The seed awards advance research through new directions and collaborations, and boost potential for subsequent external funding. Below is a description of the brain science projects supported by this year's seed awards. 

An extracellular Prion-like protein is essential for fertilization

Prions are a type of protein domain that can trigger normal proteins to fold abnormally. Human proteins with domains that resemble yeast prions form protein aggregates that cause cell death in neurodegenerative diseases. Yet, these same domains are able to form dynamic liquid-like droplets that contribute to the formation of membraneless organelles including numerous cytoplasmic and nuclear compartments. We recently learned that Bindin from sperm of a sea urchin has two prion-like domains, is secreted, and is essential for fertilization. Extracellular prions are very unusual (and no extracellular eukaryotic prion-like proteins or prion-like phase separated assemblies have been described in detail). These prion-like domains have highly variable sequences between species, thought to be species-specific recognition elements. We will dissect the prion-like domains and test their role in sperm-egg interaction and species specificity by in vitro egg interaction. Three features make this work of high impact: 1) Is the prion-like domain essential for its function? We currently know only that the Bindin product is essential. 2) Does the prion-like domain confer species-specific sperm-egg recognition? Production of the prion-like domain and modifications thereof will be used to test egg interactions species specifically. 3) Does the prion-like domain self-assemble into extracellular liquids, gels, or aggregates – the spectrum of states seen for intracellular prion-like domains? This preliminary work will have high impact in several fields of biomedical research and clinical application, breaking new ground in the molecular mechanism of critical steps in fertilization and describing the unexplored atomic details of this extracellular assembly.

Principal Investigator: Gary Wessell, Professor of Biology

Co-Principal Investigator: Nicolas Fawzi, Associate Professor of Molecular Biology, Cell Biology and Biotechnology

Axon guidance through changes in growth cone membrane potential

In order to produce a functioning nervous system, neurons must form precise connections with each other during embryonic development. The guidance of growing axons to their correct targets is central to sculpting neuronal connectivity, and understanding this process is critical, as neuronal miswiring can cause neural circuit dysfunction and disease. Our project investigates if molecular cues instruct axon pathfinding by triggering changes in the axonal membrane potential. We propose to employ and improve our cutting-edge, genetically encoded voltage sensors to monitor the membrane potential of axons in response to various attractive and repulsive guidance cues, with the goal of identifying patterns of membrane de- or hyperpolarization that dictate the axonal response to attractants versus repellants. This will lay the foundation for a long-term plan to investigate the causal relationship between guidance cues, axonal membrane potential, and axon steering. Our work will uncover fundamental mechanisms of axon guidance and neural circuit assembly, which is essential for understanding disorders of brain wiring and developing therapeutic approaches for the restoration of damaged neuronal connections after physical injury or onset of neurodegenerative disease.

Principal Investigator: Alexander Jaworski, June G. Zimmerman Associate Professor of Brain Science

Co-Principal Investigator: Ahmed Abdelfattah, Robert J. and Nancy D. Carney University Assistant Professor of Brain Science

Development of Quantum Magnetic Tunneling Junction Sensor Arrays for Magnetoencephalography (MEG)

We aim to develop a revolutionary quantum magnetic gradiometer designed to non-invasively register femtoTesla (fT) scale magnetic fields from the human brain and examine its operating characteristics during simple voluntary movements and visual stimulation. The sensor, with its miniaturized size, will substantially exceed the spatial resolution of existing systems, operate at room temperature, will not require expensive magnetic shielding, can be used untethered, thus, in the field, and the expected system will have a far lower initial purchase price and lower maintenance costs than available magnetoencephalographic (MEG) systems. These features should expand the utility, accuracy, and accessibility of magnetic field recording technology for human neuroscience applications to advance our understanding of human brain function in health and disease.

Principal Investigator: Gang Xiao, Professor of Physics, Professor of Engineering

Co-Principal Investigator: Jerome Sanes, Professor of Neuroscience

Establishing a Drosophila model for opioid self-administration

The U.S. is in the midst of an opioid epidemic and overdose crisis, which has only been exacerbated by the COVID-19 pandemic. It is imperative that the health community have access to the most effective treatments to help solve this epidemic. However, effective treatment development requires a better understanding of the neurobiology of opioid use and dependency. The lasting physiological effects of opiates on reward memory circuits contribute to cravings for the drug and change the brain’s response to other drugs of abuse. Opiate drugs bind to opioid receptors (ORs) in the brain, hijacking a complex endogenous neuromodulatory system. In mammals, µ opioid receptors (µORs) are the key molecular targets for the biological effects of clinically useful and abused opioids. The sheer number and heterogeneity of neurons within reward circuits, combined with their elaborate connectivity, has prevented a deeper understanding of the identity of µOR expressing circuits. A small but sophisticated brain and impressive array of neurogenetic tools for in vivo analysis have proven the fruit fly, Drosophila melanogaster, to be an ideal model for discovery of novel mechanisms underlying the effects of drugs of abuse on the brain. Here we propose to establish Drosophila as an effective model to understand the neural and molecular mechanisms underlying the motivation to seek the high-potency synthetic opioid fentanyl. Our goal is to use a functional neurogenetic approach to identify the Drosophila µOR and map the neural circuits through which this receptor is eliciting fentanyl-induced behavioral responses.

