Neuroscience and Neurobiology Commons^™

Understanding Behavioral And Representational Divergences Of Humans And Machines, Thomas Lasman Botch

Dartmouth College Ph.D Dissertations

Human behavior and cognition are strikingly variable: people differ from one another in their preferences and abilities, and even from themselves across situations. Yet this diversity arises from common neural machinery shaped by the complex environments humans inhabit. A central objective of cognitive neuroscience is to understand how this varied experience emerges from interactions between brains, agents, and environments. In this dissertation, I argue that comparing behavior and neural computation across humans, artificial systems, and contexts is essential for understanding the flexibility of human cognition. Across three chapters, I use this comparative approach to examine how the rich, multimodal contexts …

The Role Of Pten Subcellular Localization In Neuronal Development And Autism Spectrum Disorder, Nicole Desmet

Dartmouth College Ph.D Dissertations

Autism spectrum disorders (ASD) are genetically heterogeneous neurodevelopmental conditions that nevertheless converge on altered neuronal connectivity and circuit function. A central unresolved problem in the field is how diverse genetic perturbations, acting at different biological levels and developmental stages, give rise to shared neurodevelopmental outcomes. This dissertation addresses this problem by examining how gene function, subcellular signaling, and developmental context interact to shape neuronal morphology and circuit-relevant phenotypes.

Cell-autonomous mechanisms regulating neuronal morphology are examined through the ASD risk gene Phosphatase and Tensin Homolog (PTEN) in developing dentate gyrus granule neurons. Selective biasing of PTEN to defined intracellular compartments in …

Mitochondria Dynamics In Microglia During Health, Inflammation, And Aging, Alicia Nicole Pietramale

Dartmouth College Ph.D Dissertations

Microglia continually surveil the brain, allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain has remained unclear. In this dissertation, I combine intravital imaging, ultrastructural analyses, and metabolic and cytoskeletal markers to investigate how mitochondrial organization relates to microglial function across health, inflammation, and aging.

I first show that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. This heterogeneous partitioning is conserved …

The Serotonin 1b Receptor In Psilocybin’S Therapeutic-Like Mechanisms: From Behavior To Network Reorganization, Sixtine Fleury

Dartmouth College Ph.D Dissertations

Mood disorders represent a substantial and growing global health crisis, with ~10 million adults in the US meeting criteria for a major depressive disorder (MDD). Current first-line treatments such as SSRIs require long-term daily administration and fail a significant proportion of patients, driving renewed interest in rapid-acting alternatives. Psilocybin, a serotonergic psychedelic, shows growing clinical evidence of efficacy in treating depressive and anxiety disorders, often producing therapeutic effects persisting weeks to months following a single dose. Yet, the neural mechanisms underlying these enduring effects remain poorly understood and have been largely attributed to the serotonin 2A receptor (5-HT2AR) based on …

A Generalized Framework For The “Core” Thalamocortical Circuit Computation, Charles Liu

Dartmouth College Ph.D Dissertations

This thesis explores a biologically inspired computational framework based on a common excitatory-inhibitory circuit in the superficial layers of the cortex. By varying the strength of local feedback inhibition, this single circuit gives rise to distinct unsupervised learning behaviors: strong inhibition leads to clustering and hierarchical clustering, while weak inhibition produces principal component-like representations. From this principle, we develop three algorithms: Lateral Inhibition Clustering (LI-C), Lateral Inhibition Hierarchical Clustering (LI-HC), and Antipodal Iterative Mean Estimation (AIME).

LI-C performs clustering without requiring a predefined number of clusters, using a competitive learning rule to extract dominant patterns from data. LI-HC extends this …

From Meaning To Memory: Assessing The Capacity And Representational Structure Of Visual Working Memory With Meaningful Stimuli, Yong Hoon Chung

Dartmouth College Ph.D Dissertations

Visual working memory is thought to be strictly limited. Yet we remember meaningful, real-world objects better than abstract stimuli. Here I show that this advantage arises from the semantic structure of meaningful objects, not their perceptual features alone, and that it extends even to memory for associated features such as color. In the brain, meaningful objects elicit greater and more distributed delay activity, consistent with the recruitment of higher-level neural processes during maintenance. I propose that semantic knowledge adds representational dimensions that make items more distinctive, and that these dimensions are organized hierarchically with lower-level visual features. These findings recast …

