Regulation of adult visual cortex plasticity by endogenous nicotinic modulators

 描述(由申请人提供)：大脑可塑性增强的早期暂时性窗口，称为关键期，塑造神经回路，并有助于成人行为。这种高度的可塑性会在成年后衰退。临床上的一个中心问题是，这限制了晚年功能的恢复。这项研究的长期目标是发现新的可塑性调节机制，为重新打开成人大脑中的塑料窗提供治疗靶点。关键期研究最多的模型之一是初级视觉皮质(V1)对失明眼睛的持久反应丧失，导致弱视(视力丧失)，影响2-4%的人口，成年后尚无治愈方法。最近，属于Lynx家族的烟碱型乙酰胆碱受体(NAChR)系统及其内源性调节剂已成为成人V1可塑性的关键调节因子。先前的工作表明，Lynx1在关键期过后会增加表达，并起到刹车的作用，限制成人大脑中V1的可塑性。在初步研究中，另一种Lynx家族蛋白Lypd6被发现是成人可塑性的积极调节器。然而，Lynx家族成员调控可塑性的具体机制，如负责的细胞类型、nAChR亚型和调节的神经回路等，目前还完全不清楚。本研究的目的是通过对Lynx1和Lypd6的研究来确定新的可塑性机制。Lynx1和Lypd6代表了一类新的调节nAChR信号的可塑性调节因子。值得注意的是，这两个Lynx家族成员在GABA能中间神经元的两个主要亚型中具有相反的表达模式：Lynx1主要在小白蛋白中间神经元表达，而Lypd6仅在生长抑素中间神经元表达。此外，病毒操纵在GABA能神经元中的Lynx1和Lypd6而不是在谷氨酸能神经元中调节成体V1的可塑性，使它们成为剖析连接nAChR和GABA能系统的可塑性机制的独特靶点。我们推测Lynx1和Lypd6在GABA能中间神经元上具有不同的作用，通过调节特定的nAChRs来调节成人的可塑性，Lynx家族可能是治疗弱视的有效的临床前治疗靶点。通过结合基因和病毒技术的细胞类型特异性基因表达的获得/丢失，体内电生理学和光遗传标记辅助的细胞类型特异性测量，以及体内结构可塑性的双光子成像，我们有望确定Lynx家族成员调控可塑性的特定机制，如负责的细胞类型、nAChR亚型和神经回路。这种机制的确定将允许利用Lynx系统的操作，以促进关键期结束后的功能恢复，这反过来将带来治疗弱视和其他皮质可塑性障碍的新机会。

 DESCRIPTION (provided by applicant): Early temporary windows of heightened brain plasticity called critical periods sculpt neural circuits and contribute to adult behaviors. Such heightened plasticity declines into adulthood. A clinically central issue is that this limits recovry of function later in life. The long-term goal of this study is to discover new regulatory mechanisms of plasticity to provide therapeutic targets to re-open plastic windows in the adult brain. One of the best-studied models of a critical period is the enduring loss of responsiveness in primary visual cortex (V1) to an eye deprived of vision, resulting in amblyopia (a loss of visua acuity), affecting 2-4% of the population and without a known cure in adulthood. Recently, the nicotinic acetylcholine receptor (nAChR) system and its endogenous modulators that belong to Lynx family have emerged as key regulators of plasticity in adult V1. Previous work showed that Lynx1 increases in expression after the critical period and acts as a brake to limit V1 plasticity in the adult brain. In preliminary studies, Lypd6, another Lynx family protein, was foun to act as a positive modulator of adult plasticity. However, the specific mechanisms of plasticity regulated by the Lynx family members, such as responsible cell-types, nAChR subtypes, and neural circuits regulated, etc, are totally unknown. The objective of this study is to identify novl mechanisms of plasticity by focusing on Lynx1 and Lypd6, which represent a new class of plasticity regulators that modulate nAChR signals. Strikingly, these two Lynx family members have opposite expression patterns in two major subtypes of GABAergic interneurons: while Lynx1 is primarily expressed in parvalbumin interneurons, Lypd6 is exclusively expressed in somatostatin interneurons. Furthermore, viral manipulations of Lynx1 and Lypd6 in GABAergic neurons but not in glutamatergic neurons modulate adult V1 plasticity, making them unique targets to dissect the mechanisms of plasticity linking the nAChR and GABAergic systems. We hypothesize that Lynx1 and Lypd6 have distinct roles on GABAergic interneurons to regulate adult plasticity through modulation of specific nAChRs, and that the Lynx family can be an effective pre-clinical therapeutic target for treating amblyopia. By combining cell-type specific gain/loss of gene expression through genetic and viral techniques with in vivo electrophysiology assisted by optogenetic tagging for cell-type specific measurements, and in vivo two- photon imaging of structural plasticity, we expect to identify the specific mechanisms of plasticity regulated by the Lynx family members, such as responsible cell-types, the nAChR subtypes, and neural circuits. Identification of such mechanisms would allow exploiting manipulations of the Lynx system in order to facilitate functional recovery after the end of the critical period, which would in turn lead to new opportunities to treat amblyopia and other disorders of cortical plasticity.