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Description
The process of brain development is magnificently complex, requiring the coordination of millions of cells and thousands of genes across space and time. It is therefore unsurprising that brain development is frequently disrupted. Numerous genetic mutations underlying altered neurodevelopment have been identified and aligned with behavioral changes. However, the cellular mechanisms linking genetics with behavior are incompletely understood. The goal of my research is to understand how intracellular kinase signaling contributes to the development of ventrally derived glia and neurons. Of particular interest are GABAergic interneurons in the cerebral cortex, as GABAergic disruption is observed in multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism spectrum disorders. In addition, I investigated how kinase signaling influences the number and distribution of ventral born oligodendrocyte lineage cells to gain insight into white matter abnormalities observed in developmental disorders. This work primarily investigates the mitogen associated protein kinase (MAPK) signaling cascade, which is ubiquitously expressed but is particularly important for brain development. Hyperactive MAPK signaling causes RASopathies, a group of neurodevelopmental disorders where affected individuals often exhibit learning disability. MAPK haploinsufficiency, such as in 16p11.2 deletion syndrome, also results in intellectual disability. In both cases, the cells driving cognitive dysfunction are unknown. Using genetically modified mouse models, I found that hyperactivation of MAPK signaling disrupts a subtype of GABAergic neurons that express parvalbumin, though the same cells are resilient to MAPK deletion. In contrast, somatostatin expressing neurons require MAPK for normal development but are less responsive to hyperactivation. Oligodendrocyte lineage cells have a bidirectional response to MAPK signaling, where hyperactivating MAPK increases cell number and deletion reduces glial number.
MAPK signaling activates several hundred downstream cues, but one of particular interest to this work is called Liver Kinase B1 (LKB1). LKB1 is a protein kinase which can regulate cell proliferation, survival, and metabolism. Here, I discovered that LKB1 is necessary for the development of parvalbumin expressing neurons. Collectively, these data identify disruption to certain ventral derivatives as a candidate pathogenic mechanism in neurodevelopmental conditions.
ContributorsKnowles, Sara Jane (Author) / Newbern, Jason (Thesis advisor) / Sattler, Rita (Committee member) / Balmer, Timothy (Committee member) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2023
Description
Traumatic brain injury (TBI)—sudden impact or acceleration trauma to the head—is a major cause of death and disability worldwide and is particularly amplified in pediatric cases. TBI is the leading cause of mortality and morbidity in children and adolescents. Adolescence is a critical time where the brain undergoes cognitive development and brain injury-induced disruptions to these processes can lead to life-long debilitating morbidities. The aim of this study was to determine if exercising spatial and contextual memory circuits using a novel rehabilitation strategy called Peg Forest Rehabilitation (PFR) could mitigate the onset of injury-induced cognitive deficits in juvenile rats subjected to diffuse TBI. The PFR aims to synthesize neuroplasticity-based enrichment to improve cognitive outcomes after TBI. We hypothesized that PFR treatment would mitigate the onset of brain injury-induced cognitive deficits and reduce neuroinflammation. Juvenile male Sprague-Dawley rats (post-natal day 35) were subjected to diffuse traumatic brain injury via midline fluid percussion injury or a control surgery. One-week post-injury, rats were exposed to PFR or cage control exploration (15 min/day). PFR allowed free navigation through random configuration of the peg-filled arena for 10 days over 2 weeks. Control rats remained in home cages in the center of the arena with the peg-board removed for 15 min/day/10 days. One-week post-rehabilitation (one-month post-injury), cognitive performance was assessed for short-term (novel object recognition; NOR), long-term (novel location recognition; NLR), and working (temporal order recognition; TOR) memory performance, calculated as a discrimination index between novel and familiar objects. Tissue was collected for immunohistochemistry and stained for ionized calcium binding proteins (Iba-1) to visualize microglia morphology, and somatostatin. PFR attenuated TBI-induced deficits on the NOR task, where the TBI-PFR treatment group spent significantly more time with the novel object compared with the familiar (*p=0.0046). Regardless of rehabilitation, brain-injured rats had hyper-ramified microglia in the hypothalamus indicated by longer branch lengths and more endpoints per cell compared with uninjured shams. Analysis of somatostatin data is ongoing. In this study, passive, intermittent PFR that involved dynamic, novel spatial navigation, prevented TBI-induced cognitive impairment in adolescent rats. Spatial navigation training may have clinical efficacy and should be further investigated.
ContributorsAftab, Umar (Author) / Rowe, Rachel K. (Thesis director) / Newbern, Jason M. (Thesis director) / Ortiz, J. Bryce (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05