Development of Hippocampal-Prefrontal Interactions in Adolescence

摘要： 海马（HIPPO）功能障碍的临床范围包括广泛的神经系统， 各种精神病理状态下的行为、认知症状， 神经精神障碍（精神分裂症、自闭症谱系障碍、焦虑、创伤后障碍）。 因此，HIPPO的研究，特别是其与背外侧前额叶皮层（dlPFC）的相互作用， 成为进一步了解发育性神经精神障碍的神经生物学的主要兴趣 其中两个神经区域都受到影响并与通常难治的记忆障碍有关 接受治疗尽管啮齿动物和非人灵长类动物模型已经提出HIPPO-dlPFC断开 是一种理想的系统水平表型，可用于翻译为神经精神疾病，这些 已经在完全成熟的受试者中进行了研究，将其翻译限制在人类疾病中， 发展一个更有意义的方法是评估HIPPO的关键发展时期， dlPFC的相互作用及其在发育过程中功能障碍的后果。我们建议追踪 从青春期前到青春期，在猴子中发展HIPPO-dlPFC相互作用，重点是 关键认知功能，即分别与HIPPO和dlPFC相关的情景记忆和工作记忆。 在5个年龄阶段（青春期前：18-30个月，青春期围：32-37个月，37-42个月，43-47个月，青春期后：52- 47个月）， 58 mo），我们将测量HIPPO依赖的关系记忆（对象在位记忆任务）和PFC- 在15只雄性猴子（Aim 1）中，平行于基础记忆任务， HIPPO-dlPFC结构和功能连接的发育变化（目标2），使用非侵入性 神经成像技术（结构MRI、扩散张量成像和静息状态功能MRI）。目标1将 提供青春期前后记忆力增强的时间，目标2将表明 记忆变化与PFC-HIPPO连接强度的变化有关。在目标3中，我们将使用六个新的 青春期前的雄性猴子进行短暂HIPPO-dlPFC断开研究。通过结合HIPPO- 通过蝇蕈醇（GABA-A），一个半球失活，另一个半球失活dlPFC 激动剂）注射，我们将证明功能性HIPPO-dlPFC相互作用（目的2）是必要的， 成人表演的出现（Aim 1）。为了控制青春期对三个目标的影响，血液 将采取性腺激素和性形态学措施，并将其用作预测因素，以评估其作用 对认知和神经变化的影响。所提出的研究是新颖的，具有高转化率， 价值，并将提供一个新的模式系统，仔细和系统地研究HIPPO的发展- dlPFC的相互作用及其在青春期和成年期出轨的认知后果，避免 混杂因素（青春期年龄、横断面研究等）通常影响人类青少年的数据。

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.