Systems Neuroscience Commons^™

Towards Identifying Fear And Safety Network States Across Sex, Rhonda Kolaric

Dissertations, Theses, and Capstone Projects

Post-traumatic stress disorder (PTSD) is a trauma- and stressor-related disorder with a lifetime prevalence of 5-6% in men, and 10-12% in women (National Center for PTSD). Generalized anxiety disorder (GAD) is a highly prevalent anxiety- and depression-related psychiatric disorder with a lifetime prevalence of 1-2% in men, and 3-4% in women (National Institutes of Health). Both of these disorders disproportionately affect women. A hallmark feature of both disorders is the maladaptive generalization of fear, in which defensive responses extend beyond the original traumatic or threatening stimulus to neutral or unrelated cues. This overgeneralization can become debilitating, disrupting cognitive, emotional, and …

The Effects Of Chronic Nicotine Exposure On Dopamine-Mediated Reinforcement Learning And Striatal Neurotransmission, Srishti Bose

Dissertations, Theses, and Capstone Projects

Tobacco is one of the most widely used substances across the United States; tobacco consumption is linked with several diseases and is one of the leading causes of preventable death in the country. Nicotine is the active substrate found in tobacco products, acting as a stimulant, which reinforces continued use. The introduction of tobacco-free options such as e-cigarettes and oral pouches has driven an increase in nicotine exposure across the population, especially in young adults. Acute nicotine use induces neuroadaptations in the mesolimbic dopaminergic system, which mediates reinforcement learning and addiction, that potentiates reward-related neurotransmission. Furthermore, there are clinical studies …

History-Dependent Gain Control In The Paraventricular Thalamus: Neural Substrates Of Stress-Enhanced Fear Learning, Michael Martino

MUSC Theses and Dissertations

Post-traumatic stress disorder (PTSD) is characterized by hyperarousal and heightened reactivity that generalize beyond the original traumatic event, yet the neural mechanisms by which prior stress experience biases future fear learning remain poorly understood. Stress-enhanced fear learning (SEFL) is a well-validated rodent model of this phenomenon, in which a severe stressor produces persistent sensitization of subsequent fear acquisition. This dissertation used a 30-day SEFL paradigm to identify the brain-wide functional signature of stress sensitization and to identify candidate neural substrates.

Whole-brain cFos mapping during acute fear acquisition revealed a predominant pattern of suppressed neural activity in sensitized animals, with limbic …

Mapping And Modeling Threat-Evoked Brain States After Early Life Adversity, Taylor W. Uselman

Biomedical Sciences ETDs

Early life adversity (ELA) increases lifelong neuropsychiatric vulnerability. Yet how ELA reorganizes brain-wide activity and circuit coordination across later experience remains unclear. This dissertation tests the hypothesis that ELA alters adult brain-wide activity and responses to threat through disrupted coordination among neural systems that regulate emotional experience, including prefrontal-limbic and monoaminergic systems. Longitudinal manganese-enhanced MRI of adult mice exposed to standard or fragmented early care, combined with computational processing and statistical modeling, quantified brain states before, during, and long after innate predator threat. These studies established that acute threat evokes large-scale, distributed brain activity that evolves over time. ELA potentiates …

Transcranial Ac Modulation Of Cerebellar Nuclear Activity In Awake Animals, Nuran Kavakli

Dissertations

Entrainment of cerebellar nuclear (CN) cells via cerebellar transcranial alternating current stimulation (ctACS) has been reported in animals under ketamine/xylazine anesthesia. Our main objective was to demonstrate modulation of CN activity in unanesthetized, freely moving animals using ctACS. Multi-channel carbon-fiber electrodes were implanted into the interpositus nucleus for recording multi-unit (MU) activity, and thin-film electrodes were implanted subcutaneously over the posterior cerebellum for stimulation. A frequency-domain-based metric was developed to quantify modulation from MU signals. The results demonstrated modulation in a wide range of frequencies (4 Hz-300 Hz) as in anesthetized animals. In contrast, the amplitude of the peak in …

Rhythms Of Hippocampal Function And Memory After Moderate Prenatal Alcohol Exposure, Lilliana May Sanchez