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

Dartmouth College Ph.D Dissertations

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

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

Dartmouth College Ph.D Dissertations

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

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

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

Dartmouth College Ph.D Dissertations

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

The Role Of Cholinergic Ventral Pallidum Cells In Effortful Motivation, Elizabeth A. Bien

Dartmouth College Ph.D Dissertations

Maladaptive reward-seeking behavior can be driven by one of several different components including excessive craving elicited by cues that predict rewards, failing to effortfully pursue rewards when it is beneficial to do so, and compulsively seeking rewards when it is no longer advantageous to do so. This thesis includes experiments focusing on these three different components of reward-seeking behavior to better understand how reward-seeking can become maladaptive. First, we wanted to examine the role that sex plays in the acquisition and compulsiveness of sign-tracking behavior in the Long Evans rat, a strain that is commonly used as the background for …

Designing Accessible Ui/Ux For Epileptic Patients: A Scalable Solution For Music Therapy Delivery, Amethyst G.H. Mckenzie

Computer Science Senior Theses

How can we design an accessible, scalable UI/UX system tailored to the cognitive, visual, and motor impairments of epileptic patients, that ensures safe and effective interactions with music therapy applications? This research explores the intersection of accessibility, user-centred design, and digital health, using an iterative design process to develop and refine the SONATA app—a clinically deployable music therapy platform.

Through two prototype iterations, usability testing, and quantitative event logging, this study compares the effectiveness of structured versus flexible navigation in improving user experience. Key findings reveal that structured navigation reduces unintended detours, while progressive disclosure techniques enhance instructional clarity. Additionally, …

Behavioral And Neural Effects Of Distributing Visual Attention Across Location And Feature Space, Mert Özkan

Dartmouth College Ph.D Dissertations

Visual attention refers to the mechanisms by which relevant visual information, such as location, simple features (e.g., color, orientation), and objects, is selected and prioritized for further processing. The current dissertation investigates capacity limitations on spatial and feature–based attention in early visual processing and behavioral performance. Specifically, I examined whether attention could be efficiently tuned across narrow and broad ranges of locations and colors, or even be split across noncontiguous locations in the case of spatial attention. I used several behavioral paradigms and frequency–tagging methods in electroencephalography (EEG) to illustrate the effects of narrowing or broadening the attentional focus on …

Investigating The Human Face Processing Network: Insights From Acquired Prosopagnosia And Hyperfamiliarity For Faces, Marie-Luise Kieseler

Dartmouth College Ph.D Dissertations

Human faces provide essential social cues that we interpret rapidly, allowing us to recognize identities, interpret emotions, and gauge familiarity. This thesis explores face processing disruptions in four case studies, each offering new insights into the brain’s face recognition mechanisms.

Chapter one presents Annie, a 28-year-old woman who acquired prosopagnosia (face blindness) following COVID-19. After recovering from the severe symptoms of the infection, Annie experienced significant difficulty in recognizing familiar faces and navigating familiar environments. Testing confirmed her impairment in face recognition but showed her preserved cognitive and basic visual processing abilities. Annie was still able to recognize objects and …

Leveraging Epigenomics And Transcriptomics To Develop High-Dimensional Biomarkers Of Neuroinflammation, Steven C. Pike

Dartmouth College Ph.D Dissertations

Neuroinflammation is a critical physiological phenomenon implicated in most neurological disorders, either as a cause or a consequence of pathology. Our understanding of neuroinflammation is limited by the inability to directly profile the cells of interest. Thus, developing biomarkers of neuroinflammation is clinically urgent as we know neuroinflammation correlates with patient outcomes and treatment success. The recent advances in “omics” technologies, particularly epigenomics and transcriptomics, provides the opportunity for high-dimensional profiling of biospecimens for potential biomarkers. Within this dissertation, I demonstrate that biomarkers obtained from “omics” platforms can detect neuroimmunological phenomena in clinical and preclinical settings. In chapter one, DNA …

Characterization Of Stealth Liposome-Based Nanoparticles Encapsulating Acat1/Soat1 Inhibitor F26: Potential Therapeutics For Niemann-Pick Type C And Other Neurodegenerative Diseases., Junghoon Lee

Dartmouth College Ph.D Dissertations

Cholesterol dysregulation is implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Niemann-Pick type C disease (NPCD). This study focused on evaluating the potent ACAT1 inhibitor, F26, as a therapeutic strategy for NPCD. F26 demonstrated superior ACAT1 inhibition and efficacy compared to the previously studied inhibitor, F12511, both in vitro and in vivo. Notably, F26 exhibited enhanced pharmacokinetic properties, including prolonged duration of action and better brain retention, making it a more promising candidate for treating neurodegenerative diseases.

