Afferent Regulation of Prefrontal Maturation during Adolescence

青春期前额叶成熟的传入调节

基本信息

批准号：
10661841
负责人：
Kuei-Yuan Tseng
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-08 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661841
关键词：
Acoustics Adolescence Adolescent Adult Affective Age Anatomy Behavior Behavioral Brain Calibration Cognitive Data Decision Making Development Developmental Process Disease Electrophysiology (science)Equilibrium Event Exhibits Glutamates Goals Grant Hippocampus Incidence Infusion procedures Interneurons Intervention Knowledge Link Mediating Mental disorders Mission N-Methylaspartate National Institute of Mental Health Neurobiology Output Predisposition Prefrontal Cortex Process Public Health Regulation Reporting Research Risk Factors Schizophrenia Substance Use Disorder Synapses Testing United States National Institutes of Health antagonist behavioral response cell type cognitive ability critical period fear memory gamma-Aminobutyric Acid genetic approach hippocampal pyramidal neuron in vivo insight neural neural circuit neurodevelopment neuronal circuitry novel therapeutic intervention postnatal postnatal development postnatal period prepulse inhibition prevent response transmission process vulnerable adolescent

项目摘要

Abstract Adolescence is a vulnerable period of postnatal development for the onset of major psychiatric disorders where the prefrontal cortex (PFC) is involved. According to the NIMH Council's Workgroup Report, many psychiatric disorders can only be understood as an interaction between brain development and susceptibility to risk factors. Although many progresses have been made in the field during the past few years, a comprehensive understanding of the cellular and circuit level mechanisms regulating the developmental trajectory of neural processes involved in these disorders remains incomplete. Thus, our long-term goal is to identify sensitive developmental processes during adolescence that contribute to the onset of psychiatric disorders where the PFC is compromised. From studies performed during the preceding grant period, we have found that a hallmark of PFC maturation during adolescence is the functional re-calibration of an excitatory-inhibitory (E-I) balance state. In addition to the gain of GABA function, there is a facilitation of GluN2B and GluN2A NMDAR transmission in the PFC that is intimately linked to ventral hippocampal and basolateral amygdalar inputs. Yet, the extent to which coordinated activation of ventral hippocampal and basolateral amygdalar inputs during adolescence are required for the functional maturation of the PFC remains unclear. We will fill this gap in knowledge through the pursuit of 3 Specific Aims. We will use an input-specific chemogenetic strategy to transiently inhibit PFC afferent transmission at 3 non-overlapping adolescent periods to establish the exact window(s) of susceptibility for the gain/functional maturation of the GABA and NMDA synaptic components of the PFC E-I balance and their impact on PFC-dependent behaviors in adulthood. Together, the proposed aims are expected to uncover key neural circuit processes that contribute to the enhanced PFC vulnerability during adolescence to developmental insults. Such knowledge is expected to provide insights on the implementation of new therapeutic interventions to prevent/mitigate the incidence of cognitive and affective deficits often seen in mental illnesses that emerge during adolescence.

抽象的青春期是主要精神疾病发作的产后发展时期涉及前额叶皮层（PFC）。根据NIMH理事会的工作组报告，许多精神病学疾病只能理解为大脑发育与风险易感性之间的相互作用因素。尽管过去几年在该领域取得了许多进展，但综合了解调节神经发育轨迹的细胞和电路水平机制这些疾病涉及的过程仍然不完整。因此，我们的长期目标是确定敏感的青春期的发展过程有助于精神疾病的发作 PFC被妥协。从上一个赠款期间进行的研究，我们发现青春期PFC成熟的标志是兴奋性抑制（E-I）的功能重新校准平衡状态。除了GABA函数的获取外，还有Glun2b和Glun2a NMDAR的促进与腹侧海马和基底外侧杏仁核输入密切相关的PFC中的传播。然而，腹侧海马和基底外侧杏仁核的协调激活在多大程度上 PFC的功能成熟需要青春期尚不清楚。我们将填补这个空白通过追求3个特定目标的知识。我们将使用投入特异性的化学发生策略来在3个非重叠的青少年时期瞬时抑制PFC传播传播，以确定确切 GABA和NMDA突触组件的增益/功能成熟的易感性窗口 PFC E-I平衡及其对成年期PFC依赖性行为的影响。拟议的目标在一起预计将发现关键的神经回路过程，这些过程有助于增强的PFC脆弱性对发展侮辱的青春期。期望这样的知识提供有关实施的见解经常看到的新治疗干预措施以防止/减轻认知和情感缺陷的发生率在青春期出现的精神疾病中。