Afferent Regulation of Prefrontal Maturation during Adolescence

青春期前额叶成熟的传入调节

• 批准号: 9104556
• 负责人: Kuei-Yuan Tseng
• 金额: $ 39万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104556
• 关键词: Adolescence; Adolescent; Adult; Age; Amygdaloid structure; Behavior; Binding Proteins; Cells; Data; Decision Making; Development; Electrophysiology (science); Event; Exhibits; Extinction (Psychology); Funding; Glutamates; Goals; Grant; Hippocampus (Brain); In Vitro; Incidence; Infusion procedures; Interneurons; Intervention; Knowledge; Link; Measures; Mental disorders; Mission; Mood Disorders; National Institute of Mental Health; Neurobiology; Output; Pathway interactions; Population; Predisposition; Prefrontal Cortex; Process; Public Health; Rattus; Regulation; Research; Role; Schizophrenia; Short-Term Memory; Staging; Structure; Substance abuse problem; Synapses; System; Teacher Professional Development; Technology; Testing; Therapeutic Intervention; Time; Transgenic Organisms; United States National Institutes of Health; Work; behavior measurement; cell type; cognitive ability; critical developmental period; critical period; designer receptors exclusively activated by designer drugs; fear memory; gamma-Aminobutyric Acid; in vivo; innovation; knock-down; neuronal circuitry; postnatal; prepulse inhibition; prevent; public health relevance; reduce symptoms; relating to nervous system; response; small hairpin RNA; transcriptional coactivator p75; transmission process; young adult

 DESCRIPTION (provided by applicant): Adolescence is a vulnerable period for the onset of several psychiatric disorders where the prefrontal cortex (PFC) is involved, yet, our mechanistic understanding of this susceptibility remains incipient due to insufficient knowledge of the normative changes occurring during this developmental stage. Thus, the long-term goal of this proposal is to identify key cell- and circuit-level processes underlying the normal development of the PFC in order to understand the adolescent vulnerability to the onset of psychiatric disorders where the PFC is compromised. Studies from our previous funding period reveal that the PFC undergoes massive functional remodeling in both glutamatergic and GABAergic transmission during adolescence. Nonetheless, it is the local GABAergic system that appears to render the PFC labile during adolescence to the extent that any insult occurring during this developmental period will prevent the normal functional acquisition of inhibitory control in the PFC through a gain of local GABAergic function. Interestingly, our data indicate this GABAergic facilitation is contemporaneous with two other developmentally-regulated PFC events occurring during adolescence: 1) a functional strengthening of the ventral hippocampus-to-PFC pathway, and 2) increased glutamatergic activity onto a subset of PFC GABAergic interneurons, suggesting these events are interrelated. Thus, the objective of this application is to determine whether there is a causal relationship between specific excitatory afferents and the acquisition of PFC inhibitory control through their effect in specific GABAergic populations. The central hypothesis is that the functional maturation of GABAergic transmission in the PFC is dependent upon the activation of specific prefrontal interneurons by specific afferents that drive PFC activity during adolescence, such as those from the ventral hippocampus and basolateral amygdala. We will test this hypothesis through the pursuit of 3 Specific Aims. We will first determine the contribution of input-specific afferent drive (Aim 1) and the role of specific prefrontal interneurons (Aim 2) in enabling the gain of GABAergic function in the PFC during adolescence. Aim 3 will test if impaired GABAergic maturation in the PFC during adolescence can elicit enduring deficits in PFC-dependent behaviors as adults. All in all, the proposed research plan is innovative in our opinion because it will incorporate knowledge of the events occurring during adolescence to explain the acquisition of adult PFC faculties and development of PFC deficits, especially from the perspective of how prefrontal GABAergic maturation is regulated by afferent structures widely involved in normal and pathological neural responses. The proposed studies are significant because they will uncover key neurodevelopmental mechanisms that contribute to the acquisition of mature cognitive abilities in adults. Such knowledge is expected to have a positive impact in the development of age-specific interventions aimed at decreasing the incidence or ameliorating the symptoms of mental disorders within the adolescent/young adult population.

 描述（由适用提供）：青少年是几种精神疾病发作的脆弱时期，其中涉及前额叶皮层（PFC），但是，由于对这种发育阶段正常变化的知识不足，我们对这种敏感性的机械理解仍然很小。这是该提案的长期目标是确定PFC正常发展的基础的关键细胞和电路级过程，以了解损害PFC的精神疾病发作的青少年脆弱性。我们以前的资金期的研究表明，PFC在青少年期间都经历了谷氨酸能和GABA能传播的大规模功能重塑。尽管如此，正是局部的GABA能系统似乎在青少年期间使PFC标签呈现，以至于在此发育期间发生的任何损伤都将通过局部GABA能功能获得正常的PFC中抑制性控制功能。有趣的是，我们的数据表明，这种GABAergic设施是现代的，在青春期期间发生了另外两个发育中调节的PFC事件：1）腹侧海马到PFC途径的功能增强，而2）增加了谷氨酸氨基甲基疗法在PFC Gabaergic Internerurons的子集中，建议这些事件与这些事件相关。这是该应用程序的目的是确定特定运动传入与在特定的GABA能种群中的影响之间是否存在因果关系。中心假设是，PFC中GABA能传播的功能成熟取决于特定的传统在特定的前额叶中间神经元中激活PFC活性的特定传统 青少年，例如来自腹侧海马和基底外侧杏仁核的青少年。我们将通过追求3个特定目标来检验这一假设。我们将首先确定输入特异性传入驱动器（AIM 1）和特定前额叶中间神经元（AIM 2）在青少年期间PFC中的GABA能函数中的作用（AIM 2）的作用。 AIM 3将测试青少年期间PFC中PFC中的GABA能成熟是否会导致成年人依赖PFC依赖性行为的持久缺陷。总而言之，我们认为拟议的研究计划具有创新性，因为它将结合青少年期间发生的事件的知识，以解释成人PFC面部面部的获取和PFC的开发定义，尤其是从前额叶Gabaergic的角度来看，人们如何受到正常和病理神经病理学和病理学神经学的相关结构的调节。拟议的研究之所以重要，是因为它们将发现有助于获得成人成熟认知能力的关键神经发育机制。预计此类知识将对旨在减少事件或改善青少年/年轻成人人群中精神障碍症状的特定年龄干预措施产生积极影响。