The use of computational models of memory has been effective in adaptive learning environments and in determining the memory capabilities of learners. However, these models have not been widely applied in clinical settings. Evaluation of memory loss still heavily relies on extensive neuropsychological testing performed by neurologists or psychiatrists, especially in the context of progressive neurodegenerative disorders. Current evaluation tools lack the necessary reliability, convenience, and repeatability to effectively capture key dynamics of memory decline, including the unique and changing nature of memory over time. The goal of this study was to predict and monitor memory decline in individuals diagnosed with Mild Cognitive Impairment (MCI) using a model-based adaptive fact learning system. Participants, aged 58 to 78 years, were divided into two groups based on their cognitive classification and completed weekly online learning assessments at home, tracking their individual speed of forgetting (SoF) across various study materials. The results showed that this method was effective in accurately diagnosing mild memory impairment, with a success rate of over 80% after a single 8-minute learning session. The study also demonstrated the model’s ability to distinguish MCI subtypes through computations of participants' SoF. These findings offer novel insights into the progressive nature of memory decline and could have implications for early detection and management of Alzheimer’s disease as well as other forms of dementia and cognitive impairment. Further development of this method could serve as an alternative or complement to established diagnostic procedures and be used in clinical settings.

The leading causes of hearing and balance disorders are damage and loss of inner ear hair cells. Noise overexposure and aging can damage the fragile synaptic transmission between presynaptic hair cells (HC) and postsynaptic afferent neurons (AN), leading to “hidden” hearing loss. Hidden hearing loss is a condition where one can show normal auditory sensitivity when tested but still have difficulty in situations such as hearing one person in loud environments. Mitochondria might play an essential role in this connection by regulating transmission and energy supply. Mitochondria are known to adapt their morphologies to meet cellular demands. Studying mitochondrial morphology may reveal solutions to hearing preservation and contribute to our overall knowledge of the auditory system and general biology. Our lab has previously found that presynaptic hair cells harbor unique mitochondrial networks localized at the presynaptic HC release sites (ribbons) regulated by activity. However, the synapse requires postsynaptic neurons to function correctly to maintain healthy auditory transmission, so we examined the postsynaptic ANs. Preliminary data of two postsynaptic ANs revealed mitochondrial networks that extend between different HCs, but substantial evidence was lacking. Using the zebrafish lateral line as a model system, I microinjected fluorescent probes that tag AN mitochondria, Ca2+ uptake, and track depolarization via Channelrhodopsin. I used serial block-face scanning electron microscopy (SBFSEM) to reconstruct zebrafish AN and their mitochondria. SBFSEM cuts thin layers of the fluorescently tagged structures and images each layer to generate high-resolution 3D images. Probes successfully tracked the different functional characteristics. We observed distinctive architecture in postsynaptic mitochondria, confirming our preliminary findings. Further research will assess changes in postsynaptic mitochondria and regulation by synaptic activity. Understanding the connection between mitochondrial architecture at the synapse and its functional mechanisms will contribute to our knowledge of proper synaptic transmission and the pursuit of healthy hearing preservation.

Recent studies suggest that errors facilitate learning in certain conditions. Despite this, reinforcement paradigms dominate learning methods, subscribing to the narrative that errorless learning is the foundation of an ideal learning environment. If we continue to view learning from this restrictive perspective, we may fail to capture and apply the benefits of errors. Furthermore, although error learning is now a well-documented phenomenon, research on its underlying mechanisms is sparse. Two prominent theories have arisen out of this research; the elaborative hypothesis, in which meaningful connections are derived from errors, and the mediator hypothesis, in which errors act as secondary cues. To go beyond speculation, both must be examined empirically to successfully leverage error learning. Using a combined approach, data from computational models formulated to reflect different mechanisms of error learning were compared to behavioral data. In the behavioral task, participants (N = 61) learned word pairs in either a study or error trial before taking a final test. Supporting past error learning literature, errors before a study opportunity led to better performance on a final test. Differences in reaction times between conditions support the theory that errors increase learning through mediation by acting as a secondary cue rather than as a way to establish a deeper network between the cue and answer. Furthermore, comparing behavioral results to computational cognitive models provided insight into individual differences in mechanisms of error learning.

