Overdose deaths in the United States have rapidly increased in the past few years accounting for over 107,000 deaths in 2022 with more than half being attributed to the co-usage of opioids and stimulants. Despite the prevalence of polysubstance use, research has predominantly focused on single substance use, leaving a gap in knowledge regarding its neurological effects. Addiction-associated behaviors such as drug-seeking, drug-taking, and relapse vulnerability has been attributed dysregulation of the striatum. We recently found that polysubstance exposure to methamphetamine and fentanyl leads to behavioral differences in methamphetamine-seeking but not fentanyl-seeking relative to single-substance rats, suggesting that polysubstance use causes distinct changes in striatal circuitry. Our overarching objective is to determine to what extent pursuit of methamphetamine and fentanyl involves shared neural pathways. How do distinct striatal neuron subpopulations responsive to either methamphetamine or fentanyl regulate drug-seeking in animals exposed to both substances? To investigate this, rats are placed into self-administration boxes and undergo two phases of daily intermittent access drug self-administration. In the first phase of self-administration, lasting 10 days, a novel targeted recombination in active population (TRAP) technology and recombinant viral vector is used to target inhibitory designer receptors exclusively activated by designer drugs (DREADDs) to striatal cells that are activated during fentanyl- or methamphetamine-seeking. For the second phase of the experiment, lasting 28 days, rats are then divided into groups for either self-administration of methamphetamine, fentanyl or a polysubstance model. Using chemogenetic manipulations in polysubstance rats, we will test the hypothesis that inhibition of the striatal neuron subpopulations active during fentanyl-seeking will decrease methamphetamine-seeking whereas inhibition of methamphetamine activated neurons will have no impact on fentanyl-seeking. These experiments will provide important insights and lay the groundwork for future studies into how striatal circuits regulate behavior during single and polysubstance use of opioids and stimulants.

Oceanic currents drive all the world’s major climatic, biological, pollutant and sediment transport patterns. Many complex forces interact to produce the intricate movements of the ocean’s waters. Tidal rectification, a phenomenon caused by the spinning reference frame of the Earth acting together with island geometry and friction, is one such process which dictates how water is circulated around islands, seamounts, and other bathymetric shapes when tidal oscillations are present. Tidal rectification has been described mathematically and compared with physical measurements for many islands, but these islands fall into a few distinct categories. Many are either large and restricted to central latitudes, or small in diameter and found in far northern latitudes. Non-Island formations, such as guyots, and smaller bathymetric features in more central latitudes are not rigorously characterized through the lens of tidal rectification. This study expands the practical characterization of tidal rectification by comparing current speed data around a guyot near Namonuito Atoll, south of Guam, to a theoretical scaling of the potential forces acting on the guyot. I hypothesized that friction-based circulation would dominate over Coriolis-based circulation due to the guyot’s low latitude. Current velocity data was collected along a circular transect around the guyot by the R/V Thomas G. Thompson in December 2024. Preliminary findings, based on a scale analysis, suggest that these two cases are difficult to distinguish. Further research is needed to derive the nature of rectified circulation for small low-latitude islands. A rigorous practical analysis of the effects of tidally-rectified circulation is critical for a deeper understanding of biological processes, sediment transport, and pollutant concentrations around island communities.

Despite widespread drug abuse, treatment options for people in recovery are oftentimes ineffective, as current research fails to cover the full range of the ways in which opioid, stimulant, or other substance contribute to substance use disorders. The goal of our study is to model how polysubstance use disorders operate in the human brain utilizing a translational rat model of addiction. 64 rats were assigned into single or polysubstance cohorts. Each rat was implanted with a jugular catheter, allowing a controlled dose of methamphetamine or fentanyl to be self-administered through a lever press, along with a drug-associated cue light. The cohorts completed a 3 week period of self-administration, followed by extinction, modeling withdrawal and abstinence. After extinction, the animals went through cue-induced reinstatement, a model of relapse. No drugs are dispensed when the lever is pressed, however the light cue continues to be used as a stimulus signal. Within a large dataset following this model, we are looking to uncover patterns related to differences in drug-taking and reinstatement behavior between the different cohorts. Correlations between the rats’ sex, polysubstance use, and other measurements of their behaviors offers a crucial lens of the more nuanced ways in which methamphetamine and fentanyl influence addiction-related behaviors. Methamphetamine and fentanyl function through distinct neural circuits, thus affecting behavior in individual and synergistic manners. To complement the current work, future studies will investigate the neurocircuitry underlying polysubstance use disorders utilizing whole brain imaging. Gaining clarity into how the nervous system responds to the interaction of both drugs present would mean the ability to develop targeted treatments options. Assuming there’s one treatment that works to treat all polysubstance addictions minimizes individual experiences and ignores the reality that we need to better understand the neurobehavioral aspects of addiction so people can get accurate and effective help.

