Neurosciences Commons^™

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction In Tauopathy, Shon A. Koren, Matthew J. Hamm, Ryan Cloyd, Sarah N. Fontaine, Emad Chishti, Chiara Lanzillotta, Jennifer Rodriguez-Rivera, Alexandria Ingram, Michelle Bell, Sara M. Galvis-Escobar, Nicholas Zulia, Fabio Di Domenico, Duc Duong, Nicholas T. Seyfried, David K. Powell, Moriel Vandsburger, Tal Frolinger, Anika M. S. Hartz, John Koren Iii, Jeffrey M. Axten, Nicholas J. Laping, Jose F. Abisambra

Sanders-Brown Center on Aging Faculty Publications

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging …

Intracellular Β1-Adrenergic Receptors And Organic Cation Transporter 3 Mediate Phospholamban Phosphorylation To Enhance Cardiac Contractility, Ying Wang, Qian Shi, Minghui Li, Meimi Zhao, Raghavender Reddy Gopireddy, Jian-Peng Teoh, Bing Xu, Chaoqun Zhu, Kyle E. Ireton, Sanghavi Srinivasan, Shaoliang Chen, Paul J. Gasser, Julie Bossuyt, Johannes W. Hell, Donald M. Bers, Yang K. Xiang

Biomedical Sciences Faculty Research and Publications

Rationale:

β₁ARs (β₁-adrenoceptors) exist at intracellular membranes and OCT3 (organic cation transporter 3) mediates norepinephrine entry into cardiomyocytes. However, the functional role of intracellular β₁AR in cardiac contractility remains to be elucidated.

Objective:

Test localization and function of intracellular β₁AR on cardiac contractility.

Methods and Results:

Membrane fractionation, super-resolution imaging, proximity ligation, coimmunoprecipitation, and single-molecule pull-down demonstrated a pool of β₁ARs in mouse hearts that were associated with sarco/endoplasmic reticulum Ca²⁺-ATPase at the sarcoplasmic reticulum (SR). Local PKA (protein kinase A) activation was measured using a PKA biosensor …

Genetic Approach To Elucidate The Role Of Cyclophilin D In Traumatic Brain Injury Pathology, Ryan D. Readnower, W. Brad Hubbard, Olivia J. Kalimon, James W. Geddes, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the …

Self-Administered Behavioral Skills-Based At-Home Virtual Reality Therapy For Chronic Low Back Pain: Protocol For A Randomized Controlled Trial., Laura Garcia, Beth Darnall, Parthasarathy Krishnamurthy, Ian Mackey, Josh Sackman, Robert Louis, Todd Maddox, Brandon Birckhead

Articles, Abstracts, and Reports

BACKGROUND: Chronic pain is one of the most common and debilitating health conditions. Treatments for chronic low back pain typically focus on biomedical treatment approaches. While psychosocial treatments exist, multiple barriers prevent broad access. There is a significant unmet need for integrative, easily accessible, non-opioid solutions for chronic pain. Virtual reality (VR) is an immersive technology allowing innovation in the delivery of behavioral pain treatments. Behavioral skills-based VR is effective at facilitating pain management and reducing pain-related concerns. Continued research on these emerging approaches is needed.

OBJECTIVE: In this randomized controlled trial, we seek to test the efficacy of a …

The Multiplicity Of Caregiving Burden: A Qualitative Analysis Of Families With Prolonged Disorders Of Consciousness., Laura E Gonzalez-Lara, Sarah Munce, Jennifer Christian, Adrian M Owen, Charles Weijer, Fiona Webster

Brain and Mind Institute Researchers' Publications

Objective: To understand the multiple and sometimes conflicting roles substitute decision makers (SDMs) of individuals in a vegetative state (VS), minimally conscious state (MCS), or with locked-in syndrome (LIS) perform while caring for a loved one and the competing priorities derived from these roles.Methods: We conducted semi-structured qualitative interviews using a constructive-grounded theory design. Twelve SDMs, who were also family members for 11 patients, were interviewed at two time points (except one) for a total of 21 in-depth interviews.Results: Participants described that caregiving is often the central role which they identify as their top priority …

A High Affinity, Partial Antagonist Effect Of 3,4-Diaminopyridine Mediates Action Potential Broadening And Enhancement Of Transmitter Release At Nmjs, Kristine S Ojala, Scott P Ginebaugh, Man Wu, Evan W Miller, Gloria Ortiz, Manuel Covarrubias, Stephen D Meriney

Department of Neuroscience Faculty Papers

3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-Approved treatment for neuro muscular weakness caused by Lambert-Eaton myasthenic syn drome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the pre synaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-Target agonist effect on the Cav1 subtype ("L-Type") of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release …

