Date Available
10-1-2025
Year of Publication
2024
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Physiology
First Advisor
Dr. Kathryn E. Saatman
Abstract
Moderate contusive traumatic brain injury (TBI) results in neuronal cell death in the cortex as well as cell death and damage in underlying structures, including the hippocampus. The hippocampus is critically involved in learning and memory and is one of two regions in the brain capable of undergoing neurogenesis throughout adulthood. Adult hippocampal neurogenesis is a complex sequence of events necessary for a neural progenitor cell (NPC) to differentiate into a mature granule cell neuron located in the granule cell layer of the dentate gyrus. TBI results in a preferential loss of immature neurons in the granule cell layer of the dentate gyrus within the first few days after injury. Accompanying this cell loss of immature neurons is the activation of quiescent neural stem cells and increased generation of proliferating NPCs. NPCs born after TBI contribute to the recovery of immature neuron population over 1 – 2 weeks postinjury. However, it is unclear if posttrauma-born neurons undergo normal development, survive long-term, and functionally integrate into an injured brain. Even less is known about posttrauma-born neuron axonal projections and synaptic connections to the CA3 region of the hippocampus. Additionally, while a subset of neuroblasts and immature neurons survive a TBI, the effects of TBI on the maturation and dendritic and axonal development of these preinjury-born neurons is not well understood.
Sex differences exist in regulating adult hippocampal neurogenesis in an uninjured brain; however, the potential for sex differences in posttraumatic hippocampal neurogenesis has largely been overlooked. To address these gaps in knowledge, male and female Ascl1-CreERT2; R26R CG-floxStopTom reporter mice were used to label NPCs born either before or after injury to evaluate sex-dependent neurogenic responses to TBI. To label NPCs before injury, mice received tamoxifen injections 7 and 6 days before receiving a controlled cortical impact (CCI). Injured mice survived 3 days or 28 days post-injury. Naïve controls were time matched relative to the tamoxifen injections. To label NPCs born after the injury, mice received a CCI followed by tamoxifen injections 2 and 3 days postinjury. Injured and naïve mice survived 42 days after tamoxifen injections.
Age-matched male and female naïve mice demonstrated no sex differences in the number of granule cell neurons, dendritic arbor morphology, or in the number or surface volume of presynaptic mossy fiber boutons in the CA3 region of the hippocampus. TBI resulted in decreased posttraumatic hippocampal neurogenesis with notable sex differences. As compared to females, males demonstrated a greater deficit in posttraumatic neurogenesis in the hippocampus ipsilateral to the impact. Only females exhibited increased posttraumatic neurogenesis in the hippocampus contralateral to impact. Posttrauma-born neurons were able to project axons to the hippocampal CA3 region but in male mice they developed with significantly impaired dendrite arborization. Further, posttrauma-born neurons showed a reduction in numbers of mossy fiber boutons while those in females had increased mossy fiber bouton surface volume compared to naïve controls. Preinjury-born NPCs that survived TBI matured into granule cell neurons, although a greater subset of NPCs adopted a glial fate in brain-injured mice compared to naïve controls. Preinjury-born NPCs in both sexes developed with significantly reduced dendritic complexity after a TBI. Preinjury-born neurons also displayed increased migration to the outer two-thirds of the granule cell layer that was not observed with posttrauma-born neurons. These data suggest that TBI impairs hippocampal neurogenesis, with preinjury-born NPCs demonstrating significant developmental impairment and posttrauma-born neurons showing decreased survival and sexually dimorphic morphological development and adaptations.
In conclusion, sex differences exist in posttraumatic neurogenesis that have important implications for hippocampal function and connectivity after TBI. Additionally, preinjury-born NPCs have greater contributions to hippocampal network alterations after TBI with increased dendrite impairment, outward migration, and NPCs adopting glial fates within the dentate gyrus.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.403
Funding Information
National Institutes of Health Graduate Training in Integrative Physiology (1T32GM118292-04) 2019-2020
National Institutes of Health Neurobiology of CNS Injury and Repair (5T32NS077889) 2022-2024
Kentucky Spinal Cord Head Injury Research Trust grant Preclinical development of IGF-1 therapy for TBI (#19-5A) 2020-2024
Kentucky Spinal Cord Head Injury Research Trust grant Unraveling TBI-mediated dysregulation of adult hippocampal neurogenesis at multiple stages in the neurogenic cascade (#23-12) 2024
Recommended Citation
Downing, Hannah, "DIFFERENTIAL EFFECTS OF TRAUMATIC BRAIN INJURY ON PREINJURY AND POSTINJURY BORN HIPPOCAMPAL NEURAL PRECURSOR CELLS" (2024). Theses and Dissertations--Physiology. 67.
https://uknowledge.uky.edu/physiology_etds/67
