Development of Hippocampal-Prefrontal Interactions in Adolescence

青春期海马-前额叶相互作用的发展

基本信息

批准号：
10194565
负责人：
MARIA C ALVARADO
金额：
$ 59.34万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194565
关键词：
Address Adolescence Adolescent Adolescent Development Adult Affect Age Agonist Animals Anxiety Attention deficit hyperactivity disorder Behavioral Biological Models Blood Brain Brain scan Clinical Cognitive Contralateral Cross-Sectional Studies Data Development Diffusion Magnetic Resonance Imaging Disease Endocrine Episodic memory Evaluation Fragile X Syndrome Functional Magnetic Resonance Imaging Functional disorder Future Genetic Predisposition to Disease Gonadal Hormones Hippocampus (Brain)Hormonal Change Human Impaired cognition Injections Ipsilateral Lead Learning Lesion Link Macaca mulatta Magnetic Resonance Imaging Male Adolescents Maps Measures Mediating Memory Memory impairment Modeling Monitor Monkeys Morphology Muscimol Neonatal Neurobehavioral Manifestations Neurobiology Neurologic Onset of illness Paired Comparison Pathology Patients Performance Periodicity Phase Transition Phenotype Prefrontal Cortex Primates Puberty Refractory Rest Rodent Role Saline Schizophrenia Severities Short-Term Memory Source Statistical Models Structure System Techniques Testing Time TimeLine Translations Visual Williams Syndrome Work aged autism spectrum disorder clinically relevant cognitive development cognitive function critical developmental period design developmental neurobiology experimental study gamma-Aminobutyric Acid in vivo interest male memory process neuroimaging neuropathology neuropsychiatric disorder nonhuman primate novel peripubertal period preadolescence prepuberty relating to nervous system relational memory skills tool translation to humans

项目摘要

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.

抽象的：海马（HIPPO）功能障碍的临床光谱包括广泛的神经系统行为，各种心理病理状态的认知症状，重要的是发展神经精神疾病（精神分裂症，自闭症谱系障碍，焦虑，创伤后疾病）。因此，对河马的研究，尤其是其与背外侧前额叶皮层（DLPFC）的相互作用的研究成为进一步了解发育神经精神疾病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记忆障碍相关，而记忆障碍通常是难治性的治疗。尽管啮齿动物和非人类灵长类动物模型提出了河马-DLPFC断开连接是一种理想的系统级表型，可用于转化为神经精神病疾病，这些已经在完全成熟的受试者中进行了研究，将其翻译成在期间出现的人类疾病发展。一种更有意义的方法是评估河马的关键发展时期 DLPFC相互作用及其在开发过程中的功能障碍的后果。我们建议追踪从青春期到青春期的猴子中河马-DLPFC相互作用的发展，重点关键的认知功能，即分别与河马和DLPFC相关的情节和工作记忆。在五个年龄时期（预伯蒂：18-30 mo，peri-puberty：32-37 MO，37-42 MO，43-47 MO和PUBERTY：52-- 58 mo），我们将测量与HIPPO有关的关系记忆（位置内存任务）和PFC- 与基础的15位男猴（AIM 1）中的依赖性工作记忆（串行订单记忆任务）使用无创的Hippo-DLPFC结构和功能连接的发展变化（AIM 2）神经影像技术（结构MRI，扩散张量成像和静止状态功能性MRI）。目标1意志提供在细胞周期期间增强记忆的时间，AIM 2将指示是否表明内存变化与PFC-Hippo连接强度的变化有关。在AIM 3中，我们将使用六个新的瞬时河马DLPFC断开研究的青春期前雄性猴子。通过结合河马 - 在一个半球中灭活和另一半球的DLPFC灭活，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（AIM 2）对于成人绩效的出现（AIM1）。为了控制对3个目标措施的青春期影响，血液性腺激素和性形态学措施将采取并用作评估角色的预测因子在认知和神经变化方面的青春期时代。拟议的研究是新颖的，具有很高的翻译价值，并将提供一个新的模型系统，以仔细，系统地研究河马的发展 DLPFC相互作用以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，横断面研究等）通常会影响人类青少年的数据。