Psychology ETDs

Fetal Alcohol Spectrum Disorders involve morphologic and neurobiological abnormalities in offspring subjected to prenatal alcohol exposure. Although not as well studied as high exposure, moderate prenatal alcohol exposure represents the most common and undetected form in humans. While learning and memory deficits have been well characterized at the behavioral level in humans with Fetal Alcohol Spectrum Disorders and in animal models of moderate prenatal alcohol exposure, few studies have determined the circuit or systems level mechanisms of the behavioral deficits. A complete understanding of the neural bases of memory deficits after moderate prenatal alcohol exposure is needed to ultimately identify …

Expanding Access To Noninvasive Spinal Neuromodulation For Pediatric Spinal Cord Injury Rehabilitation: A Comparative Device Study, Alice E C Palmer

College of Arts & Sciences Senior Theses

Paralysis following spinal cord injury (SCI) has traditionally been considered permanent due to the disruption of supraspinal input to spinal motor circuits. However, growing evidence suggests that spinal networks below the level of injury retain intrinsic motor-generating capabilities through central pattern generators. Transcutaneous spinal cord stimulation (scTS) is a noninvasive neuromodulation technique that delivers electrical stimulation through the skin to reactivate these spinal networks. Although prior studies demonstrate that scTS delivered through research-grade devices is safe and effective in adults and children with chronic SCI, clinical translation remains limited by lack of FDA-approved systems, high costs, and restricted access to …

Circuit And Synaptic Mechanisms Of Methamphetamine Induced Cognitive Deficits During Abstinence: Roles Of The Perirhinal-Prefrontal Pathway And The Nucleus Reuniens, Sarah Goldsmith

MUSC Theses and Dissertations

Cognitive deficits during abstinence are a hallmark of methamphetamine (meth) use and indicative of negative treatment outcomes. In rats, both long access meth self-administration and meth binge produce recognition memory deficits due to drug-induced plasticity within the perirhinal cortex (PRH). PRH projections are numerous and include the medial prefrontal cortex (mPFC) and the Nucleus Reuniens (NRe). In the first study, the role of the PRH-mPFC reciprocal circuit in novel object recognition memory was investigated by infusing an rgAAV encoding GFP-tagged Cre recombinase into the PRH or the mPFC. Following surgery, rats explored objects. During exploration, PRH neurons receiving input from …

How To Search For The Engram: Optogenetics And Network Dynamics, Claudia Garcia Jou

Dissertations, Theses, and Capstone Projects

Memories are thought to be encoded by ensembles of neurons called "engram cells", because their artificial activation with optogenetics leads to the behavioral expression of a memory. However, the physiological mechanisms that mediate this process remain unknown. In this thesis, I investigate how optogenetic stimulation of memory-tagged cells changes neuronal firing, spatial coding, and the geometry of neural manifolds. I used an active place avoidance task and a foraging task to label engram cells in the dorsal hippocampus with Channelrhodopsin2 (ChR2). I then recorded the hippocampal activity response to optogenetic stimulation in mice under anesthesia, head-fixed, or freely moving. I …

Perinatal Inflammation And Oxidative Stress Alter Adult Rat (Rattus Norvegicus) Motor Behavior, Alexander Young

Honors College Theses

Recent evidence in comparative animal models suggests that early life exposure to elevated inflammation (via LPS exposure) and oxidative stress (via acetaminophen exposure) may synergistically interact to alter typical neurodevelopmental trajectories, resulting in lasting effects on both behavior and gut-brain neurochemistry. The current study observed emotional and motor behaviors and collected fecal-boli to measure Tyrosine (TE) levels in male and female Long-Evans (Rattus norvegicus) rats. Subjects were either treated with [1] saline [2] lipopolysaccharide (LPS) to introduce an inflammatory state, [3] acetaminophen (APAP) to introduce oxidative stress, or [4] a dual-hit of both LPS + APAP on postnatal day (PD) …

A Framework For Characterizing The Peripheral Immune Isonome Using Long-Read Single-Cell Rna Sequencing And Its Relevance To Neurological Disease, Patricia Hayes Doyle

Theses and Dissertations--Neuroscience

Long-read single-cell RNA sequencing provides an opportunity to understand human health and disease at isoform resolution, revealing cellular diversity and disease mechanisms difficult to resolve with bulk or short-read methodologies.

