Recovering plasticity in adult ferret V1 by cross-modal deprivation

 描述（由申请人提供）：在任何视觉体验之前开始的长期单眼剥夺（MD）导致通过被遮挡的眼睛永久性丧失视力，并且与正常视力一段时间后开始的MD相比，在以后的生活中更难恢复。在功能和解剖学水平上，已知长期MD导致初级视觉皮层（V1）中的眼优势（OD）的转变。特别是，V1神经元失去了对剥夺眼睛的反应，这被认为是由类似长期抑郁（LTD）的机制引起的。虽然最近的研究报告使用遗传操作或侵入性药物干预从长期MD中恢复，但这些病例仅限于在早期发育期间正常视力约一周后的长期MD。研究表明，在不同的动物模型中，在睁眼前启动的MD对恢复的弹性要大得多，并且被认为涉及V1的丘脑皮质（TC）输入的变化。因此，恢复TC突触可塑性的方法将有利于慢性长期MD无初始视力的恢复。我们最近发现，成年小鼠短暂的耳聋导致V1第4层（L4）TC突触增强。在这里，我们建议检查是否震耳欲聋的成年雪貂短暂的时间将允许跨模态增强TC突触在V1，以促进恢复从慢性长期MD开始前睁眼。雪貂V1的组织类似于人类，具有OD柱和方向风车，这克服了小鼠V1缺乏这种模块化组织的限制。为了验证我们的假设，即在成年雪貂V1中，耳聋促进TC可塑性，我们将利用基于通道视紫红质的光遗传学工具来定量测量在有或没有耳聋的情况下V1的L4中TC突触的强度（目的1）。此外，将量化L4中的皮质内突触强度。为了研究TC突触的跨模态增强是否促进慢性长期MD的恢复，我们将使用多位点层流记录探针比较V1神经元功能，包括OD和视敏度（目的2）。我们的研究结果将确定成人的跨通道感觉剥夺是否会通过恢复TC可塑性来促进慢性长期MD的恢复。我们的研究结果可以推广到促进其他形式的感觉丧失的恢复，并为开发非侵入性手段来恢复成人剥夺性弱视铺平了道路。

 DESCRIPTION (provided by applicant): Long-term monocular deprivation (MD) initiated before any visual experience leads to permanent loss of vision through the occluded eye, and is much more resistant to recovery later in life compared to MD initiated after a period of normal vision. At a functional and anatomical level, it is known that long-term MD leads to a shift in ocular dominance (OD) in the primary visual cortex (V1). In particular, V1 neurons lose responses from the deprived eye, which are thought to result from mechanisms resembling long-term depression (LTD). While recent studies have reported recovery from long-term MD using either genetic manipulations or invasive pharmacological interventions, these cases have been limited to long-term MD after about a week of normal vision during early development. Studies have shown that MD initiated before eye opening in diverse animal models is much more resilient to recovery, and is thought to involve changes in thalamocortical (TC) inputs to V1. Hence methods to recover plasticity at TC synapses would benefit recovery from chronic long-term MD without initial vision. We recently found that deafening adult mice for a brief duration leads to potentiation of TC synapses in layer 4 (L4) of V1. Here we propose to examine whether deafening adult ferrets for a brief duration would allow cross-modal potentiation of TC synapses in V1 to promote recovery from chronic long-term MD initiated before eye opening. Ferret V1 is organized similar to humans with OD columns and orientation pinwheels, which overcomes the limits of mouse V1 lacking such modular organization. To test our hypothesis that deafening promotes TC plasticity in adult ferret V1, we will utilize channelrhodopsin based optogenetic tools to quantitatively measure the strength of TC synapses in L4 of V1 with or without deafening (Aim 1). In addition, intracortical synaptic strength in L4 will be quantified. T investigate whether cross-modal potentiation of TC synapses promotes recovery from chronic long-term MD, we will compare V1 neuronal functions, including OD and visual acuity, using multi-site laminar recording probes (Aim 2). The results from our study will determine whether cross-modal sensory deprivation in adults would promote recovery from chronic long-term MD by restoring TC plasticity. Our results could be generalized to promote recovery from sensory loss in other modalities, and pave a way to develop non-invasive means to recover from deprivation amblyopia in adults.