Neuroscience and Neurobiology Commons^™

Cortisol And Alpha-Synuclein Stability In Saliva Under Varying Storage And Handling Conditions, Mo Zheng, Sujata Srikanth, Jeremiah Carpenter, Delphine Dean

Journal of the South Carolina Academy of Science

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor impairments and non-motor symptoms, significantly impacting patients' quality of life. Currently, cerebrospinal fluid (CSF) is the primary biofluid used for PD biomarker studies, notably α-synuclein, despite the invasive nature of lumbar puncture procedures. Recent work has shown that some of these PD biomarkers have been measured in saliva. As an alternative to CSF, saliva can be non-invasively self-collected by patients repeatedly over time to monitor biomarker levels. However, the stability of these biomarkers in saliva needs to be evaluated before saliva can be considered for patient self-collection studies. Therefore, …

Sex-Dependent Gene Expression Alterations In Social Defeat Stress Model Of Major Depression Disorder, Juan Diego Torres, Javier Vargas Medrano, Anapaula Themann, Elias Arellano Villanueva, Nina Mourao, Tyler Torres, Sridhar Srinivasan, Anesu Karen Murambadoro, Kory Deshawn Punch, Kevin Valdez Garcia, Nikhilesh Anand, Kelsey Baker, Sergio Iniguez, Bharathi Shrikanth Gadad

Research Colloquium

Introduction: Major Depression Disorder (MDD) is a prevalent, recurrent, and chronic disorder that represents a leading cause of disability worldwide. Millions are affected with symptoms that go from constant sadness to even suicidal thoughts. In the U.S., major depression and fatal suicide have increased by 57.4% among adolescents and young adults. Myelin and inflammation-related genes have been found to play a role in individuals with MDD.

Methods: Adolescent males and females C57BL/6 mice underwent a vicarious defeat stress (VDS) procedure in which a mouse witnessed a conspecific being defeated. VDS and control (CON) mice underwent the Social Interaction (SI) test. …

Molecular Studies In Understanding Novel Curcumin-Glucoside Role In The Prevention Of Alpha-Synuclein Aggregation In Relevance To Parkinson's Disease, Natasha N. Quailes, Nina Mourao, Sridhar Srinivasan, Sriya Gullapalli, Elias Arellano Villanueva, Tyler Torres, Meghan Whitley, Kory Deshawn Punch, Anesu Karen Murambadoro, Blake Martin, Kelsey Baker, Nikhilesh Anand, Hansapani Rodrigo, Bharathi Shrikanth Gadad

Research Colloquium

Background: The synuclein deposition in the brain of Parkinson’s Disease (PD) is the hallmark pathology of the neurodegenerative pathway. The transformation of alpha-synuclein into synuclein monomer, toxic oligomer, and insoluble fibrils are key steps in cell dysfunction. We synthesized a novel molecule, Curcumin-glucoside (Curc-gluc), which has good water solubility and a favorable partition coefficient.

Methods: The present study focuses on α-syn aggregation kinetics in the presence and absence of Curc-gluc and Curcumin; we also tested the effect of Copper (Cu) and Iron (Fe) Fe binding through a mathematical approach, biophysical techniques, and docking models. In the mathematical approach, we applied …

Repurposing Bt-11 To Treat Alzheimer’S Disease: Exploring The Glutathione-S-Transferase Lancl2 As A Target, Emily Birnbaum

Dissertations, Theses, and Capstone Projects

Approximately 99.6% of potential Alzheimer’s drugs fail, thus developing successful drugs is a high priority. The failure at developing successful drugs relates to the complex nature of the disease itself. Many components act together to trigger a cascade that ultimately results in neurodegeneration and cognitive dysfunction associated with the disease. In building a multiplex model of Alzheimer’s it is important to understand its specific biological mechanisms. One of these key pathological mechanisms is neuroinflammation. Understanding the pathways involved in neuroinflammation in Alzheimer’s is an urgent need, as it poses a promising avenue for future effective therapeutics. Specifically, as many investigational …

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations & Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

The Role Of The Circadian Clock In The Paraventricular Nucleus Of The Hypothalamus In Diurnal Energy Balance, Rachel Van Drunen