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 …

Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, Chao Ma, Jerry B. Hunt, Maj-Linda B. Selenica, Awa Sanneh, Leslie A. Sandusky-Beltran, Mallory Watler, Rana Daas, Andrii Kovalenko, Huimin Liang, Devon Placides, Chuanhai Cao, Xiaoyang Lin, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1 …

Abnormal Nutritive Sucking As An Indicator Of Neonatal Brain Injury, Sabrina Shandley, Gilson J. Capilouto, Eleonora Tamilia, David M. Riley, Yvette R. Johnson, Christos Papadelis

Communication Sciences and Disorders Faculty Publications

A term neonate is born with the ability to suck; this neuronal network is already formed and functional by 28 weeks gestational age and continues to evolve into adulthood. Because of the necessity of acquiring nutrition, the complexity of the neuronal network needed to suck, and neuroplasticity in infancy, the skill of sucking has the unique ability to give insight into areas of the brain that may be damaged either during or before birth. Interpretation of the behaviors during sucking shows promise in guiding therapies and how to potentially repair the damage early in life, when neuroplasticity is high. Sucking …

Encephalopathy And Complex Hyperkinesia In A Patient With Severe Acute Respiratory Syndrome Coronavirus-2 Infection, Wenyang Li, Elif Pinar Coskun, Rolando Berger, John T. Slevin, L. Creed Pettigrew

Neurology Faculty Publications

No abstract provided.

Dystrophic Microglia Are Associated With Neurodegenerative Disease And Not Healthy Aging In The Human Brain, Ryan K. Shahidehpour, Rebecca E. Higdon, Nicole G. Crawford, Janna H. Neltner, Eseosa T. Ighodaro, Ela Patel, Douglas Price, Peter T. Nelson, Adam D. Bachstetter

Spinal Cord and Brain Injury Research Center Faculty Publications

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were performed for total microglia, 2 microglia morphologies (hypertrophic and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could …

Mitochondria Exert Age-Divergent Effects On Recovery From Spinal Cord Injury, Andrew N. Stewart, Katelyn E. Mcfarlane, Hemendra J. Vekaria, William M. Bailey, Stacey A. Slone, Lauren A. Tranthem, Bei Zhang, Samir P. Patel, Patrick G. Sullivan, John C. Gensel

Physiology Faculty Publications

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue …

Maternal Hpa Axis Function During Parenting Is Associated With Reduced Brain Activation To Infant Cry And More Intrusive Parenting Behavior, Andrew Erhart

Electronic Theses and Dissertations

Previous research indicated that maternal cortisol function and maternal brain response to infant stimuli are separately related to differences in parenting behavior. Evidence from animal models have demonstrated that chronically high cortisol concentration alters brain structure and function, suggesting that studying these two mechanisms together may further improve understanding of parental behavior in human mothers. First time mothers of infants aged 1-7 months old (M age = 3 months) were recruited to participate. Mother’s cortisol concentration was measured during a naturalistic interaction with their infant and their behavior was coded for maternal sensitivity and nonintrusiveness. In a separate session using …

I Hear You: The Everyday Struggle Living With Misophonia, Ashton Jones

Mahurin Honors College Capstone Experience/Thesis Projects

The term misophonia is derivated from the Greek words misos, (hate), and phónè, (voice); it translates as hatred of sound. It is the term used to describe people who are irregularly affected by everyday noises. The first scientific observations by Pawel J. Jastreboff regarding misophonia indicate “individuals with misophonia are sensitive to a specific set of trigger sounds, which are usually recognized since childhood.” These types of sounds tend to be trivial noises, such as chewing or crunching, sniffing, breathing, clicking, lip smacking, and tapping. The noises can trigger an onslaught of negative emotions and violent reactions.

This documentary film …

New Frontiers In Translational Research: Touchscreens, Open Science, And The Mouse Translational Research Accelerator Platform, Jacqueline A. Sullivan, Julie R. Dumont, Sara Memar, Miguel Skirzewski, Jinxia Wan, Maryam H. Mofrad, Hassam Zafar Ansari, Yulong Li, Lyle Muller, Vania F. Prado, Marco A.M. Prado, Lisa M. Saksida, Timothy J. Bussey

Brain and Mind Institute Researchers' Publications

© 2020 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd Many neurodegenerative and neuropsychiatric diseases and other brain disorders are accompanied by impairments in high-level cognitive functions including memory, attention, motivation, and decision-making. Despite several decades of extensive research, neuroscience is little closer to discovering new treatments. Key impediments include the absence of validated and robust cognitive assessment tools for facilitating translation from animal models to humans. In this review, we describe a state-of-the-art platform poised to overcome these impediments and improve the success of translational research, the Mouse Translational Research Accelerator Platform (MouseTRAP), which is …

