Molecular and Cellular Neuroscience Commons^™

A 40-Week Phase 2b Randomized, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating The Safety And Efficacy Of Memantine In Amyotrophic Lateral Sclerosis, Salman Bhai, Todd Levine, Dan Moore, Robert Bowser, Andrew J. Heim, Maureen Walsh, Aziz Shibani, Zachary Simmons, James Grogan, Namita A. Goyal, Raghav Govindarajan, Yessar Hussain, Tania Papsdorf, Tiffany Schwasinger-Schmidt, Nick Olney, Kim Goslin, Michael Pulley, Edward J. Kasarskis, Michael Weiss, Susan W. Katz, Suzan Moser, Duaa Jabari, Omar Jawdat, Jeffrey Statland, Mazen M. Dimachkie, Richard Barohn, Neuromuscular Study Group And Western Als Consortium Memantine Als Study Group

Neurology Faculty Publications

Introduction: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.

Aims: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.

Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer’S Disease Detection And Monitoring, Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O’Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg

Neurology Faculty Publications

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer’s Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

Protonic Capacitor Cell Energetics: Transmembrane-Electrostatically Localized Protons/Cations, James Weifu Lee

Chemistry & Biochemistry Faculty Publications

The transmembrane-electrostatically localized protons/cations charges (TELPs/TELCs) theory can serve as a theoretical framework to better explain cell electrophysiology and elucidate bioenergetic systems including both delocalized and localized protonic coupling. According to the TELCs model, the excess positive charges of TELCs at one side of the membrane are balanced by the excess negative charges of transmembrane-electrostatically localized hydroxides anions (TELAs) at the other side of the membrane. Through the TELCs-membrane-TELAs capacitor model, the energetics of oxidative phosphorylation have recently been better elucidated in mitochondria and alkalophilic bacteria, leading to the identification of a novel Type-B energetic process. Both the TELCs model …

Morphology And Synaptic Connections Of A T7 Bipolar Cell In Mouse Retina, Lauren Groen

Williams Honors College, Honors Research Projects

This project will aim to identify ribbon outputs and post-synaptic partners of type 7 bipolar cells in a mouse retina. Using the software WebKnossos, a three-dimensional skeleton of three to four type 7 bipolar cells will be traced. Ribbon synapses will then be located along the cells' axon terminals, and the types of cells that are receiving the synaptic output will be identified. The goal of this project is to provide a better understanding of how type 7 bipolar cells interact with other neurons in the inner plexiform layer (IPL) of the retina.

The Role Of The Nasal Migratory Mass In Olfactory Bulb Formation And Fertility, Charisse Martin

Electronic Theses & Dissertations (2024 - present)

The olfactory migratory mass plays an essential role in the development of the olfactory bulb by facilitating the migration of the gonadotropin-releasing hormone neurons from the olfactory placode to the pre-optic hypothalamic area in the brain. In mammals, the migration of GnRH neurons is critical for establishing the hypothalamic-pituitary-gonadal axis (HPG axis), which regulates reproductive function through the production and secretion of gonadotropins. Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) instruct the gonads to function appropriately, ensuring sexual maturation and fertility. Disruptions in this migratory pathway have been linked with Kallmann syndrome, a condition characterized by low levels of GnRH, …

A Spectroscopy Study Of The Brain: Exploring Sex Differences In Healthy Older Adults, Angela Gushue

CMC Senior Theses

Cognitive decline and aging-related disorders, such as Alzheimer’s, disproportionately affect patients based on sex, but the mechanisms underlying these skewed effects are unknown. This proton magnetic resonance spectroscopy (H-MRS) study seeks to understand if sex disparities in aging exist in neurometabolite concentrations of older adult brains. Sixty-seven participants, ranging from 60 to 85 years of age, underwent the Montreal Cognitive Assessment (MoCA) and H-MRS of the brain. Concentrations of myo-inositol, total creatine, total NAA, and total choline were calculated in the dorsal posterior cingulate cortex, left hippocampal cortex, left medial temporal gyrus, left primary sensorimotor cortex, and right dorsolateral prefrontal …

