Recovering plasticity in adult ferret V1 by cross-modal deprivation

 描述(申请人提供)：在任何视觉体验之前开始的长期单眼剥夺(MD)会导致被遮挡的眼睛永久丧失视力，并且与在一段时间正常视力后开始的MD相比，在以后的生活中更难恢复。在功能和解剖学水平上，众所周知，长期的MD会导致初级视觉皮质(V1)的眼优势(OD)发生改变。特别是，V1神经元失去了剥夺眼睛的反应，这被认为是类似长期抑郁(LTD)的机制造成的。虽然最近的研究报道了使用基因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大约一周的正常视力后的长期MD。研究表明，在不同的动物模型中，在睁眼之前开始的MD对恢复的弹性要强得多，并且被认为涉及丘脑皮质(TC)对V1的输入的变化。因此，恢复TC突触可塑性的方法将有利于慢性长期MD的恢复。我们最近发现，耳聋的成年小鼠在短暂的时间内会导致V1层(L4)TC突触的增强。在这里，我们建议研究在短时间内震耳欲聋的成年雪貂是否会允许跨模式增强V1中的TC突触，以促进从睁眼前开始的慢性长期MD的恢复。雪貂V1的组织类似于人类，带有外向柱和定向风车，这克服了老鼠V1缺乏这种模块化组织的限制。为了验证我们的假设，即耳聋促进成年雪貂V1的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有或没有耳聋的V1的L4中TC突触的强度(目标1)。此外，L4的皮质内突触强度将被量化。为了研究TC突触的跨模式增强是否促进慢性长期MD的恢复，我们将使用多部位层流记录探针比较V1神经元的功能，包括OD和视力(目标2)。我们的研究结果将确定成人的跨模式感觉剥夺是否会通过恢复TC的可塑性来促进慢性长期MD的恢复。我们的结果可以推广到促进其他形式的感觉丧失的恢复，并为开发非侵入性方法从成人剥夺性弱视中恢复铺平了道路。

 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.