Principal Investigator: Karla Kaun, Associate Professor of Neuroscience

Observational study of the safety, accuracy and usability of digital diagnosis apps in primary care and for TIA and stroke patients

Patients commonly search their symptoms and diseases online, and mobile phone apps for digital diagnosis (“Symptom Checkers”, SC) are used by >40 million US patients annually. However there is minimal evidence from real patient use in the community on accuracy of diagnosis or triage, patient safety, or usability. This research builds on collaborations between Brown Center for Biomedical Informatics, The Rhode Island Hospital (RIH) Emergency Department (ED) and Brown Medicine to research the role and potential impact of symptom checker (SC) apps used by patient seeking urgent primary care, and the performance of SCs and new algorithms for diagnosis of transient ischemic attacks (TIA) and stroke. AIM 1 will extend an evaluation of a leading SC from Ada Health, with use by 200 patients requesting urgent care appointments at Brown Medicine, including a usability questionnaire, prior to their appointment. Reviews of the symptom data and results from the App and the physician who sees the patient will allow comparison of diagnosis and triage. AIM 2 will analyze the accuracy of symptom checkers including Ada and develop new algorithms using 2 data sets of symptoms of patients presenting with TIA or stroke - high risk diseases with hard to recognize symptoms, requiring urgent treatment. Data sets include 1800 patients admitted with suspected TIA to the clinical observation unit, RIH, and 100,000 patient consults with Ada App, and possible stroke diagnosis. We will study diagnostic performance of multiple SCs and new algorithms including effects of age and gender, Quick patient recognition of stroke and prompt arrival in the ED should reduce the current high morbidity and mortality.

Principal Investigator: Hamish Fraser, Associate Professor of Medical Science

Safety, feasibility, and acceptability of MDMA-assisted therapy for the treatment of co-occurring posttraumatic stress disorder and alcohol use disorders in combat veterans

Co-occurring PTSD and alcohol use disorder (PTSD-AUD) is common following combat and associated with more severe symptomatology, increased suicidality, and poorer response to treatment than either disorder alone. Available PTSD-AUD treatments effectively treat only a fraction of people who engage in them for adequate dose and duration, leading to growing interest in alternative medications, including psychedelics. The combined neurobiological effects of MDMA increase compassion, reduce defenses and fear of emotional injury, and enhance communication and introspection, making MDMA-AT especially useful for treating PTSD-AUD. This pilot trial will be the first to assess feasibility and acceptability of MDMA-assisted psychotherapy (MDMA-AT) in veterans with combat-related PTSD and AUD (N=20) and will result in a new interdisciplinary collaboration at Brown. Participants will be recruited via social media and clinician referrals and will complete an initial screen and baseline appointment including informed consent. Eligible participants will receive MDMA-AT, including three Experimental Sessions with MDMA administration that will be conducted under established protocols. Follow-up data will be collected at post-treatment and at one-month. This project will allow us to: 1) assemble a research team including the training of two MDMA-AT clinicians, 2) determine the feasibility of recruitment, 3) determine the acceptability of and safety of MDMA-AT, 4) provide preliminary evidence of the effects of MDMA-AT, and 5) refine study procedures in preparation for a fully powered RCT to test the effectiveness of MDMA-AT for PTSD-AUD. This collaboration will help to position Brown at the forefront of psychedelic research for common and impairing mental health problems.

Principal Investigator: Carolina Hass-Koffler, Associate Professor of Behavioral and Social Sciences, Associate Professor of Psychiatry and Human Behavior

Co-Principal Investigator: Erica Eaton, Assistant Professor of Psychiatry and Human Behavior (Research), Assistant Professor of Behavioral and Social Sciences (Research)

Targeting purinergic receptors in synaptic glia to treat ALS

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disease that causes paralysis and death within 5 years of diagnosis. Although the disease has been clinically recognized for over 140 years, effective therapies for ALS have yet to be developed. Riluzole and Radicava (Edaravone), the only therapies approved for ALS, are minimally effective, only extending life by several months. A hallmark of ALS is early and progressive destruction of the neuromuscular junction (NMJ), the peripheral synapse that controls all skeletal muscles and thus voluntary movements. Development of treatments that target the NMJ have been hampered by the paucity of information about molecular mechanisms critical for NMJ maintenance and repair. To address this gap, our lab has focused on the molecular composition of synaptic glial cells of the NMJ, which have been largely overlooked. We have discovered that these cells express three purinergic receptors with well-characterized roles in synaptic maintenance in the central nervous system. In this work, we will test the hypothesis that modulating the activity of these purinergic receptors, using FDA-approved pharmacological agents, will mitigate NMJ degeneration in a mouse model of ALS. The preclinical data arising from this work may set the stage to target purinergic receptors to treat patients suffering with ALS.

Principal Investigator: Gregorio Valdez, GLF Translational Associate Professor of Molecular Biology, Cell Biology and Biochemistry