F26 was encapsulated in a liposome-based nanoparticle system, DSPE-PEG2000 with phosphatidylcholine (PC), for enhancing its …

Behavioral And Neural Evidence For Perceptual Inference Of Position, Sharif Saleki

Dartmouth College Ph.D Dissertations

Extensive neuroscientific research has advanced our knowledge of the mechanisms involved in the detection and recognition of visual stimuli. However, to guide flexible behavior in a changing world, the brain must also construct stable and coherent perceptual representations from retinal images that are often ambiguous. To resolve ambiguities and uncertainties, the visual system combines its input with other sources of information such as context and prior knowledge to infer the most likely interpretation of a scene. Thus, perception is inherently an inferential process that goes beyond simple detection or recognition of stimuli. Although inference has been studied in many areas …

Robust And Generalizable Representations In The Hippocampus, Hung-Tu Chen

Dartmouth College Ph.D Dissertations

An intelligent system must balance generalizing across similar experiences with maintaining the distinctiveness of each experience. This thesis explores how the hippocampus manages this balance through its neural representations to support adaptive behavior. In Chapter 1, I provide an overview of key hippocampal phenomena that contribute to this process, including remapping, splitter signal, and replay. In Chapter 2, I challenge the concept of random remapping by showing that it is possible to predict, better than chance, how a given experience will be encoded in the hippocampus across different subjects. This suggests that encoding of related experiences, which was previously thought …

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 …

Integrating Higher-Order Cognition With Sensory Experience: Insights From Cue-Based Expectations Across Diverse Domains, Heejung Jung

Dartmouth College Ph.D Dissertations

Higher-order cognition, such as expectations about the future, cannot be studied in isolation from sensory representations. This thesis explores the dynamic interplay of higher-order cognition and sensory experiences, examining the important role of expectations across multiple domains: sensory, cognitive, and affective. First, a systematic review outlines the origins of higher-order cognitive functions – e.g., social interaction, memory, and attentional control – and how they arise at the convergence of hierarchically organized gradients that extend from primary sensory areas. These convergence zones are rich in information crucial for the human capacity for making projections, such as thinking about another person’s mental …

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 …

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 …

Targeting Cholinergic Signaling In Glioblastoma, Sumyuktha Vijay Anand

Dartmouth College Ph.D Dissertations

Primitive stem cell-like populations that are prone to malignant transformation reside in the brain throughout adulthood. My lab’s reports and many others have characterized subsets of glioma cells reminiscent of adult stem-like cells implicating them rational candidates for cell-targeted therapies. Emerging evidence suggests that the neurotransmitter microenvironment influences these stem-like cells during glioma progression providing an inroad to study neuromodulators in glioma. Some glioma stemlike cells share characteristics with adult tissue oligodendrocyte progenitor cells. Primitive cells of the oligodendroglial lineage express muscarinic acetylcholine receptors (mAChRs), and their “stemness” is maintained by the acetylcholine (ACh) neurotransmitter. Here, I conduct transcriptomic, electrophysiological, …

Elucidating Neuroinflammation In Multiple Sclerosis By Network Analysis, Nora C. Welsh

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a heterogeneous disease, differing on many variables, including disease course, sex, and overall activity. Key characteristics of the disease encompass demyelination, axonal damage, neuronal loss, glial cell activation, and the infiltration of peripheral immune cells. Molecular proxies of these functions are secreted proteins, including cytokines and immunoglobulins, which, in the central nervous system (CNS), can be secreted into the cerebrospinal fluid (CSF). A detailed analysis of these secreted proteins can offer insights into the evolving immunological and neurodegenerative features as the disease progresses. To understand the dynamic biological processes involved in MS, I used network analysis …

Cholinergic Activation Of Corticofugal Circuits In The Adult Mouse Prefrontal Cortex, Allan Gulledge