Technological Development Of In-Cell Nmr: Microfluidic, Metabolomic, And Fluxomic Approaches, Nicholas Sciolino

Electronic Theses & Dissertations (2024 - present)

In the fields of structural biology, metabolomics, and fluxomics, there is a driving, technique-based concern when it comes to high-resolution spectrometry and its marriage to biological and physiological relevance. Sample preparation often involves cellular perturbation, lysate separation schemes, combinations with non-biological reagents, and timeline slack. Conceptually, the farther we get from the cell, the greater the potential disparity between what exists in vivo and our in vitro manipulations. This is particularly true when seeking to collect data on transfected targets of interest, and on sensitive metabolic equilibria that occur on the order of minutes. The question remains: if we are …

Co-Transmission Is Co-Opted For The Coordination Of Auditory Sensory Integration, Marryn M. Bennett

Graduate Theses, Dissertations, and Problem Reports (ETD)

Corollary discharge circuits (CDCs) are conserved mechanisms for sensory modulation during species specific behavioral programs. Many behaviors require multiplexed differential sensory modulation for proper execution. Co-transmission of fast and slow neurotransmitters allows for distinct modulation of different downstream targets within one sensorimotor circuit. However, studying co-transmission within the context of modulatory circuits like CDCs requires complete knowledge of behavioral circuits and precise tools for individually determining the implications of each transmitter on its targets. In this dissertation, I used a conserved set of corollary discharge interneurons in Drosophila melanogaster as a model to study the intricacies of sensory modulation through …

Ciliary Arl14b In Vision, Alexis Breann Crockett

Graduate Theses, Dissertations, and Problem Reports (ETD)

Primary cilia are highly specialized organelles that regulate signaling, trafficking, and sensory perception across multiple tissues, including the retina. The small GTPase ADP Ribosylation Factor-Like Protein 13B (ARL13B) is an atypical ARF-family protein enriched in cilia. ARL13B acts as a guanine exchange factor (GEF) for another small GTPase ARF-like Protein 3 (ARL3). Mutations in ARL13B cause Joubert syndrome, a ciliopathy characterized by brain malformation, developmental delays, and retinal degeneration. Despite ARL13B’s known ciliary localization and clinical relevance, ARL13B’s precise functions in cilia remain poorly defined. This dissertation investigates the cilia-specific roles and GEF-specific roles of ARL13B in photoreceptors using two …

Characterization Of A Descending Neuron That Modulates Flight Performance And Provides Input Onto A Flight-Related Predictive Motor Circuit, Andisheh Balouchi

Graduate Theses, Dissertations, and Problem Reports (ETD)

Descending neurons (DNs) play a critical role in sensorimotor integration by relaying motor information to the ventral nerve cord (VNC). Within the VNC, local interneurons, other DNs, and ascending neurons (ANs) make circuits with sensory and motor neurons to modify flies’ behavior. One important AN pair in Drosophila Melanogaster is mesothoracic ascending histaminergic neurons (MsAHNs), which are known to convey predictive wing motor signals to the brain. DNg32 is the primary upstream synaptic partner of MsAHNs, integrating DNg32 input with other inputs to generate predictive motor signals. The goals of this study were to 1) map the synaptic connectivity of …

A Novel Positive Allosteric Modulator Of Glun1/3 Nmda Receptors, Samuel A. Galindo

Graduate Student Theses, Dissertations, & Professional Papers

The GluN3-containing (GluN1/3) N-methyl-D-aspartate (NMDA) receptors are glycine activated ligand-gated ion channels that are members of the family of excitatory ionotropic glutamate receptors. Compared to the glycine/glutamate-activated GluN2- containing NMDA receptors (GluN1/2), which have been extensively studied, the GluN1/3 receptors are poorly understood, but are implicated in neuronal processes related to synaptic maturation and plasticity. GluN1/3 receptors are also implicated in a variety of neurological diseases. In addition to their poor understanding, we lack proper pharmacological tools for the study and modulation of these GluN1/3 receptors. In this study, we evaluate the activity and mechanism of action for AIMS-129 as …

