Apolipoprotein E4, Tauopathy, And Brain Injury: Molecular Insights Into Alzheimer's Disease Pathology, Nashanthea J. Roland

Theses & Dissertations

Alzheimer’s disease (AD) is the world’s leading cause of dementia, characterized by progressive atrophy of the hippocampal and cortical brain regions, synapse damage and loss, and a buildup of senile plaques and neurofibrillary tangles composed of β-amyloid peptides and hyperphosphorylated tau, respectively. While age is the most significant risk factor for developing AD, apolipoprotein E4 (APOE4) is the strongest genetic risk factor for AD. Although it is known that APOE4 influences tau pathology, the molecular mechanisms by which APOE4 drives AD pathogenesis and progression remain unclear. In addition to intrinsic contributions to AD, there are many extrinsic factors that can …

The Endocannabinoid System's Influence And Modulation Of Nociception, Doreen M. Flannery

Honors Thesis

The anatomy and physiology of pain is a well-defined pathway where noxious stimuli is processed by different systems in the brain. The central research question of this review is how can we better understand the neurobiological effects pain has, and assess if there is therapeutic potential in using endocannabinoids to modulate these effects. Endocannabinoids are signaling molecules that play a key role at both the cellular and molecular level in modulating both acute and chronic pain by influencing different processes within each level that affect how the body responds to both internal and external stimuli. The endocannabinoid system is a …

The Role Of Presynaptic Proteins In Alcohol Sensitivity And Tolerance, Madhumitha Gundluru

Honors Theses

Mammalian Unc13 (Munc13) and Drosophila Unc13 (Dunc13) are presynaptic active zone proteins essential for synaptic vesicle docking and priming in a neuron. Alcohol binds to the C1 domain of Munc13, which inhibits DAG binding. The reduction in DAG binding by Munc13 decreases the probability of vesicle fusion with the membrane, decreasing neurotransmitter release. Heterozygotes for a Dunc13 loss-of-function allele are behaviorally resistant to alcohol, physiologically resistant to alcohol, molecularly resistant to alcohol, and self-administer significantly more alcohol than control flies. Therefore, genetically reducing Dunc13 mimics a state of alcohol tolerance in the fly. The two main Dunc13 isoforms, Dunc13A and …

Claiming More To Cope: Does Ostracism Increase Overclaiming?, Katy Q. Chen

Honors Theses

In a pre-registered online study, we investigated the relationship between ostracism and overclaiming. Ostracism is the act of deliberately or unintentionally excluding and ignoring others. Overclaiming refers to the behavior of exaggerating one’s knowledge or familiarity with specific topics, often as a way of attempting to present oneself as more knowledgeable or competent than one actually is. Drawing from the temporal need-threat model, we hypothesized that ostracized individuals, as a compensatory response, would likely overclaim more compared to included individuals. This online study simulated a work experience where participants were asked to answer questions about their work-related experiences and opinions. …

Neurodegenerative Disease Mechanisms: Mitochondrial Impairment, Tau Aggregation, And Neuroinflammation As Central Drivers Of Disease Progression, Luis D. Estrella

Theses & Dissertations

The study of the intricate molecular mechanisms behind the pathology of neurodegenerative diseases has become a primary research area in the past decades. The major branches of these studies involve both disease progression and disease pathogenesis, in which neuroscientists have studied, and continue to study, the role that mitochondrial dysfunction, aberrant protein aggregation (like Tau), and immune cell reactions have on these. However, more recent studies have shined light to the fact that these three pathological features are not independent from one another and that their synchronous contributions may be the ultimate driver of neurodegeneration. This dissertation encompasses four different …

Impaired Dnajb2 Response To Heat Shock In Fibroblasts From A Neuropathy Patient With Dnajb2/Hsj1 Mutation: Cystamine As A Potential Therapeutic Intervention, Raj K. Pradhan, Nikolas G. Kinney, Brigid K. Jensen, Hristelina Ilieva

