics that are used and/or in development for treating spinal anatomically characterize s subset of neurons in the spinal cord, long ascending propriospinal neurons, that are involved in interlimb coordination. Characterization of these neurons allows for subsequent evaluation of their potential involvement in injury induced neuroplasticity. This dissertation is divided into five chapters, covering spinal cord injury and therapeutics. …

Positron Emission Tomography And Magnetic Resonance Imaging Methods And Datasets Within The Dominantly Inherited Alzheimer Network (Dian), Nicole S. Mckay, Brian A. Gordon, Russ C. Hornbeck, Aylin Dincer, Shaney Flores, Sarah J. Keefe, Nelly Joseph-Mathurin, Clifford R. Jack, Robert Koeppe, Peter R. Millar, Beau M. Ances, Charles D. Chen, Alisha Daniels, Diana A. Hobbs, Kelley Jackson, Deborah Koudelis, Parinaz Massoumzadeh, Austin Mccullough, Michael L. Nickels, Farzaneh Rahmani, Laura Swisher, Qing Wang, Ricardo F. Allegri, Sarah B. Berman, Adam M. Brickman, William S. Brooks, David M. Cash, Jasmeer P. Chhatwal, Gregory S. Day, Martin R. Farlow, Christian La Fougère, Nick C. Fox, Michael Fulham, Bernardino Ghetti, Neill Graff-Radford, Takeshi Ikeuchi, William Klunk, Jae-Hong Lee, Johannes Levin, Ralph Martins, Colin L. Masters, Jonathan Mcconathy, Hiroshi Mori, James M. Noble, Gerald Reischl, Christopher Rowe, Stephen Salloway, Raquel Sanchez-Valle, Peter R. Schofield, Hiroyuki Shimada, Mikio Shoji, Yi Su, Kazushi Suzuki, Jonathan Vöglein, Igor Yakushev, Carlos Cruchaga, Jason Hassenstab, Celeste Karch, Eric Mcdade, Richard J. Perrin, Chengjie Xiong, John C. Morris, Randall J. Bateman, Tammie L. S. Benzinger, Dominantly Inherited Alzheimer Network

Research outputs 2022 to 2026

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case–control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual’s point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during …

Neuro-Immune Interactions And Immuno-Oncology, Narmina Khanmammadova, Shajedul Islam, Padmanee Sharma, Moran Amit

Faculty, Staff and Student Publications

The nervous system is an important component of the tumor microenvironment (TME), driving tumorigenesis and tumor progression. Neuronal cues (e.g., neurotransmitters and neuropeptides) in the TME cause phenotypic changes in immune cells, such as increased exhaustion and inhibition of effector cells, which promote immune evasion and cancer progression. Two types of immune regulation by tumor-associated nerves are discussed in this review: regulation via neuronal stimuli (i.e., by neural transmission) and checkpoint-mediated neuronal immune regulation. The latter occurs via the expression of immune checkpoints on the membranes of intratumoral nerves and glial cells. Here, we summarize novel findings regarding the neuroimmune …

Combining Voltage-Sensitive Dye, Carbon Fiber Array, And Extracellular Nerve Electrodes Using A 3-D Printed Recording Chamber And Manipulators, Curtis L Neveu, Yu Huan, Yuto Momohara, Paras R Patel, Hillel J Chiel, Cynthia A Chestek, John H Byrne

Faculty, Staff and Student Publications

BACKGROUND: The analyses of neuronal circuits require high-throughput technologies for stimulating and recording many neurons simultaneously with single-neuron precision. Voltage-sensitive dyes (VSDs) have enabled the monitoring of membrane potentials of many (10-100 s) neurons simultaneously. Carbon fiber electrode (CFE) arrays allow for stimulation and recording of many neurons simultaneously, including intracellularly.

NEW METHOD: Combining CFE with VSD leverages the advantages of both technologies, allowing for stimulation of single neurons while recording the activity of the entire network. 3-D printing technology was used to develop a chamber to simultaneously perform VSD imaging, CFE array recording, and extracellular recording from individual glass …

Cerebellar Dysfunction As A Source Of Dystonic Phenotypes In Mice, Amanda M Brown, Meike E Van Der Heijden, H A Jinnah, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

There is now a substantial amount of compelling evidence demonstrating that the cerebellum may be a central locus in dystonia pathogenesis. Studies using spontaneous genetic mutations in rats and mice, engineered genetic alleles in mice, shRNA knockdown in mice, and conditional genetic silencing of fast neurotransmission in mice have all uncovered a common set of behavioral and electrophysiological defects that point to cerebellar cortical and cerebellar nuclei dysfunction as a source of dystonic phenotypes. Here, we revisit the Ptf1aCre/+;Vglut2flox/flox mutant mouse to define fundamental phenotypes and measures that are valuable for testing the cellular, circuit, and …

C9orf72 Poly(Pr) Mediated Neurodegeneration Is Associated With Nucleolar Stress, M. E. Cicardi, J. H. Hallgren, D. Mawrie, K. Krishnamurthy, S. S. Markandaiah, A. T. Nelson, V. Kankate, E. N. Anderson, P. Pasinelli, U. B. Pandey, C. M. Eischen, D. Trotti

Farber Institute for Neuroscience Faculty Papers

The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is aberrantly translated in the sense and antisense directions into dipeptide repeat proteins, among which poly proline-arginine (PR) displays the most aggressive neurotoxicity in-vitro and in-vivo. PR partitions to the nucleus when heterologously expressed in neurons and other cell types. We show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR strongly accumulates in the nucleolus, a nuclear structure critical in regulating the cell stress response. We determined that, in neurons, PR caused nucleolar stress and increased levels of the transcription factor p53. …