Neurosciences Commons^™

Pathogenic Tau Accelerates Aging-Associated Activation Of Transposable Elements In The Mouse Central Nervous System, Paulino Ramirez, Gabrielle Zuniga, Wenyan Sun, Adrian Beckmann, Elizabeth Ochoa, Sarah L Devos, Bradley Hyman, Gabriel Chiu, Ethan R Roy, Wei Cao, Miranda Orr, Virginie Buggia-Prevot, William J Ray, Bess Frost

Faculty, Staff and Student Publications

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class …

Usability Of Abattoir-Acquired Pig Eyes For Refractive Excimer Laser Research, Marius Topka, Yao Zhang, Antonia Bock, Peter Riedel, Johannes Lörner, Alexander Hammer, Eva Maier, Friedrich Paulsen, Christian M Hammer

Faculty, Staff and Student Publications

The purpose of this study was to elucidate, under which conditions abattoir-acquired pig eyes are suitable for refractive excimer laser experiments. Porcine eyes from tunnel-scalded (n = 5) and tank-scalded (n = 10) pigs were compared to unscalded eyes (n = 5) and to eyes scalded in the laboratory (n = 5). The corneal epithelium was removed before an excimer laser was used to perform a - 8.0 D photoablation. Corneal thickness was measured by optical coherence topography before and after photoablation. The ablation depth was determined with a contour measuring station, the morphology of the ablated areas was characterized …

Exogenous Inter-Α Inhibitor Proteins Prevent Cell Death And Improve Ischemic Stroke Outcomes In Mice, Louise D Mccullough, Meaghan Roy-O'Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C Kraushaar, Anjali Chauhan, Lauren H Sansing, Barbara S Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

Faculty, Staff and Students Publications

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when …

Sharing Voxelwise Neuroimaging Results From Rhesus Monkeys And Other Species With Neurovault, Andrew S. Fox, Daniel Holley, Peter Christiaan Klink, Spencer A. Arbuckle, Carol A. Barnes, Jörn Diedrichsen, Sze Chai Kwok, Colin Kyle, J. Andrew Pruszynski, Jakob Seidlitz, Xu Feng Zhou, Russell A. Poldrack, Krzysztof J. Gorgolewski

Brain and Mind Institute Researchers' Publications

© 2020 The Authors Animal neuroimaging studies can provide unique insights into brain structure and function, and can be leveraged to bridge the gap between animal and human neuroscience. In part, this power comes from the ability to combine mechanistic interventions with brain-wide neuroimaging. Due to their phylogenetic proximity to humans, nonhuman primate neuroimaging holds particular promise. Because nonhuman primate neuroimaging studies are often underpowered, there is a great need to share data amongst translational researchers. Data sharing efforts have been limited, however, by the lack of standardized tools and repositories through which nonhuman neuroimaging data can easily be archived …

Interleukin 1 Alpha Administration Is Neuroprotective And Neuro-Restorative Following Experimental Ischemic Stroke, Kathleen E. Salmeron, Michael E. Maniskas, Danielle N. Edwards, Raymond Wong, Ivana Rajkovic, Amanda L. Trout, Abir A. Rahman, Samantha Hamilton, Justin F. Fraser, Emmanuel Pinteaux, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et …

A Consensus Guide To Capturing The Ability To Inhibit Actions And Impulsive Behaviors In The Stop-Signal Task., Frederick Verbruggen, Adam R Aron, Guido Ph Band, Christian Beste, Patrick G Bissett, Adam T Brockett, Joshua W Brown, Samuel R Chamberlain, Christopher D Chambers, Hans Colonius, Lorenza S Colzato, Brian D Corneil, James P Coxon, Annie Dupuis, Dawn M Eagle, Hugh Garavan, Ian Greenhouse, Andrew Heathcote, René J Huster, Sara Jahfari, J Leon Kenemans, Inge Leunissen, Chiang-Shan R Li, Gordon D Logan, Dora Matzke, Sharon Morein-Zamir, Aditya Murthy, Martin Paré, Russell A Poldrack, K Richard Ridderinkhof, Trevor W Robbins, Matthew Roesch, Katya Rubia, Russell J Schachar, Jeffrey D Schall, Ann-Kathrin Stock, Nicole C Swann, Katharine N Thakkar, Maurits W Van Der Molen, Luc Vermeylen, Matthijs Vink, Jan R Wessel, Robert Whelan, Bram B Zandbelt, C Nico Boehler

Brain and Mind Institute Researchers' Publications

Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the …

Translational Evaluation Of Acid/Base And Electrolyte Alterations In Rodent Model Of Focal Ischemia, Sarah R. Martha, Lisa A. Collier, Stephanie M. Davis, Hilary A. Seifert, Christopher C. Leonardo, Craig T. Ajmo, Elspeth A. Foran, Justin F. Fraser, Keith R. Pennypacker

Neurology Faculty Publications

BACKGROUND AND PURPOSE: Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion.