Farber Institute for Neuroscience Faculty Papers

Background and Objectives: Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C>T was discovered in an adult patient with severe sensory–motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase …

Biomarkers That Could Explain Parasite-Induced Behavioral Alterations In The Golden Shiner (Notemigonus Crysoleucas) – Posthodiplostomum System, Laura D. Nicolas

All HCAS Student Capstones, Theses, and Dissertations

Trophically transmitted parasites require an intermediate host to be consumed and often manipulate host phenotype (i.e., morphology, physiology, and/or behavior) to increase predation risk by definitive hosts. Posthodiplostomum is a trematode with a complex life cycle involving snails as first hosts, fish as second intermediate hosts, and piscivorous birds as definitive hosts. In fish hosts, Posthodiplostomum infection has been linked to increased predation, suggesting suppression of antipredator behaviors. However, the specific physiological pathways remained unexplored and changes in the host’s neural, endocrine, and immune systems could be involved. Thus, I examined whether Posthodiplostomum infection intensity was associated with brain serotonin …

Behavioral And Neural Microstructures Of Dynamic Cue-Motivated Responses, Erica Townsend

Dartmouth College Ph.D Dissertations

Sign-tracking, a conditioned response in which animals are physically attracted to reward-predictive cues due to motivational value attribution, is known to be persistent but can be flexible under some circumstances. For example, during an omission paradigm, in which vigorous responses must be withheld to avoid reward cancellation, animals can quickly restructure their responses. However, sign-tracking does not cease entirely, and cue attraction persists. This dissertation explores the behavioral and neural mechanisms underlying the simultaneous persistence and flexibility of sign-tracking during omission procedures. First, a novel method for behavioral analysis is introduced to accurately depict sign-tracking animals in dynamic tasks such …

Mitochondrial Network Expansion And Loss During Oligodendrocyte Life And Death, Xhoela Bame

Dartmouth College Ph.D Dissertations

Oligodendrocytes are the myelinating cells of the central nervous system, known for modulating signal transmission, refining neural circuits, and providing metabolic support to axons. Oligodendrocytes are generated throughout life from oligodendrocyte precursor cells (OPCs) and are damaged or lost in demyelinating and neurodegenerative diseases and age-related pathologies. Thus, understanding the cellular checkpoints that occur during the generation and degeneration of oligodendrocytes is crucial for maintaining their population in health and recovering it in disease and aging.

Using high-resolution optical imaging, I have discovered a dynamic redistribution and subcellular partitioning of mitochondria during oligodendrogenesis. Mitochondria transiently expanded towards the differentiating OPC …

The Impact Of Insufficient Sleep On The Serial Reproduction Of Information, David L. Dickinson, Sean P. A. Drummond

ESI Publications

Story retelling is an important form of communication, cultural practice, and message transmission. Insufficient sleep is known to affect relevant cognitive skill areas necessary for story retelling or transmission fidelity. We conducted a preregistered randomized cross-over study on n = 155 young adults with exogenously assigned nightly sleep levels experienced in their at-home environments. A serial story reproduction task was administered online, and chains of up to three retells of a given story involved varied numbers of sleep restricted (SR) versus well-rested (WR) retellers. While story content decayed with each retell, group-level analysis showed that additional SR retellers in a …

Know Thyself: A History Of Ancient Neuroscience, Alex Delano

Departmental Honors & Graduate Capstone Projects

Neuroscience is often described as one of the youngest bodies of science, but documented study of the brain begins as early as the Neolithic period. The ancient Mediterranean was a hub for science, mathematics, philosophy, and literature, all disciplines necessary for the study of the brain. Evidence of neurosurgical procedures like trepanation and craniotomy began in the Neolithic period and were practiced and improved upon throughout the ancient Mediterranean. The first detailed studies on brain anatomy were carried out in the 3^rd century BCE in Greece which created a necessary structure for future scientists to build on. While many …

Developing A Trial Unique Sequencing Task For Mice, Yader Gomez, Lilly Hagos, Gage Pompa, Ariana Mitic, Orlando Montiel, Talha Soluoku

Undergraduate Research Symposium Posters

The hippocampus and the anterior cingulate cortex (ACC) play distinct yet complimentary roles in the performance of cognitively demanding tasks.

