Neurosciences Commons^™

Anatomy And Function Of Vasopressin Receptor 1a-Expressing Neurons In The Limbic Thalamus, David Joseph Kahn

Theses and Dissertations

The vasopressin (Avp) system modulates social behavior through region-specific and sex-dependent mechanisms, yet the role of Avp receptor 1a (Avpr1a) signaling in the thalamus has remained largely unexplored. This dissertation examined the distribution and functional contributions of Avpr1a-expressing neurons across the mouse thalamus using a combination of genetic labeling, anatomical quantification, and chemogenetic manipulation. Mapping of Avpr1a-expressing neurons revealed a presence in most thalamic nuclei, with highest densities in the anterior thalamic nuclei and midline nuclei. Notably, Avpr1a-expressing neuron densities did not mirror previously described patterns of Avp innervation, and no sex differences in Avpr1a-expressing neuron density were observed. Chemogenetic …

Mapping The Neuroexposome: Integrative Analysis Of Dementia Risk Factors Through Multi-Omics And Environmental Profiling In The Egyptian Population., Mai Ahmed Saadzaghloul Othman

Theses and Dissertations

Background: Dementia represents one of the most pressing public health challenges of the twenty-first century, with the global burden projected to reach 153 million cases by 2050. Egypt, as the most populous Arab nation, faces a corresponding rise in age-related diseases, yet comprehensive data from low- and middle-income countries remain severely limited. The neuroexposome framework, integrating genetic susceptibility, environmental exposures, and metabolic alterations, offers a powerful strategy to characterize the complex interplay between internal and external risk factors for Alzheimer's disease (AD) and Alzheimer's disease Related Dementias (ADRD).

Objectives: This thesis aimed to: (1) examine the distribution of APOE alleles …

Environmental And Pharmacological Modulation Of Opioid-Mediated Behavioral Effects In Rats, Corinne Ann Gallagher

Theses and Dissertations

Opioid Use Disorder (OUD) and opioid-associated overdoses continue to pose significant burden to US healthcare systems—both financially and in lives lost. It is imperative to identify risk factors which may predispose vulnerability to OUD development, which could aid in discovery of new therapeutic strategies for susceptible populations. This dissertation investigated the impacts of two such risk factors which modulate opioid-induced reward and behavioral effects: adolescent stress and the adulteration of illicit opioids by xylazine. In Chapter 2, we examined the effects of acute adolescent stress on oxycodone self-administration in rats, and the potential involvement of the locus coeruleus in these …

Investigating Tau Pathology In The Retina And Anterior Segment Structures Of The Eye In A 3-Nitropropionic Acid–Induced Tauopathy Mouse Model, Mohamed Sayed Ahmed Abdel-Kader Qasem

Theses and Dissertations

Background and Objectives: Alzheimer's disease, the most prevalent neurodegenerative disorder in older adults, is characterized by accumulation of hyperphosphorylated tau and amyloid-beta (Aβ) plaques in the central nervous system. Given the retina's shared embryological origin with the brain, its direct neural connectivity via the optic nerve, and similarities in vasculature and age-related degeneration patterns, retinal pathology may serve as an early, non-invasive biomarker for Alzheimer's disease. This study employed 3-nitropropionic acid (3NP) as a pathway-specific tauopathy model driven by mitochondrial dysfunction. The study particularly aimed to investigate whether retinal and corneal tau pathology reflects underlying tau-related neurodegeneration triggered by …

Effects Of Stressor Exposure And Locus Coeruleus Opioid Signaling On Coping And Anxiety-Like Behavior In Rats, John Arthur Tkaczynski

Theses and Dissertations

Stress is a physiological state of altered neuroendocrine signaling and heightened indices of behavioral vigilance and arousal in response to threatening stimuli. This project aimed to investigate the adaptations to stress that occur in the noradrenergic locus coeruleus (LC) and how these changes affect stress coping behavior. We began by investigating how adolescent restraint and predator odor stress affects coping when presented with a secondary noxious stimulus in the defensive shock probe burying task one week following stressor exposure, finding that stressed male rats demonstrate a more active coping response and stressed female rats demonstrate a more passive coping response, …

