No abstract

Purpose: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness.Methods: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how geneenvironment interactions might alter effectiveness of NAC therapy. Results:The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. Conclusion:These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

Mapping sex-specific neurodevelopmental alterations in neurite density and morphology in a rat genetic model of psychiatric illness

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In this paper a Multi-Level System (MLS) optimization algorithm is presented and utilized for the multi-discipline design of a ground vehicle track. The MLS can guide the decision making process for designing a complex system where many alternatives and many mutually competing objectives and disciplines need to be considered and evaluated. Mathematical relationships between the design variables and the multiple discipline performance objectives are developed adaptively as the various design considerations are evaluated and as the design is being evolved. These relationships are employed for rewarding performance improvement during the decision making process by allocating more resources to the disciplines which exhibit the higher level of improvement. The track analysis demonstrates how a multi-discipline design approach can be pursued in ground vehicle applications. The main elements of the optimization analysis along with the results and the physical insight which can be gained from the optimal configuration are presented and discussed.Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. Public Release18. NUMBER OF PAGES 11 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT unclassified c. THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18