Developmental Neuroscience Commons^™

Perinatal Buprenorphine Effects On Offspring Growth, Opioid Withdrawal, And Brain Morphology In Rats, Parker Barnes

Electronic Theses and Dissertations

Opioid use disorder (OUD) impacts 5.6 million people in the US. Buprenorphine (BUP) is a commonly prescribed opioid medication used to treat OUD, including in pregnant women. However, opioid use during pregnancy is associated with poorer infant outcomes including reduced fetal growth, neurodevelopmental deficits, and neonatal opioid withdrawal syndrome (NOWS). Recent clinical data suggests that providing mothers with a lower dose of BUP may result in fewer negative outcomes in infants. Here, a preclinical rodent model of low-dose perinatal BUP exposure was used to study offspring health outcomes in the neonate, juvenile, and adolescent offspring. Dams were given clinically relevant …

Exploring The Developmental Effects Of Antidepressants In Caenorhabditis Elegans, Alexandra Van Stone

Annual Research Symposium

It is so important to explore the potential side effects of antidepressants especially if these side effects could lead to a future detriment to an individual’s financial and social well-being. A better understanding of these side effects in regards to human developmental issues is imperative considering issues related to mental health and depression affect a large percentage of the population. In this study, we tested if Caenorhabditis (C.) elegans could be a potential model organism to predict possible side effects associated with select antidepressants. Their developmental problems potentially encountered upon drug treatment may be encountered in humans.

Alzheimer’S Disease And Inflammatory Biomarkers Positively Correlate In Plasma In The Uk-Adrc Cohort, Kate E. Foley, Zachary Winder, Tiffany L. Sudduth, Barbara J. Martin, Peter T. Nelson, Gregory Jicha, Jordan P. Harp, Erica M. Weekman, Donna M. Wilcock

Neurology Faculty Publications

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer’s Disease Research Center cohort. We evaluated six Alzheimer’s disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p- tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD–inflammatory biomarker correlations showed significant associations between AD and inflammatory …

Azithromycin Reduces Hemoglobin-Induced Innate Neuroimmune Activation, Chirayu D. Pandya, Hemendra J. Vekaria, Miriam Zamorano, Amanda L. Trout, Rodney M. Ritzel, Gary Guzman, Christopher Bolden, Patrick G. Sullivan

Neurology Faculty Publications

Neonatal intraventricular hemorrhage (IVH) releases blood products into the lateral ventricles and brain parenchyma. There are currently no medical treatments for IVH and surgery is used to treat a delayed effect of IVH, post-hemorrhagic hydrocephalus. However, surgery is not a cure for intrinsic brain injury from IVH, and is performed in a subacute time frame. Like many neurological diseases and injuries, innate immune activation is implicated in the pathogenesis of IVH. Innate immune activation is a pharmaceutically targetable mechanism to reduce brain injury and post-hemorrhagic hydrocephalus after IVH. Here, we tested the macrolide antibiotic azithromycin, which has immunomodulatory properties, to …

Different Cohort, Disparate Results: Selection Bias Is A Key Factor In Autopsy Cohorts, Kathryn Gauthreaux, Walter A. Kukull, Karin B. Nelson, Charles Mock, Yen-Chi Chen, Kwun C. G. Chan, David W. Fardo, Yuriko Katsumata, Erin L. Abner, Peter T. Nelson

Neurology Faculty Publications

INTRODUCTION: Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences.

METHODS: The National Alzheimer’s Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit.

RESULTS: Cohorts with more participants who were cognitively normal at recruitment contained more individuals who …

Cognitive Decline, Aβ Pathology, And Blood–Brain Barrier Function In Aged 5xfad Mice, Geetika Nehra, Sasivimon Promsan, Ruedeemars Yubolphan, Wijitra Chumboatong, Pornpun Vivithanaporn, Bryan J. Maloney, Anusorn Lungkaphin, Bjoern Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background

Patients with Alzheimer’s disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, blood–brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aβ levels, barrier function, and cognitive decline over time.

Methods

5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the …

Oxidative Stress Alters Mitochondrial Homeostasis In Isolated Brain Capillaries, Gopal V. Velmurugan, Hemendra J. Vekaria, Anika M. S. Hartz, Björn Bauer, William Brad Hubbard

Markey Cancer Center Faculty Publications

Background

Neurovascular deficits and blood-brain barrier (BBB) dysfunction are major hallmarks of brain trauma and neurodegenerative diseases. Oxidative stress is a prominent contributor to neurovascular unit (NVU) dysfunction and can propagate BBB disruption. Oxidative damage results in an imbalance of mitochondrial homeostasis, which can further drive functional impairment of brain capillaries. To this end, we developed a method to track mitochondrial-related changes after oxidative stress in the context of neurovascular pathophysiology as a critical endophenotype of neurodegenerative diseases.