Mechanisms Underlying Estrous Cycle-Dependent Changes In Incubated Cocaine Craving, Erin Elizabeth Wannen

Theses and Dissertations

Cues associated with cocaine use are one of the most common relapse triggers and understanding what promotes cue-induced cocaine craving and relapse is a critical question in the field. Human studies have shown that these measures are impacted by fluctuations in ovarian hormone levels, as higher levels of estradiol promote cue-induced cocaine craving in women while higher levels of progesterone reduce craving in both sexes. Enhanced or incubated cue-induced cocaine seeking or craving also changes across the rodent reproductive (estrous) cycle as levels of estradiol and progesterone fluctuate, with enhanced seeking behavior observed during the estrus stage of the cycle. …

Exploring The Effects Of Serotonin And Selective Serotonin Reuptake Inhibitors On The Neurological, Behavioral, And Cardiovascular Systems Using The Animal Model Of The Syrian Hamster (Mesocricetus Auratus), Ariana Vianey Hinojosa

Theses and Dissertations

Serotonin is a neurotransmitter widely recognized for its role in neuropsychological processes, particularly in regulating mood, cognition, and emotional responses. However, its influence extends beyond the central nervous system (CNS), playing a crucial role in various physiological functions, including metabolism, the gastrointestinal system, reproductive processes, and cardiovascular regulation. As a key modulator of homeostasis, serotonin contributes to maintaining equilibrium within these systems, ensuring proper function and response to environmental stimuli. Despite its well-documented effects on mood and behavior, the broader physiological implications of serotonin remain less understood, particularly in the context of its interactions among neural, behavioral, and cardiovascular systems. …

Investigating The Effects Of Sex And Estrous Cycle On The Incubation Of Cue-Induced Oxycodone Craving, Bhumiben Pradipkumar Patel

Theses and Dissertations

The overprescription and misuse of opioids like oxycodone has played a significant role in the ongoing opioid crisis. While effective painkillers, drugs like oxycodone are also reinforcing and often misused. While sex and ovarian hormones can impact the analgesic effects of these drugs, the impact of these factors on oxycodone reinforcement are not fully understood. This relationship between ovarian hormones and opioid reward is further complicated by the fact that opioid use can disrupt ovarian hormone levels and produce reproductive cycle irregularities. Using a rat model of drug craving and relapse vulnerability, we found that chronic oxycodone exposure produced reproductive …

Activation Of Basal Forebrain Afferents Following Systemic Inflammation, Alexis Morgan Blas

Theses and Dissertations

Sepsis is a large-scale immune response typically due to an imbalance of pro- and anti-inflammatory responses due to some type of infection or insult. Around 1.7 million adults in the United States will develop it each year, making it the leading cause of increased morbidity and mortality in hospitals. Sepsis can lead to many different symptoms, one of which is delirium. Delirium is a mental state of confusion and disorientation and involves delusions, hallucinations, memory issues, and most commonly inattention. Delirium is more prevalent in older individuals which leads to further complications and a higher likelihood of development of long-term …

Behavioral And Neuroactivational Correlates Of Psychosocial Stress-Induced Cocaine Seeking In The Rat, Nicole Hinds

Theses and Dissertations

Abstract Nicole Maria Hinds BEHAVIORAL AND NEUROACTIVATIONAL CORRELATES OF PSYCHOSOCIAL STRESS-INDUCED COCAINE SEEKING IN THE RAT 2024 Molecular Cell Biology & Neuroscience Doctor of Philosophy Cocaine Use Disorder is characterized by a high risk for relapse that can persist over extended periods of abstinence. Psychosocial stressors are well-established to promote drug craving and relapse in humans but have rarely been employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not yet been thoroughly explored. This project aimed to identify brain regions recruited during psychosocial stress-induced cocaine seeking in rats, with a …

