Neurosciences Commons^™

Glutamatergic Lateral Habenula Neurons Modulate Consolidation Of Associative Memories, Snigdha Srivastava, I-Ching Wang, Mikhail Y Kochukov, Jessica L Swanson, Mauro Costa-Mattioli, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

INTRODUCTION: Despite the rise in psychiatric disorders worldwide, the underlying brain circuits responsible for these devastating conditions remain elusive. The lateral habenula (LHb) has emerged as a key brain structure in depression studies due to its hyperactive state in both patients and animal models. While this aligns with known roles in driving aversive states and regulating serotonin release, it is still unclear how acute and transient activity changes in the LHb can influence higher order cognitive processes such as learning, memory, and behavioral adaptation. Given the importance of these processes to psychiatric conditions, understanding how LHb activity impacts cognitive function …

Optimizing Decision-Making In A Cerebral Palsy Model Using Reinforcement Learning, Richard Ampah

Pitzer Senior Theses

This study presents an original interdisciplinary investigation into how reinforcement learning (RL) can model motor and cognitive defects and potentially improve motor and cognitive functions in individuals with cerebral palsy (CP), a non-progressive neurological disorder that impairs movement and adaptability. Integrating computational neuroscience and machine learning, the research applies policy gradient methods and Markov Decision Processes (MDPs) to simulate adaptive learning in agents with and without CP-related constraints.

The central aim is to compare the cumulative rewards of optimal policies, derived from value iteration, and human-like learning policies using the REINFORCE algorithm, both with and without the Bellman baseline. The …

Neuropsychological Assessment Accuracy In Diagnosing Early-Onset Alzheimer’S Disease, Elise Thomas

Master's Theses and Doctoral Dissertations

Early-onset Alzheimer’s disease (EOAD), a progressive neurological condition, is often difficult to diagnose before substantial neuronal damage. Neuropsychological assessments offer a more cost-effective and accessible method for detecting early cognitive decline, yet limited research exists on optimal combinations for EOAD identification. This study analyzed data from 24 clinical studies to determine the diagnostic accuracy of FDA-approved EOAD assessments used in combination. No single combination was found to be superior across all diagnostic metrics. MMSE + MoCA + ADAS-Cog showed the highest sensitivity, MMSE + MoCA + RBANS the highest specificity, MMSE + RBANS the highest AUC value, and MMSE + …

Motor Cortex Inhibition And Facilitation Changes Within Two Weeks Of Anterior Cruciate Ligament Reconstruction (Aclr): A Case Series, Colin Sylvester, Ann Maree Vallence, Casey Whife, Peter D'Alessandro, Christopher Latella, Ebonie Rio, Myles C. Murphy

Research outputs 2022 to 2026

Purpose: Anterior cruciate ligament reconstruction (ACLR) can cause arthrogenic muscle inhibition (AMI) or persistent muscle weakness that impairs physical function and return to sport. Deficits in voluntary activation (one method to measure AMI) are thought to contribute to AMI, however, the specific neurophysiological underpinnings remain inconclusive. The primary objective of this study was to explore changes in intracortical excitability (inhibition and facilitation) of the quadriceps representation in the primary motor cortex pre- and post-ALCR. Our secondary objective was to explore changes in hamstrings intracortical excitability pre- and post-ALCR. Methods: Prospective case-series pre-post-ACLR. Single- and paired-pulse transcranial magnetic stimulation (TMS) was …

Association Of High-Sensitivity Cardiac Troponin I Levels Below The Sex-Specific 99th Percentile With Late-Life Dementia: The Perth Longitudinal Study Of Ageing Women, Carlos J. Toro-Huamanchumo, Abadi Kahsu Gebre, Tiago Pecanha, Craig Sale, Wai Lim, Elizabeth Byrnes, Ee Mun Lim, Simon Laws, Kun Zhu, Carl Schultz, Richard L. Prince, Blossom C.M. Stephan, Mario Siervo, Joshua R. Lewis, Marc Sim

