Molecular and Cellular Neuroscience Commons^™

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 …

Unveiling The Nexus Of Cellular Quality Control: Exploring The Interplay Between Ribosome-Associated Protein Quality Control And Mitochondrial Quality Control Pathways, Foozhan Tahmasebinia

Biological Sciences Theses and Dissertations

In eukaryotic cells, the intricate interplay between cellular quality control mechanisms is crucial for maintaining homeostasis and safeguarding the integrity of vital processes, spanning from macromolecule synthesis to the renewal of entire cellular organelles.

Disruption of these networks can lead to severe diseases such as metabolic disorders, underscoring the interconnected nature and feedback control mechanisms inherent in biological systems, including cellular quality control systems. This interconnectedness extends to the intricate communication between organelles, enabling coordinated functioning and adaptation to changing cellular conditions, particularly in response to stressors.

While the exact mechanisms governing these communications within cellular quality control systems remain …

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. …

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 …

Microglial Dynamics And Mechanisms Underlying The Phagocytosis Of Dying Oligodendrocytes, Genaro E. Olveda

Dartmouth College Ph.D Dissertations

Myelin is a complex multilamellar structure, generated by oligodendrocytes, that ensheaths axons and is a vital component for neural processing. Degeneration of both oligodendrocytes and their myelin sheaths is a common pathological feature associated with aging and neurodegenerative diseases. Efficient removal of the cellular and myelin debris is crucial for remyelination and prevention of further degeneration. Microglia, the primary phagocytes of the CNS, are thought to play a key role in this process. To investigate the cellular dynamics underlying microglia-mediated clearance of degenerating oligodendrocytes and myelin sheaths, at the single cell level, we developed a novel model for inducible cortical …

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 …

Exploring The Neuroprotective Effects Of Cannabinoids On Oxygen Glucose Deprived Neurons In An In-Vitro Model Of Stroke, Bhavya Chatragadda, Emily Potts, Hang Ma, Navindra Seeram, Claudia Fallini

Senior Honors Projects

Stroke is a leading cause of long-term disability and decreased mobility worldwide. During stroke, neuronal damage results from both the initial oxygen-glucose deprivation and the increase in excitotoxicity and oxidative stress after restoration of blood flow, a phase called Ischemia-Reperfusion Injury (IRI). Reducing the impact of these processes could result in better outcomes for post-stroke patients by preventing excessive neuronal death. Many natural compounds derived from the Cannabis Sativa plant have been tested for neuroprotective effects due to their potential antioxidant properties. We hypothesized that neurons treated with cannabinoids immediately after experiencing an acute ischemic event will have an overall …

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

College of Arts & Sciences Senior 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 …

The Role Of Oncomodulin In The Central Nervous System Inflammation, Evan Paltjon

Honors Theses

Acoustic overexposure in mice leads to an excess of calcium influx in outer hair cells (OHCs) and causes permanent hearing loss due to death of OHCs. Oncomodulin is a parvalbumin calcium buffering protein located in OHCs of the cochlea. Early pilot studies indicate that genetic deletion of OCM results in immune-related pathology throughout the cochlea. Why and how this occurs is unknown. Studies in wild type (WT) and OCM knockout (KO) mice demonstrate greater numbers of immune cells are associated with noise exposure in an OCM knockout than in WT. Expression of toll-like receptor 4 (TLR4) leads to the recruitment …

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

Dissertations and 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 …

Novel Roles Of Microtubule-Associated Tau In Radiation-Induced Brain Injury, Riya Thomas, Riya Thomas

Dissertations and Theses (Open Access)

Injury responses in cells lacking proliferation capacity such as terminally differentiated neurons consists of complex mechanisms to ensure cellular homeostasis. Brain tumor patients undergoing radiation therapy experience cognitive impairments similar to those seen in patients suffering from neurodegenerative diseases. Despite the plethora of research into radiation effects on proliferating brain cells, the impact of radiation on differentiated, post-mitotic neurons, including their structural and functional alterations, remain largely elusive. However, microtubule-associated tau, an important partner of cytoskeletal structural stability emerges as a pivotal player in the radiation-induced neuronal injury response, demonstrating compartmentalized functions such as repair-centric mechanisms and synaptic homeostasis. This …

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

Dissertations and 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 …

Biosensor-Enhanced Organ-On-A-Chip Models For Investigating Glioblastoma Tumor Microenvironment Dynamics, Gayathree Thenuwara, Bilal Javed, Baljit Singh, Furong Tian

Articles

Glioblastoma, an aggressive primary brain tumor, poses a significant challenge owing to its dynamic and intricate tumor microenvironment. This review investigates the innovative integration of biosensor-enhanced organ-on-a-chip (OOC) models as a novel strategy for an in-depth exploration of glioblastoma tumor microenvironment dynamics. In recent years, the transformative approach of incorporating biosensors into OOC platforms has enabled real-time monitoring and analysis of cellular behaviors within a controlled microenvironment. Conventional in vitro and in vivo models exhibit inherent limitations in accurately replicating the complex nature of glioblastoma progression. This review addresses the existing research gap by pioneering the integration of biosensor-enhanced OOC …

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 …