METHODS: Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient …

Cortical And Thalamic Connectivity To The Second Auditory Cortex Of The Cat Is Resilient To The Onset Of Deafness., Blake E Butler, Alexandra De La Rua, Taylor Ward-Able, Stephen G Lomber

Brain and Mind Institute Researchers' Publications

It has been well established that following sensory loss, cortical areas that would normally be involved in perceiving stimuli in the absent modality are recruited to subserve the remaining senses. Despite this compensatory functional reorganization, there is little evidence to date for any substantial change in the patterns of anatomical connectivity between sensory cortices. However, while many auditory areas are contracted in the deaf, the second auditory cortex (A2) of the cat undergoes a volumetric expansion following hearing loss, suggesting this cortical area may demonstrate a region-specific pattern of structural reorganization. To address this hypothesis, and to complement existing literature …

Sensory Processing In Autism Spectrum Disorders And Fragile X Syndrome-From The Clinic To Animal Models., D Sinclair, B Oranje, K A Razak, S J Siegel, S Schmid

Brain and Mind Institute Researchers' Publications

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and …

Adolescent Cannabinoid Exposure Induces A Persistent Sub-Cortical Hyper-Dopaminergic State And Associated Molecular Adaptations In The Prefrontal Cortex., Justine Renard, Laura G Rosen, Michael Loureiro, Cleusa De Oliveira, Susanne Schmid, Walter J Rushlow, Steven R Laviolette

Brain and Mind Institute Researchers' Publications

Considerable evidence suggests that adolescent exposure to delta-9-tetrahydrocanabinol (THC), the psychoactive component in marijuana, increases the risk of developing schizophrenia-related symptoms in early adulthood. In the present study, we used a combination of behavioral and molecular analyses with in vivo neuronal electrophysiology to compare the long-term effects of adolescent versus adulthood THC exposure in rats. We report that adolescent, but not adult, THC exposure induces long-term neuropsychiatric-like phenotypes similar to those observed in clinical populations. Thus, adolescent THC exposure induced behavioral abnormalities resembling positive and negative schizophrenia-related endophenotypes and a state of neuronal hyperactivity in the mesocorticolimbic dopamine (DA) pathway. …

Quantifying And Comparing The Pattern Of Thalamic And Cortical Projections To The Posterior Auditory Field In Hearing And Deaf Cats., Blake E Butler, Nicole Chabot, Stephen G Lomber

Brain and Mind Institute Researchers' Publications

Following sensory loss, compensatory crossmodal reorganization occurs such that the remaining modalities are functionally enhanced. For example, behavioral evidence suggests that peripheral visual localization is better in deaf than in normal hearing animals, and that this enhancement is mediated by recruitment of the posterior auditory field (PAF), an area that is typically involved in localization of sounds in normal hearing animals. To characterize the anatomical changes that underlie this phenomenon, we identified the thalamic and cortical projections to the PAF in hearing cats and those with early- and late-onset deafness. The retrograde tracer biotinylated dextran amine was deposited in the …

Tau Phosphorylation At Alzheimer's Disease-Related Ser356 Contributes To Tau Stabilization When Par-1/Mark Activity Is Elevated., Kanae Ando, Mikiko Oka, Yosuke Ohtake, Motoki Hayashishita, Sawako Shimizu, Shin-Ichi Hisanaga, Koichi M. Iijima

Department of Neuroscience Faculty Papers

Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, …

Loss Of Vglut3 Produces Circadian-Dependent Hyperdopaminergia And Ameliorates Motor Dysfunction And L-Dopa-Mediated Dyskinesias In A Model Of Parkinson's Disease., Christopher B. Divito, Kathy Steece-Collier, Daniel T. Case, Sean-Paul G. Williams, Jennifer A. Stancati, Lianteng Zhi, Maria E. Rubio, Caryl E. Sortwell, Timothy J. Collier, David Sulzer, Robert H. Edwards, Hui Zhang, Rebecca P. Seal