Research outputs 2022 to 2026

Background: Elevated high-sensitivity cardiac troponin (hs-cTn) levels are linked with cardiovascular disease and cognitive impairment, both of which are strong risk factors for late-life dementia (LLD). This study examined the association between hs-cTnI levels below the sex-specific 99th percentile for myocardial injury and the incidence of LLD in older women. Methods: 986 community-dwelling women aged ≥70 years without prior LLD and with hs-cTnI < 15.6 ng/L (stratified into quartiles) were included from the Perth Longitudinal Study of Ageing Women. The primary outcome was incident LLD events, including LLD hospitalisation or death, over 14.5 years obtained from linked health records. Associations between hs-cTnI and LLD outcomes were explored using multivariable-adjusted Cox models, as part of restricted cubic splines. Results: At baseline, participants' mean (±SD) age was 75.2±2.7 years. Over 14.5 years of follow-up, LLD events (n=174, 17.7%), hospitalisations (n=155, 15.7%) and deaths (n=68, 6.9%) were recorded. Compared with those in the lowest quartile (Q1, median 3.1 ng/L), women in the highest quartile of hs-cTnI (Q4, median 7.3 ng/L) had a greater risk of developing LLD-related events (adjusted HR: 1.88, 95% CI: 1.22 to 2.91), hospitalisation (adjusted HR: 1.65, 95% CI: 1.04 to 2.64) and death (adjusted HR: 2.27, 95% CI: 1.13 to 4.59), after adjusting for established cardiovascular and dementia risk factors, including apolipoprotein E (APOE) genotype. Conclusion: Among older women, hs-cTnI levels below the sex-specific 99th percentile for myocardial injury were associated with an increased risk of LLD events over 14.5 years. These findings suggest that hs-cTnI may identify older women at higher risk of LLD, capturing both cardiovascular and brain health vulnerability in older age.

Distinct Contributions Of Cerebrospinal Fluid Biomarkers To Cognitive Impairment And Neuropsychiatric Symptoms In Young-Onset Dementia, Wei Hsuan Chiu, Anita M.Y. Goh, Dhamidhu Eratne, Charles B. Malpas, Matthew J.Y. Kang, Wendy Kelso, Mark Walterfang, Dennis Velakoulis, Samantha M. Loi

Research outputs 2022 to 2026

Objective: Young-onset dementia (YOD), defined by symptom onset before age 65, encompasses diverse aetiologies and presents with prominent neuropsychiatric symptoms (NPS) that often accompany or exacerbate cognitive decline. However, the pathological mechanisms linking NPS, cognition, and biomarkers remain unclear. It was hypothesised that relationships between NPS and cognition would be mediated or moderated by cerebrospinal fluid (CSF) biomarker levels in individuals with YOD. Methods: This retrospective, cross-sectional study included 46 participants with YOD (24 with Alzheimer's disease [AD], 22 with non-AD dementias) diagnosed at the Neuropsychiatry Centre, Royal Melbourne Hospital. NPS were measured using the Depression Anxiety and Stress Scale …

The Role Of Glial Fibrillary Acidic Protein In The Neuropathology Of Alzheimer’S Disease And Its Potential As A Blood Biomarker For Early Diagnosis And Progression, Ekanayaka M.S. Bandara, Prita R. Asih, Steve Pedrini, Eugene Hone, Warnakulasuriya Mary Ann Dipika Binosha Fernando, Ralph N. Martins

Research outputs 2022 to 2026

Alzheimer’s disease (AD) is a neurodegenerative disease characterised by neuropathological hallmarks, including extracellular amyloid plaques and neurofibrillary tangles. The disease is clinically defined by cognitive dysfunction, including learning, memory deficits, and behavioural changes. With the rising global prevalence of AD, early diagnosis is critical for implementing effective interventions before irreversible neuronal damage occurs. Biomarkers correlating amyloid deposition, tau pathology, neuroinflammation, and neurodegeneration are currently being investigated using cerebrospinal fluid analysis and positron emission tomography imaging. These methods are invasive or costly, limiting their widespread clinical utility. Blood-based biomarkers offer a promising alternative due to accessibility, cost-effectiveness, and feasibility for large-scale …

Blood Biomarker Profiles In Young-Onset Neurocognitive Disorders: A Cohort Study, Oneil G. Bhalala, Jessica Beamish, Dhamidhu Eratne, Patrick Summerell, Tenielle Porter, Simon M. Laws, Matthew J.Y. Kang, Aamira J. Huq, Wei Hsuan Chiu, Claire Cadwallader, Mark Walterfang, Sarah Farrand, Andrew H. Evans, Wendy Kelso, Leonid Churilov, Rosie Watson, Nawaf Yassi, Dennis Velakoulis, Samantha M. Loi

