Afferent Regulation of Prefrontal Maturation during Adolescence

摘要 青春期是出生后发育的脆弱时期，容易出现重大精神障碍 前额叶皮质(PFC)受累。根据NIMH理事会的工作组报告，许多精神病患者 障碍只能被理解为大脑发育和风险易感性之间的相互作用。 各种因素。尽管在过去的几年里在这一领域取得了许多进展，但全面的 对调节神经发育轨迹的细胞和电路水平机制的理解 参与这些疾病的过程仍然不完整。因此，我们的长期目标是识别敏感的 青春期的发育过程导致精神障碍的发生，其中 PFC被攻破了。从上一次资助期间进行的研究中，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功能的增强，还有GluN2B和GluN2ANMDAR的易化 PFC中与腹侧海马和杏仁基底外侧传入密切相关的传递。然而， 腹侧海马区和杏仁基底外侧区传入的协调激活程度 青春期是PFC功能成熟所必需的，目前尚不清楚。我们将填补这一空白 通过追求3个具体目标获得知识。我们将使用特定于输入的化学发生策略来 在3个不重叠的青春期瞬时抑制PFC传入传递，以建立准确的 GABA和NMDA型突触成分获得/功能成熟的易感性窗口(S) PFC E-I平衡及其对成年PFC依赖行为的影响总之，提出的目标 预计将发现导致PFC漏洞增强的关键神经电路过程 青春期对发育的侮辱。这些知识预计将为实施提供见解 为预防/减轻常见的认知和情感缺陷的发生率而进行的新的治疗干预 在青春期出现的精神疾病。

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.