Dartmouth Scholarship

Acetylcholine (ACh) promotes neocortical output to the thalamus and brainstem by preferentially enhancing the postsynaptic excitability of layer 5 pyramidal tract (PT) neurons relative to neighboring intratelencephalic (IT) neurons. Less is known about how ACh regulates the excitatory synaptic drive of IT and PT neurons. To address this question, spontaneous excitatory postsynaptic potentials (sEPSPs) were recorded in dual recordings of IT and PT neurons in slices of prelimbic cortex from adult female and male mice. ACh (20 µM) enhanced sEPSP amplitudes, frequencies, rise-times, and half-widths preferentially in PT neurons. These effects were blocked by the muscarinic receptor antagonist atropine (1 …

Target Selection And Enhancement During Attentional Tracking, Marvin R. Maechler

Dartmouth College Ph.D Dissertations

At any waking moment, we are bombarded with more sensory information than we can fully process. Attention is necessary to deal with the dynamic world we live in. One fundamental function of vision and attention is to keep track of moving objects, but what are the targets of attention during tracking?

One of the first theories of attentional tracking predicted that targets would be selected at early processing stages. By employing the double-drift illusion, which dissociates physical and perceived positions of moving objects, we investigated which of these positions is selected for tracking. Contrary to earlier theories and in line …

Measuring Spontaneous Neurotransmission Using Genetically Encoded Fluorescent Indicators, Amelia Jane Ralowicz

Dartmouth College Ph.D Dissertations

Synaptic connections throughout the nervous system exhibit two forms of neurotransmitter release caused by synaptic vesicle fusion, evoked and spontaneous release. Despite being discovered 70 years ago, the mechanisms governing spontaneous release have remained elusive. Our understanding of spontaneous release lacks mechanistic details including discrepancies in the sources of synaptic vesicles supporting it, the source(s) of calcium supporting it, and most importantly an unclear relationship (cooperative or antagonistic) with evoked release. These gaps exist due to a lack of experimental methods specific to the study of spontaneous release at individual synapses.

This thesis addresses these gaps in two ways. Firstly, …

Biogenesis And Function Of Microglial Extracellular Vesicles In Neuroinflammation And Parkinson’S Disease, Karl E. Biggs

Dartmouth College Ph.D Dissertations

Microglia are subject to chronic proteinaceous and environmental stress during the progression of prevalent neurodegenerative diseases such as Parkinson’s Disease (PD). Chronic stress can activate the NLR family pyrin domain containing 3 (NLRP3) pattern recognition receptor resulting in the formation of the NLRP3 inflammasome, proinflammatory signaling, and pyroptotic cell death. A distinct subset of extracellular vesicles (EVs) are released from cells upon NLRP3 activation. We studied WT and Nlrp3^-/- primary microglia exposed to bacterial stimulating agents and alpha synuclein preformed fibrils (αsyn PFFs), which model Parkinson’s disease and associated synucleinopathies. We identified the NLRP3-dependent release of the endosome fate …

Dna Methylation-Based Epigenetic Biomarkers In Cell-Type Deconvolution And Tumor Tissue Of Origin Identification, Ze Zhang

Dartmouth College Ph.D Dissertations

DNA methylation is an epigenetic modification that regulates gene expression and is essential to establishing and preserving cellular identity. Genome-wide DNA methylation arrays provide a standardized and cost-effective approach to measuring DNA methylation. When combined with a cell-type reference library, DNA methylation measures allow the assessment of underlying cell-type proportions in heterogeneous mixtures. This approach, known as DNA methylation deconvolution or methylation cytometry, offers a standardized and cost-effective method for evaluating cell-type proportions. While this approach has succeeded in discerning cell types in various human tissues like blood, brain, tumors, skin, breast, and buccal swabs, the existing methods have major …

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

Self-Supervised Pretraining And Transfer Learning On Fmri Data With Transformers, Sean Paulsen

Dartmouth College Ph.D Dissertations

Transfer learning is a machine learning technique founded on the idea that knowledge acquired by a model during “pretraining” on a source task can be transferred to the learning of a target task. Successful transfer learning can result in improved performance, faster convergence, and reduced demand for data. This technique is particularly desirable for the task of brain decoding in the domain of functional magnetic resonance imaging (fMRI), wherein even the most modern machine learning methods can struggle to decode labelled features of brain images. This challenge is due to the highly complex underlying signal, physical and neurological differences between …