Lis1 Depletion In Adult Mouse Projection Neurons Causes Neurodegeneration And Severe Neurological Phenotypes, Anne Ventrone

Theses and Dissertations

Proper LIS1 function is crucial for human brain development, as mutations in LIS1 lead to lissencephaly, a severe neurodevelopmental disorder caused by defective proliferation, differentiation and migration of neural precursors. Our understanding of LIS1's functions after brain development is limited. LIS1 regulates cytoplasmic dynein 1 (dynein), an essential microtubule motor protein in cell division and migration, but also a cellular transport motor. We previously showed that tamoxifen (TX)-induced global knockout of LIS1 using a Cre/Lox system (Act-Lis1iKO) in young adult mice results in severe neurological defects and rapid lethality. This strongly supports LIS1's critical post- developmental role, but the underlying …

Development Of A Mediation Model Of Pain Cognition In Adult Patients With Sickle Cell Disease, Daniel M. Sop

Theses and Dissertations

Pain is a hallmark of Sickle Cell Disease (SCD), a genetic hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusion, and organ damage. While acute vaso-occlusive crises (VOC) have been extensively studied, the mechanisms underlying chronic pain and its interplay with brain function remain unclear. This dissertation investigates the relationships between cerebral blood flow (CBF), fluid cognition, and pain sensitivity in adults with SCD, utilizing advanced imaging techniques and validated assessment tools.

Arterial spin labeling (ASL) and functional magnetic resonance imaging (fMRI) were employed to measure CBF and brain activity, respectively. Pain sensitivity was assessed using the Pain Sensitivity Questionnaire (PSQ), and …

Scopolamine-Induced Modulation Of Serotonin And Dopamine Transporters Activity: Behavioral And Molecular Insights Into Rapid Antidepressant Action, Deepak Karunakaran

Theses and Dissertations

Major depressive disorder (MDD) affects over 350 million individuals worldwide and is characterized by profound dysregulation of serotonin (5-HT) and dopamine (DA) systems that govern mood, reward processing, and motivation. The serotonin transporter (SERT) and dopamine transporter (DAT), both dynamically regulated through phosphorylation, serve as critical determinants of synaptic monoamine signaling. Despite decades of therapeutic development, current antidepressants require 4-6 weeks to achieve efficacy, and approximately one-third to half of patients develop treatment-resistant depression. The emergence of rapid-acting antidepressants like ketamine represents a paradigmatic shift, demonstrating symptom relief within hours; however, ketamine's therapeutic potential remains constrained by abuse liability, dissociative …

Regulation And Function Of The Rna-Binding Protein Khsrp During Neuronal Development, Regeneration And Axonal Injury Response, Courtney Nicole Buchanan

Theses and Dissertations

Axons, which extend long distances from neuronal cell bodies, rely on localized mRNA translation to swiftly respond to extracellular stimuli and physiological states. This work investigates the mechanism underlying the RNA-binding protein KHSRP’s, axonal mRNA translation and regulatory pathways involved in neuronal growth and regeneration. Our results indicate that KHSRP deletion in mice leads to upregulation of growth-associated mRNAs linked to neuronal morphology and function, resulting in increased axon growth and altered memory consolidation. Indicating a critical role for KHSRP in neuronal development and function through post-transcriptional regulation (Chapter 2). Additionally, we show there is a rapid increase in axonal …

Dysregulation Of Dopamine Dynamics Through Monoamine Transporters By The Hiv-1 Protein Transactivator Of Transcription, Sarah Davis

