Development of Hippocampal-Prefrontal Interactions in Adolescence

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Abstract: The clinical spectrum of hippocampal (HIPPO) dysfunction encompasses a wide range of neurological, behavioral, cognitive symptoms in various psychopathological states, and importantly developmental neuropsychiatric disorders (Schizophrenia, Autism Spectrum Disorders, anxiety, post-traumatic disorders). Thus, the study of HIPPO and, in particular, of its interactions with dorsolateral prefrontal cortex (dlPFC) has become of major interest to further understand the neurobiology of developmental neuropsychiatric disorders in which both neural regions are affected and associated with memory impairment that are generally refractory to treatment. Although rodent and nonhuman primate models have proposed that HIPPO-dlPFC disconnection is an ideal systems-level phenotype that can be used for translation to neuropsychiatric diseases, these studies have been done in fully mature subjects limiting their translation to human disorders that emerge during development. A more meaningful approach would be to assess the critical developmental periods of HIPPO- dlPFC interactions and the consequences of their dysfunction across development. We propose to trace the development of HIPPO-dlPFC interactions in monkeys from pre-adolescence to adolescence, focusing on critical cognitive functions, i.e. episodic and working memory associated with HIPPO and dlPFC, respectively. At five age periods (pre-puberty: 18-30 mo, peri-puberty: 32-37 mo, 37-42 mo, 43-47 mo, and post-puberty: 52- 58 mo), we will measure HIPPO-dependent relational memory (object-in-place memory task) and PFC- dependent working memory (serial order memory task) in 15 male monkeys (Aim 1) in parallel to underlying developmental changes in HIPPO-dlPFC structural and functional connectivity (Aim 2), using noninvasive neuroimaging techniques (structural MRI, diffusion tensor imaging and resting state functional MRI). Aim 1 will provide the timing of strengthening of memory during peri-pubertal period and Aim 2 will indicate whether the memory changes are linked to changes in strength of PFC-HIPPO connections. In Aim 3, we will use six new pre-adolescent male monkeys for a transient HIPPO-dlPFC disconnection study. By combining HIPPO- inactivation in one hemisphere and dlPFC-inactivation in the other hemisphere, via muscimol (GABA-A agonist) injections, we will demonstrate that functional HIPPO-dlPFC interactions (Aim 2) are necessary for the emergence of adult-performance (Aim1). To control for pubertal effects on measures of the 3 aims, blood gonadal hormone and sexual morphological measures will be taken and used as predictors to assess the role of pubertal age on cognitive and neural changes. The proposed studies are novel, have high translational value, and will provide a new model system to carefully and systematically study the development of HIPPO- dlPFC interactions and the cognitive consequences of their derailment in adolescence and adulthood, avoiding confounding factors (pubertal age, cross-sectional studies etc) usually affecting data on human adolescents.