Dissertations & Theses (Open Access)

Circadian rhythms are internal biological rhythms that drive oscillations in physiology and metabolism. Maintained at the level of individual cells throughout the body, the circadian clock is necessary for driving tissue-specific temporal programs of energy balance. Though loss of the circadian transcription factor, BMAL1, in the paraventricular nucleus (PVN) of the hypothalamus has revealed its importance in driving rhythms in energy intake and metabolism, its transcriptional functions across time and in individual cell types in the PVN are not well understood. In this study, we show that loss of BMAL1 in the PVN not only results in arrhythmicity in processes …

Prenatal Alcohol Exposure Induces Anatomical Changes In The Mouse Somatosensory Cortex., Zahra Saad Siddiqui

Dartmouth College Master’s Theses

Atypical tactile responses are implicated in Fetal Alcohol Spectrum Disorders (FASD). Our lab reported diminished tactile sensitivity in young adolescent mice with a history of prenatal alcohol exposure (PAE). Here, I employed immunohistochemistry to investigate the anatomical correlates of altered tactile sensitivity observed in mice with PAE. Using our 3-day binge paradigm, I examined changes in the distribution pattern of pre- (thalamocortical afferents) and postsynaptic (pyramidal neurons) partners involved in processing tactile information in the SSC of Postnatal day (P) 7 mice. In rodents, tactile information is relayed somatotopically to the SSC via TC afferents expressing vesicular glutamate transporter 2 …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Inflammaging In The Alzheimer’S Brain And Beyond: Insights From A Transgenic Mouse Model On The Sex-Specific Pathophysiology Of Alzheimer’S Disease, Alicia Jeanne Barber

Dartmouth College Ph.D Dissertations

Aging and sex are major risk factors for developing late-onset Alzheimer’s disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer’s disease, no longer consistently exhibit standard Alzheimer’s neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer’s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.

We aged male and female, 3xTg-AD and B6129 …

Screen For Beneficial Genetic And Chemical Modifiers In Drosophila Models Of Als And Traumatic Brain Injury, Will Bonderer

Biological Sciences Theses and Dissertations

The underlying molecular processes of aberrant protein expression in neurodegeneration are intricate and multifaceted, with ribosome-associated quality control (RQC) emerging as a promising avenue of exploration. Ribosome-associated quality control is integral to cellular function. Its evolutionarily conserved pathway encompasses a network of mechanisms designed to ensure the fidelity of protein synthesis, folding, and degradation within the cells of all eukaryotes. The ribosome, central to protein synthesis, plays a pivotal role in this quality control network, and its malfunction can lead to the accumulation of misfolded or aberrant proteins. In the context of neurodegenerative disorders, this dysfunction can have dire consequences. …

Estrogen Replacement Therapy To Reduce Neurodegeneration And Socio-Cognitive Deficits In A Female Sprague Dawley Rat Model Of Early-Onset Alzheimer’S Disease, Miriam Kirylo

Senior Theses and Projects

No abstract provided.

Mitochondrial Structure And Function In Oligodendrocytes; A Preliminary Study, Dimosthenis Sampatakos

Senior Theses and Projects

Oligodendrocytes are glial cells responsible for the creation of myelin, a fatty substance that maximizes axon potential efficiency by creating a sheath around axons. The process of creating myelin is called myelination and is exclusively performed by oligodendrocytes. Myelination requires a lot of energy output to cover the needs of creating myelin. Oligodendrocytes have numerous mitochondria that help them meet that energy requirement fulfill their function. Oligodendrocyte progenitors are cells that differentiate to become myelinating oligodendrocytes. Not a lot is known about progenitors’ mitochondria and their mitochondrial metabolism. Differentiation is necessary to replenish oligodendrocytes that degrade. If the levels of …

The Relationship Between Amygdala And Orbitofrontal Cortex Volume In The Context Of Oppositional Defiant Disorder, Rahul Alla

Honors Scholar Theses

Disobedient and rebellious attitude in children is on the rise and this type of behavior is categorized as Oppositional Defiant Disorder (ODD). ODD in children can be identified as a persistent pattern of angry or irritable mood, argumentative or defiant behavior or vindictiveness toward others according to the Diagnostic and Statistical Manual (DSM-5, Fifth Edition) of Mental Disorders.1 Children with ODD typically have difficulty regulating and processing their emotions. Issues with regulating emotions is defined as the process by which individuals “influence which emotions they have, when they have them, and how they experience and express them”.2 Dysregulation of emotions …