Effects Of Mp2rage B1+ Sensitivity On Inter-Site T1 Reproducibility And Hippocampal Morphometry At 7t, Roy A.M. Haast, Jonathan C. Lau, Dimo Ivanov, Ravi S. Menon, Kâmil Uludağ, Ali R. Khan

Brain and Mind Institute Researchers' Publications

Most neuroanatomical studies are based on T -weighted MR images, whose intensity profiles are not solely determined by the tissue's longitudinal relaxation times (T ), but also affected by varying non-T contributions, hampering data reproducibility. In contrast, quantitative imaging using the MP2RAGE sequence, for example, allows direct characterization of the brain based on the tissue property of interest. Combined with 7 Tesla (7T) MRI, this offers unique opportunities to obtain robust high-resolution brain data characterized by a high reproducibility, sensitivity and specificity. However, specific MP2RAGE parameter choices – e.g., to emphasize intracortical myelin-dependent contrast variations – can substantially impact image …

Normative Analysis Of Individual Brain Differences Based On A Population Mri-Based Atlas Of Cynomolgus Macaques, Qiming Lv, Mingchao Yan, Xiangyu Shen, Jing Wu, Wenwen Yu, Shengyao Yan, Feng Yang, Kristina Zeljic, Yuequan Shi, Zuofu Zhou, Longbao Lv, Xintian Hu, Ravi Menon, Zheng Wang

Brain and Mind Institute Researchers' Publications

The developmental trajectory of the primate brain varies substantially with aging across subjects. However, this ubiquitous variability between individuals in brain structure is difficult to quantify and has thus essentially been ignored. Based on a large-scale structural magnetic resonance imaging dataset acquired from 162 cynomolgus macaques, we create a species-specific 3D template atlas of the macaque brain, and deploy normative modeling to characterize individual variations of cortical thickness (CT) and regional gray matter volume (GMV). We observed an overall decrease in total GMV and mean CT, and an increase in white matter volume from juvenile to early adult. Specifically, CT …

Symbols Are Special: An Fmri Adaptation Study Of Symbolic, Nonsymbolic, And Non-Numerical Magnitude Processing In The Human Brain, H Moriah Sokolowski, Zachary Hawes, Lien Peters, Daniel Ansari

Brain and Mind Institute Researchers' Publications

How are different formats of magnitudes represented in the human brain? We used functional magnetic resonance imaging adaptation to isolate representations of symbols, quantities, and physical size in 45 adults. Results indicate that the neural correlates supporting the passive processing of number symbols are largely dissociable from those supporting quantities and physical size, anatomically and representationally. Anatomically, passive processing of quantities and size correlate with activation in the right intraparietal sulcus, whereas symbolic number processing, compared with quantity processing, correlates with activation in the left inferior parietal lobule. Representationally, neural patterns of activation supporting symbols are dissimilar from neural activation …

Spinal Cord Compression Is Associated With Brain Plasticity In Degenerative Cervical Myelopathy., Alicia E Cronin, Sarah A Detombe, Camille A Duggal, Neil Duggal, Robert Bartha

Brain and Mind Institute Researchers' Publications

The impact of spinal cord compression severity on brain plasticity and prognostic determinates is not yet fully understood. We investigated the association between the severity of spinal cord compression in patients with degenerative cervical myelopathy, a progressive disease of the spine, and functional plasticity in the motor cortex and subcortical areas using functional magnetic resonance imaging. A 3.0 T MRI scanner was used to acquire functional images of the brain in 23 degenerative cervical myelopathy patients. Patients were instructed to perform a structured finger-tapping task to activate the motor cortex to assess the extent of cortical activation. T

High-Contrast, Moving Targets In An Emerging Target Paradigm Promote Fast Visuomotor Responses During Visually Guided Reaching, Rebecca A. Kozak, Brian D. Corneil

Brain and Mind Institute Researchers' Publications

Humans have a remarkable capacity to rapidly interact with the surrounding environment, often by transforming visual input into motor output on a moment-to-moment basis. But what visual features promote rapid reaching? High-contrast, fast-moving targets elicit strong responses in the superior colliculus (SC), a structure associated with express saccades and implicated in rapid electromyographic (EMG) responses on upper limb muscles. To test the influence of stimulus properties on rapid reaches, we had human subjects perform visually guided reaches to moving targets varied by speed (experiment 1) or speed and contrast (experiment 2) in an emerging target paradigm that has recently been …