Neuroscience and Neurobiology Commons^™

Thiamine Deficiency Causes Long-Lasting Neurobehavioral Deficits In Mice, Hui Li, Hong Xu, Wen Wen, Liying Wu, Mei Xu, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Thiamine deficiency (TD) has detrimental effects on brain health and neurobehavioral development, and it is associated with many aging-related neurological disorders. To facilitate TD-related neuropsychological studies, we generated a TD mouse model by feeding a thiamine-deficient diet for 30 days, followed by re-feeding the control diet for either one week or 16 weeks as recovery treatment. We then performed neurobehavioral tests in these two cohorts: cohort of one week post TD treatment (1 wk-PTDT) and 16 weeks post TD treatment (16 wks-PTDT). The TD mice showed no significant difference from control in any tests in the 1 wk-PTDT cohort at …

Combination Of Investigational Cell-Based Therapy And Deep Brain Stimulation To Alter The Progression Of Parkinson’S Disease, Nader El Seblani

Theses and Dissertations--Pharmacy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of …

Novel Post-Translational Modification And Function Of Fus: The Relevance To Amyotrophic Lateral Sclerosis, Alexandra Arenas

Theses and Dissertations--Toxicology and Cancer Biology

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in Sarcoma (FUS) is a ubiquitously expressed RNA binding protein implicated in familial ALS and frontotemporal dementia (FTD). FUS is ubiquitously expressed in cells and has a variety of functions in the nucleus and cytoplasm. FUS mutations in the nuclear localization sequence (NLS) causes mislocalization of FUS in the cytoplasm, where it can undergo liquid-liquid phase separation and become stress granules or protein inclusions. Although FUS inclusion bodies can be found in …

Exploring The Role Of Insulin Receptor Signaling In Hippocampal Learning And Memory, Neuronal Calcium Dysregulation, And Glucose Metabolism, Hilaree N. Frazier

Theses and Dissertations--Pharmacology and Nutritional Sciences

In the late 90’s, emerging evidence revealed that the brain is insulin-sensitive, highlighted by broad expression of brain-specific insulin receptors and reports of circulating brain insulin. Contemporary literature robustly supports the role of insulin signaling in normal brain function and suggests that insulin-related processes diminish with aging, evidenced by decreased signaling markers, reduced insulin receptor density, and lower levels of insulin transport across the blood-brain barrier. In the context of pathological cognitive decline, clinical trials using intranasal insulin delivery have reported positive outcomes on memory and learning in patients with mild cognitive decline or early-stage Alzheimer’s disease. However, while the …

Enriched Physical Environment Attenuates Spatial And Social Memory Impairments Of Aged Socially Isolated Mice, Linmei Wang, Min Cao, Tinglin Pu, Huang Huang, Charles Marshall, Ming Xiao

Physical Therapy Faculty Publications

Background: Social isolation in the elderly is one of the principal health risks in an aging society. Physical environmental enrichment is shown to improve sensory, cognitive, and motor functions, but it is unknown whether environmental enrichment can protect against brain impairments caused by social isolation.

Methods: Eighteen-month-old mice were housed, either grouped or isolated, in a standard or enriched environment for 2 months, respectively. Behavioral tests were performed to evaluate cognitive functional and social interaction ability. Synaptic protein levels, myelination, neuroinflammation, brain derived neurotrophic factor, and NOD-like receptor protein 3 inflammasome signaling pathways were examined in the medial prefrontal cortex …

Role Of Mcp-1 And Ccr2 In Ethanol-Induced Neuroinflammation And Neurodegeneration In The Developing Brain, Kai Zhang, Haiping Wang, Mei Xu, Jacqueline A. Frank, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Background: Neuroinflammation and microglial activation have been implicated in both alcohol use disorders (AUD) and fetal alcohol spectrum disorders (FASD). Chemokine monocyte chemoattractant protein 1 (MCP-1) and its receptor C-C chemokine receptor type 2 (CCR2) are critical mediators of neuroinflammation and microglial activation. FASD is the leading cause of mental retardation, and one of the most devastating outcomes of FASD is the loss of neurons in the central nervous system (CNS). The underlying molecular mechanisms, however, remain unclear. We hypothesize that MCP-1/CCR2 signaling mediates ethanol-induced neuroinflammation and microglial activation, which exacerbates neurodegeneration in the developing brain.

