ABSTRACT Substance use disorder is a chronic relapsing disease that is characterized by repeated drug use despite negative consequences. Despite extensive efforts into examining the underlying molecular mechanisms of methamphetamine use disorder, there are currently no FDA approved therapeutics to treat this debilitating disease.
Project Summary/Abstract Traumatic brain injury (TBI) is a leading health concern for both children and adults worldwide. Similarities between pig and human brain anatomy, development, and neuroinflammatory response have brought attention to the domestic pig as a highly promising model animal for studying age-specific responses to mechanical trauma. To date, I have quantified baseline behavioral data in healthy Yucatan minipigs.
1 PROJECT SUMMARY 2 Alzheimer's disease (AD) is the most common form of dementia worldwide, incurring a projected healthcare 3 burden of $1 trillion in the United States alone by 2060. It is the 7th leading cause of mortality in the United States 4 and it disproportionately impacts minoritized racial and ethnic groups. Although many pharmacologic 5 therapeutics have been tested to slow or remove the hallmark amyloid and tau aggregates, none have proved 6 effective at reversing AD cognitive decline.
PROJECT SUMMARY Efforts to understand the mechanisms of brain-based disease have been hindered by the limited ability of animal models to reflect the full complexity of human brain and behavior. Brain organoids represent a potential solution, allowing scientists to model human neurodevelopmental and disease processes in-vitro. These multicellular, three-dimensional tissue structures are derived from induced pluripotent stem cells and self-organize to recapitulate aspects of human cortical development.
Project Summary Towards the end of nervous system development, neural circuits are extremely plastic. Small perturbations during this time can cause lifelong circuit and behavioral changes. Not surprisingly, mounting evidence suggests that several neurodevelopmental disorders, including autism spectrum disorder and epilepsy, have origins in defective late neural circuit formation. During this late stage, neural circuits refinement takes place, and components of the mature behavior gradually appear. As this occurs, stimulus-independent bursts of activity sweep through neuronal populations.
PROJECT SUMMARY/ABSTRACT How the brain generates the correct number of neurons and how these neurons determine the size of their arbors to innervate the receptor field is a critical question in neurobiology. The Drosophila visual system is hard wired and iteratively organized into columns, providing an excellent model to answer these questions. Drosophila medulla multicolumnar neurons exhibit 5 to 750 neurons per cell type; each neuron class possesses a distinct morphology and projects its arbors across multiple columns in the optic lobe.
Project Summary There is currently an unmet need for accurate model systems of the human brain to study its cellular and molecular features. The cerebral cortex regulates our cognitive capacity, yet the cellular diversity, circuit formation, and function that establish this potential, largely remains a mystery. The cortex is expanded in humans compared to other species; it contains more cellular diversity and abundance, making model organisms limited for translational studies.
PROJECT SUMMARY A key problem in neuroscience is understanding how internal and external information are integrated in the brain to produce sensory experiences, cognition, and behavioral responses. This integration relies on flexible modulation of sensory processing in response to behavioral states like motivation, attention, and arousal. Neurons in the basal forebrain are key mediators of these behavioral states. At the same time, basal forebrain neurodegeneration in Alzheimer’s and Parkinson’s disease is associated with deficits in both cognitive and sensory processing.
Project Summary High-throughput profiling of hundreds of thousands of cells in the central nervous system (CNS) is currently underway.
Project Summary This application describes a 5-year plan to investigate the neural dynamics that underpin distortion in memory, integrating computational modeling approaches with functional neuroimaging (fMRI) and non-invasive brain stimulation techniques (TMS). The candidate, a cognitive neuroscientist with a background in memory consolidation and experience in fMRI and TMS methods, seeks new training in computational modeling and model-based fMRI analysis under the mentorship of Dr. Anna Schapiro and Dr. Sharon Thompson-Schill.