Methods

To study brain capillary-specific mitochondrial function and dynamics in response to oxidative stress, we developed an ex vivo model in which …

Utilizing Ai Integrated Neuroimaging Technology To Expand Upon Machine Learning In Positron Emission Tomography Technology With The Aim Of Detecting Amyloid Beta Biomarkers Early In The Onset Of Alzheimer's., Ethan S. Terman

UROP Posters

Early intervention in Alzheimer's is vital for treatment. The earlier a professional can detect symptoms and make a diagnosis the earlier a prognosis can be implemented. With the prevalence of data in our day-to-day world combined with Artificial intelligence (AI), utilizing both for machine learning can pave the way for more accurate and efficient detection of Alzheimer's and other neurodegenerative diseases. AI combined with Machine learning (ML) increases diagnostic efficiency and reduces human errors, making it a valuable resource for physicians and clinicians alike. With the increasing amount of data processing and image interpretation required, the ability to use AI …

Neurodevelopmental Vulnerability To Gestational Ozone Exposure, Vishnupriya Alavala, Sarah E. Brent, Christopher G. Canal, Joseph Wang, Russell P. Hunter, Matthew J. Campen, Andrew K. Ottens

UROP Posters

Ambient air pollution accounts for about 4.2 million premature deaths annually per the World Health Organization. Ozone (O3) is a highly reactive air pollutant found in smog and is implicated in cellular damage leading to organ dysfunction. Ambient air pollution is associated with neurodevelopmental, behavioral, and cognitive disorders though ozone’s role is unknown. Studies here look at ozone exposure shortly after implantation vs. shortly before term to evaluate differences in neurodevelopmental susceptibility over time.

To inquire on the effects of ozone on the fetal brain, pregnant Sprague-Dawley rats were exposed once to 0.3 ppm of O3 or filtered air (FA) …

Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.

Methods We treated hAPP mice with …

Bisphenol-A And Phthalate Metabolism In Children With Neurodevelopmental Disorders, T Peter Stein, Margaret D Schluter, Robert A Steer, Xue Ming

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: The etiology of autism spectrum (ASD) and Attention Deficit/Hyperactivity (ADHD) disorders are multifactorial. Epidemiological studies have shown associations with environmental pollutants, such as plasticizers. This study focused on two of these compounds, the Bisphenol-A (BPA) and Diethylhexyl Phthalate (DEHP). The major pathway for BPA and DEHP excretion is via glucuronidation. Glucuronidation makes insoluble substances more water-soluble allowing for their subsequent elimination in urine.

HYPOTHESIS: Detoxification of these two plasticizers is compromised in children with ASD and ADHD. Consequently, their tissues are more exposed to these two plasticizers.

METHODS: We measured the efficiency of glucuronidation in three groups of children, …

Novel Insights Into Oligodendrocyte Biology From Developmental Myelination Studies In Autophagy Deficient Mice And Analysis Of Oligodendrocyte Translatome Response To Contusive Spinal Cord Injury., Michael David Forston

Electronic Theses and Dissertations

Loss of myelin causes severe neurological disorders and functional deficits in white matter injuries (WMI) such as traumatic spinal cord injury (SCI). This dissertation is focused on autophagy in OL development and the OL translatome after SCI. Chapter I describes the history of myelin, OL development, and their involvement in neurodegenerative diseases and SCI. The proteostasis network, in particular autophagy, and its contributions to white matter pathology is discussed. It concludes examining advantages and disadvantages of unbiased omics tools, like RiboTag, to study transcriptional/translational landscapes after SCI. Chapter II focuses on autophagy in OPC/OL differentiation, survival, and proper myelination in …

Adolescents With Family History Of Alcohol-Use Disorders Have Reduced Structural Coherence Of Anterior Insula To Nucleus Accumbens Tract, Grace Wood