Methods: C57BL/6 mice and …

Transcriptional Correlates Of Proximal-Distal Identify And Regeneration Timing In Axolotl Limbs, S. Randal Voss, David Murrugarra, Tyler B. Jensen, James R Monaghan

Neuroscience Faculty Publications

Cells within salamander limbs retain memories that inform the correct replacement of amputated tissues at different positions along the length of the arm, with proximal and distal amputations completing regeneration at similar times. We investigated the possibility that positional memory is associated with variation in transcript abundances along the proximal-distal limb axis. Transcripts were deeply sampled from Ambystoma mexicanum limbs at the time they were administered fore arm vs upper arm amputations, and at 19 post-amputation time points. After amputation and prior to regenerative outgrowth, genes typically expressed by differentiated muscle cells declined more rapidly in upper arms while cell …

Binge Alcohol Exposure Causes Neurobehavioral Deficits And Gsk3Β Activation In The Hippocampus Of Adolescent Rats, Zhe Ji, Lin Yuan, Xiong Lu, Hanqing Ding, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

Heavy alcohol exposure causes profound damage to the adolescent brain, particularly the hippocampus, which underlie some behavioral deficits. However, the underlying molecular mechanisms remain inconclusive. The current study sought to determine whether binge alcohol exposure affects the hippocampus-related behaviors and key signaling proteins that may mediate alcohol neurotoxicity in adolescent rats. Alcohol exposure reduced the number of both NeuN-positive and doublecortin-positive cells in the hippocampus. Alcohol also induced neurodegeneration which was confirmed by ultrastructural analysis by electronic microscopy and was accompanied with the activation of microglia. Binge alcohol exposure impaired spatial learning and memory which was evaluated by the Morris …

Minocycline Protects Developing Brain Against Ethanol-Induced Damage, Xin Wang, Kai Zhang, Fanmuyi Yang, Zhenhua Ren, Mei Xu, Jacqueline A. Frank, Zun-Ji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during the pregnancy and is the leading cause of mental retardation. Ethanol exposure during the development results in the loss of neurons in the developing brain, which may underlie many neurobehavioral deficits associated with FASD. It is important to understand the mechanisms underlying ethanol-induced neuronal loss and develop appropriate therapeutic strategies. One of the potential mechanisms involves neuroimmune activation. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that ethanol induced a wide-spread neuroapoptosis, microglial activation, and neuroinflammation in C57BL/6 mice. Minocycline is an antibiotic that inhibits …

An Aged Canid With Behavioral Deficits Exhibits Blood And Cerebrospinal Fluid Amyloid Beta Oligomers, Clare Rusbridge, Francisco J. Salguero, Monique Antoinette David, Kiterie M. E. Faller, Jose T. Bras, Rita J. Guerreiro, Angela C. Richard-Londt, Duncan Grainger, Elizabeth Head, Sebastian G. P. Brandner, Brian Summers, John Hardy, Mourad Tayebi

Pharmacology and Nutritional Sciences Faculty Publications

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides. We report that soluble oligomers were specifically detected in the dog's blood and …

Fk506-Binding Protein 12.6/1b, A Negative Regulator Of [Ca2+], Rescues Memory And Restores Genomic Regulation In The Hippocampus Of Aging Rats, John C. Gant, Eric M. Blalock, Kuey-Chu Chen, Inga Kadish, Olivier Thibault, Nada M. Porter, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca²⁺ release, reverses aging-induced memory impairment and neuronal Ca²⁺ dysregulation. Here, we tested the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with FKBP1b substantially outperformed age-matched vector controls and performed similarly …

Potential Candidates For Treating Deficits Associated With Developmental Ethanol Exposure In A Rodent Model: Solidago Nemoralis & Dimethoxybenzylidene-Anabasine, Logan James Fields