While rodent models cannot truly capture human cognition, there is a serious need to develop more cognitively demanding rodent tasks to better understand human cognition to develop new tools to fight neurodegeneration.

Sequencing tasks are some of the most difficult for rodents to perform and are notoriously difficult to train.

Cutting edge interactive touch screen technology allows us to test an endless array of sequences, in a sound-controlled enclosure featuring a simple behavioral response for the mice.

Study Aim: To …

Characterizing The Medial Forebrain Bundle In Adolescents With Anhedonic Depression, Tina Nguyen

Biological Sciences Undergraduate Honors Theses

Adolescent depression has quickly grown in prevalence, yet the underlying neuropathology remains poorly understood. Anhedonia–the diminished ability to experience pleasure–is a core symptom of melancholic depression. Early identification of biomarkers associated with anhedonic depression could help mitigate the severity of the disorder by enhancing treatment efficacy. Blunted functionality of the nucleus accumbens (NAcc), the reward center of the brain, and abnormal dopaminergic activity in the ventral tegmental area (VTA) have both been linked to depression. Furthermore, glutamatergic input from the hypothalamus modulates the VTA which in turn, downregulates dopamine release in the NAcc. However, there is limited evidence supporting that …

Effects Of Novel Dopamine D4 Receptor-Targeted Compounds On Locomotor Activity And Anxiety-Like Behavior In Male And Female Sprague Dawley Rats, Samantha Alyse Walkow, Noah A. Ivak, Daniel Chandler, John Tkaczynski, Thomas M. Keck, Comfort A. Boateng, Eleni Papadopoulos, Barry D. Waterhouse, Rachel L. Navarra

Rowan-Virtua Research Day

The consequences of modulating subtypes of G protein coupled dopamine receptors are broadly studied for their role in decision making behavior, specifically in situations involving uncertain risk and reward. The actions of dopamine D4 receptors (D4Rs) on these complex processes are the least understood, particularly due to a lack of available compounds with suitable selectivity for D4Rs. Further, current research often fails to evaluate how modulating specific dopamine receptor subtypes may affect locomotor activity and anxiety-like behavior as confounding factors prior to assessing their function in behavioral assays of higher order decision making. The goal of the current study was …

Poor Sleep Quality Is Associated With Decreased Structural Coherence Of Mesolimbic Dopamine Projections In Children, William A. Walker

Psychological Science Undergraduate Honors Theses

Insomnia is the second most common mental disorder that affects approximately 10% of the population. An additional one-third of the population experiences occasional symptoms of insomnia like difficulty falling asleep or staying asleep. Sleep quality is also a key indicator of overall mental and physical health; however, researchers have only begun to study the effects of the structure of the mesolimbic pathway on sleep cycle regulation and quality. Emerging research suggests that mesolimbic dopamine projections from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAcc) play a role in sleep-wake regulation. In this study, I analyzed data from the …

Involvement Of The Mpfc In Narcissism And Celebrity: A Transcranial Magnetic Stimulation Study, Sydney Ash

Theses, Dissertations and Culminating Projects

Narcissism is typically characterized by extreme self-focus, lack of empathy for others, and emotional regulation deficits. Grandiose narcissism has been linked to an increased desire for fame, while vulnerable narcissism has been linked to an increase in celebrity worship. While there is a lack of research concerning the neural correlates of desire for fame and celebrity worship, narcissism has been correlated with the medial prefrontal cortex (mPFC) in various studies. The current study aimed to identify relationships between grandiose and vulnerable narcissism, fame appeal, celebrity attitudes, need to belong, and self-esteem using six scales. We also targeted the mPFC with …

Dabigatran Reduced Acute Microgliosis In A Mouse Model With Tbi, Nicholas R. Eltman, Rashmeena Abbasi, Mary C. Kosciuk, Syed Ahmed, Jose L. Pascual, Randel L. Swanson, Nimish K. Acharya

Rowan-Virtua Research Day

Objective:

The study objective was to investigate the acute anti-inflammatory effects of dabigatran in a preclinical mouse controlled cortical impact (CCI) model of severe traumatic brain injury (TBI).