Using a modified PIPseq workflow and computational pipeline adapted for Oxford Nanopore (ONT) sequencing, we profiled isoform usage across immune cells, integrating marker expression and isoform discovery, generating the largest long-read single-cell dataset of human immune cells from a single individual to date. We identified non-canonical protein-coding variants of GZMB and CD3G enriched in unexpected cell types. We also discovered novel transcripts from CMC1 and LYAR with cell-type-specific signatures that …

Metabolism As A Regulator Of Sleep And Cortical Activity In Health And Alzheimer’S Disease, Nicholas J. Constantino

Theses and Dissertations--Neuroscience

Metabolic flexibility is essential for maintaining normal physiological function, enabling an organism to sense, flux, utilize, and switch fuel sources in response to changing energetic availability, demand, and cellular needs. Energetic demands are state-dependent, with wake and sleep exhibiting distinct metabolic profiles. Sleep is highly sensitive to changes in metabolism and requires metabolic flexibility to both transition into and maintain sleep stability. Alzheimer’s disease (AD) is increasingly recognized as a disease of altered metabolism yet is often framed as a disease of energetic failure. We instead define AD as a disease of metabolic inflexibility, characterized not by insufficient energy availability, …

Design And Advancement Of Analytical Frameworks For In Vivo Single-Photon Calcium Imaging To Characterize Temporal- And Treatment-Dependent Neural Adaptations To Opioid Exposure And Withdrawal In The Medial Prefrontal Cortex, Alexia R. Alsum Dr.

Theses and Dissertations--Pharmacy

Despite the availability of several approved medications for opioid use disorder (OUD), it remains a significant public health concern characterized by persistent neurobiological adaptations that drive relapse and impede successful recovery. The medial prefrontal cortex (mPFC), a region critical for executive control and decision-making, undergoes pronounced functional changes during chronic opioid exposure and withdrawal, yet the cellular mechanisms underlying these adaptations remain poorly understood. This dissertation aims to investigate longitudinal alterations in mPFC neural activity across opioid exposure and withdrawal using in vivo single-photon calcium imaging and newly developed computational frameworks.

Following standard preprocessing to extract and normalize calcium traces, …

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 …

The Role Of The Amygdala In Huntington Disease-Associated Aggression, Luis Torres

Honors Undergraduate Theses

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a trinucleotide CAG expansion in the huntingtin gene (HTT). HD is characterized by motor, cognitive, and psychiatric symptoms that significantly impact patient and caregiver quality of life. Psychiatric symptoms, including depression, anxiety, and irritability, are common manifestations of HD and can emerge years before the onset is clinically diagnosed. Aggression is a common and challenging psychiatric symptom in HD, often misunderstood and associated with caregiver stress, early institutionalization, and reduced quality of life. Despite its clinical impact, aggression in HD lacks effective, targeted treatment options. Similar to HD …

Assessing The Effects Of Theta Transcranial Alternating Current Stimulation During Working Memory Performance On Theta-Gamma Phase Amplitude Coupling In Healthy Adults, Samantha M. Zimmer

UNF Graduate Theses and Dissertations

Transcranial alternating current stimulation (tACS) is an emerging form of noninvasive brain stimulation with substantial effects on behavior and brain function due to its ability to entrain endogenous neural oscillations. Working memory is a cognitive process that involves holding onto information that is no longer present in the environment and manipulating or reorganizing information for immediate use. Theta oscillations are critical for the functionality of the frontoparietal network and are involved in strengthening communication and coordination between frontal and parietal brain regions, especially during working memory processing. TACS applied at the theta frequency, targets theta oscillations, strengthens network communications, and …

Integration And Modulation Of Visual Signals In Dorsal Thalamus., James Whitley

Electronic Theses and Dissertations

The visual thalamus is influenced by a diverse array of cortical and subcortical inputs that shape how information is transmitted to cortex. Using a variety of anatomical, optogenetic, and in vitro physiological techniques I investigated the differential impacts of modulation and integration of first and higher-order thalamic nuclei, while relying on influential concepts on the general organization of thalamic nuclei. In the first data chapter, I determined how GABAergic pretectum (PT) projections to the dorsal lateral geniculate nucleus (dLGN) and visual thalamic reticular nucleus (vTRN) can influence retinogeniculate signal transfer. We found that the PT provides over 75% of the …

Genetic Identification Of A Rapidly-Adapting Low-Threshold Mechanoreceptor Innervating Fungiform Papillae., Thomas Alexander Myers Ii

