Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 511 S. Floyd St., Louisville, KY, 40292, USA.
Division of Neurology and Developmental Neurosciences, Baylor College of Medicine, Houston, USA.
Neural Dev. 2024 Jun 18;19(1):6. doi: 10.1186/s13064-024-00183-5.
The thalamic reticular nucleus (TRN) serves as an important node between the thalamus and neocortex, regulating thalamocortical rhythms and sensory processing in a state dependent manner. Disruptions in TRN circuitry also figures prominently in several neurodevelopmental disorders including epilepsy, autism, and attentional defects. An understanding of how and when connections between TRN and 1st order thalamic nuclei, such as the dorsal lateral geniculate nucleus (dLGN), develop is lacking. We used the mouse visual thalamus as a model system to study the organization, pattern of innervation and functional responses between TRN and the dLGN. Genetically modified mouse lines were used to visualize and target the feedforward and feedback components of these intra-thalamic circuits and to understand how peripheral input from the retina impacts their development.Retrograde tracing of thalamocortical (TC) afferents through TRN revealed that the modality-specific organization seen in the adult, is present at perinatal ages and seems impervious to the loss of peripheral input. To examine the formation and functional maturation of intrathalamic circuits between the visual sector of TRN and dLGN, we examined when projections from each nuclei arrive, and used an acute thalamic slice preparation along with optogenetic stimulation to assess the maturation of functional synaptic responses. Although thalamocortical projections passed through TRN at birth, feedforward axon collaterals determined by vGluT2 labeling, emerged during the second postnatal week, increasing in density through the third week. Optogenetic stimulation of TC axon collaterals in TRN showed infrequent, weak excitatory responses near the end of week 1. During weeks 2-4, responses became more prevalent, grew larger in amplitude and exhibited synaptic depression during repetitive stimulation. Feedback projections from visual TRN to dLGN began to innervate dLGN as early as postnatal day 2 with weak inhibitory responses emerging during week 1. During week 2-4, inhibitory responses continued to grow larger, showing synaptic depression during repetitive stimulation. During this time TRN inhibition started to suppress TC spiking, having its greatest impact by week 4-6. Using a mutant mouse that lacks retinofugal projections revealed that the absence of retinal input led to an acceleration of TRN innervation of dLGN but had little impact on the development of feedforward projections from dLGN to TRN. Together, these experiments reveal how and when intrathalamic connections emerge during early postnatal ages and provide foundational knowledge to understand the development of thalamocortical network dynamics as well as neurodevelopmental diseases that involve TRN circuitry.
丘脑网状核 (TRN) 作为丘脑和新皮层之间的重要节点，以依赖于状态的方式调节丘脑皮质节律和感觉处理。TRN 电路的中断也在包括癫痫、自闭症和注意力缺陷在内的几种神经发育障碍中起着重要作用。对于 TRN 与第一级丘脑核（如背外侧膝状体核 (dLGN)）之间的连接如何以及何时发育，我们知之甚少。我们使用小鼠视觉丘脑作为模型系统，研究 TRN 与 dLGN 之间的组织、支配模式和功能反应。使用遗传修饰的小鼠品系来可视化和靶向这些丘脑内回路的前馈和反馈成分，并了解来自视网膜的外周输入如何影响它们的发育。通过 TRN 逆行追踪丘脑皮质 (TC) 传入，发现在成年时出现的模态特异性组织在围产期存在，并且似乎不受外周输入损失的影响。为了研究 TRN 和 dLGN 之间视觉区域的丘脑内回路的形成和功能成熟，我们检查了每个核的投射何时到达，并使用急性丘脑切片准备和光遗传学刺激来评估功能突触反应的成熟度。尽管丘脑皮质投射在出生时穿过 TRN，但通过 vGluT2 标记确定的前馈轴突侧支在出生后第二周出现，并在第三周通过密度增加。TRN 中 TC 轴突侧支的光遗传学刺激在第 1 周结束时显示出罕见的、微弱的兴奋性反应。在第 2-4 周期间，反应变得更加普遍，幅度增大，并在重复刺激期间表现出突触抑制。来自视觉 TRN 的反馈投射早在出生后第 2 天就开始向 dLGN 支配，在第 1 周出现微弱的抑制性反应。在第 2-4 周期间，抑制性反应继续增大，并在重复刺激期间表现出突触抑制。在此期间，TRN 抑制开始抑制 TC 放电，到第 4-6 周时影响最大。使用一种缺乏视网膜投射的突变小鼠表明，视网膜输入的缺失导致 TRN 对 dLGN 的支配加速，但对 dLGN 到 TRN 的前馈投射的发育几乎没有影响。总的来说，这些实验揭示了丘脑内连接在出生后早期是如何以及何时出现的，并为理解丘脑皮质网络动力学以及涉及 TRN 电路的神经发育疾病提供了基础知识。
