Research Projects

CNDD research projects will study the genetic, molecular, cellular, and brain circuit mechanisms underlying risk and pathology of brain development disorders. By promoting excellence in basic and translational NDD-related research for both established investigators and early stage investigators, the CNDD will advance research capacity through the following key goals: 1) provide high-impact mentorship and training, 2) enhance relevant research infrastructure, and 3) support an interdisciplinary, collaborative research environment that brings together basic, translational, and clinical researchers at MUSC and across SC to improve the health and well-being of affected individuals. The CNDD will support 4-5 research projects developed by talented Research Project Leaders (RPLs) studying different aspects of neurodevelopment. The following research projects were selected based on CNDD thematic relevance, publication and grant track-record, and potential for successful transition to independence.

Research Project 2: Brent Wilkerson, Ph.D.

His current research focuses on inner ear development and hearing loss. His CNDD project will explore the role of hearing impairments in autism-like behaviors in mice. His JI Project will utilize the CNDD cores, and he will serve as an Associate Director of the GBC to develop his core leadership skills. His primary co-mentors are Dr. Hainan Lang of the MUSC Department of Pathology and Lab Medicine, an expert in cochlear development and hearing function, and Dr. Judy Dubno, a hearing expert and Vice-Chair for Research for Otolaryngology–Head & Neck Surgery at MUSC. Dr. Brad Walters of U of Mississippi Department of Otolaryngology–Head & Neck Surgery will serve as his external mentor. Specific contribution to CNDD: There is a growing appreciation that NDD risk genes can produce symptoms through functions within the peripheral sensory systems, and changes in sound perception are commonly observed in ASD and related disorders. Dr. Wilkerson’s studies of inner ear development and function are important contributions to the overall scope of modern NDD research.

Research Project 3: Onder Albayram, Ph.D.

Dr. Albayram's project explores the role of the neuroimmune complement system in the disruption of neurotypical development produced by neonatal brain injury. His project provides molecular mechanistic insights and candidate therapeutic evaluation, which could lead to future treatments. His project will utilize the CNDD cores. Dr. Steve Tomlinson will serve as his primary mentor. His external mentor is Dr. Rebekah Mannix from Harvard Medical School and Boston Children’s Hospital (see LOS). Specific contribution to CNDD: Dr. Albayram will provide the CNDD with an important translational research perspective and advanced knowledge of neuroimmune biology. His research interests align well with Drs. Cowan, Tomlinson, Lang, Kautz, and several others, and his molecular mechanistic and therapeutic approaches add an important aspect to the CNDD group that will increase overall competitiveness for future program project grants. Finally, his extensive experience with mouse behavior makes him an ideal Associate Director of the MBPC.

Research Project 4: Stefano Berto, Ph.D.

Dr. Berto has over 10 years of experience in bioinformatic and computational methods applied to next generation sequencings, and his proposed independent research will span human and animal models. His innovative CNDD project expands upon an exciting discovery that the ASD and ID risk gene, IL1RAPL2, expression in temporal lobe co-vary with cortical oscillations associated with memory functions in human. He will examine the novel functions of IL1RAPL2 in both a human iPSC-based model and in mutant mice to understand whether IL1RAPL2 affect behaviors and cortical neuronal circuits associated with both ASD and memory. His project utilizes the CNDD Cores, and he will leverage the extensive electrophysiology and circuit analysis experience of his primary mentor, Dr. Lori McMahon. His external mentor is Dr. Genevieve Konopka from UT Southwestern. Specific contribution to CNDD: Dr. Berto provides a critical expertise in modern genomics analyses, and as such, is an ideal Associate Director of the GBC. He seeks to leverage the CNDD resources to create a truly multidisciplinary research program, and his work aligns well with Drs. Cowan, Ewoud Schmidt, and many others, and his focus on human iPSC-derived neurons provide an important expansion of the scope of research at MUSC.