Design

Mice were separated into three groups: controlled cortical impact (CCI) with dabigatran (drug treatment, n=5), CCI with saline (positive control, n=5), and sham CCI without saline or dabigatran (negative control, n=3). Dabigatran (80mg/kg) or saline was administered orally at 2, 10, 18, 26, 34, and 42 hours following experimental CCI in the drug treatment or positive control groups, respectively. Animals in the negative control group received sham CCI only. 48h following …

Effects Of The Non-Stimulant Norepinephrine Reuptake Inhibitor, Atomoxetine, On Cognitive Flexibility In Healthy Adult Long-Evans Rats, Noah A. Ivak, Samantha Walkow, Christopher Knapp, Eleni Papadopoulos, Barry D Waterhouse, Rachel L Navarra

Rowan-Virtua Research Day

Executive function is the control of multiple higher order cognitive processes that include attention, working memory, and cognitive flexibility. Cognitive flexibility is the ability to shift behavioral strategies

in response to changing environmental demands and task complexity. This cognitive modality is often impaired in many neuropsychiatric disorders like attention deficit hyperactivity disorder (ADHD). Deficits in cognitive flexibility are associated with dysregulation of the catecholamines, norepinephrine (NE) and dopamine (DA) within the prefrontal cortex (PFC). Atomoxetine (ATX), a non-stimulant NE reuptake inhibitor, elevates levels of NE and DA in the PFC by inhibiting the norepinephrine transporter (NET). ATX is used to …

Effects Of Social Isolation On Cecum Opioid Receptor Expression And Affective Behavior, Jordan Riser, John Tkaczynski, Nicole Shellenbarger, Maya Patel, Daniel Chandler, Daniel Manvich

Rowan-Virtua Research Day

BACKGROUND

Psychological stress can induce gastrointestinal symptoms and exacerbate existing gastrointestinal disorders, indicating an interaction between the central and enteric nervous systems. Central nervous system activation of opioid receptors stimulates sympathetic outflow to the enteric nervous system, delaying motility and reducing gastrointestinal secretions, producing a similar clinical presentation to IBS.

HYPOTHESIS

We hypothesize that social isolation induces anxiety states, disrupting homeostatic noradrenergic activity in the brain and gut, leading to neurophysiological changes in the cecum characterized by altered expression of opioid receptors.

METHODS

Sprague-Dawley rats were housed in either group (control) or socially isolated conditions. Affective behavior was assessed using …

Identifying Cognitive, Affective, And Developmental Mechanisms Linking Threat And Deprivation With Adolescent Psychopathology, Ekaterina Sadikova, David G. Weissman, Maya L. Rosen, Elise Robinson, Liliana J. Lengua, Margaret A. Sheridan, Henning Tiemeier, Katie A. Mclaughlin

Neuroscience: Faculty Publications

Background: The mechanisms linking early-life adversity with psychopathology over the life-course are complex. In this prospective study, we collectively examined cognitive, affective, and developmental mediators previously found to individually link childhood threat and deprivation experiences to adolescent psychopathology to identify the most potent mechanisms. Methods: Data came from a community sample of 227 children (mean child age 11.5 ± 0.5 years, 48.5% female) from the Seattle metro area with recruitment designed to reflect diversity in family income. Candidate mechanisms included self-rated pubertal development and task-measured attention bias to threat, emotion regulation, theory of mind, fear learning, inhibitory control, language ability, …

Acetylcholine Release In The Dorsal Lateral Straitum During Social Approach Task, Taylor Good, Oyku Dinckol, Noah Wenger, Jake Caselli, Munir Gunes Kutlu

