Neurosciences Commons^™

Jun Upregulation Drives Aberrant Transposable Element Mobilization, Associated Innate Immune Response, And Impaired Neurogenesis In Alzheimer’S Disease, Chiara Scopa, Samantha Barnada, Maria Cicardi, Mo Singer, Davide Trotti, Marco Trizzino

Farber Institute for Neuroscience Faculty Papers

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death …

Neuroanatomical And Neurochemical Effects Of Prolonged Social Isolation In Adult Mice, Vibol Heng, Michael Zigmond, Richard Jay Smeyne

Department of Neuroscience Faculty Papers

INTRODUCTION: As social animals, our health depends in part on interactions with other human beings. Yet millions suffer from chronic social isolation, including those in nursing/assisted living facilities, people experiencing chronic loneliness as well as those in enforced isolation within our criminal justice system. While many historical studies have examined the effects of early isolation on the brain, few have examined its effects when this condition begins in adulthood. Here, we developed a model of adult isolation using mice (C57BL/6J) born and raised in an enriched environment.

METHODS: From birth until 4 months of age C57BL/6J mice were raised in …

Microrna (Mirna) Complexity In Alzheimer’S Disease (Ad), Walter J. Lukiw

School of Medicine Faculty Publications

AD is a complex, progressive, age-related neurodegenerative disorder representing the most common cause of senile dementia and neurological dysfunction in our elderly domestic population. The widely observed heterogeneity of AD is a reflection of the complexity of the AD process itself and the altered molecular-genetic mechanisms operating in the diseased human brain and CNS. One of the key players in this complex regulation of gene expression in human pathological neurobiology are microRNAs (miRNAs) that, through their actions, shape the transcriptome of brain cells that normally associate with very high rates of genetic activity, gene transcription and messenger RNA (mRNA) generation. …

A Learned Map For Places And Concepts In The Human Medial Temporal Lobe, Nora A. Herweg, Lukas Kunz, Daniel Schonhaut, Armin Brandt, Paul A. Wanda, Ashwini D. Sharan, Michael R. Sperling, Andreas Schulze-Bonhage, Michael J. Kahana

Department of Neurology Faculty Papers

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information …

Adolescence, Alcohol, And Astrocytes: The Impact Of Adolescent Alcohol Use On Astrocyte-Synaptic Interactions, Structure, Function, And Behavior, Christopher Douglas Walker

Theses, Dissertations and Capstones

Alcohol is the third leading cause of preventable death in the United States and has substantial social and economic burdens. Excessive alcohol consumption in the form of binge drinking is highly prevalent among adolescents and emerging adults. Binge drinking is a form of excessive drinking, defined as consuming enough alcohol on a single occasion to result in blood alcohol concentrations above 0.08%. Approximately 55% of full-time college students aged 18- 22 years old have reported consuming alcohol in a binge manner. Furthermore, studies have shown that approximately 20% of college students meet the criteria for an alcohol use disorder (AUD). …

Exploring The Structural And Functional Effects Of Pediatric Hydrocephalus On The Hippocampus, Lili Meng

Undergraduate Student Research Internships Conference

Hydrocephalus is one of the most common pediatric neurological problems that requires brain surgery in children. Pediatric hydrocephalus is characterized as an abnormal cerebrospinal fluid (CSF) buildup in the brain’s ventricles due to ineffective CSF reabsorption. When this fluid builds up in these cavities, it increases intracranial pressure and has a direct mass effect on the surrounding brain tissue and structures. Ultimately, various functions are affected including—but not limited to—vision, learning, memory, motor control, and hearing. Despite current literature suggesting that hydrocephalus may be associated with reduced hippocampal volume among rats and human adults, findings remain limited in the human …

Intrabody-Mediated Postsynaptic Recruitment Of Camkiiα Improves Memory, Anthony Chifor, Jeongyoon Choi Dr., Joongkyu Park Dr.