Theses and Dissertations--Psychology

Prenatal alcohol exposure (Fetal Alcohol Syndrome [FAS] and Fetal Alcohol Spectrum Disorders [FASD’s]) represents the leading preventable cause of intellectual disabilities in the western world, with FASDs estimated to affect approximately 2-5% of live births in the United States at an approximate annual cost of $3.6 billion (CDC, 2015; May et al., 2009). Ethanol (ETOH) exposure during development can lead to a variety of long-term behavioral impairments including problems with executive functioning, motor coordination, spatial learning, attention, and hyperactivity (Jones, 2011; Mattson & Riley, 1998). Much research has been conducted to develop pharmacological and/or environmental interventions to reduce these deficits, …

Novel Calcium-Related Targets Of Insulin In Hippocampal Neurons, Shaniya Maimaiti, Hilaree N. Frazier, Katie L. Anderson, Adam O. Ghoweri, Lawrence D. Brewer, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

Both insulin signaling disruption and Ca²⁺ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer's disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca²⁺-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca²⁺-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in …

Thiamine Deficiency And Neurodegeneration: The Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, And Autophagy, Dexiang Liu, Zunji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Thiamine (vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamine deficiency (TD) can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. TD affects multiple organ systems, including the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems. In the brain, TD causes a cascade of events including mild impairment of oxidative metabolism, neuroinflammation, and neurodegeneration, which are commonly observed in …

Calcium's Role As Nuanced Modulator Of Cellular Physiology In The Brain, Hilaree N. Frazier, Shaniya Maimaiti, Katie L. Anderson, Lawrence D. Brewer, John C. Gant, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can …

Effects Of Chromium On Mouse Splenic T Lymphocytes And Effects Of Ethanol Exposure During Early Neurodevelopment On Behaviors In Mice, Lu Dai

Theses and Dissertations--Toxicology and Cancer Biology

The dissertation consists of three major projects with the focus on the immunotoxicity of chromium and the behavior disorders caused by early ETOH exposure respectively.

Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells compromises host anti-tumor immunity resulting in oncogenesis. Using mouse splenic T cells as an in vitro …

Blockade Of Astrocytic Calcineurin/Nfat Signaling Helps To Normalize Hippocampal Synaptic Function And Plasticity In A Rat Model Of Traumatic Brain Injury, Jennifer L. Furman, Pradoldej Sompol, Susan D. Kraner, Melanie M. Pleiss, Esther J. Putman, Jacob Dunkerson, Hafiz Mohmmad Abdul, Kelly N. Roberts, Stephen William Scheff, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate …

Flavonoids With Novel Nicotinic Activity As Potential Pharmacotherapies To Treat Ethanol-Induced Neurotoxicity, Joseph A. Lutz

Theses and Dissertations--Pharmacy

Ethanol causes neurotoxicity via several mechanisms at different points in the cycle of dependence, including neuroinflammation and oxidative stress during ethanol exposure as well as excitotoxicity during ethanol withdrawal. The primary therapeutic implication is that ethanol-induced neurotoxicity requires multifunctional pharmacotherapies which reduce all mechanisms. Using an innovative pharmacological high throughput screening method on a large plant extract library we discovered flavonoids with alpha7 nicotinic acetylcholine receptor (nAChR) activity. In addition to their well-known anti-inflammatory and antioxidant properties, this novel activity means they can potentially reduce excitotoxicity and therefore makes them ideal for inhibition of ethanol-induced neurotoxicity. Rhamnetin, the candidate compound, …

Diet-Induced Obesity: Dopaminergic And Behavioral Mechanisms As Outcomes And Predictors, Vidya Narayanaswami

Theses and Dissertations--Pharmacy

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to …

Targeting Astrocytes Ameliorates Neurologic Changes In A Mouse Model Of Alzheimer's Disease, Jennifer L. Furman, Diana M. Sama, John C. Gant, Tina L. Beckett, M. Paul Murphy, Adam D. Bachstetter, Linda J. Van Eldik, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific …