The rationale for this proposal is that synaptic integrity is essential for neuronal function. Disruptions to synaptic integrity are downstream of common TBI pathophysiological events including neuronal cell death, axonal injury, p-tau aggregation, and neuroinflammation. The ability to detect discrete changes in synaptic integrity ? regardless of the upstream mechanism of synapse loss ? will allow clinicians to track the ability of clinical interventions to improve chronic outcome in patients. The objective of this proposal is to use measures of synaptic integrity to predict chronic behavioral outcomes, and to validate Hcorr as a non-invasive marker of synaptic integrity for use in TBI.
The purpose of this proposal is to validate pathophysiological changes to synapses and neuronal circuitry after traumatic brain injury (TBI) as a marker that aligns closely with assessments of neurobehavior. We will use a combination of synapse morphology, receptor biology, and electrophysiology to show that changes to synaptic integrity and neural networks can predict behavioral outcomes in mice. We will also adapt a novel functional MRI (fMRI) analysis technique called Hcorr for TBI research. Hcorr is a local regional heterogeneity analysis that use fMRI activation patterns to infer neuronal selectivity, which may have the potential to serve as an indirect measure of synaptic function. Synaptic changes have been extensively reported after experimental TBI, with synapse loss occurring in multiple different animal models of mild, moderate and severe TBI including controlled cortical impact (CCI) and fluid percussion injury (FPI), and mild closed head impact. Thus the loss of synapses appears to be a common event, regardless of injury type and injury severity. Despite this common pathophysiology, there are clear differences between injury models in regard to acute and chronic synaptic integrity. We have selected an assessment battery consisting of validated techniques to measure synapse integrity, biology, and function. We will use regression analysis to determine the techniques with the best predictive validity for cognitive function after TBI, and assess if Hcorr can be used to predict these outcomes from non-invasive fMRI scans. We will examine synaptic responses in three different TBI paradigms: 1) a single mild TBI that presents with transient synapse loss, no axonal injury, and no cognitive impairments; 2) repeat mTBI (30 mTBI) that presents with functional synapse changes including altered brainwave patterns, impaired hippocampal long term potentiation (LTP), and chronic behavioral deficits in learning and memory; 3) CCI that presents with widespread synapse loss, neuronal cell death, inflammation, and traumatic axonal injury. For each injury paradigm and their respective controls we will study acute (1d and 7d) and chronic (1m and 3m) timepoints to determine the continuum of synapse responses to each type of injury. We have established a multidisciplinary team based in the Washington DC area that will work independently using a blind study design, to study synaptic changes and recovery after TBI. The TBI injuries will occur in the Burns Lab (Georgetown). Synaptic counts, morphology, and architecture will be studied in the Dickstein Lab (USUHS). Behavior, synaptic biochemistry and molecular biology will be conducted in the Burns Lab (Georgetown). Electrophysiology will be conducted in the Wu Lab (Georgetown). MRI will be conducted in the Dardzinski Lab (USUHS), and Hcorr analysis by the Jiang Lab (Georgetown). Internal and external assessments on whether go/no-go targets have been achieved will be made according to the TOP-NT guidelines. If transition milestones are achieved, the UH3 phase will focus on external replication and validation of the information, and expand to include animal models that exist within the TOP-NT consortium. Georgetown and USUHS Investigators will work with the consortium investigators to confirm that their experimental paradigms align with the protocols established in the UG3 phase, and establish data sharing activities with the consortium.