Rowan-Virtua Research Day

Nicotine Decreases ACh Release in the DS leading to a Serenic Effect during Social Approach Task

Acetylcholine (ACh) regulates attention, learning, and stress responses (Benarroch E. E., 2012). The dorsal striatum (DS), essential for stimulus-response learning, is also linked to anxiety and compulsivity (Casado-Sainz et al., 2021). We used behavioral pharmacology and in vivo fiber photometry to study ACh responses during social approach tasks in the dorsal striatum. Male and female C57BL/6J mice underwent stereotaxic surgeries to inject a fluorescent ACh sensor (ACh.Sn.Fr) and implant fiber optic cannulas in the DS. Using in vivo fiber photometry, we tracked ACh release …

Modulation Of Opioid Receptor Expression In The Ventral Tegmental Area Following Stress Exposure In Rats, Maya Patel, John Tkaczynski, Jordan Riser, Nicole Shellenbarger, Jin Park, Daniel Manvich, Daniel J. Chandler

Rowan-Virtua Research Day

Background: The ventral tegmental area (VTA) contains dopamine-producing neurons projecting to various brain regions. VTA dysfunction is linked to addiction and depression. Delta opioid receptor upregulation relates to chronic pain, inflammation, cancer, and early adversity. Kappa receptors in the VTA influence stress, drug-seeking, mood, and reward. Notably, chronic substance abuse upregulates the κ-receptor/dynorphin system, and the opioid system regulates social interaction needs.

Hypothesis: Stress will upregulate opioid receptors.

Methods: We compared group-housed and individually-housed rats using stress tests, analyzing behavior and quantifying VTA opioid receptor expression.

Results: Social isolation upregulated delta and kappa opioid receptors in …

Atypical Morphometry And Connectivity Of The Cortico-Striatal-Thalamo-Cortical Circuit In Children And Adolescents With Chromosome 22q11.2 Deletion Syndrome: A Population At Ultra-High Risk For Developing Obsessive-Compulsive And Schizophrenia Spectrum Disorders, Amanda I. Rowan

LSU New Orleans Theses and Dissertations

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex neurodevelopmental disorder associated with serious medical, cognitive, and psychiatric conditions, including significantly elevated risk for obsessive-compulsive (OCD) and/or schizophrenia spectrum disorders (SCZ). The cortico-striato-thalamo-cortical (CSTC) neural circuit is critical for cognitive and emotional processing. Dysfunction of the CSTC circuit is implicated in the etiopathology of both OCD and SCZ but has not been specifically examined in individuals with 22q11.2DS. This study used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), along with standardized psychological and cognitive measures, to investigate atypical morphometry and white matter connectivity within CSTC-related brain regions in …

The Effects Of Pfos Exposure On Zebrafish Dopaminergic Neurodevelopment, Allison G. Fletcher

Departmental Honors & Graduate Capstone Projects

Per- and polyfluoroalkyl substances (PFAS) are a group of environmental contaminants that cause disruptions to the nervous and endocrine systems. Perfluorooctanesulfonate (PFOS) is considered one of the most disruptive PFAS to the nervous system, and may disrupt neurodevelopment of the dopaminergic system, which has been linked to neurodevelopmental disorders like Attention Deficit/Hyperactivity Disorder (ADHD) in humans. I hypothesized that early life PFOS exposure disrupts the development of the dopaminergic system. To test this hypothesis, I exposed zebrafish to 0.05, 0.5, and 5.0 mg/L PFOS through 5 days of embryonic and larval development. To assess acute effects of PFOS on the …

Neural Patterns Reflect Semantic Representation In Novice Sign Language Learners, Megan E. Hillis

Dartmouth College Ph.D Dissertations

How do novice language learners represent semantic information in their new language? The extent to which languages are supported by distinct or overlapping neural representations in bilinguals has been the topic of much research, but less is known about how new knowledge is integrated into established representational networks, especially at the earliest stages of language acquisition. Furthermore, most investigations have compared languages which share a modality (spoken). Signed languages can provide insight into language unconfounded by perceptual qualities that spoken languages share. Chapter 1 presents an initial study in which hearing English-speaking non-signers learned a set of nouns in American …