Psychological Science Undergraduate Honors Theses

Genetics play a significant role in predisposition towards alcohol use disorders. Analyzing the neural phenotypes related to alcohol use disorder development could allow researchers to predict one’s predisposition. The anterior insula (AIns) contributes to binge drinking tendencies while exhibiting downstream signaling towards the nucleus accumbens (NAcc). Recent research has examined this relationship simultaneously with alcohol consumption, but the genetic effect of the AIns and NAcc functional relationship prior to alcohol consumption has yet to be examined. In this study, we used data from the Adolescent Brain Cognitive Development (ABCD) study to analyze the structural coherence of the AIns to NAcc …

Early Life Stress Predicts Future Conduct Disorder In Adolescents, Savannah Ellis

Biological Sciences Undergraduate Honors Theses

Early Life Stress (ELS) and adversity increase people’s risk for developing mental, social, or emotional dysregulation and disorders later in life. The objective of this study was to test whether ELS in adolescents could prospectively predict future conduct disorder. The study additionally tested potential neural mediators of the effect of ELS on future conduct disorder, and specifically targeted the structural connections from the anterior insula and medial prefrontal cortex to the Nucleus Accumbens (NAcc). Data for the project came from the Adolescent Brain Cognitive Development Study (ABCD study), which is a longitudinal multi-site consortium funded by the National Institutes of …

Recent Advances In The Role Of Rehabilitative Therapies For Parkinson’S Disease: A Literature Review, Bazza Sohail, Muhammad Affan Iqbal, Aisha Razzaq, Abdul Wasay Nafe, Robina Malik

Journal of Mind and Medical Sciences

Regardless of medical therapies and surgical interventions for Parkinson’s disease, patients develop progressive disability. The role of therapies is to maximize functional ability and minimize secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimize independence, safety and wellbeing, thereby enhancing quality of life. Trials have shown that physiotherapy has short-term benefits in Parkinson’s disease. However, which physiotherapy intervention are most effective remains unclear. This article provides a guidance framework rather than a ’recipe’ for treatment. This review shows that a wide range of rehabilitative therapy interventions to …

Neural Mechanisms Of Language Development In Infancy, Scott Huberty, Christian O'Reilly, Virginia Carter Leno, Mandy Steiman, Sara J. Webb, Mayada Elsabbagh, The Basis Team

Publications

Understanding the neural processes underpinning individual differences in early language development is of increasing interest, as it is known to vary in typical development and to be quite heterogeneous in neurodevelopmental conditions. However, few studies to date have tested whether early brain measures are indicative of the developmental trajectory of language, as opposed to language outcomes at specific ages. We combined recordings from two longitudinal studies, including typically developing infants without a family history of autism, and infants with increased likelihood of developing autism (infant-siblings) (N = 191). Electroencephalograms (EEG) were recorded at 6 months, and behavioral assessments at …

Heterodyned Whole-Body Vibration Ameliorates Anxiety In Opioid-Use Disorder, Kailee Edwards, Braden Cunningham, Alfred Amendolara, Marryam Anwar, Jon Gonzales, Roshni Jogin, Wyatt Magoffin, Amar Paul, Ryan Perry, James Pike, Nathan Swallow, Steven Tung, Mary Seamons, Andrew Payne, John A. Kriak, David W. Sant, David W. Sant

Annual Research Symposium

No abstract provided.

Analysis Of Electrophysiological Markers And Correlated Components Of Neural Responses To Discourse Coherence, Kurt M. Masiello

Dissertations, Theses, and Capstone Projects

Constructing meaning from spoken language is invaluable for learning, social interaction, and communication. In clinical populations with developmental disorders of speech comprehension, the severity of disruption can persist and vary from limiting occupational opportunities to lower performance outcomes. Previous research has reported an event-related potential (ERP) neural positivity over right hemisphere lateral anterior sites in response to semantic and discourse processing. Although useful as a marker for clinical populations of autism spectrum disorder (ASD) and developmental language disorder (DLD), little is understood about the dynamics and neural sources of this biological marker. In addition to traditional methods of ERP analysis, …

Benefits Of A Family-Based Judo Program For Parents Of Children With Autism Spectrum Disorder, Jeslin George

Honors Undergraduate Theses

A diagnosis of Autism Spectrum Disorder (ASD) can impact the entire family. Parents of children with ASD reportedly have greater stress levels, family conflict, financial concerns, and poor health habits than parents of neurotypical (NT) children. While many parent-focused interventions have been developed, these interventions focus on parent training and child behavior outcomes rather than the health and well-being of the parents. Therefore, this study aimed to examine the effects of a 15-week family judo program on physical and psychosocial health in parents of children with ASD. A total of 18 parents of children with ASD participated in a weekly …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations and Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …

Distinct Thalamic And Frontal Neuroanatomical Substrates In Children With Familial Vs. Non-Familial Attention-Deficit/Hyperactivity Disorder (Adhd), Rahman Baboli, Meng Cao, Jeffrey M. Halperin, Xiaobo Li

Publications and Research

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent, inheritable, and heterogeneous neurodevelopmental disorder. Children with a family history of ADHD are at elevated risk of having ADHD and persisting its symptoms into adulthood. The objective of this study was to investigate the influence of having or not having positive family risk factor in the neuroanatomy of the brain in children with ADHD. Cortical thickness-, surface area-, and volume-based measures were extracted and compared in a total of 606 participants, including 132, 165, and 309 in groups of familial ADHD (ADHD-F), non-familial ADHD (ADHD-NF), and typically developed children, respectively. Compared to controls, …

Respiratory Morbidity And Neurodevelopmental Outcomes In Infants Born Preterm: A Complex Web, Anna Maria Hibbs

Faculty Scholarship

This commentary is on the original article by Yu et al. on pages 1246–1253 of this issue.

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 …

Linking Spinal Cord Circuits With Upper Limb Sensorimotor Control In Adults With Cerebral Palsy, Saihari Dukkipati

Theses & Dissertations

Cerebral palsy (CP) is the most common neurological disorder originating in childhood, but most of the people living with CP are currently adults. While people with CP continue to get older, the amount of research focused on adults has been rather limited. The early childhood insults leading to CP are thought to originate in the brain, but the effects on the entire neuromuscular system across the lifespan have only recently started to be explored. Of note, recent neuroimaging evidence suggests that the cervical spinal cord structure is atypical in adults with CP. However, it is largely unclear how the neurophysiological …

Self-Conscious Emotions And The Right Fronto-Temporal And Right Temporal Parietal Junction, Adriana Lavarco, Nathira Ahmad, Qiana Archer, Matthew Pardillo, Ray Nunez Castaneda, Anthony Minervini, Julian Keenan

Department of Biology Faculty Scholarship and Creative Works

For more than two decades, research focusing on both clinical and non-clinical populations has suggested a key role for specific regions in the regulation of self-conscious emotions. It is speculated that both the expression and the interpretation of self-conscious emotions are critical in humans for action planning and response, communication, learning, parenting, and most social encounters. Empathy, Guilt, Jealousy, Shame, and Pride are all categorized as self-conscious emotions, all of which are crucial components to one’s sense of self. There has been an abundance of evidence pointing to the right Fronto-Temporal involvement in the integration of cognitive processes underlying the …

Chronic Adolescent Stress As A Predictive Factor For The Risk Of Developing Ptsd-Like Symptoms In Adulthood, Grace K. Young

Theses and Dissertations

Post-traumatic stress disorder is a stress and trauma based psychological disorder that is defined by the DSM-IV as an anxiety disorder that affects approximately 7.8% of people in the United States. PTSD is when those who suffer a traumatic event have intense and distressing feelings, emotions, and memories for a prolonged period of time after the event. A prominent feature of PTSD is the impaired ability to properly extinguish a fear response after a dangerous trigger or stressor is no longer present, also known as safety learning. Stressors are threats perceived within the environment that activate a response within the …

Clinical, Neuroimaging, And Molecular Spectrum Of Tecpr2-Associated Hereditary Sensory And Autonomic Neuropathy With Intellectual Disability, Sonja Neuser, Barbara Brechmann, Gali Heimer, Ines Brösse, Susanna Schubert, Lauren O'Grady, Michael Zech, Siddharth Srivastava, Shahnaz Ibrahim, Fatima Khan

Department of Paediatrics and Child Health

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a …

Molecular Characterization Of A Unique Population Of Human Cortical Interneurons; Implications For Primate-Specific Development, Crina Peterson

Biomedical Sciences ETDs

The human brain consists of 86 billion neurons compared to rodent brain, which consists of 75 million neurons, and the underlying mechanisms for the increased complexity of the primate cortex are not fully elucidated. However, an increase in specific cell populations, including calretinin-expressing (CALB2/CR) interneurons (INs), has been identified. In my thesis work, I demonstrate that human pluripotent stem cells (hPSCs) differentiated to neurons by default patterning give rise to this CR population in vitro, providing a method to study their development.

Chapter I reviews cortical development and hPSCs as an appropriate proxy for studying human cortical development. Chapter …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

University Scholar Projects

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

Honors Scholar Theses

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …