Individualized High-Resolution Analysis to Categorize Diverse Learning and Memory Deficits in Tau rTg4510 Mice Exposed to Low-Intensity Blast Provisionally Accepted

Amitai Zuckerman^{1, 2} Heather R. Siedhoff^{1, 2} Ashley Balderrama^{1, 2} Runting Li^{1, 2} Grace Y. Sun^{1, 3} David X. Cifu⁴ Ibolja Cernak⁵ Jiankun Cui^{1, 2} Zezong Gu^{1, 2*}

• ¹Department of Pathology & Anatomical Sciences, School of Medicine, University of Missouri, United States
• ²Harry S. Truman Memorial Veterans’ Hospital Research Service, United States
• ³Biochemistry Department, University of Missouri, United States
• ⁴Department of Physical Medicine and Rehabilitation, School of Medicine, Virginia Commonwealth University, United States
• ⁵Thomas F. Frist, Jr. College of Medicine, Belmont University,, United States

Mild traumatic brain injury (mTBI) resulting from low-intensity blast (LIB) exposure in military and civilian individuals is linked to enduring behavioral and cognitive abnormalities. These injuries can serve as confounding risk factors for the development of neurodegenerative disorders, including Alzheimer's disease-related dementias (ADRD). Recent animal studies have demonstrated LIBinduced brain damage at the molecular and nanoscale levels. Nevertheless, the mechanisms linking these damages to cognitive abnormalities are unresolved. Challenges preventing the translation of preclinical studies into meaningful findings in "real-world clinics" encompass the heterogeneity observed between different species and strains, variable time durations of the tests, quantification of dosing effects and differing approaches to data analysis. Moreover, while behavioral tests in most preclinical studies are conducted at the group level, clinical tests are predominantly assessed on an individual basis. In this investigation, we advanced a high-resolution and sensitive method utilizing the CognitionWall test system and applying reversal learning data to the Boltzmann fitting curves. A flow chart was developed that enable categorizing individual mouse to different levels of learning deficits and patterns. In this study, rTg4510 mice, which represent a neuropathology model due to elevated levels of tau P301L, together with the non-carrier genotype were exposed to LIB. Results revealed distinct and intricate patterns of learning deficits and patterns within each group and in relation to blast exposure. With the current findings, it is possible to establish connections between mice with specific cognitive deficits to molecular changes. This approach can enhance the translational value of preclinical findings and also allow for future development of a precision clinical treatment plan for ameliorating neurologic damage of individuals with mTBI.