Isolation Of Aged Mouse Primary Microglia As A Model System For Alzheimer’S Disease Research, Michael Landis

Biology Honors Papers

Microglia and their role as the immune cells of the central nervous system are an emerging area of interest within Alzheimer’s research, particularly as they have shown in a benevolent and malevolent cellular context. Models of Alzheimer’s disease are very light in studying microglia, so in this study a model of microglia isolated from aged mice is established in order to study the phagocytic activity and protein expression of microglia in response to Amyloid Beta. The cells were isolated from aged mice and cultured before being used to confirm cellular identity, as well as to measure phagocytic activity. This study …

Molecular Mechanisms Of Opioid Use Disorder In Human Brain Models, Emily Mendez

Dissertations & Theses (Open Access)

Opioid use disorder (OUD) is a national and global public health crisis with no end in sight. While studies from animal models hint at widespread epigenetic and transcriptomic alterations of opioid drugs, the molecular consequences of long-term exposure to opioid drugs in human brain is still unclear, and human-centered translational models are necessary to discern the human cell type-specific effects of OUD.

Using postmortem brain Brodmann area 9 (BA9) from the UTHealth Brain Collection for Research on Psychiatric Disorders, I identified angiogenic gene networks perturbed in the RNA and protein of OUD subjects, as well as downregulation of many neuron-correlated …

Assessing The Role Of Stim1 And Stim2 In Microglial Response To Spinal Cord Injury., Sarayu Alli

College of Arts & Sciences Senior Honors Theses

Microglia, immune cells of the central nervous system, constantly survey their environment for damage. Once damage is detected, they are activated into become reactive, resulting in morphological changes, such as larger cell bodies, and functional changes, such as releasing inflammatory mediators. The switch from surveying to reactive occurs because the microglia received signals that sense danger in the environment. The release of Ca2+ from intracellular stores is involved in store-operated calcium entry (SOCE), a signaling pathway. Recent studies have shown that calcium release from the intracellular stores is a factor of microglial activation. SOCE is specific to monitoring low calcium …

Optimization Of Tyrosine Hydroxylase Antibody For Immunohistochemistry Fluorescence Detection In Zebrafish (Danio Rerio), Madison Thurber

Theses/Capstones/Creative Projects

Dopamine is an important neurotransmitter produced through the catecholamine synthesis pathway that affects brain activity. Unregulated dopamine levels can lead to various diseases such as Parkinson’s Disease or attention deficit hyperactivity disorder (ADHD). Optimization of an immunohistochemistry protocol will allow for the quantification of tyrosine hydroxylase antibody, which indirectly allows for dopamine quantification in dopaminergic regions within the brain. However, the antibody concentration to give the optimal signal-to-noise ratio in IHC varies across studies. Through this experiment, I determined the concentration of tyrosine hydroxylase (TyrH) antibody for immunohistochemistry that gave the best signal-to-background noise ratio within several known dopaminergic regions …

Biophysical Model Of Retraction Motor Neurons And Their Modification By Operant Conditioning, Maria Rasheed

Dissertations & Theses (Open Access)

Operant conditioning (OC) is a form of associative learning in which an animal modifies its behavior based on the consequences that follow that behavior. Despite its ubiquity, the underlying mechanisms of OC are poorly understood. Insights into the mechanisms of OC can be obtained by studying Aplysia feeding behavior as it can be modified by OC. This behavior is mediated by a central pattern generator (CPG) network in the buccal ganglia that contains a relatively small number of neurons. This CPG generates rhythmic motor patterns (BMPs) that move food into the gut by closing a tongue-like structure (i.e., radula) during …

Development Of Vasculature Patterns In A Mouse Model Of Supratentorial Ependymoma, Jackson Ayers

