Optical imaging and automated behavior as tools for the diagnostic monitoring of brain function in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are a class of variegated conditions affecting 1-2% of the general population, characterized by cognitive impairment, behavioral abnormalities, sensory and motor changes, and speech and language deficits resulting as developmental disorders of the brain and nervous system. The pathological mechanism is not fully understood and may be related to hereditary or environmental factors. NDDs occurs during infancy, and in most cases, has a chronic progression over a lifetime. NDDs encompasses a heterogeneous group of disorders including, but not limited to, CDKL5 deficiency disorders, creatine transporter deficiency syndrome, Krabbe disease, and Angelman syndrome. These conditions have a robust, known genetic origin and a devastating impact on patients and their families. Recently, it has been indicated that brain energetics might concur to the pathophysiology of these diseases as a common mechanism. Unfortunately, there is no cure for these disorders; however, various mutant mice are now available, resulting in good models for evaluating the pathophysiology of the disease. Moreover, some therapies are beginning to be tested at the preclinical level and the evaluation of the efficacy of these experimental therapies needs a robust, translational, unbiased, and quantitative biomarker to non-invasively and quantitatively monitor brain function. To respond to this demand, I used physiological techniques, such as intrinsic optical signal (IOS) imaging and VEP, to investigate the cortical functions of these disorders. Monitoring visual function proved to be a precise tool, highlighting alterations in the intrinsic spectral properties of oxygenated and deoxygenated hemoglobin in the primary visual cortex in each of the strains investigated. Moreover, employing this biomarker to monitor brain function during treatment reveals a solid ability to accurately detect modifications of visual responses; overall, these findings identify novel, translational and non-invasive biomarkers for the analysis of brain function in NDDs. As mentioned above, NDDs have a wide range of cognitive and behavioral manifestations and their assessment represents a primary point for physicians, psychologists and researchers. Mouse models recapitulate these behavioral and cognitive alterations; however, classical paradigms used in neuroscience to evaluate these aspects are subjected to different biases. Here, I implemented, validated, and applied in C57BL/6J and CDKL5 mice a novel automated and 3D printed tool, based on appetitive conditioning protocols that perform operant conditioning on freely moving mice. Thanks to the complete automaticity of the test and the ability to accurately detect parameters, its results as a robust behavioral tool, applicable to monitor longitudinally the effectiveness of treatments and washout effects in preclinical, and possibly clinical, studies in NDDs.