Afferent Regulation of Prefrontal Maturation during Adolescence

 描述(申请人提供)：青春期是几种涉及前额叶皮质(PFC)的精神障碍发病的脆弱时期，然而，由于对这一发育阶段发生的规范变化了解不足，我们对这种易感性的机械理解仍处于起步阶段。因此，这项建议的长期目标是确定PFC正常发育的关键细胞和电路水平的过程，以了解青少年对PFC受损的精神障碍的易感性。我们上一个资助期的研究表明，在青春期，PFC在谷氨酸和GABA能传递中经历了大规模的功能重构。然而，正是局部的GABA能系统似乎使PFC在青春期变得不稳定，以至于在这个发育期发生的任何侮辱都会阻止PFC通过获得局部GABA能功能而获得抑制控制的正常功能。有趣的是，我们的数据表明，这种GABA能促进作用与青春期发生的另外两个发育调节的PFC事件是同时发生的：1)腹侧海马到PFC通路的功能增强，以及2)PFC GABA能间神经元上谷氨酸能活动的增加，这表明这些事件是相互关联的。因此，本研究的目的是确定特定的兴奋性传入与通过其在特定GABA能群体中的作用而获得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间神经元的激活，这些特定的传入驱动PFC的活动。 青春期，如腹侧海马体和基底外侧杏仁核。我们将通过追求3个具体目标来检验这一假设。我们将首先确定特定于输入的传入驱动(目标1)和特定的前额叶中间神经元(目标2)在青春期PFC内GABA能功能获得中所起的作用。目标3将测试青春期PFC中GABA能成熟受损是否会导致成年后PFC依赖行为的持久缺陷。总而言之，我们认为拟议的研究计划是创新的，因为它将结合青春期发生的事件的知识来解释成人PFC功能的获得和PFC缺陷的发展，特别是从前额叶GABA能成熟是如何由广泛参与正常和病理神经反应的传入结构调节的角度。这项拟议的研究意义重大，因为它们将揭示有助于成人获得成熟认知能力的关键神经发育机制。这些知识预计将对制定针对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/青壮年人口中精神障碍的发生率或改善其症状。

 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.