Honors Scholar Theses

Supratentorial Ependymoma (ST-EPN) is a subtype of ependymoma, a primary solid tumor found throughout the nervous system. ST-EPN are most commonly caused by an oncogenic fusion between the zinc finger gene ZFTA and the RELA, and this distinct ependymoma subtype is readily modeled in mice by conditional expression of ZFTA-RELA in radial glial cells. ST-EPN are known to have a distinctive arrangement of tumor cells and vasculature forming pseudo-rosettes in which polarized tumor cells surround blood vessels within the tumors. It is not known how these pseudo-rosettes or the tumor vasculature form and develop in ST-EPN, so in this study …

Ethanol-Induced Alterations To Astrocytic Glutamate Transporter Mrna Expression In The Mpfc Of Adult Mice, Zachary Evans

Undergraduate Honors Theses

The medial prefrontal cortex (mPFC) is one of several brain structures that is contained in the mesolimbocortical pathway and controls many processes involved in alcohol use disorder (AUD). There is vast glutamatergic output from the mPFC to other mesolimbocortical regions; neuroplastic changes to this system are believed to be closely tied to the development and maintenance of AUD. Astrocytes are key regulators of glutamatergic transmission through their uptake of excess glutamate from the synapse and recycling back into neurons. Ethanol (EtOH) alters the expression of astrocytic genes that encode for transporters that control glutamate homeostasis; these include the glutamate transporter-1 …

Gucy2c Signaling Limits Dopaminergic Neuron Vulnerability To Toxic Insults, Lara Cheslow, Matthew Byrne, Jessica Kopenhaver, Lorraine Iacovitti, Richard Smeyne, Adam Snook, Scott Waldman

Farber Institute for Neuroscience Faculty Papers

Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation within the substantia nigra pars compacta (SNpc) are central drivers of dopaminergic (DA) neuron death in Parkinson's disease (PD). Guanylyl cyclases and their second messenger cyclic (c)GMP support mitochondrial function, protecting against ROS and promoting cell survival in several tissues. However, the role of the guanylyl cyclase-cGMP axis in defining the vulnerability of DA neurons in the SNpc in PD remains unclear, in part due to the challenge of manipulating cGMP levels selectively in midbrain DA neurons. In that context, guanylyl cyclase C (GUCY2C), a receptor primarily expressed by intestinal epithelial cells, …

The Role Of Spreading Depolarizations In Mild Traumatic Brain Injuries, Natalie J. Pinkowski

Biomedical Sciences ETDs

Mild traumatic brain injuries (mTBIs) often lead to acute symptoms like disorientation and discoordination, but the underlying mechanisms are unknown. Although most patients recover quickly from a single mTBI, repeated injuries can be debilitating. After an mTBI, a neurometabolic cascade produces metabolic burden and vulnerability. Spreading depolarizations (SDs) have been observed after mTBIs. Here we investigated SDs’ role in short-term motor behavioral deficits post-mTBI. We hypothesized that SDs contribute to the deficits, and exacerbated symptoms after repeated mTBIs. To test this, we used acute motor behavioral tests and long-term behavioral and cognitive tests after initiating SDs by mTBI, chemical, or …

In Silico Identification Of Small Molecule Agonist Binding Sites On Kcc2, Kenyon Mitchell, Alfred Amendolara, Ruth Hunter, Jaden Miner, Andrew Payne

Annual Research Symposium

Purpose: Potassium-Chloride Cotransporter 2 (KCC2) is a neuronal membrane protein specific to the central nervous system. It is responsible for removing Cl- ions from the intracellular space, maintaining a normal Cl- gradient essential for proper function at inhibitory synapses. Dysregulation causes an upward shift in the Cl- reversal potential resulting in a hyperexcitable state of the postsynaptic neuron. Existing literature indicates that KCC2 may be involved in the addiction pathway of a variety of drugs of abuse, including opioids and alcohol. This makes KCC2 an attractive potential drug target when treating substance use disorders. A novel direct KCC2 agonist, VU0500469, …

Dissecting The Tissue-Specific Contributions To Seizures, Cardiorespiratory Dysfunction, And Sudden Death In The Kv1.1 Mouse Model Of Epilepsy Using Conditional Knockout Approaches, Kelsey Paulhus

Biological Sciences Theses and Dissertations

Sudden unexpected death in epilepsy (SUDEP), the primary cause of mortality in epilepsy, remains poorly understood. Studies suggest seizures may trigger dangerous signals affecting the heart and lungs leading to collapse and death. The Kv1.1 deficiency mouse model mirrors clinical SUDEP cases, showing spontaneous seizures, cardiorespiratory issues, and premature death. However, this model lacks regional specificity in Kv1.1 deletion, hindering insights into SUDEP’s mechanisms and anatomical substrates.