Medical Student Research Symposium

Long-term potentiation (LTP), the selective strengthening of specific synapses based on recent activity, has widely been accepted as the biological mechanism responsible for learning and memory. N-methyl-D-aspartate receptors (NMDARs) play a critical role in LTP, which when activated, result in a surge of postsynaptic intracellular calcium levels. The calcium rise during LTP results in the activation of Ca²⁺/calmodulin-dependent kinase II alpha (CaMKIIa), which consequently enacts multiple cellular effects that ultimately result in the strengthening of synaptic connections. Previous work has examined the effects of CaMKIIa overexpression in rat hippocampi on spatial memory, however, significant but limited improvement in …

The Effects Of Astrocytic Derived Insulin-Like Growth Factor (Igf-1) On Cognition And Astrocytes, Destiny Wilson

Honors Theses

Insulin-like growth factor 1 (IGF-1) is a neuroendocrine signaling hormone that plays a vital role in growth and development, as well as learning and memory. Inhibition of this hormone results in cognitive impairments like those seen with age-related decline. While a majority of research has focused on the role of IGF-1 on neurons, the role of astrocytes still needs to be explored. Our research investigates how astrocytes and cognition are affected as a result of direct regulation of localized IGF-1 production in early development and after puberty. Preliminary studies in our laboratory established a connection between IGF-1 and glial fibrillary …

Sex Differences In Hippocampal O-Glcnacylation Of The Adult Mouse Brain, Makenzie Johnson

Selected Honors Theses

The hippocampus is a structure in the brain crucial for learning and memory. This occurs by synaptic remodeling known as long term potentiation and long term depression. Modifications of proteins in the hippocampus can affect its function. One of these modifications is the addition of O-linked β-N-acetylglucosamine, also known as O-GlcNAc. This is a sugar produced from glucose by the hexosamine biosynthetic pathway that is reversibly added onto serine and threonine residues of proteins by O-GlcNAc Transferase, or OGT. It is reversibly removed from these residues by O-GlcNAcAse, or OGA. This modification has been implicated in diabetes, cardiac dysfunction, and …

Assessing Rat Behavioral Response To Novelty, Neha Mathew

Honors Scholar Theses

The hippocampus is the part of the brain that is involved in memory and navigation. Neurons in the hippocampus, known as place cells, fire in specific locations within this region of the brain as the subject navigates through their environment. As these cells fire, they create a map-like representation of this environment. However if the environment is altered in any way, the place cell firing pattern is adjusted to incorporate this new information. This adjustment will inevitably cause subjects to take more time to complete their task. The goal of our testing was to assess how various manipulations, both spatial …

Recovery Of Hippocampal-Dependent Learning Despite Blunting Reactive Adult Neurogenesis After Alcohol Dependence, Chelsea G. Nickell, K. Ryan Thompson, James R. Pauly, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Background:

The excessive alcohol drinking that occurs in alcohol use disorder (AUD) causes neurodegeneration in regions such as the hippocampus, though recovery may occur after a period of abstinence. Mechanisms of recovery are not clear, though reactive neurogenesis has been observed in the hippocampal dentate gyrus following alcohol dependence and correlates to recovery of granule cell number.

Objective:

We investigated the role of neurons born during reactive neurogenesis in the recovery of hippocampal learning behavior after 4-day binge alcohol exposure, a model of an AUD. We hypothesized that reducing reactive neurogenesis would impair functional recovery.

Methods:

Adult male rats were …

Electrophysiological And Imaging Calcium Biomarkers Of Aging In Male And Female 5×Fad Mice, Adam O. Ghoweri, Lara Ouillette, Hilaree N. Frazier, Katie L. Anderson, Ruei-Lung Lin, John C. Gant, Rachel Parent, Shannon Moore, Geoffrey G. Murphy, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker.

OBJECTIVE: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on …

Chronic Effects Of Methylphenidate On Neuronal Viability And Plasticity, Hannah Oakes

Electronic Theses and Dissertations

Methylphenidate (MPH) is the most commonly prescribed drug to treat Attention Deficit Hyperactivity Disorder (ADHD). ADHD is now considered a life-long disorder; therefore, patients take MPH from adolescence into adulthood, highlighting the need for research studying chronic MPH use. MPH increases dopamine and norepinephrine within the synaptic cleft; therefore, chronic use of MPH may lead to changes within important dopaminergic pathways. One pathway, the mesolimbic pathway, includes the hippocampus, an area where adult neurogenesis occurs. We investigated the effects of chronic low and high doses of MPH on neurogenesis and examined levels of a few key proteins linked to cell …

Neuronal Calcium Imaging, Excitability, And Plasticity Changes In The Aldh2-/- Mouse Model Of Sporadic Alzheimer's Disease, Adam O. Ghoweri, Peter Gagolewicz, Hilaree N. Frazier, John C. Gant, R. David Andrew, Brian M. Bennett, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer's disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear.