The opioid crisis is an escalating public health emergency, with fentanyl posing major challenges due to its potency and addictive properties. Current treatments address withdrawal but fail to target persistent cravings and relapse triggers. Under Dr. Susan Ferguson and Dr. Alex Whitebirch, I investigate the neural mechanisms underlying fentanyl addiction using rodent models. This research focuses on dopamine (DA) dynamics within the prefrontal cortex (PFC), a key brain region implicated in addiction. Our approach employs the conditioned place preference (CPP) paradigm, a behavioral test that measures a rodent's preference for a drug-paired environment. DA activity in the PFC is monitored in real-time during CPP via fiber photometry of the GRABDA2m fluorescent DA sensor, expressed in glutamatergic neurons through an intersectional virus strategy. We aim to determine whether the development of fentanyl CPP is accompanied by altered DA signaling in the PFC. DA input to the PFC originates from neurons in the VTA, while pyramidal tract (PT) neurons in the PFC project to the VTA and are implicated in suppressing drug-seeking behaviors. To investigate how PT neurons regulate DA signaling, we use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to selectively inhibit them. Investigating the behavioral and neurochemical consequences of PT inhibition will provide insight into whether this pathway enhances or suppresses dopamine release. We hypothesize that our conditioning paradigm will lead to enhanced PFC DA signals associated with entry into a fentanyl-paired environment, and that PT neuron inhibition will further enhance DA signals and fentanyl-associated place preference. My role in this research includes surgical procedures, photometry and chemogenetic experiments, data analysis, and histological processing. By advancing our understanding of fentanyl’s impact on dopamine pathways and the role of the PFC, this project aims to inform the development of more effective therapeutic interventions for opioid use disorder and relapse prevention.

People experiencing homelessness are disproportionately affected by alcohol-related morbidity and mortality, with a 7 times higher prevalence of alcohol use disorder (AUD) than the general population. Past research shows that in-person harm reduction treatment for alcohol (HaRT-A) within Housing First facilities is preferred because it focuses on client-centered goals and improving quality of life. This study is a pilot study which is part of an ongoing project adapting HaRT-A into a digital platform (eHaRT-A), to assess the feasibility, usability & acceptability of the electronic harm reduction treatment for alcohol (eHaRT-A). Participants were recruited from low-barrier, permanent supportive housing.  Residents (N = 34) were interested in participating in the study. Participants (n=19), who were interested and eligible, first completed a 45-minute assessment questionnaire asking them about their substance use, quality of life, and pain. Then, they completed one eHaRT-A session, followed by a feedback interview. Recruitment and completion rates were used to assess eHaRT-A feasibility (i.e., percentage screened who expressed interest, qualified, and completed eHaRT-A). My teammates and I utilized self-report measures, including the Acceptability of Intervention Measure (AIM) and the System Usability Scale (SUS) to evaluate participants’ perceptions of eHaRT-A. A priori thresholds for high acceptability (AIM≥3/5) and usability (SUS≥ 70/100) were established. Among those eligible, 86.4% completed the full study, demonstrating high feasibility. The data we analyzed showed a mean AIM score of 4.45 and a mean SUS score of 81.2, indicating strong acceptability and usability.  eHaRT-A’s feasibility, acceptability, and usability, demonstrate its potential as a scalable, harm reduction intervention. These findings support the integration of telehealth interventions into supportive house programs, offering a promising approach to addressing health disparities and improving access to care for this vulnerable population.

Obesity in youth populations is an increasingly prevalent issue in the U.S., affecting 14.7 million children between ages 2-19. Evidence shows that poor diet quality directly contributes to inflammation in body-weight regulating areas of the brain, which predates the occurrence of obesity. Controlled-feeding studies can improve diet quality and assess health outcomes in children with overweight or obesity but require thoughtful execution and strict participant adherence to the study-prescribed diet. This project will assess the feasibility of a short-term controlled feeding study using two measures: acceptability from children of a high-quality diet menu and caregiver opinion on their child’s participation in a controlled feeding study. In collaboration with the Fred Hutch Nutrition Kitchen, I created a high-quality diet menu to meet study goals including: standard nutritional principles of USDA guidelines, whole foods, and low-fat, as well as age-appropriate and easy to prepare. Furthermore, I developed a child-appropriate taste-test questionnaire using a 5-point Likert scale and contributed to an interview guide in order to capture the qualitative and quantitative data from parents. These tools will be applied in a study of 7-10 families with healthy children aged 9-11. Families will attend a focus group where child caregivers will undergo the structured interview and children will taste-test the menu items. Quantitative survey data from the taste-test will assess menu acceptability to help ensure participant adherence to a study-provided diet. Qualitative data themes from adult caregivers will assess feasibility of child participation in a controlled feeding study by illuminating social and logistical concerns of parents. Understanding child acceptability of a high-quality diet menu and the perceived feasibility of study participation from families will inform the most optimal design of our planned controlled-feeding study in children to test if high-quality diet can acutely reduce inflammation in body-weight regulating areas of the brain.