Theses and Dissertations

Prevalence of HIV-1 Associated Cognitive Disorders (HAND) persists in the era of combined antiretroviral therapies, causing impaired memory, motor function, and decreased quality of life. Evidence from clinical samples of persons with HAND has implicated dopamine, as well as the HIV-1 viral protein transactivator of transcription (Tat) as key molecules associated with disease progression. Through molecular modeling, in vitro and in vivo mutagenesis our lab has characterized Tat as a negative allosteric modulator for monoamine transporters, including the dopamine transporter (DAT), vesicular monoamine transporter (VMAT-2), and norepinephrine transporter. While this work has shed light on how Tat impacts the function …

Neural Mechanisms Of Estrogen And Inflammation In Female Stress Susceptibility, Samantha Jane Bouknight

Theses and Dissertations

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are highly debilitating psychiatric disorders that notably share stress as an etiological factor. Stress is a common occurrence experienced daily by virtually everyone and, while most people are resilient, a substantial portion of the population exhibit risk factors that yield them susceptible to developing stress-related psychiatric disorders. One prominent factor that has long been known to increase this risk is the female biological sex with women presenting at least twice as often with disorders like PTSD and MDD compared to men. Interestingly, this bias exists distinctly during the reproductive years and …

Assessing The Effects Of Repetitive Mild Traumatic Brain Injury On Risk/Reward Decision Making And Catecholamine Associated Proteins, Christopher Knapp

Theses and Dissertations

Mild traumatic brain injury (mTBI) disrupts cognitive processes that influence risk taking behavior; however, the effects of repetitive mild injury (rmTBI) or whether these outcomes are sex specific are unknown. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is densely innervated by catecholaminergic fibers. Aberrant PFC catecholamine activity has been documented following TBI and may underlie TBI-induced risky behavior. Here, we exposed rats to sham (no injury), single, or three closed-head controlled cortical impact (CH-CCI) injuries to characterize the effects of rmTBI on 1) risk/reward decision making behavior using a probabilistic discounting task (PDT) and 2) levels …

Investigating The Association Between Gut Bacteria And Childhood Neuropsychiatric Disorders, Maha Abdo

Theses and Dissertations

Background: The etiology of autism spectrum disorder (ASD) remains unclear. However, it’s believed to be a multifactorial condition. Several studies suggest the involvement of gut and oral microbiome in the predisposition of ASD symptoms. Understanding the pathophysiology could aid in developing better treatment strategies that improve the quality of life of ASD individuals and their caregivers.

Aim: The current study aims at characterizing the gut and oral microbiome composition of ASD children compared to their healthy siblings and mothers as control groups.

Methods: Stool and saliva samples were collected from fourteen families at Ain Shams University Hospital, Outpatient Clinic. The …

Exploring Drivers Of Sex-Based Disparities In Relapsing Multiple Sclerosis, Stephanie K. Buxhoeveden

Theses and Dissertations

Females are three times more susceptible to relapsing multiple sclerosis (MS) and males typically have more severe disease, but the molecular underpinnings of these sex-based disease disparities are unknown and represent a critical knowledge gap.Subject Population: Blood samples from a demographically homogenous group of treatment naïve males and females with relapsing-MS and healthy controls. Research Design: Cross-sectional combinatorial omics pilot study. Instruments: Whole transcriptomic analysis with messenger RNA (mRNA) expression profiling using next generation sequencing (RNA-seq) and micro-RNA (miRNA) expression using NanoString technology. Aim 1) Identify and compare the actively expressed mRNAs in the transcriptome of males and …

Memory Impairments Due To Binge Ethanol Are Impacted By Age And Sex, Maria Alexis M. Bent

Theses and Dissertations

Ethanol is the most consumed drug among adolescents, which can cause long-term effects on memory and changes in gene and protein expression. While both adolescents and adults engage in binge drinking, the neurological and behavioral effects differ, with adolescents showing fewer adverse physiological effects but greater memory deficits than adults. Sex differences related to ethanol occur with women showing higher BEC than men and similar cognitive deficits despite fewer years of ethanol consumption. During adolescence the mPFC and dHPC undergo maturation development with both brain regions playing a role in spatial and recognition memory. Proteins critically involved in memory and …