OBJECTIVE: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with …

Meaning In Architecture: Affordances, Atmosphere And Mood, Bob Condia, Michael Arbib, Colin Ellard, Brent Chamberlain, Kevin Rooney

NPP eBooks

Abstract: Meaning in Architecture: Affordances, Atmosphere and Mood, began as a public forum about human awareness of building, specifically speaking to the significance of affordances, embodied simulation theory, atmosphere and mood. It is herewith presented in copy form for broader distribution. An exchange between scientists and architects, this symposium was the inaugural Interface event of ANFA (the Academy of Neuroscience for Architecture, Salk Institute) held 17 April 2018 in the Regnier Forum of APDesign, Kansas State University. The authors for Meaning in Architecture: Affordances, Atmosphere and Mood will escort you to the intersection of deep brain function, as studied by …

Hippocampal Subfields Revealed Through Unfolding And Unsupervised Clustering Of Laminar And Morphological Features In 3d Bigbrain, J. Dekraker, J. C. Lau, K. M. Ferko, A. R. Khan, S. Köhler

Brain and Mind Institute Researchers' Publications

© 2019 Elsevier Inc. The internal structure of the human hippocampus is challenging to map using histology or neuroimaging due to its complex archicortical folding. Here, we aimed to overcome this challenge using a unique combination of three methods. First, we leveraged a histological dataset with unprecedented 3D coverage, BigBrain. Second, we imposed a computational unfolding framework that respects the topological continuity of hippocampal subfields, which are traditionally defined by laminar composition. Third, we adapted neocortical parcellation techniques to map the hippocampus with respect to not only laminar but also morphological features. Unsupervised clustering of these features revealed subdivisions that …

Age Differences In Hippocampal Glutamate Modulation During Associative Learning And Memory: A Proton Functional Magnetic Resonance Spectroscopy (1h Fmrs) Study, Chaitali Anand

Wayne State University Dissertations

Episodic and associative memory decline is one of the earliest cognitive impairments in normal aging and among the defining cognitive features of Alzheimer’s disease (AD). Since, age-related cognitive decline gradually devolves into AD, with neuropathology preceding cognitive changes by many years, the identification of biomarkers of early disease progression is crucial. Reduction in glutamate, the main excitatory neurotransmitter involved in associative memory, in key brain regions such as the hippocampus, has been theorized as one of the cellular mechanisms underlying cognitive decline in aging and AD. A few neuroimaging studies that demonstrated a link between older adults’ weaker cognitive performance …

The Role Of Medial Septum Cholinergic Function In Processing Self-Movement Cues To Maintain Spatial Orientation, Jenna Rae Osterlund

Graduate Research Theses & Dissertations

Wandering is the most life-threatening and commonly reported symptom of Alzheimer’s Disease (AD), a neurodegenerative disorder characterized by an inability to maintain spatial orientation. The often deadly consequences of wandering are projected to rise in the coming decades due to the advancing aged population. These upcoming challenges necessitate a more comprehensive understanding of the neurobiology of spatial orientation in order to evaluate novel therapeutic techniques for symptoms such as wandering. The inability to maintain spatial orientation in AD may be due to the pathological degeneration of the hippocampal cholinergic system. This neurological system is conserved across species for its function …

Changes In Hippocampal-Anterior Cingulate Cortex Interactions During Remote Memory Recall, Ryan A. Wirt

UNLV Theses, Dissertations, Professional Papers, and Capstones

Spatial memory is an important cognitive process that relies on extensive neural networks throughout the brain. The hippocampus (HC) is important for the formation of these memories but over time, in a process referred to as consolidation, recall becomes increasingly reliant on other brain areas. The anterior cingulate cortex (ACC), a region within the medial prefrontal cortex, is important for spatial learning, spatial working memory, and remote memory recall, but the mechanisms underlying recall processes are still unknown. To better understand the role of the ACC and HC during memory recall, we introduced rodents into a series of spatially and …

Understanding Perirhinal Contributions To Perception And Memory: Evidence Through The Lens Of Selective Perirhinal Damage, Marika C. Inhoff, Andrew C. Heusser, Arielle Tambini, Chris B. Martin, Edward B. O'Neil, Stefan Köhler, Michael R. Meager, Karen Blackmon, Blanca Vazquez, Orrin Devinsky, Lila Davachi

Brain and Mind Institute Researchers' Publications

© 2019 Elsevier Ltd Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood …

Characterizing The Development Of Episodic Memory And Assessing The Reliability Of Fmri Measures, Lingfei Tang