Fiber Photometry Analysis Of Spontaneous Dopamine Signals: The Z-Scored Data Are Not The Data, Conner W. Wallace, Clare Y. Slinkard, Rachael Shaughnessy, Katherine M. Holleran, Samuel W. Centanni, Christopher C. Lapish, Sara R. Jones

Department of Medicine Faculty Publications

Fluorescent sensors have revolutionized the measurement of molecules in the brain, and the dLight dopamine sensor has been used extensively to examine reward- and cue-evoked dopamine release, but only recently has the field turned its attention to spontaneous release events. Analysis of spontaneous events typically requires evaluation of hundreds of events over minutes to hours, and the most common method of analysis, z-scoring, was not designed for this purpose. Here, we compare the accuracy and reliability of three different analysis methods to identify pharmacologically induced changes in dopamine release and uptake in freely moving C57BL/6J mice. The D1-like receptor antagonist …

Leveraging Epigenomics And Transcriptomics To Develop High-Dimensional Biomarkers Of Neuroinflammation, Steven C. Pike

Dartmouth College Ph.D Dissertations

Neuroinflammation is a critical physiological phenomenon implicated in most neurological disorders, either as a cause or a consequence of pathology. Our understanding of neuroinflammation is limited by the inability to directly profile the cells of interest. Thus, developing biomarkers of neuroinflammation is clinically urgent as we know neuroinflammation correlates with patient outcomes and treatment success. The recent advances in “omics” technologies, particularly epigenomics and transcriptomics, provides the opportunity for high-dimensional profiling of biospecimens for potential biomarkers. Within this dissertation, I demonstrate that biomarkers obtained from “omics” platforms can detect neuroimmunological phenomena in clinical and preclinical settings. In chapter one, DNA …

Inductions Of Long-Term Potentiation With Biomimetic Electromagnetic Fields In Primary Neurons, Cooper E. Kansala

Theses and Dissertations (Comprehensive)

Endogenous brain rhythms guide neural communication and plasticity, raising the question of whether weak, temporally structured electromagnetic fields (EMFs) that mimic these rhythms can modulate neuronal activity in a targeted, biomimetic manner. This thesis investigates whether patterned EMFs designed to reflect the temporal structure of hippocampal long-term potentiation (LTP) are more effective at inducing neural plasticity than conventional sinusoidal fields or no stimulation at all. Cortical neurons cultured from postnatal rats were exposed to patterned EMFs for 30 minutes and assessed across three distinct experimental domains. In Chapter 2, microelectrode array (MEA) recordings revealed that the LTP-patterned field significantly increased …

Hippocampal Insulin Exists! In Vivo Sampling Methods, Basal Concentrations, Recurrent Hypoglycemia, And Behavioral Extracellular Insulin Responses, Starlette R. Douglass

Electronic Theses & Dissertations (2024 - present)

Insulin has widespread actions within the brain, including energy homeostasis, modulation of feeding, and as a key component of memory processes. Further, brain insulin dysfunction correlates with Alzheimer's disease and other neurodegenerative disorders. To this point, measurement of hippocampal insulin has been limited. Determining in vivo hippocampal insulin levels both at a healthy baseline and after, e.g., induction of a disease state or in response to cognitive challenge, is essential to advance our understanding of both insulin's procognitive actions and to guide potential therapeutic interventions.

We first sought to establish a sampling technique for insulin within awake and moving rats …

Characterization Of Corticotropin Releasing Factor Receptor 2 In Stress-Regulating Regions Of The Mouse Brain, Jennifer J. Lafrican

Electronic Theses & Dissertations (2024 - present)

Sex differences in the morphology of the brain are thought to underlie the sex differences we see in anxiety and depression, where women are twice as likely to be diagnosed when compared to men. Stress, or a disruption to homeostasis, can exacerbate these mood disorders. Corticotropin releasing factor (CRF), and its receptors, play an important role in regulating the stress response. Binding of CRF with CRFR2 has been shown to reduce behavioral and neuroendocrine stress responses, yet whether there are sex differences in CRFR2 expressing neurons and stress-induced activation of these neurons in mice is unknown, in part due to …