Behavioral Effects Of Adolescent Social Isolation Stress And/Or Binge Drinking And The Role Of The Vhip --> Mpfc Circuit, Jyoti Lodha

Theses and Dissertations

Adolescence is characterized by heightened social interaction and risk-taking behavior. Disruptions to cortical development by binge ethanol or social isolation can lead to attention, social, and cognitive deficits later in life, and increase risk for alcohol use disorders. During adolescence, proper development of a monosynaptic connection from the ventral hippocampus (vHip) to the medial prefrontal cortex (mPFC) is critical to proper social and working memory. We ask whether these factors affect neurobiological factors such as gene expression and the role of the vHipmPFC circuit in these behaviors. Social stress was modeled by social isolation (aSI) during adolescence. We expect aSI …

Mild Traumatic Brain Injury In Yucatan Minipigs: Assessing Changes In Approachability And Mechanical Nociception Following Diffuse Central Fluid Percussion Injury, Mark D. Pavlichenko

Theses and Dissertations

Traumatic brain injury (TBI) is a major healthcare concern affecting millions. Symptoms of TBI include sensory sensitivity and social changes that may persist long-term. Due to similarities in cytoarchitecture, metabolism, and inflammation, higher order minipig models are advantageous for translational TBI research, however, there remains a shortage of information regarding their behavioral and sensory sequelae following injury. Therefore, in this study, we assessed changes in sociability and somatosensation in adult male and female Yucatan minipigs for up to one-week following a sham or central fluid percussion injury (cFPI). Specifically, the voluntary human approach task (VHAT) and the forced human approach …

Investigating The Role Of Vasopressin Receptor 1a Expressing Neurons In Mouse Dorsal Raphe, Tirth Nimishbhai Patel

Theses and Dissertations

Human social interactions heavily impact our physical and mental wellbeing. Arginine-vasopressin (Avp) and serotonin have both been implicated in modulation of social behaviors ranging from affiliation to aggression. In male mice, Avp neurons in the bed nucleus of stria terminalis (BNST) show increased activity during prosocial behavior. BNST sends Avp afferents to the dorsal raphe (DR) in the midbrain, a home to a large portion of serotonin neurons in the mouse brain. Previous data suggests that DR is activated during male prosocial behavior with a female stimulus, and Avp indirectly excites serotonin neurons. We hypothesized that DR contains a population …

Molecular Target And Circuitry Underlying The Preclinical Effects Of Psychedelics In Models Of Opioid Use Disorder, Alaina M. Jaster

Theses and Dissertations

Opioid use disorder (OUD), like other substance use disorders (SUD), is characterized by maladaptive behavioral allocation away from other rewarding aspects of life following prolonged use, as well as large rates of relapse. While pharmacotherapies exist for OUD, they tend to only target the opioid receptors rather than the underlying mechanisms behind the maladaptive behaviors. Serotonin (5-hydroxytryptamine; 5-HT) is involved in modulation of cravings and regulation of motivational reward-related behaviors, thought to be due to a top-down processing method of external and internal stimuli. Serotonin 2A receptors (5-HT_2AR) are widespread throughout the brain and most densely populate layer …

Vulnerability And Adaptation Of Neocortical Neuron Subtypes In Models Of Concussive Traumatic Brain Injury And Multiple Sclerosis, Alan C. Harris Jr.

