Development of Hippocampal-Prefrontal Interactions in Adolescence

摘要： 海马体(河马)功能障碍的临床谱系包括广泛的神经学、 各种精神病理状态下的行为、认知症状，重要的是发育 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，对河马的研究，特别是它与背外侧前额叶皮质(Dlpfc)的相互作用的研究已经 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 在这种情况下，两个神经区域都会受到影响，并与通常难治性的记忆损害有关 去接受治疗。尽管啮齿动物和非人灵长类动物模型提出河马-dlPFC断开 是一种理想的系统级表型，可用于转化为神经精神疾病，这些 已经在完全成熟的受试者中进行了研究，将它们的翻译限制为在 发展。一个更有意义的方法是评估河马的关键发育期- DLPFC的相互作用及其在整个发育过程中功能障碍的后果。我们建议追查 河马-dlPFC相互作用在猴子从青春期前到青春期的发展，重点是 关键认知功能，即分别与河马和dlPFC相关的情景记忆和工作记忆。 在五个年龄阶段(青春期前：18-30个月，青春期前：32-37个月，青春期37-42个月，青春期43-47个月，青春期后：52个月- 58个月)，我们将测量河马依赖的关系记忆(物体就地记忆任务)和PFC- 15只雄性猕猴(目标1)平行于底层的相关工作记忆(序列顺序记忆任务) 河马-dlPFC结构和功能连接性的发育变化(目标2)，使用非侵入性 神经成像技术(结构磁共振成像、扩散张量成像和静息功能磁共振成像)。目标1将 提供青春期前后加强记忆的时间，目标2将表明 记忆的变化与PFC-河马连接强度的变化有关。在目标3中，我们将使用六个新的 对青春期前雄性猴子进行短暂性河马-dlPFC断开研究。通过结合河马- 一个半球的失活和另一个半球的dlPFC-失活，通过麝香酚(GABA-A) 激动剂)注射，我们将证明功能性河马-dlPFC相互作用(目标2)对于 成人的出现-表演(Aim1)。控制青春期对血液三项指标的影响 性腺激素和性形态测量将被作为预测因素来评估其作用 青春期年龄对认知和神经变化的影响。所提出的研究是新颖的，具有很高的可翻译性 为深入系统地研究河马的发展提供了一种新的模式体系。 DLPFC交互作用及其在青春期和成年期脱轨的认知后果，避免 混杂因素(青春期年龄、横断面研究等)通常会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.