Memory loss is a debilitating symptom of neurodegenerative diseases. The exact process of memory decline or forgetting in the brain remains unclear. To address this issue, the development of technologies to preserve or improve memory is a continuous objective in translational medicine. This study aimed to uncover the brain networks involved in forgetting and investigate if reducing forgetting was possible through the use of transcranial alternating current stimulation (tACS; 60 Hz or sham) targeted to the dorsolateral prefrontal cortex (dlPFC). The dlPFC was considered a potential target for memory interventions as it had been linked to various aspects of memory function including working memory, executive control, encoding, and retrieval, as well as memory and attention functional connectivity networks. Participants took part in four visits, each consisting of three 8-minute memory tasks using an adaptive fact-learning software. The memory tasks assessed recognition memory (multiple choice), recall memory (fill-in-the-blank), and retrieval learning (response generation). The software used a neurocomputational model that adapted to each participant's performance. This cognitive model is based on established cognitive and biological principles and simulates memory encoding and passive forgetting. The model's α parameter, which represents the speed of forgetting and measures how quickly an individual's memories fade, was used as a dependent variable. Additionally, participants completed two resting state functional MRI (fMRI) scans to evaluate their brain's functional connectivity before and after stimulation. The study compared individual speeds of forgetting to individual patterns of functional connectivity to identify the neural networks most predictive of forgetting, and compared functional connectivity between participants who received tACS and those who received a sham stimulation. We hypothesize that tACS to the dlPFC will decrease forgetting rates and be associated with increases in functional connectivity. In conclusion, tACS has the potential to become a low-cost and non-invasive method to ameliorate memory impairments.

In mammals, hair cell loss or damage leads to permanent loss of auditory and vestibular function due to the inability of mammals to regenerate these cells. The primary function of hair cells is to respond to auditory and vestibular stimuli to facilitate perception of sound, head movement, and gravity. Hair cells are particularly sensitive to changes in their mitochondria, a membrane enclosed organelle that provides ATP in all eukaryotic cells. Disturbances or damages to the mitochondria can be caused by mitochondrial deafness genes, aminoglycoside-induced death, or senescence. Currently, there is very little known about the biology of hair cell mitochondria.The zebrafish neuromasts within the lateral line can serve as a functional model for cochlear hair cells because of its homology with the mammalian inner ear at genetic and structural levels. We use the zebrafish lateral line system in conjunction with the serial-block face scanning electron microscopy (SBFSEM) to produce three dimensional imaging of hair cell mitochondrial morphology. SBFSEM allows us to measure and quantify mitochondrial phenotypes. We have identified structural characteristics of mitochondrial networks adjacent to post-synaptic release sites that interact with afferent neurons and regulate synaptic transmission. The information gained from SBFSEM on hair cell mitochondrial morphologies will provide valuable insight on protective intracellular mechanisms that can prevent synaptopathy and protect against hearing loss. In our future work, we will quantify this mitochondrial networking morphology. These data will further inform functional experiments regarding the role of mitochondria at these synapses.

Implicit bias refers to unconscious attitudes and stereotypes in patient-provider communication that can lead to discrimination based on race, sexual orientation, gender, or other characteristics. This disproportionately impacts historically marginalized communities, including Black, Indigenous, and People of Color (BIPOC) and Lesbian, Gay, Bisexual, Transgender, Queer, and/or Questioning people (LGBTQ+). Although interventions have been developed to improve provider awareness of implicit bias, there has been little exploration of patient perspectives. With the help of my team, I conducted an analysis of 7 previously conducted co-design workshops with 32 BIPOC and LGBTQ+ people to understand patient perspectives on interventions to mitigate the impact of provider implicit bias in healthcare interactions. These workshops included group discussions about personal experiences with healthcare discrimination and a storyboarding activity to envision solutions for improving patient-provider interactions. Across workshops, participants created 13 storyboards that depict solutions in a primary care setting, several of which focus on improving patient-provider communication and promoting self-advocacy and empowerment. Through our collaborative qualitative analysis, my team and I identified two prominent themes from the workshops: communication tools and patient advocates. Participants shared experiences of feeling dismissed and unheard during healthcare visits, leading to storyboard proposals of communication tools, such as "smart boards" that allow patients to describe their symptoms in a nuanced manner. Another storyboard proposed a "panic button" that helps patients ask for help or request a different provider. Other storyboards focus on strategies to hold providers accountable, such as a "patient advocate" who approaches the provider about the patient's experience of discrimination and recommends a communication training intervention that raises awareness of bias. These findings can inform future research on interventions to address implicit bias in provider-patient communication. By prioritizing patient perspectives, we can create a healthcare system that is equitable and inclusive for all.

 Cancer metastasis, the spread of tumor cells to different parts of the body, significantly increases patient mortality. An early step in the metastasis process is invasion into surrounding tissues. One way that tumor invasion is studied is through tumor organoids. Tumor organoids mimic tumors in vitro through 3D cell culture. While it is generally held that invasion continues to increase monotonically over time, I recently discovered that invasion of tumor organoids has a temporal pattern, where invasion spikes up, then decreases after a certain time. This finding suggests more complex regulation of invasion dynamics than thought previously. The goal of this project is to investigate the temporal dynamics of cell-matrix associated RNAs and proteins during breast tumor organoid invasion. I can perform a qPCR time course of particular genes related to invasion to measure the levels of RNA at specific time points. In addition, I can check for protein levels using a novel method developed in the Cheung lab. This method utilizes bio-orthogonal click-chemistry to perform rapid, selective pairing of intracellular proteins with azidohomoalanine, a clickable methionine analog. Click-chemistry allows us to pick up proteins that cells are either secreted or on the surface of the cells. To define a cancer-specific invasion signature of tumor invasion, I compare RNA and protein dynamics in breast tumor organoids with normal mammary organoids (FVB) migrating in 3D collagen gels. I hypothesize that there will be specific genes associated with increased and decreased invasion levels. In future work we will target those genes by either suppressing those genes that increase with invasion or increasing the expression of invasion suppressors. We expect this work to reveal new regulators of the metastatic process.