This dissertation employs three distinct conditional knockout (cKO) techniques to investigate the individual roles for the forebrain, brainstem, and heart in SUDEP related phenotypes. The findings reveal that the forebrain alone can trigger …

The Binding And Mechanism Of A Positive Allosteric Modulator Of Kv3 Channels, Qiansheng Liang, Gamma Chi, Leonardo Cirqueira, Lianteng Zhi, Agostino Marasco, Nadia Pilati, Martin Gunthorpe, Giuseppe Alvaro, Charles Large, David Sauer, Werner Treptow, Manuel Covarrubias

Farber Institute for Neuroscience Faculty Papers

Small-molecule modulators of diverse voltage-gated K⁺ (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the …

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.

Outclimbing Cognitive Decline: Age, Western Diet, Resistance Exercise, And The Brain., Leila Dzinic

Electronic Thesis and Dissertation Repository

Increased age and obesity diminish motivation, perseverance, and spatial memory function. Aerobic exercise interventions have successfully rescued some of these processes. However, in older and heavier populations aerobic exercise is not as sustainable due to high risk of injury. Resistance exercise consists of physical activity where maximum oxygen consumption is not increased and has been proposed as a safe and effective intervention for this population. Here, we used touchscreen-based cognitive testing to elucidate the influence of resistance exercise on motivation and spatial memory in aged, diet-induced obese mice, using a water restriction procedure I develop in Chapter 2. Mice underwent …

Exploring A Gene Panel For Parkinson’S Disease In An Egyptian Cohort, Asmaa Saeed Gabr

Theses and Dissertations

Parkinson’s disease is a highly heterogeneous disorder characterized by diverse neuropathological features, clinical presentations and progression patterns. In Egypt, Parkinson’s disease incidence rates lie outside the range reported elsewhere. The genetic background to the pathogenesis of Parkinson's disease has been postulated for a long time. However, Parkinson’s disease has never been systematically investigated in Egypt. This study aimed to explore genetic variants and interactions that are associated with the familial and sporadic forms of Parkinson's disease in an Egyptian cohort. This includes examining variants in PD-related genes, exploring the role of specific genes like MAPT and adjacent genomic regions, and …

The Role Of Glutamate In The Medial Prefrontal Cortex In The Acquistion And Expression Of Conditioned Approach, Rudolf Nisanov

Dissertations, Theses, and Capstone Projects

A series of experiments were conducted to assess the role of glutamatergic stimulation in the dorsal and ventral regions of the medial prefrontal cortex (mPFC) in both the acquisition and expression of reward-related learning using a Pavlovian conditioning paradigm, the conditioned-approach paradigm. Rats with surgically implanted cannulas were exposed to Pavlovian conditioning sessions that occurred on three alternative days (acquisition) or seven consecutive days (expression). These 60-min conditioning sessions consisted of 30 pairings of light (CS) and food pellets (US) presented under a random time schedule. After a two-day break, rats underwent a session with no CS or US and …

Methamphetamine-Induced Dna Double-Stranded Breaks: The Impact Of The Dopamine Transporter And Insights Into The Mechanisms Of Dna Damage In Mouse Neuro 2a Cells, Lizette Couto

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) abuse remains a global health concern, with emerging evidence highlighting its genotoxic potential. In the central nervous system METH enters dopaminergic cells primarily through the dopamine transporter (DAT), which controls the dynamics of dopamine (DA) neurotransmission by driving the reuptake of extracellular DA into the presynaptic neuronal cell. Additional effects of METH on the storage of DA in synaptic vesicles lead to the dysregulated cytosolic accumulation of DA. Previous studies have shown that after METH disrupts intracellular vesicular stores of DA, the excess DA in the cytosol is rapidly oxidized. This generates an abundance of reactive oxygen species …