Research outputs 2022 to 2026

Introduction: Young-onset neurocognitive symptoms result from a heterogeneous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the Biomarkers in Younger-Onset Neurocognitive Disorders cohort, a study of individuals < 65 years old presenting with neurocognitive symptoms for a diagnosis and who have undergone cognitive and biomarker analyses. Methods: Sixty-five participants (median age at assessment of 56 years, 45% female) were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia, and categorized as either early-onset Alzheimer’s disease (n = 18), non-Alzheimer’s disease neurodegeneration (n = 23) or primary psychiatric disorders (n = 24). Levels of neurofilament light chain, glial fibrillary acidic protein …

Circulating Medium- And Long-Chain Acylcarnitines Are Associated With Plasma P-Tau181 In Cognitively Normal Older Adults, Tahmida Sharmin, Pratishtha Chatterjee, James D. Doecke, Nicholas J. Ashton, Kevin Huynh, Steve Pedrini, Hamid R. Sohrabi, Benjamin Heng, Shaun Eslick, Henrik Zetterberg, Kaj Blennow, Manohar Garg, Ralph N. Martins

Research outputs 2022 to 2026

Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ …

Endoneurial Immune Interplay In Peripheral Nerve Repair: Insights And Implications For Future Therapeutic Interventions, Alina Sprenger-Svačina, Martin K R Svačina, Husniye G Otlu, Tong Gao, Kazim A Sheikh, Gang Zhang

Faculty, Staff and Student Publications

The mechanisms underlying axonal injury and repair in peripheral nerves, whether due to traumatic damage or autoimmune neuropathies, are complex and not yet fully understood. Recent research indicates that an orchestrated interplay between damaged neurons, Schwann cells, and especially endoneurial immune cells such as macrophages or T cells is crucial to achieve satisfactory nerve recovery. Following axonal injury, degenerating axons and reactive Schwann cells release chemoattractants and cytokines that recruit immune cells into the endoneurium. Among them, macrophages play a pivotal role by clearing axonal and myelin debris and subsequently creating a pro-regenerative microenvironment that supports axonal outgrowth. There is …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Who Calls For Urgent Action To Ban Flavoured Tobacco And Nicotine Products

Neurosciences

No abstract provided.

Early Changes In Inflammation-Related Proteins In The Cerebrospinal Fluid And Plasma Of Patients With Aneurysmal Subarachnoid Hemorrhage, David J. Braun, Kevin W. Hatton, Justin F. Fraser, Robert M. Flight, Hunter N. B. Moseley, Caleb S. Bailey, Josh M. Morganti, Bingqing Zhang, Ishara S. Ariyapala, Tae K. Kim, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Background

Aneurysmal subarachnoid hemorrhage (aSAH) is a relatively uncommon but high mortality form of stroke that can result in long-lasting disability. A better understanding of key neuroinflammatory changes during the early phase (< 72 h) may provide potential avenues of treatment.

Methods

In an attempt to understand these early changes, we recruited 7 aSAH patients for profiling of longitudinal plasma and cerebrospinal fluid (CSF) proteins at up to 72 h post injury. We additionally compared this to control plasma obtained previously from healthy elderly volunteers. Using the Alamar Biosciences NULISAseq platform, we obtained a comprehensive picture of early peripheral and central inflammatory changes after injury.

Results

This study …

Nicorandil Treatment Improves Survival And Spatial Learning In Aged Granulin Knockout Mice, Dana M. Niedowicz, Wang-Xia Wang, Paresh Prajapati, Yu Zhong, Shuling X. Fister, Colin B. Rogers, Pradoldej Sompol, David K. Powell, Indumati Patel, Christopher M. Norris, Kathryn E. Saatman, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). We studied a Grn knockout (Grn-KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9-encoded regulatory subunit of the “K⁺ATP” channel that is well-tolerated in humans. Aged (13 months) Grn-KO and wild-type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral …

Gait Variability As A Marker Of White Matter Integrity In Individuals With Down Syndrome, Elizabeth M. Leach, David K. Powell, Amanda C. Glueck, Elizabeth Head, Moaz W. Ibrahim, Amelia J. Anderson-Mooney, Kathryn L. Van Pelt, Jordan P. Harp, Frederick A. Schmitt, Ahmed A. Bahrani

Sanders-Brown Center on Aging Faculty Publications

Introduction: Individuals with Down syndrome (DS) face a significant risk of neurodegeneration, and gait variability may serve as a clinical biomarker of neurological health. This longitudinal parent substudy aimed to explore relationships between gait, white matter (WM) integrity, and cognitive function in DS.

