The functional connectivity of the brain evolves throughout the life of every individual. These changes, often referred to as neuroplasticity, can be impacted by a wide range of variables from diseases to eating a favorite dessert. How can these changes be modulated to treat neurological diseases and disorders such as post traumatic stress and major depressive disorder? My colleagues and I are intrigued with the prospects of neuromodulation as a therapeutic for abnormal brain connectivity and network dynamics, leading me to the question “At what rate do these connections accumulate and decay with optogenetic modulation; Optogenetics, a technique that uses light to activate or inhibit genetically targeted neurons, offers high cell-specificity and temporal resolution that allows us to zoom into the network dynamics and find more finely tuned results that can help in the development of neuromodulation therapies. I plan to use both single site and paired-pulse optogenetic inhibition to gain a clearer understanding of how functional connectivity behaves during and after repeated modulation periods followed by extended recordings of spontaneous activity with no modulation. By analyzing the pairwise coherence of the local field potentials collected using electrocorticographic recordings in non-human primates, I anticipate seeing targeted changes in functional connectivity when comparing before and after each inhibition session. By analyzing the rate of change in connectivity I plan to understand the timeline of neuroplasticity following optogenetic modulation, thus informing the development of future neuromodulation therapies. This research could have a profound impact on the future therapeutic paradigms for neurological and neuropsychiatric disorders that can accelerate recovery for individuals with these conditions.

Non-Human Primates (NHPs) have gained importance in neural engineering preclinical studies as their brains are relevant models to investigate and better understand neural function. The Yazdan lab uses optogenetics to control neuronal activity in order to develop stimulation-based therapies for neurological disorders such as stroke. These experiments require the implantation of various devices such as headposts, cranial chambers, electrode arrays, and optical windows. The use of head posts and cranial chambers requires customization to the curvature of the skull prior to implantation in order to prevent gaps that could introduce complications, including infection or decreased stability. Using an in-house method of NHP neurosurgery preparation that processes MRI data, we can develop 3D brain and skull models. This technique has allowed for chambers to be customized and implanted chronically in two NHPs. My project builds off of this implementation by creating custom chambers for future implantation surgeries and designing custom-fit headposts, which had never been done before. In order to design these components, I extracted the skull and brain using custom Matlab code which allowed for the craniotomy location to be determined and provided a footprint for the chamber and headpost implants. I then imported the skull extraction into a design software where the chambers and headposts could be built off of to ensure a tight fit to the skull. With the components designed, I will 3D print the brain, skull, chamber, and headpost to be assembled together. This platform will simulate the surgical and experimental setup, which provides a template for various experimental components to be modified and tested. It will provide a simple and affordable solution for neurosurgical planning, reducing in-surgery and in-experiment complications. This model's versatility, ease of use and low cost allow for further expansion to other labs and to a wider scope of surgeries.

Infection from Mycobacterium tuberculosis is the second leading infectious cause of death worldwide after COVID-19, with rates of tuberculosis infection greatest in low and middle-income countries (LMICs). Tuberculous meningitis (TBM) is one of the most severe forms of M. tuberculosis disease with over half of all cases resulting in death or neurological consequences. Recent studies in our lab have found that single-nucleotide polymorphisms (SNPs) in MUC5AC, a secretory lung mucin, are associated with increased TBM susceptibility, morbidity, and mortality. The purpose of my study is to identify the functional MUC5AC SNP. Four candidate SNPs were selected within the MUC5AC promoter region based on high linkage-disequilibrium scores across multiple global populations with a SNP in the MUC5AC promoter, rs28737416. I utilized molecular cloning techniques to combine a luciferase-expressing plasmid with isolated regions of the human MUC5AC promoter containing the SNPs of interest, and subsequently transformed this recombinant plasmid into competent cells. Next, I am performing in-vitro, site-directed mutagenesis to investigate how genotypic variation in each candidate SNP influences promoter function by measuring luciferase expression. I anticipate variants in at least one SNP of interest will reduce gene expression (measured by luciferase expression), indicating functionality. Characterization of this genetic mutation will provide insight into TBM susceptibility across populations and could inform studies of novel therapeutics to treat TBM.


Alveolar macrophages are vital immune cells, residing in the distal lung parenchyma. They provide the first line of defense against pathogens like mycobacterium tuberculosis (Mtb). They help initiate immune response within the lung and respond to viral infection. Mtb is the pathogen causes tuberculosis. This disease is fatal, and is the leading cause of death among infectious diseases globally. TOLLIP is a ubiquitin-binding protein that is involved in regulating innate immune responses by interacting with many receptors and the transport of endosomal cargo. Currently, TOLLIP’s role in TB pathogenesis is unknown, however, mice without the TOLLIP gene (Tollip-/-) have more severe Mtb disease. The goal of my project was to measure effects of adding mycolic acid and integrated stress response inhibitor (ISRIB) to macrophages of Tollip-/- and B6 Wild Type mice in vitro. I conducted the Bronchoalveolar Lavage (BAL) technique to extract macrophages from the lung via the trachea of B6 Wild Type and Tollip-/- mice. After macrophages were harvested, I plated them in mycolic acid and ISRIB in according wells with media. The cells were then infected with tuberculosis in the animal BSL-3, and data was collected through enzyme-linked immunosorbent assay technique and critically analyzed. Results illustrate that in both B6 Wild Type and Tollip-/- macrophages, adding ISRIB and mycolic acid results in an increase in production of the cytokine TNF, but Tollip-/- had a higher increase. Furthermore, the Tollip-/- samples had high variation in amount of TNF produced while Wild Type had minor amounts, raising further questions about how TOLLIP-deficient alveolar macrophages react when mycolic acid or ISRIB is added. Ultimately, the findings from this research, which is better understanding what specifically stimulates certain cytokines to help immune response to tuberculosis, is essential, and this is a small stepping stone in the broader goal of developing therapeutics for tuberculosis.