Sliding Window Method For Simulating Action Potentials In Axons, Hayden Reed

Honors Theses

ABSTRACT Hodgkin and Huxley’s nonlinear partial differential equations model the excitation and propagation of action potentials in neurons, and there have been numerous attempts at finding the best numerical solution method. This thesis proposes a novel approach to solving these equations: the Sliding Window method, in which a fixed sub-interval is found through capturing the signal’s head and tail. The system is then solved on the sub-interval instead of the entire interval. Using the Sliding Window technique also involves implementing the backward and forward Euler methods and the finite difference method. It will be demonstrated that, in utilizing the Sliding …

Simulating Chill: Exploring The Cognitive And Therapeutic Potential Of Cold Vr Environments, Jessica Turner, Piper Hutson, James Hutson

Faculty Scholarship

This study investigates the cognitive and therapeutic potential of immersive virtual reality (VR) environments designed to simulate cold conditions. Through the engagement of participants through multisensory stimuli—including vivid visual representations of the Athabasca Glacier, auditory effects of icy winds, and corresponding haptic feedback—the research evaluates neurological and physiological responses associated with attention, emotional regulation, and stress modulation. Participants experienced virtual scenarios featuring icy winds and snow, activating specific neurological pathways involving the occipital lobe, primary visual cortex, superior colliculus, and insula, thus reinforcing sensory integration. Through predictive coding, the anterior insula and hypothalamus were engaged, prompting thermoregulatory simulations and subconscious …

The Bullied Prairie Vole: Modeling Depression And Anxiety Through Social Defeat Stress, Minerva Rodriguez

Open Access Theses & Dissertations

Stress-induced illnesses, such as major depression and anxiety, are significant global causes of disability. This highlights the need for reliable animal models that accurately mimic social stress-induced maladaptations, thus, allowing the experimental study of the etiology of such disorders. Prairie voles (Microtus ochrogaster), known for their human-like bi-parental behavior and monogamous partner preferences, are a relevant model for the study of stress-induced psychopathologies. For this reason, in this dissertation, I examined whether exposing voles to the social defeat stress (SDS) paradigm, an experimental approach that captures bullying behavior, would result in both depression and anxiety-related profiles. To do this, experimental …

Minimizing Secondary Spinal Cord Injuries With Hypertonic Saline., Francisco A. Cortez-Thomas

Master of Engineering Theses

Spinal cord injury (SCI) disrupts white matter, causing periaxonal swelling, axonal degeneration, and impaired function. To examine vascular edema’s role, we developed a 3Dprinted dual-compartment imaging chamber to mimic and manipulate interstitial and vascular fluid dynamics in real time. We hypothesized that hypertonic saline (HTS) in the "vascular" chamber would osmotically shift fluid from the periaxonal space and preserve myelinated fibers after SCI. Using two-photon excitation microscopy, we imaged myelin and axons ex vivo in Thy1^YFP+ transgenic mice following C5 contusive SCI and assessed three clinically relevant HTS concentrations versus normal saline for their effectiveness in mitigating periaxonal swelling …

A Neuroimmune Circuit Mediates Chemo Brain Pathology, Daniel Ahmadi

McKelvey School of Engineering Graduate Student Theses & Dissertations

Chemotherapeutic agents, while effective in targeting malignant tumors, often reduce the patients’ quality of life by inducing fatigue, pain, and motivational deficits. These symptoms are collectively referred to as “chemo brain.” The mechanisms underlying these adverse effects, and specifically whether fatigue and motivational impairments share a common etiology, remain poorly understood. The neural–immune substrates of these symptoms remain obscure, in part because standard preclinical regimens either bypass key systemic signals or introduce local toxicity confounds. Here, I establish and validate a three‑day, low‑dose intravenous cisplatin protocol that avoids peritoneal inflammation and severe renal injury yet produces robust, reversible fatigue and …