Substance use disorders are a devastating global issue and using multiple substances simultaneously has become common among drug users. Polysubstance use has been linked with higher rates of mortality, overdose, and relapse when compared to single substance use. There is currently little research on how using multiple substances simultaneously affects behavior and motivation to take drugs. Our goal is to better understand the motivations of drug seeking and consumption in rats with a history of polysubstance use compared to rats with a history of single substance use. Rats (n=18 male,18 female) were implanted with jugular catheters and trained to press a lever for an infusion of either 0.0015 mg/kg/infusion of fentanyl (fentanyl-only: FENT) or 0.1mg/kg/infusion of methamphetamine (methamphetamine-only: METH), or both (polysubstance: POLY). The rats then underwent a behavioral economics threshold test, in which the concentrations of fentanyl and methamphetamine were decreased over ten days in an attempt to determine the level of effort and motivation for the drug at each dose. The FENT and METH rats only underwent the behavior economics test for one drug and POLY rats were randomly assigned to either fentanyl or methamphetamine. Our preliminary results suggest that polysubstance use increases the motivation for consuming fentanyl but not methamphetamine; however, sample sizes are small right now and further analysis is needed. In future experiments, we will image the brains of these rats using light sheet microscopy to map the neurocircuit activation that may point to differences between polysubstance and single substance use. Understanding the differences between polysubstance and single-substance use is imperative for designing effective treatment plans that address the motivations behind drug use.

The opioid epidemic remains a critical public health crisis, with opioid use disorder (OUD) affecting millions worldwide. Research indicates significant sex differences in addiction patterns, with women exhibiting faster addiction progression, heightened cravings, and increased relapse rates compared to men. However, the biological mechanisms underlying these differences remain poorly understood. This study aims to investigate how chronic heroin use and withdrawal impact gonadal hormone levels in male and female rats, shedding light onto the role of opioid addiction on hormonal regulation. Using a 20-day heroin treatment followed by a 20-day withdrawal period, we examined changes in locomotor response, fluctuations in key gonadal hormones (testosterone, estradiol, and progesterone), and differences in brain activity patterns. Our preliminary data  suggest that females more consistently develop sensitization to heroin and also do so at an earlier time point compared to males. Our ongoing research is working to quantify serum hormone levels across heroin treatment, as well as developing a way to measure neural estradiol activity in real-time during sensitization. Future work will focus on the long-term effects of hormonal disruptions on brain signaling pathways and opioid receptor regulation, with the ultimate goal of informing sex-specific therapeutic interventions for individuals struggling with opioid addiction. Understanding these hormonal changes is crucial for developing more effective, personalized treatment strategies for OUD. By furthering the research on opioid addiction and endocrine function, this research highlights the need to consider sex as a biological variable in addiction studies.

HCoV-OC43 is a member of the viral family Coronaviridae, commonly known as coronavirus, and is known to cause respiratory infections in humans. HCoV-OC43 is therefore categorized as a human coronavirus, which includes the virus SARS-CoV-2, known to cause COVID-19. Previous studies showed that human coronavirus infections, specifically HCoV-OC43 and SARS-CoV-2, activate the IRE1α component of the unfolded protein response, leading to a splicing of XBP1 mRNA, which then encodes for a transcription factor. Additionally, the IRE1α and XBP1 host factors were found to be necessary for ideal viral replication. However, the specific genes upregulated by XBP1 that contribute to viral replication remain unknown. Given data suggesting XBP1 regulates genes involved in lipid metabolism, our research aims to explore whether Acetyl-CoA Carboxylase (ACC), an enzyme involved in fatty acid synthesis, is upregulated by IRE1α and involved in human coronavirus replication. We used quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure relative gene expression of ACC after HCoV-OC43 infection, and in the presence of the IRE1α inhibitor, 4μ8c. We found that activation of IRE1α during HCoV-OC43 infection caused increased expression of the gene encoding ACC, which was blocked by 4μ8c. We then tested the hypothesis that ACC supports viral infection using small molecule inhibitors and found that viral RNA was decreased after inhibition of ACC. Next, we bypassed ACC by adding the downstream product, palmitate, and found restoration of viral RNA. Our results indicate that IRE1α induced splicing of XBP1 mRNA increases ACC transcription, which then promotes optimal viral replication. A greater understanding of the mechanisms behind human coronavirus replication allows for the development of potential therapies targeting these viruses. In our continuation of this research, we plan to expand our knowledge of human coronaviruses by investigating the role of IREα and ACC expression in SARS-CoV-2 infections. 

