Synaptic plasticity in young versus aged visual cortex

描述（由申请人提供）：在动物的一生中，调节皮质功能的经验能力显著下降。在早期，出生后的关键时期，单眼剥夺（MD）通过服务于被剥夺眼睛的突触强度的快速下降，诱导双眼神经元的眼优势（OD）的转移。此外，观察到服务于非被剥夺的眼睛的突触强度的缓慢增长。我们的实验室和其他人最近的工作表明，在典型的关键时期之后，成人也可以诱导眼优势转移，但需要更长的MD时间。在成人中，被剥夺只参与慢速的部分，增加了服务于非被剥夺输入的突触的强度。这表明，外径可塑性会持续到成年期，并提出了一种有趣的可能性，即调节外径可塑性的机会也可能持续一生。我们的初步实验验证了这一假设，并证明了视觉剥夺，通过黑暗暴露（DE），在单眼剥夺的反应中重新激活了快速的幼年样OD可塑性。暴露于黑暗后引起的OD偏移是由于服务于被剥夺的眼睛的突触强度的迅速下降，以前只在幼体中描述过，而服务于未被剥夺的眼睛的突触强度迅速增加，这通常在幼体和成体中发展缓慢。拟议的实验检查了黑暗暴露的时间要求和功能后果，并使用一系列转基因和药理学操作来验证黑暗暴露降低视觉皮层抑制的假设，使其回到更具可塑性的青少年状态。此外，我们验证了DE将增加出生时视力丧失的眼睛恢复功能的成功率的假设。这种非侵入性的方法恢复哺乳动物皮层中经验依赖的突触可塑性，具有巨大的治疗潜力，因为人类弱视导致的视觉缺陷通常在10岁时是不可逆转的。

DESCRIPTION (provided by applicant): The ability of experience to regulate the cortical function decreases significantly over the lifetime of an animal. During an early, postnatal critical period, monocular deprivation (MD) induces a shift in the ocular dominance (OD) of binocular neurons through a rapid decrease in the strength of synapses serving the deprived eye. In addition, a slower increase in the strength of synapses serving the non-deprived eye is observed. Recent work, by our lab and others, demonstrates that ocular dominance shifts can also be induced in adults, after the classical critical period, however longer periods of MD are required. In adults, deprivation engages only the slow component, increasing the strength of synapses serving the non-deprived input. This demonstrates that OD plasticity persists into adulthood, and suggests the intriguing possibility that opportunities to regulate OD plasticity may also persist throughout lifetime. Our preliminary experiments tested this hypothesis, and demonstrate that visual deprivation, through dark exposure (DE), reactivates rapid juvenile-like OD plasticity in response to monocular deprivation. The OD shift induced after dark exposure is due to a rapid decrease in the strength of synapses serving the deprived eye, previously only described in juveniles, and a rapid increase in the strength of synapses serving the non-deprived eye, which typically develops slowly in juveniles and adults. The proposed experiments examine the temporal requirements and functional consequences of dark exposure, and use a battery of transgenic and pharmacological manipulations to test the hypothesis that dark exposure decreases inhibition in the visual cortex, allowing a return to a more plastic, juvenile-like state. In addition, we test the hypothesis that DE will increase the success of regaining function in an eye deprived of vision from birth. Such a non-invasive method to restore experience-dependent synaptic plasticity in the mammalian cortex holds great therapeutic potential, as the visual deficit resulting from amblyopia in humans is often irreversible by age 10.