Afferent Regulation of Prefrontal Maturation during Adolescence

 描述（由申请人提供）：青春期是几种精神疾病发作的脆弱时期，其中涉及前额叶皮层（PFC），然而，由于对这一发育阶段发生的规范性变化了解不足，我们对这种易感性的机械理解仍然处于初期阶段。因此，本提案的长期目标是确定PFC正常发育的关键细胞和回路水平过程，以了解PFC受损时青少年对精神疾病发作的脆弱性。我们上一个资助期的研究表明，在青春期，PFC在多巴胺能和GABA能传递中经历了大规模的功能重塑。尽管如此，局部GABA能系统似乎使PFC在青春期不稳定，以至于在此发育期发生的任何损伤都将通过获得局部GABA能功能阻止PFC中抑制控制的正常功能获得。有趣的是，我们的数据表明，这种GABA能易化与青春期发生的其他两种发育调节PFC事件是同时发生的：1）腹侧海马-PFC通路的功能增强，2）PFC GABA能中间神经元亚群的突触能活动增加，表明这些事件是相互关联的。因此，本申请的目的是确定特定兴奋性传入和通过其在特定GABA能群体中的作用获得PFC抑制控制之间是否存在因果关系。中心假设是，PFC中GABA能传递的功能成熟依赖于特定的前额叶中间神经元的激活，这些中间神经元由特定的传入神经驱动PFC活动， 青春期，如腹侧海马和基底外侧杏仁核。我们将通过追求3个具体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（目标1）的贡献和特定的前额叶中间神经元（目标2），使在青春期PFC的GABA能功能的增益的作用。目标3将测试青春期前额叶皮质中GABA能成熟受损是否会导致成年后后前额叶皮质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是创新的，因为它将纳入青春期发生的事件的知识，以解释成人PFC功能的获得和PFC缺陷的发展，特别是从前额叶GABA能成熟如何受到广泛参与正常和病理性神经反应的传入结构的调节的角度。这些研究具有重要意义，因为它们将揭示有助于成年人获得成熟认知能力的关键神经发育机制。预计这种知识将对制定针对具体年龄的干预措施产生积极影响，这些干预措施旨在减少青少年/年轻成年人中精神障碍的发病率或改善其症状。

 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.