Department of Neuroscience Faculty Papers

UNLABELLED: The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion …

Differential Modification Of Cortical And Thalamic Projections To Cat Primary Auditory Cortex Following Early- And Late-Onset Deafness., Nicole Chabot, Blake E Butler, Stephen G Lomber

Brain and Mind Institute Researchers' Publications

Following sensory deprivation, primary somatosensory and visual cortices undergo crossmodal plasticity, which subserves the remaining modalities. However, controversy remains regarding the neuroplastic potential of primary auditory cortex (A1). To examine this, we identified cortical and thalamic projections to A1 in hearing cats and those with early- and late-onset deafness. Following early deafness, inputs from second auditory cortex (A2) are amplified, whereas the number originating in the dorsal zone (DZ) decreases. In addition, inputs from the dorsal medial geniculate nucleus (dMGN) increase, whereas those from the ventral division (vMGN) are reduced. In late-deaf cats, projections from the anterior auditory field (AAF) …

Prolonged In Vivo Retention Of A Cathepsin D Targeted Optical Contrast Agent In A Mouse Model Of Alzheimer's Disease., Jonatan A Snir, Mojmir Suchy, Keith St Lawrence, Robert H E Hudson, Stephen H Pasternak, Robert Bartha

Brain and Mind Institute Researchers' Publications

BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that is elevated early in Alzheimer's disease (AD). We have previously developed a Targeted contrast agent (CA) to detect CatD activity in vivo, consisting of a magnetic resonance imaging/fluorescent moiety linked to a cell penetrating peptide (CPP) by means of a CatD cleavage site and have demonstrated its uptake in the brain of an AD mouse model.

OBJECTIVE: The purpose of this study was to characterize the in vivo retention of a near infra-red fluorescent dye labeled version of this CA.

METHODS: Six adult C57Bl/6 wild-type mice and six adult 5XFAD transgenic …

Developmental Stress, Condition, And Birdsong: A Case Study In Song Sparrows., Kim L Schmidt, Elizabeth A Macdougall-Shackleton, Shawn P Kubli, Scott A Macdougall-Shackleton

Brain and Mind Institute Researchers' Publications

Sexual-selection theory posits that ornaments and displays can reflect a signaler's condition, which in turn is affected both by recent and developmental conditions. Moreover, developmental conditions can induce correlations between sexually selected and other traits if both types of traits exhibit developmental phenotypic plasticity in response to stressors. Thus, sexually selected traits may reflect recent and/or developmental characteristics of signalers. Here, we review data on the relationships between birdsong, a sexually selected trait, and developmental and current condition of birds from a long-term study of a population of song sparrows (Melospiza melodia). Field studies of free-living birds indicate that the …

Defects In Synapse Structure And Function Precede Motor Neuron Degeneration In Drosophila Models Of Fus-Related Als., Mohammad Shahidullah, Sylvain J Le Marchand, Hong Fei, Jiaming Zhang, Udai Bhan Pandey, Matthew B. Dalva, Piera Pasinelli, Irwin B. Levitan

Department of Neuroscience Faculty Papers

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. In one, human FUS with ALS-causing mutations is expressed in fly motor neurons; in the other, the gene cabeza (caz), the fly homolog of FUS, is ablated. These FUS-ALS flies exhibit larval locomotor defects indicative of neuromuscular dysfunction and early death. The locus and site of initiation of this neuromuscular dysfunction remain unclear. We show here …

Exosome-Mediated Shuttling Of Microrna-29 Regulates Hiv Tat And Morphine-Mediated Neuronal Dysfunction., Guoku Hu, H Yao, A D. Chaudhuri, Sowmya V. Yelamanchili, H Wen, P D. Cheney, Howard S. Fox, Shilpa J. Buch

Journal Articles: Pharmacology & Experimental Neuroscience

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance …

Nociceptive Neuropeptide Increases And Periorbital Allodynia In A Model Of Traumatic Brain Injury., Melanie B. Elliott, Michael L. Oshinsky, Peter S. Amenta, Olatilewa Awe, Jack I. Jallo

Department of Neurosurgery Faculty Papers

OBJECTIVE: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury.