Research Project 5: Estefania Azevedo, Ph.D.

Neurodevelopmental disorders (NDD) affect the development of the nervous system, leading to abnormal brain function which may affect emotion and self-control. Obesity is an important co-morbidity of NDDs and is thought to arise from the impairment of important feeding-relevant circuits. Early life stress (ELS) can remodel feeding relevant circuits and contribute to obesity, yet the underlying mechanisms driving these changes are unknown. The current project aims to provide a link between early life stress and obesity. Our preliminary data show that in adult rodents, chemogenetic inhibition of neurotensin-expressing neurons in the lateral septum (LSNTS) increase standard chow intake. When exposed to HFD, silencing of LSNTS neurons increase HFD intake and accelerate obesity. Interestingly, LSNTS neurons respond to stressful but also to rewarding stimuli (i.e. HFD) and are key to the brain circuitry regulating feeding behavior. Additionally, ELS has been shown to alter neuronal activity in the LS and affect motivated behaviors, such as social interaction. We will extend these preliminary data to test the hypothesis that ELS reprograms LSNTS neurons activity downregulating important molecular pathways, ultimately impacting feeding behavior. The project will benefit from the CNDD cores for behavioral assays, in vivo imaging, bioinformatics approaches, and advanced biostatistical consulting. Specific contribution to CNDD: Dr. Azevedo provides critical expertise to CNDD as an expert in animal behavior, viral tools for circuits neuroscience, feeding and obesity. Her research interests align well with other CNDD members such as Dr. Cowan, Berto and Sato and contributes to the understanding of mechanisms by which environmental factors during development (i.e. stress) affect brain circuits and adult behavior.

Research Project 6: Jose Ledo, Ph.D.

Dr. Ledo's research proposal explores the role of microglial cells in neurodevelopmental and neuropsychiatric disorders, particularly focusing on habituation deficits induced by maternal immune activation (MIA). Novelty habituation, a fundamental form of behavioral plasticity where the response to a repeated stimulus diminishes over time, is often disrupted in conditions like autism spectrum disorders (ASD). The underlying brain circuits and cellular mechanisms responsible for these deficits remain poorly understood, posing a significant barrier to developing effective therapeutic interventions. Our study hypothesizes that MIA, a model for prenatal infection, shifts microglial cells from a homeostatic to a reactive state, impairing their ability to regulate neuronal activity and thus disrupting habituation processes, via loss of GABA-receptive microglia, which play a critical role in maintaining proper neuronal function. To test this hypothesis, our research will employ cutting-edge techniques such as in vivo fiber photometry to monitor neuronal activity in freely behaving mice and 10x multiome which is a high-throughput single-cell method that aims to capture the transcriptome and chromatin accessibility profiles of individual cells. The proposal is structured around specific aims to define the effect of MIA on habituation via microglial cells and, to profile the molecular alterations in microglia and neurons in the hippocampus induced by MIA. Our study will also explore the effects of deleting and repopulating microglia to determine their role in habituation deficits, specifically focusing on the potential loss of GABA-receptive microglia as a critical mechanism. The expected outcomes include identifying the neuroimmune mechanisms that drive habituation deficits, which could reveal novel therapeutic targets for ASD and other related disorders. By linking MIA-induced changes in microglia, including the loss of GABA-receptive microglia, to specific behavioral outcomes, the research aims to provide a deeper understanding of how immune challenges during development can lead to long-term neuropsychiatric conditions.

Relevance:
Autism Spectrum Disorder (ASD) has been reported to affect as many as 1 in 36 children in the US. Deficits in learning and novelty processing are an important hallmark of ASD. However, the brain mechanisms driving these deficits in ASD are unknown. Using mouse intersectional genetics combined with state-of-the-art neuroimaging and molecular approaches, our study will help uncover neuroimmune mechanisms underlying learning and habituation deficits in ASD, which might reveal new therapeutic avenues for treating ASD.