Stephany Céleste-Élise, Ikrar Taruna, Nguyen Collins, Xu Xiangmin, McGee Aaron W
Developmental Neuroscience Program, Saban Research Institute, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, and.
Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, California 92697.
J Neurosci. 2016 Oct 26;36(43):11006-11012. doi: 10.1523/JNEUROSCI.0935-16.2016.
A characteristic of the developing mammalian visual system is a brief interval of plasticity, termed the "critical period," when the circuitry of primary visual cortex is most sensitive to perturbation of visual experience. Depriving one eye of vision (monocular deprivation [MD]) during the critical period alters ocular dominance (OD) by shifting the responsiveness of neurons in visual cortex to favor the nondeprived eye. A disinhibitory microcircuit involving parvalbumin-expressing (PV) interneurons initiates this OD plasticity. The gene encoding the neuronal nogo-66-receptor 1 (ngr1/rtn4r) is required to close the critical period. Here we combined mouse genetics, electrophysiology, and circuit mapping with laser-scanning photostimulation to investigate whether disinhibition is confined to the critical period by ngr1 We demonstrate that ngr1 mutant mice retain plasticity characteristic of the critical period as adults, and that ngr1 operates within PV interneurons to restrict the loss of intracortical excitatory synaptic input following MD in adult mice, and this disinhibition induces a "lower PV network configuration" in both critical-period wild-type mice and adult ngr1 mice. We propose that ngr1 limits disinhibition to close the critical period for OD plasticity and that a decrease in PV expression levels reports the diminished recent cumulative activity of these interneurons.
Life experience refines brain circuits throughout development during specified critical periods. Abnormal experience during these critical periods can yield enduring maladaptive changes in neural circuits that impair brain function. In the developing visual system, visual deprivation early in life can result in amblyopia (lazy-eye), a prevalent childhood disorder comprising permanent deficits in spatial vision. Here we identify that the nogo-66 receptor 1 gene restricts an early and essential step in OD plasticity to the critical period. These findings link the emerging circuit-level description of OD plasticity to the genetic regulation of the critical period. Understanding how plasticity is confined to critical periods may provide clues how to better treat amblyopia.
发育中的哺乳动物视觉系统的一个特点是存在一段短暂的可塑性时期，称为“关键期”，在此期间初级视觉皮层的神经回路对视觉经验的扰动最为敏感。在关键期剥夺一只眼睛的视力（单眼剥夺[MD]）会通过改变视觉皮层中神经元的反应性来偏向未被剥夺的眼睛，从而改变眼优势（OD）。一个涉及表达小白蛋白（PV）的中间神经元的去抑制性微回路启动了这种OD可塑性。编码神经元Nogo-66受体1（ngr1/rtn4r）的基因是关闭关键期所必需的。在这里，我们将小鼠遗传学、电生理学和电路图谱与激光扫描光刺激相结合，以研究去抑制是否受ngr1限制于关键期。我们证明，ngr1突变小鼠成年后仍保留关键期的可塑性特征，并且ngr1在PV中间神经元内发挥作用，以限制成年小鼠MD后皮质内兴奋性突触输入的丧失，这种去抑制在关键期野生型小鼠和成年ngr1小鼠中均诱导出“较低的PV网络构型”。我们提出，ngr1限制去抑制以关闭OD可塑性的关键期，并且PV表达水平的降低反映了这些中间神经元近期累积活动的减少。
在特定的关键期内，生活经验会在整个发育过程中优化脑回路。在这些关键期内的异常经验会导致神经回路中持久的适应不良变化，从而损害脑功能。在发育中的视觉系统中，生命早期的视觉剥夺会导致弱视（懒眼），这是一种常见的儿童疾病，包括空间视觉的永久性缺陷。在这里，我们发现Nogo-66受体1基因将OD可塑性的一个早期且关键的步骤限制在关键期。这些发现将OD可塑性的新兴回路水平描述与关键期的遗传调控联系起来。了解可塑性如何局限于关键期可能为更好地治疗弱视提供线索。
