Synaptic plasticity in young versus aged visual cortex

描述(由申请人提供)：在动物的一生中，经验调节皮质功能的能力显著下降。在出生后的早期关键期，单眼剥夺(MD)通过服务于被剥夺眼的突触强度的迅速下降，导致双眼神经元的眼优势(OD)发生改变。此外，观察到为非剥夺眼提供服务的突触强度增加较慢。我们实验室和其他人最近的工作表明，在经典的临界期之后，成年人也可以诱导眼睛优势的转移，尽管需要更长的MD周期。在成年人中，剥夺只涉及慢速成分，增加了为非剥夺输入提供服务的突触的强度。这表明外径可塑性持续到成年，并暗示了一种耐人寻味的可能性，即调节外径可塑性的机会也可能贯穿一生。我们的初步实验验证了这一假说，并证明了视觉剥夺通过暗暴露(DE)重新激活单眼剥夺后快速的青少年样外径可塑性。黑暗暴露后引起的OD漂移是由于服务于剥夺眼的突触强度迅速下降，而服务于非剥夺眼的突触强度迅速增加，而非剥夺眼通常在青少年和成年人中发育缓慢。拟议中的实验考察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物操作来测试这样一个假设，即黑暗暴露减少了视觉皮质的抑制，允许返回到更具可塑性、更像青少年的状态。此外，我们还检验了这样的假设，即DE将增加出生时就丧失视力的眼睛恢复功能的成功率。这种非侵入性的方法恢复哺乳动物皮质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.