Memory impairments are common to many developmental disorders in humans, such as schizophrenia, autism, Williams syndrome, and anxiety, and are associated with dysfunction of the medial temporal lobe structures and prefrontal cortex. These disorders of unknown origin have significant impact on the normal cognitive development of a young individual, resulting in severe disabilities in the realms of perception, memory, language thinking, experience of emotions and social intelligence that span the entire life. The goal of our research program is to continue to follow the anatomical and functional development of the hippocampus and perirhinal cortex, and compare and contrast the long-term behavioral and neuroanatomical effects of early vs. late damage to this region. The overall hypothesis to be tested is whether early damage to the medial temporal lobe region yields the same behavioral changes, and anatomical and chemical re-organization than those seen after similar damage in adulthood. To achieve this we have characterized the normal development of macaque memory and compared it with that of monkeys with neonatal hippocampal (H) or perirhinal cortex (PRh) damage. We have completed the behavioral studies on normal and H lesioned infants up to 7 years of age, and of PRh lesioned infants up to 2.5 years old.
The specific aims of the present application are 1) to continue our investigation of the role of the perirhinal cortex (PRh) in the development of memory processes and compare that with normal memory development as well as the impact of hippocampal (H) damage, as evaluated in the previous funding period, 2) to compare and contrast the effects of early PRh on behavioral responses and cognitive processes, such as emotional reactivity, social skills, and reward assessment, and compare that with controls and neonatal H lesioned animals from the previous funding period, 3) to characterize the impact of neonatal H damage on the maturation of the prefrontal cortex (PFC), using neuroimaging procedures to measure (a) metabolic activity of PFC with PET imaging and (b) structural, metabolites and white matter changes with T1W, MRS and DTI imaging. Post-mortem immunocytochemistry techniques will be used to quantify and correlate neuroanatomical and neurochemical changes in the PFC with those found with the neuroimaging techniques to validate the neuroimaging tools. These developmental studies will provide insights into the pathophysiology and etiology of devastating developmental human disorders and primate model of extreme value for the development of new therapies.
The effects of focal perinatal brain damage to the medial temporal lobe, though mild at first, can have serious and amplified consequences as the organism matures. Mild disturbances to one structure may grossly affect the development of another, potentially resulting in psychiatric disorders such as schizophrenia, autism, depression, posttraumatic stress disorder, and anxiety. However, our knowledge of the normal development, anatomically or behaviorally, is sparse at best in humans or non-human primates. Further, the behavioral and cognitive consequences of selective damage to this region are not well characterized. Finally, it is unknown whether brain plasticity mechanisms alleviate or worsen these effects by compromising the development of otherwise-undamaged brain regions. Understanding these consequences is key to early detection of the otherwise subtle effects of neonatal focal lesions, and of developing treatments in the future. The proposed studies provide a first step to that end and the results will broaden our understanding of developmental disorders and possibly lead to new therapeutic treatments.
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