Electronic Theses and Dissertations

Mechanosensory innervation of the oral cavity enables us to detect the texture and location of the foods we consume. Our goal was to find a genetic identifier for a mechanoreceptive subtype. Toward this goal, we examined neurons expressing the neurotrophin receptor TrkC, parvalbumin (Pvalb), and the glutamate transporter Vglut3. Because different papilla types contribute to food detection in different ways, we examined the innervation patterns of these neuron subtypes. We found that Pvalb+ and Vglut3+ neurons were fungiform papilla specific, where TrkC innervated both papilla types. We examined the anatomy of the three genetic populations, finding that the Pvalb+ neurons …

Sensory And Motor Tectothalamic Circuits: Two Sides Of The Same Coin., Nazratan Naeem

Electronic Theses and Dissertations

Integration of sensorimotor information in the visual system has always been an intriguing topic to scientists, yet the subcortical sensory and motor circuits that are essential components of this process have remained elusive. In these studies, we used a blend of classical and contemporary techniques such as viral tracing, immunohistochemistry, optogenetics in-vitro whole cell electrophysiology, and electron microscopy in mice to characterize sensory and motor circuits of the superior colliculus (SC), a conserved visuomotor structure with connections with a wide variety of brain structures, including the thalamus. We focused on two SC cell types: visually responsive widefield vertical (WFV) cells …

Neural Dynamics Supporting Flexible Cognition, Meredith J. Mccarty

Dissertations and Theses (Open Access)

Flexible cognition enables humans to adapt their behavior to changing circumstances by prioritizing relevant information and filtering out distractions. This process is thought to be supported by the integration of ongoing behavioral goals with incoming sensory information, but how this integration is realized in the human brain remains unclear. It is unknown how high-order sensory cortices can balance specialized processing with flexible integration of changing behavioral goals. In the following investigations, we use intracranial EEG (iEEG) recordings in humans to study the neural dynamics of flexible cognition during high-order sensory processing. First, we validated assumptions about the locality of iEEG …

Investigation Of Motor Neuronal And Circuit Level Mechanistic Determinants Of Spinal Excitability Following Cst Injury, Thelma Bethea

Dissertations, Theses, and Capstone Projects

The corticospinal tract (CST) is the primary descending motor pathway in mammals, essential for precise, dexterous movements, especially in humans and nonhuman primates. Damage to the CST, such as from spinal cord injury (SCI), impairs skilled motor function and triggers maladaptive changes including aberrant proprioceptive afferent sprouting and increased spinal excitability. These changes are closely linked to both muscle weakness and the development of hyperreflexia, compounding the functional deficits. Animal models of SCI are valuable for investigating mechanisms of injury and recovery, though traditional models often limit the ability to isolate circuit-specific contributions. To address this, I employed selective unilateral …

Hierarchy In Sensation: Exploring The 40 Hz Auditory Steady State Synchrony In The Primary Auditory And Prefrontal Association Cortices, Deepshila Gautam

Electronic Theses and Dissertations

Auditory processing begins in the cochlea and ascends through brainstem relays to the cortex, where sound features with increasing complexity are encoded. The 40 Hz auditory steady-state response (ASSR) reflects induced gamma synchrony shaped by local cortical circuit dynamics. Disrupted 40 Hz ASSR is a consistent finding in schizophrenia, linked to N-methyl-D-aspartate receptor (NMDAR) hypofunction in inhibitory interneurons, making it a promising translational biomarker. While multiple ASSR generators have been identified, it is not known if these are redundant or represent unique activity. This dissertation investigates regional differences in 40 Hz ASSR across two principal generators: the primary auditory cortex …

Parvalbumin Interneuron-Oligodendrocyte Interactions In The Infralimbic Cortex Promote Extracellular Plasticity Mechanisms After Safety Learning, Lucy Emma Denholtz

Dissertations, Theses, and Capstone Projects

The ability to differentiate between threat and safety cues is essential for adaptive behavior, yet this process is disrupted in psychiatric disorders, such as post-traumatic stress disorder (PTSD), where safety cues fail to downregulate fear expression. To better understand the neurobiological mechanisms of safety learning, I investigate how safety conditioning vs contextual fear conditioning modify behavioral and cellular mechanisms in the infralimbic (IL) region of the medial prefrontal cortex (mPFC) at several time points after learning. Through this work, I identify a novel mechanism whereby safety learning promotes learning dependent neuro-glial interactions that promote conditions for plasticity in the mPFC. …