Methods: The associations were investigated between magnetic resonance imaging diffusion tensor imaging (DTI), cognition, and self-paced gait data from 22 DS participants (mean age ± SD 37 ± 7.5 years).

Results: DTI measures, such as lower fractional anisotropy (FA) and higher mean diffusivity, were correlated with greater step time variability but not normalized velocities. Lower cognitive scores …

Disrupted Calcium Dynamics In Reactive Astrocytes Occur With End Feet–Arteriole Decoupling In An Amyloid Mouse Model Of Alzheimer’S Disease, Blaine Weiss, John C. Gant, Ruei-Lung Lin, Jenna L. Gollihue, Colin B. Rogers, Susan D. Kraner, Edmund B. Rucker, Yuriko Katsumata, Yang Jiang, Peter T. Nelson, Donna M. Wilcock, Pradoldej Sompol, Olivier Thibault, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

While cerebrovascular dysfunction and reactive astrocytosis are extensively characterized hallmarks of Alzheimer's disease (AD) and related dementias, the dynamic relationship between reactive astrocytes and cerebral vessels remains poorly understood. Here, we used jGCaMP8f and two-photon microscopy to investigate calcium signaling in multiple astrocyte subcompartments, concurrent with changes in cerebral arteriole activity, in fully awake 7- to 8-month-old male and female 5xFAD mice, a model for AD-like pathology, and wild-type (WT) littermates. In the absence of movement, spontaneous calcium transients in barrel cortex occurred more frequently in astrocyte somata, processes, and perivascular regions of 5xFAD mice. However, evoked arteriole dilations (in …

Cellular And Behavioral Consequences Of Psychedelic Drug Action In The Claustrum, Tanner L. Anderson

Theses and Dissertations--Neuroscience

Psychedelics are rapidly garnering research attention for their ability to successfully treat a variety of psychiatric diseases after one or a handful of treatments in recent clinical research. Among the conditions treated is substance use disorder (SUD), which afflicted 48.5 million (16.7%) Americans aged 12 and older in 2023 (NSDUH). As clinical trial results continue to show lasting positive effects of psychedelic psychotherapy, there remains an enormous gap in knowledge regarding how these drugs cause lasting changes in the brain to achieve these therapeutic effects. It has been suggested that psychedelics must induce rapid and long-lasting neuronal plasticity in order …

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 …

Immune Dynamics And B Cell Contributions To Neuroplasticity And Recovery After Stroke, Thomas A. Ujas

Theses and Dissertations--Neuroscience

This dissertation explores the dynamic interplay between the immune system and the brain across stroke and aging using clinical, post-mortem, and pre-clinical models. The immune system plays critical roles in shaping brain function, responding to injury, and mediating recovery. These studies aim to enhance our understanding of neuroimmune dynamics across spatial and temporal dimensions.

In the first part, we conducted longitudinal sampling of aneurysmal subarachnoid hemorrhage (aSAH) patients to track immune cell and cytokine changes at days 3, 5, 7, 10, and 14 post-stroke, with a focus on delayed cerebral ischemia (DCI), a common complication. We observed distinct temporal patterns, …

Anxiolytic Intervention: Modulation Of Cell Types Due To Nicotine Withdrawal, Taylor Elder

Theses and Dissertations--Pharmacy

Nicotine use disorder (NUD) remains a leading cause of preventable disease, yet the neurobiological mechanisms underlying nicotine withdrawal are incompletely understood. Emerging evidence implicates neuroimmune signaling and astrocytic regulation of glutamate in shaping the withdrawal-associated affective phenotype. This dissertation investigated these processes using multiple nicotine administration paradigms including osmotic minipump implant, cigarette smoke exposure, and nicotine vapor inhalation to model diverse routes of human nicotine intake.

Chapter 2 examines the effects of these three modes of administration on neuroinflammation and validation of nicotine delivery. Nicotine exposure was confirmed through receptor [³H]Epibatidine nAChR binding assay and serum cotinine measurements. …