METHODS: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled …

Paradoxical Reversal Learning Enhancement By Stress Or Prefrontal Cortical Damage: Rescue With Bdnf., Carolyn Graybeal, Michael Feyder, Emily Schulman, Lisa M Saksida, Timothy J Bussey, Jonathan L Brigman, Andrew Holmes

Brain and Mind Institute Researchers' Publications

Stress affects various forms of cognition. We found that moderate stress enhanced late reversal learning in a mouse touchscreen-based choice task. Ventromedial prefrontal cortex (vmPFC) lesions mimicked the effect of stress, whereas orbitofrontal and dorsolateral striatal lesions impaired reversal. Stress facilitation of reversal was prevented by BDNF infusion into the vmPFC. These findings suggest a mechanism by which stress-induced vmPFC dysfunction disinhibits learning by alternate (for example, striatal) systems.

Human Glial-Restricted Progenitor Transplantation Into Cervical Spinal Cord Of The Sod1 Mouse Model Of Als., Angelo C Lepore, John O'Donnell, Andrew S Kim, Timothy Williams, Alicia Tuteja, Mahendra S Rao, Linda L Kelley, James T Campanelli, Nicholas J Maragakis

Department of Neuroscience Faculty Papers

Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1(G93A) rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1(G93A) rat. Those findings demonstrated the feasibility and efficacy of transplantation-based …

The Levels Of Analysis Revisited., Scott A Macdougall-Shackleton

Brain and Mind Institute Researchers' Publications

The term levels of analysis has been used in several ways: to distinguish between ultimate and proximate levels, to categorize different kinds of research questions and to differentiate levels of reductionism. Because questions regarding ultimate function and proximate mechanisms are logically distinct, I suggest that distinguishing between these two levels is the best use of the term. Integrating across levels in research has potential risks, but many benefits. Consideration at one level can help generate novel hypotheses at the other, define categories of behaviour and set criteria that must be addressed. Taking an adaptationist stance thus strengthens research on proximate …

Chronic Spontaneous Activity Generated In The Somata Of Primary Nociceptors Is Associated With Pain-Related Behavior After Spinal Cord Injury, Supinder S Bedi, Qing Yang, Robyn J Crook, Junhui Du, Zizhen Wu, Harvey M Fishman, Raymond J Grill, Susan M Carlton, Edgar T Walters

Faculty, Staff and Student Publications

Mechanisms underlying chronic pain that develops after spinal cord injury (SCI) are incompletely understood. Most research on SCI pain mechanisms has focused on neuronal alterations within pain pathways at spinal and supraspinal levels associated with inflammation and glial activation. These events might also impact central processes of primary sensory neurons, triggering in nociceptors a hyperexcitable state and spontaneous activity (SA) that drive behavioral hypersensitivity and pain. SCI can sensitize peripheral fibers of nociceptors and promote peripheral SA, but whether these effects are driven by extrinsic alterations in surrounding tissue or are intrinsic to the nociceptor, and whether similar SA occurs …

Glutamate Receptors In Perirhinal Cortex Mediate Encoding, Retrieval, And Consolidation Of Object Recognition Memory., Boyer D Winters, Timothy J Bussey

Brain and Mind Institute Researchers' Publications

Object recognition is consistently impaired in human amnesia and animal models thereof. Results from subjects with permanent brain damage have revealed the importance of the perirhinal cortex to object recognition memory. Here, we report evidence from rats for interdependent but distinct stages in object recognition memory (encoding, retrieval, and consolidation), which require glutamate receptor activity within perirhinal cortex. Transient blockade of AMPA receptor-mediated synaptic transmission within perirhinal cortex disrupted encoding for short- and long-term memory as well as retrieval and consolidation. In contrast, transient NMDA receptor blockade during encoding affected only long-term object recognition memory; NMDA receptor activity was also …

Fornix Lesions Can Facilitate Acquisition Of The Transverse Patterning Task: A Challenge For "Configural" Theories Of Hippocampal Function., T J Bussey, E Clea Warburton, J P Aggleton, J L Muir

Brain and Mind Institute Researchers' Publications

Configural theories of hippocampal function predict that hippocampal dysfunction should impair acquisition of the transverse patterning task, which involves the concurrent solution of three discrimination problems: A+ versus B-; B+ versus C-; and C+ versus A-. The present study tested this prediction in rats using computer-graphic stimuli presented on a touchscreen. Experiment 1 assessed the effects of fornix lesions when the three problems were introduced sequentially (phase 1: A+ vs B-; phase 2: A+ vs B-, B+ vs C-; phase 3: A+ vs B-, B+ vs C-, C+ vs A-). Fornix lesions significantly facilitated acquisition of the complete transverse patterning …