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Author ORCID Identifier

https://orcid.org/0000-0002-4693-8286

Date Available

5-14-2028

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Graduate School

Department/School/Program

Neuroscience

Faculty

Adam D. Bachstetter

Faculty

Richard Grandin

Abstract

Mild traumatic brain injury (TBI) can produce persistent cognitive and behavioral symptoms even when overt structural damage is limited or absent. The hippocampus is especially vulnerable to these delayed consequences, but the cellular mechanisms that translate a transient post-injury inflammatory signal into lasting synaptic dysfunction remain incompletely defined. Interleukin-1 receptor type 1 (IL-1R1) is a central mediator of post-traumatic neuroinflammation and is expressed by multiple central nervous system cell types, including brain endothelial cells and neurons. However, most prior studies have manipulated IL-1R1 globally or pharmacologically, leaving unresolved which IL-1R1-expressing cell populations are responsible for specific components of post-traumatic hippocampal dysfunction. This dissertation tested the hypothesis that IL-1R1 signaling on brain endothelial cells and excitatory forebrain neurons makes mechanistically distinct contributions to hippocampal synaptic dysfunction after a single mild closed-head injury (CHI) in mice. A common electromagnetic CHI model was applied across experimental aims using wild-type C57BL/6J mice, a global Il1r1 knockout, conditional endothelial (Slco1c1-Cre) and neuronal (CaMKIIα-Cre) IL-1R1 knockouts, and complementary cell-type-specific Il1r1-restore lines in which IL-1R1 expression was selectively reinstated on endothelial cells or neurons on an otherwise global knockout background. Hippocampal function was quantified ex vivo using extracellular field potential recordings in CA1 and the dentate gyrus, with endpoints spanning presynaptic fiber recruitment, postsynaptic response scaling, synaptic strength, maximal synaptic output, and population spike threshold. These electrophysiological studies were complemented by bulk RNA sequencing, NanoString neuroinflammatory profiling, dendritic spine morphology, behavioral testing, and immunohistochemistry. In wild-type mice, a single mild CHI produced a paradoxical electrophysiological phenotype in which reduced synaptic strength coexisted with increased hippocampal excitability. Synaptic strength, measured by the relationship between fEPSP slope and fiber volley amplitude and by the fEPSP/fiber volley ratio, was reduced after injury in both CA1 and dentate gyrus. At the same time, population spike threshold was lowered, indicating that less synaptic drive was required to recruit synchronized neuronal firing. These abnormalities peaked at one week post-injury and, in CA1, re-emerged at six weeks. Presynaptic fiber recruitment and maximum fEPSP amplitude remained largely intact, indicating that the injury did not produce a gross failure of axonal activation or reduce the ceiling of postsynaptic transmission. Instead, mild CHI selectively impaired the efficiency with which preserved presynaptic input was converted into postsynaptic responses and spike output. Acute transcriptomic profiling demonstrated that CHI induced a rapid, time-structured molecular response that largely resolved within 72 hours. NanoString profiling further showed that nearly the entire injury-induced inflammatory transcriptional response at 9 hours post-injury was IL-1R1-dependent, coinciding with the known peak of post-injury IL-1β signaling. Despite this transient molecular window, electrophysiological deficits persisted for weeks, supporting a model in which acute IL-1R1 activation initiates downstream changes that outlast the inflammatory signal itself. Consistent with this model, global IL-1R1 deletion attenuated chronic behavioral impairment and reduced reactive gliosis at 14 weeks post-injury. Cell-type-specific deletion experiments revealed that endothelial and neuronal IL-1R1 signaling were not redundant. Endothelial IL-1R1 was preferentially required for injury-induced synaptic strength depression, particularly in CA1, whereas neuronal IL-1R1 was required for the full post-traumatic reduction in population spike threshold. Complementary restore experiments confirmed the sufficiency of these pathways. Endothelial IL-1R1 restoration alone was sufficient to reconstitute the wild-type injury phenotype, including both synaptic depression and hyperexcitability. Neuronal IL-1R1 restoration, by contrast, selectively reconstituted hyperexcitability without producing synaptic depression in CA1. Across these experiments, presynaptic recruitment and maximal synaptic output remained preserved, reinforcing the conclusion that IL-1R1-dependent dysfunction occurs primarily through altered postsynaptic response efficiency and altered synaptic drive-to-spike coupling rather than loss of afferent input. Together, these data establish a double dissociation in which a transient acute IL-1R1 signal acting on two distinct cell types initiates two mechanistically separable cascades that propagate into two coexisting chronic deficits within the same hippocampal circuits. Endothelial IL-1R1 primarily drives post-traumatic synaptic depression, likely through inflammatory and vascular-associated signaling that indirectly disrupts postsynaptic function. Neuronal IL-1R1 contributes more directly to hippocampal hyperexcitability, likely through modulation of excitatory-inhibitory balance, ion channel regulation, or synaptic drive-to-spike coupling. These findings reframe post-traumatic hippocampal dysfunction as the parallel output of cell-type-specific cytokine pathways rather than a unitary inflammatory insult. They also identify population spike threshold as a sensitive electrophysiological readout of IL-1R1-dependent post-traumatic dysfunction and position endothelial and neuronal IL-1R1 as distinct, tractable therapeutic targets for dissociable components of mild TBI pathophysiology.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.355

Archival?

Archival

Funding Information

This dissertation research was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke through the research grants “Neuronal IL-1R1 Signaling in Mild Closed Head Injury” (award no. R01NS120882; 2022–2026) and “Cell-Specific Actions of IL-1/IL-1R1 Signaling Following Traumatic Brain Injury” (award no. R01NS103785; 2022–2023), awarded to Adam D. Bachstetter at the University of Kentucky.

Jonathan C. Vincent also received support from the National Institutes of Health, National Institute on Aging through the “Training in Translational Research in Alzheimer’s and Related Dementias” institutional training grant (award no. T32AG078110; 2023–2025) for the project “From Inflammation to Synaptic Dysfunction: Uncovering the Role of Neuronal IL-1R1 in the Aftermath of Mild Traumatic Brain Injury.”

Additional support was provided by the National Institutes of Health, National Institute of Neurological Disorders and Stroke through the “Neurobiology of Central Nervous System Injury and Repair” institutional training grant (award no. T32NS077889; 2025–2026) for the project “The Functional Role of Neuronal IL-1R1 in Synaptic Plasticity and Recovery Following Traumatic Brain Injury.”

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