Injuries to the spinal cord are among the most debilitating injuries to the human body. The task of repairing this dense network of nerve cells and fibers has been seen as insurmountable. However, new techniques emerging from the field of regenerative medicine have illustrated the possibility of encouraging the body to repair these injuries on its own. In the Wills Lab, we study the model organism Xenopus tropicalis, or the Western clawed frog, which has the incredible ability to regenerate its spinal cord and associated tissue following amputation. My project focuses on how Xenopus uses the classic developmental morphogen Sonic Hedgehog (Shh) to recapitulate the dorsal-ventral patterning of the spinal cord during regeneration. Previous research in a closely related organism showed that a switch to non-canonical mode of Shh signaling, not involving the Gli family of transcription factors, was important during regeneration. In order to investigate this further, I used chemical inhibitors of the canonical Shh signaling pathway to confirm this pathway’s limited importance in terms of gross regeneration. Next I used in-situ hybridization to visualize the expression of Shh and its associated genes along a regenerative time-course. It is anticipated that inhibition of the canonical pathway will decrease these expression levels and confirm the selectivity of our inhibitors. An understanding of the role of key biological signals like Shh will be integral in the development of regenerative therapies for spinal cord injury.

Emotional obstacles affecting those living with chronic Inflammatory Bowel Disease (IBD) are a pain point that often lacks support. Emotional obstacles include feelings of depression, anxiety, body image issues, experiencing isolation, or feeling unheard, which can impact one’s quality of life. Support systems, or individuals who provide emotional or physical support, can help people manage the effects of these obstacles to support illness self-management. Research on IBD and emotional support demonstrate that many people do not know how to best support their loved ones with IBD. Poor understanding of patients’ needs often results in ineffective support that is not perceived by IBD patients as beneficial; support system members are perceived as being overly worried, being hyper-fixated on physical IBD symptoms, or trying to distract the patient from emotional pain. These strategies carry the risk of IBD patients suppressing their emotional obstacles, withdrawing from their support system, and struggling on their own. I want to improve social support systems for IBD patients. As a first step, I administered online surveys asking people with IBD what emotional obstacles they face, and how these burdens affect their daily life. To date, respondents (n = 57) reported experiencing body image issues (57%), anxiety (68%), feeling hindered from their potential (51%), depression (66%), and social isolation (61%). Respondents stated that their emotional obstacles inhibit their IBD self-management (73%), ability to follow medical advice (38%), and ability to follow their medication regime (40%). These findings characterize common emotional obstacles and key impacts on self-management, a principal factor in disease remission. As we continue to survey people with IBD, we are conducting follow-up interviews to understand their experience and support needs in greater depth to inform improvements to social support systems.

Unlike mammals, western clawed frog (Xenopus tropicalis) tadpoles are able to completely regenerate their spinal cord after tail amputation. This complete spinal cord regeneration is due to the ability of their neural progenitor cells (NPCs) to differentiate into neurons successfully. Our research focuses on two transcription factors—Meis1 and Pbx3– that are upregulated by regenerating neurons and are necessary for successful regeneration. We aim to elucidate how these two proteins are working together to guide successful spinal cord regeneration in X. tropicalis tadpoles. I am specifically investigating Meis1 and Pbx3 splice variant expression during neural regeneration. Previous work in mice found that different known splice variants of Pbx3 have different expression patterns. While X. tropicalis has two predicted splice variants each of Meis1 and Pbx3, nothing is known about their individual expression or function. I sought to fill in this gap by looking at Meis1 and Pbx3 splice variant expression in different tissues and over regenerative time. Based on previous research in mice, I hypothesize that both splice variants of Meis1 and Pbx3 have different gene expression patterns in different cell types over regenerative time. I aimed to investigate this hypothesis by doing two experiments. My first experiment was to study the expression of each splice variant over regenerative time by performing qPCRs in order to look at the presence of splice variant mRNA in uninjured, 24, and 72 hours post-amputation. For my second experiment, I made in situ hybridization probes specific for each splice variant to identify their tissue-specific expression patterns. Based on previous literature, we expect to see differential amounts of expression from each splie variants as spatial expression centralized on the spinal cord. Understanding the transcriptional network that is behind the regenerative mechanism of X. tropicalis can help us develop therapeutic tools to address spinal cord injury in humans.