Neural Mechanisms Of Context-Sensitive Behavior In The Adult Male Zebra Finch, Katherine L. Anderson

Dissertations, Theses, and Capstone Projects

Adapting behaviors to the perceived external environment is key to the success and survival of individuals in social species. This context-sensitive modulation of behavior is critical for informative interactions with conspecifics, like alerting a neighbor to a nearing predator or capturing the attention of a potential mate. For the adult male zebra finch (Taeniopygia guttata), a vocal-learning songbird, context-sensitive adaptions to a learned song are key for developing and maintaining pair-bonds with females who are extremely attentive to subtle modulations of song structure. In this thesis, I explore the hypothesis that the influence of a social behavior network …

Memory Interference In The Lateral Entorhinal Cortex, Omar Ghazy

Dissertations, Theses, and Capstone Projects

Memory interference occurs when previously formed memories disrupt the acquisition or retrieval of new information. A prominent example of proactive interference is latent inhibition (LI), defined as a reduced ability to form or express Pavlovian associations with a stimulus following non-reinforced exposure. The interference-based model suggests that LI arises because the memory that the pre-exposed stimulus is inconsequential interferes with the memory that it predicts a reinforcer.

Because interference increases with age, identifying its neural basis may help prevent or slow cognitive decline. Prior studies using the LI paradigm implicate the entorhinal cortex (EC) in retrieving the memory that a …

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 …

A Neuroimmune Circuit Mediates Chemo Brain Pathology, Daniel Ahmadi

McKelvey School of Engineering Graduate Student Theses & Dissertations

Chemotherapeutic agents, while effective in targeting malignant tumors, often reduce the patients’ quality of life by inducing fatigue, pain, and motivational deficits. These symptoms are collectively referred to as “chemo brain.” The mechanisms underlying these adverse effects, and specifically whether fatigue and motivational impairments share a common etiology, remain poorly understood. The neural–immune substrates of these symptoms remain obscure, in part because standard preclinical regimens either bypass key systemic signals or introduce local toxicity confounds. Here, I establish and validate a three‑day, low‑dose intravenous cisplatin protocol that avoids peritoneal inflammation and severe renal injury yet produces robust, reversible fatigue and …

Investigating Prefrontal Cortex Neuronal Signatures Of Opioid-Induced Risk-Taking Behavior, Cana Quave

Dissertations and Theses (Open Access)

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed an approach-avoidance conflict task using a modified conditioned place preference procedure to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision-making. Following morphine conditioned place preference, rats underwent a conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline-exposed control group avoided cat odor, the morphine group included two subsets of rats that either maintained a preference for the paired side despite the presence of …

Neural Activity Within And Between Visual And Executive Areas Is Modulated Post-Locomotion In Rhesus Macaques, Sergey Egranov

Dissertations and Theses (Open Access)

Physical activity has been shown to benefit cognitive and mental health by improving cerebrovascular perfusion and regulating hormone-mediated processes on a systemic level. However, the acute effects of physical activity, such as locomotion, on the neuronal circuits underlying cognitive processes have yet to be fully characterized. This body of work seeks to rectify this gap in knowledge through analysis of how both behavioral performance and neuronal activity signatures in visual and executive brain regions are modulated post-locomotion in rhesus macaques.

To this end, we performed high-yield electrophysiological recordings simultaneously from area V4, a mid-tier visual cortical region, and the dorsolateral …

Leveraging Clinical Standards To Improve The Translational Relevance Of Therapies For Experimental Spinal Cord Injury, Aaron L. Silverstein

Theses and Dissertations--Neuroscience

Efforts to improve treatment of spinal cord injury (SCI) often use animals to develop effective therapeutics, intending to improve the survival and the quality of life of persons with SCI. Over half of all SCIs in the United States occur at the cervical level and often cause locomotor deficits and life-threatening breathing dysfunction. Thus, my dissertation is focused on this important patient population.

After beginning with a description of translational research and surveying SCI from a clinical standpoint, I turned to describe experimental models of cervical SCI and more detailed neuroimmunological findings relevant to my work. Then, I conducted a …