As incidences of opioid use disorder (OUD) have surged to an astonishing 2.5 million individuals, trends of concurrent opioid and psychostimulant use have also risen to a dire degree. Despite this growing number of polysubstance related overdose deaths, current research has primarily focused on the effects of single-substance drug exposure–creating a knowledge gap in our understanding of polysubstance use and corresponding treatment modalities. Thus, we aimed to investigate the differential effects of fentanyl and methamphetamine (METH) polysubstance exposure compared to single substance exposure on drug-induced hyperlocomotion and social interaction in male and female Sprague Dawley rats (n=40). We initially hypothesized that polysubstance exposure to fentanyl and METH would generate distinct behavioral effects on locomotor behavior compared to single-substance exposed animals. We found that in polysubstance and METH-only rats, METH-induced locomotion increased over time in males, but not in females. Additionally, we observed that polysubstance exposure exacerbated fentanyl-induced locomotion in males compared to their fentanyl-only counterparts. We further hypothesized that polysubstance exposure would amplify drug-induced social deficits compared to METH-only and fentanyl-only groups. Seeing how recent literature suggests that psychedelic drugs may have substantial therapeutic and prosocial effects, we also hypothesized that the psychedelic compound R-(-)2,5-dimethoxy-4-iodoamphetamine (DOI) would reverse social deficits observed in both single and polysubstance exposure. We found that social deficits emerged in our polysubstance males and females. We additionally observed a social deficit in our METH-only treated females, but not males. We are currently investigating if the effects of DOI may reverse these deficits. Considering these sex-specific findings, it is crucial that we continue investigating the diverging impacts between males and females to develop targeted therapeutic interventions for polysubstance use.

Globally, men who have sex with men (MSM) are at disproportionate risk of contracting STIs like HIV, particularly in sub-Saharan Africa (sSA). This epidemic is further compounded due to the sexual stigma and heteronormative culture present in countries like Kenya, where male-male sex remains illegal. MSM must maintain discretion surrounding their sexual behaviors, commonly preventing them from accessing sexual health services and disclosing their sexual orientation and activity. Consequently, female partners of men who have sex with both men and women (MSMW) may be at greater risk of STI transmission not only due to physiological causes but also because of social factors, such as being unaware of the same-sex sexual activity that their partners engage in. Kenya is a resource-limited area where preventative STI screening is prohibitively expensive and inaccessible, and the standard of care is syndromic treatment – individuals only seek medical care if they experience STI symptoms, yet over 80% of STIs are untreated due to individuals being asymptomatic. Despite the significance of this issue, few studies have attempted to distinguish the psychosocial characteristics and sexual behaviors of MSMW from those of men who have sex with men exclusively (MSME). This baseline analysis of the Tatu Pamoja Study explores differences in risk factors for STI transmission between MSMW and MSME in Kenya. We hypothesize that, compared to MSME, MSMW will exhibit a higher prevalence of poor mental health and partnership-level sexual risk behaviors, including one-time partners, condomless anal sex, and group sex – all characteristics associated with STI transmission. The findings of this study aim to identify MSMW as a subpopulation of MSM at particularly high risk of STI transmission who may benefit from being offered further preventative interventions – such as doxyPEP and routine STI testing – to prevent onward transmission and reduce the incidence of STIs in sSA.

Heroin, a commonly used opioid, has played a significant role in the escalating opioid crisis, highlighting the urgent need to better understand the neural mechanisms underlying its addictive properties. Despite well-documented sex differences in opioid use disorder (OUD), the majority of preclinical research has been conducted in male animal models, limiting our understanding of how biological sex influences addiction-related behaviors. This study investigates the role of sex differences in heroin-induced locomotor sensitization and hormonal adaptations in a rodent model. Using a rodent model, we administered intravenous heroin and tracked activity to assess sensitization to the effects of heroin on locomotion. Following treatment, the rats underwent 20 days of withdrawal from heroin. Blood samples were collected throughout treatment and withdrawal to track changes in serum hormone levels. Our findings indicate that female rats show locomotor sensitization at an earlier time point and exhibit a greater degree of escalation compared to males. This suggests potential sex-specific mechanisms influencing opioid addiction vulnerability and progression. We aim to continue quantifying gonadal hormone fluctuations throughout heroin exposure and withdrawal with additional cohorts of animals. Future experiments aim to use fiber photometry to image estradiol activity in the brain during sensitization, providing a real-time insight into its role in opioid-induced changes in behaviors.