Wayne State University Dissertations

The ability to remember past events is critical for everyday life and showed robust improvement over development from childhood to adulthood. With advances in noninvasive neuroimaging methods such as functional MRI in recent years, research efforts have been focused on identifying neural correlates underpinning developmental gains in memory performance. In my dissertation work, using a widely-validated subsequent memory paradigm, I aim to characterize functional MRI correlates of memory development. Specifically, I focused my investigation on identifying age differences in the functional patterns of two brain regions critical for memory, the prefrontal cortex and the hippocampus. Focusing on the prefrontal cortex …

Ketogenic Diet Modulates Nad+-Dependent Enzymes And Reduces Dna Damage In Hippocampus, Marwa Elamin, David N. Ruskin, Susan A. Masino, Paola Sacchetti

Faculty Scholarship

© 2018 Elamin, Ruskin, Masino and Sacchetti. The ketogenic diet’s (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 …

Different Behavioral Experiences Produce Distinctive Parallel Changes In, And Correlate With, Frontal Cortex And Hippocampal Global Post-Translational Histone Levels., Marissa Sobolewski, Garima Singh, Jay S. Schneider, Deborah A. Cory-Slechta

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic "biomarkers" could be extracted to classify different types of behavioral experience. To begin to address this question, male and female mice were subjected to either a Fixed Interval (FI) schedule of food reward, or a single episode of forced swim followed by restraint stress, or no explicit behavioral experience after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) …

Defining The Radioresponse Of Mossy Cells, Devon Ivy

Electronic Theses, Projects, and Dissertations

Clinical radiotherapy is used to treat a variety of brain tumors within the central nervous system. While effective, it can result in progressive and debilitating cognitive impairment that can diminish quality of life. These impairments have been linked to hippocampal dysfunction and corresponding deficits in spatial learning and memory. Mossy cells are a major population of excitatory neurons located within the dentate hilus and highly involved in hippocampal circuitry. They play critical roles in spatial navigation, neurogenesis, memory, and are particularly vulnerable to a variety of neurotoxic insults. However, their sensitivity to ionizing radiation has yet to be investigated in …

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 …

Baseline White Matter Hyperintensities And Hippocampal Volume Are Associated With Conversion From Normal Cognition To Mild Cognitive Impairment In The Framingham Offspring Study., Katherine J Bangen, Sarah R Preis, Lisa Delano-Wood, Philip A Wolf, David J Libon, Mark W Bondi, Rhoda Au, Charles Decarli, Adam M Brickman

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

INTRODUCTION: We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up.

METHODS: Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified.

RESULTS: Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion …

Epigenetic Suppression Of Hippocampal Calbindin-D28k By Δfosb Drives Seizure-Related Cognitive Deficits., Jason C. You, Kavitha Muralidharan, Jin W. Park, Iraklis Petrof, Mark S. Pyfer, Brian F. Corbett, John J. Lafrancois, Yi Zheng, Xiaohong Zhang, Carrie A. Mohila, Daniel Yoshor, Robert A. Rissman, Eric J. Nestler, Helen E. Scharfman, Jeannie Chin

Department of Neuroscience Faculty Papers

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. …

Multi-Scale Spatial Cognition Models And Bio-Inspired Robot Navigation, Martin I. Llofriu Alonso

USF Tampa Graduate Theses and Dissertations

The rodent navigation system has been the focus of study for over a century. Discoveries made lately have provided insight on the inner workings of this system. Since then, computational approaches have been used to test hypothesis, as well as to improve robotics navigation and learning by taking inspiration on the rodent navigation system.

This dissertation focuses on the study of the multi-scale representation of the rat’s current location found in the rat hippocampus. It first introduces a model that uses these different scales in the Morris maze task to show their advantages. The generalization power of larger scales of …

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

Hippocampal Neurogenesis And Volume In Migrating And Wintering Semipalmated Sandpipers (Calidris Pusilla)., Nara Gyzely De Morais Magalhães, Cristovam Guerreiro Diniz, Daniel Guerreiro Diniz, Ediely Pereira Henrique, Patrick Douglas Corrêa Pereira, Isis Ananda Matos Moraes, Mauro André Damasceno De Melo, David Francis Sherry, Cristovam Wanderley Picanço Diniz

Brain and Mind Institute Researchers' Publications

Long distance migratory birds find their way by sensing and integrating information from a large number of cues in their environment. These cues are essential to navigate over thousands of kilometers and reach the same breeding, stopover, and wintering sites every year. The semipalmated sandpiper (Calidris pusilla) is a long-distance migrant that breeds in the arctic tundra of Canada and Alaska and winters on the northeast coast of South America. Its fall migration includes a 5,300-kilometer nonstop flight over the Atlantic Ocean. The avian hippocampus has been proposed to play a central role in the integration of multisensory spatial information …