Theses and Dissertations

The pathognomonic sequela of traumatic brain injury is traumatic axonal injury, the

burden of which correlates with less favorable outcomes. Elucidation of

the intrinsic variables that endow delineated neuronal subgroups and microanatomical domains with outsized vulnerability to injury represents a critical domain of inquiry toward the successful translation of disease-modifying therapeutics. To this end, we studied mild traumatic brain injury (mTBI) within the central fluid percussion model to examine the consequences of mTBI on the morphology and functional integrity of the axon initial segment (AIS) and the relative contributions to network homeostasis mediated by distinct populations of inhibitory interneurons. One …

A Preliminary Investigation Of Neuroantibody Levels, Prevalence, And Environmental Factors In Patients With Neurological Dysfunction, Jihan Azar

Theses and Dissertations

Nervous system damage comprises a large proportion of diseases worldwide. It is also the most difficult to diagnose. Biomarkers for nervous system damage are needed in order to diagnose these diseases early enough to allow for intervention. In this study, we recruited patients from two Egyptian hospitals with MCI, ET and NMS and health references. Serum autoantibody levels against neural proteins and heavy metals were analyzed and compared. Immunoglobulin G (IgG) antibodies against neurofilament H (NFH), Glial Fibrillary Acidic Protein (GFAP), Myelin Basic Protein (MBP) and alpha synuclein (a-SYN) and Immunoglobulin M (IgM) antibody against neurofilament light (NFL) were among …

Selective Gsk3Β Inhibition Mediates An Nrf2-Independent Anti-Inflammatory Microglial Response, Mohamed H. Yousef

Theses and Dissertations

Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with Nuclear factor kappa B (NF-κB). . GSK3 is also a suppressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies, Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition.

The …

Theta Burst Brain Stimulation In Painful Diabetic Neuropathy Patients: Investigating Neural Mechanisms, Bhushan Thakkar

Theses and Dissertations

Chronic pain (CP) is a significant contributor to disability and disease burden globally. In 2019, approximately 50.2 million adults (20.4% of the US population) experienced chronic pain, contributing to $560-635 billion in direct medical costs. In addition, the worldwide prevalence of diabetes mellitus has reached epidemic proportions and is set to increase to 629 million by 2045. Almost 50% of patients with diabetes present with diabetic neuropathy (DN), and one in five patients with diabetes presents with painful DN (pDN) which is the most common cause of neuropathic pain (NP) in the US. Symptomatic treatment is the mainstay of management …

Relationship Between Cognitive Performance, Physical Activity, And Socio-Demographic/ Individual Characteristics Among Aging Americans, Imtiaz Masfique Dowllah

Theses and Dissertations

Despite the attenuation of association following adjustments for covariates, participants who engaged in 3–6 hr/wk of vigorous- and > 1 hr/wk of moderate-intensity PA scored significantly higher in tests that assessed executive function and processing speed domains of cognition compared to inactive peers (η2 = 0.005 & 0.007 respectively, p < 0.05). Also, after adjustment, the effects of 1–3 hr/wk of vigorous-intensity PA became trivial for the delayed recall memory domain test scores (β = 0.33; 95% CI: –0.01, 0.67; η2 = 0.002; p = 0.56). There was no clear dose-response relationship between the cognitive test scores and weekly moderate-intensity PA. Interestingly, higher handgrip strength and higher late-life body-mass-index were associated with a higher performance across all cognitive domains. Observed associations provide evidence linking habitual PA with superior cognition health among older adults. Furthermore, increased muscle strength and higher late-life adiposity may …

Glycosaminoglycan Modulation Of Key Proteins In Alzheimer's Disease, Tamim Chiba

Theses and Dissertations

Glycosaminoglycans (GAGs) are linear polysaccharides whose disaccharide building blocks consist of an amino sugar (D-glucosamine) and either uronic acid (D-glucuronic acid or L-iduronic acid) or galactose. Nearly all GAGs (with the exception of hyaluronic acid) are covalently attached to proteins, forming proteoglycans, and are ubiquitous in nature. The monomeric units, chain length, degree and pattern of sulfation, and epimerization are important properties that determine the influence of these molecules. Through Coulombic forces, hydrogen bonds and hydrophobic interactions, they regulate many physiological and pathophysiological processes such as blood coagulation, cell growth and differentiation, inflammatory processes, host defense and viral infection mechanisms. …