Department of Pharmacology and Physiology, and Institute for Neuroscience, George Washington University, Washington, DC 20037.
Department of Pharmacology and Physiology, and Institute for Neuroscience, George Washington University, Washington, DC 20037
J Neurosci. 2018 Oct 10;38(41):8772-8786. doi: 10.1523/JNEUROSCI.1519-18.2018. Epub 2018 Aug 27.
Two major checkpoints of development in cerebral cortex are the acquisition of continuous spontaneous activity and the modulation of this activity by behavioral state. Despite the critical importance of these functions, the circuit mechanisms of their development remain unknown. Here we use the rodent visual system as a model to test the hypothesis that the locus of circuit change responsible for the developmental acquisition of continuity and state dependence measured in sensory cortex is relay thalamus, rather than the local cortical circuitry or the interconnectivity of the two structures. We conducted simultaneous recordings in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (VC) of awake, head-fixed male and female rats using linear multielectrode arrays throughout early development. We find that activity in dLGN becomes continuous and positively correlated with movement (a measure of state dependence) on P13, the same day as VC, and that these properties are not dependent on VC activity. By contrast, silencing dLGN after P13 causes activity in VC to become discontinuous and movement to suppress, rather than augment, cortical firing, effectively reversing development. Thalamic bursting, a core characteristic of non-aroused states, emerged later, on P16, suggesting these processes are developmentally independent. Together our results indicate that cellular or circuit changes in relay thalamus are critical drivers for the maturation of background activity, which occurs around term in humans. The developing brain acquires two crucial features, continuous spontaneous activity and its modulation by arousal state, around term in humans and before the onset of sensory experience in rodents. This developmental transition in cortical activity, as measured by electroencephalogram (EEG), is an important milestone for normal brain development and indicates a good prognosis for babies born preterm and/or suffering brain damage such as hypoxic-ischemic encephalopathy. By using the awake rodent visual system as a model, we identify changes occurring at the level of relay thalamus, the major input to cortex, as the critical driver of EEG maturation. These results could help understand the circuit basis of human EEG development to improve diagnosis and treatment of infants in vulnerable situations.
大脑皮层发育的两个主要检查点是获得连续的自发性活动和通过行为状态调节这种活动。尽管这些功能至关重要，但它们的发展电路机制仍然未知。在这里，我们使用啮齿动物视觉系统作为模型，来检验这样一个假设，即负责在感觉皮层中测量的连续性和状态依赖性的发育获得的回路变化的位置是中继丘脑，而不是局部皮质回路或这两个结构的互连性。我们在雄性和雌性清醒、头部固定的大鼠的背外侧膝状体核（dLGN）和初级视觉皮层（VC）中使用线性多电极阵列进行了同时记录，整个早期发育过程中都使用了这种方法。我们发现，dLGN 的活动在 P13 日变得连续且与运动（状态依赖性的一种衡量标准）呈正相关，这与 VC 的情况相同，并且这些特性不依赖于 VC 的活动。相比之下，在 P13 日之后沉默 dLGN 会导致 VC 中的活动变得不连续，运动抑制而不是增强皮质放电，有效地逆转了发育。丘脑爆发，一种非唤醒状态的核心特征，出现在 P16 日之后，表明这些过程在发育上是独立的。我们的结果表明，中继丘脑的细胞或回路变化是背景活动成熟的关键驱动因素，这种成熟发生在人类足月时。发育中的大脑在人类足月前后和啮齿动物感觉体验开始之前获得了两个关键特征，即连续的自发性活动及其对唤醒状态的调制。这种皮质活动的发育性转变，如脑电图（EEG）所测量的，是正常大脑发育的重要里程碑，并表明早产儿和/或患有缺氧缺血性脑病等脑损伤的婴儿预后良好。通过使用清醒的啮齿动物视觉系统作为模型，我们确定在中继丘脑（皮质的主要输入）水平上发生的变化是 EEG 成熟的关键驱动因素。这些结果可以帮助理解人类 EEG 发育的电路基础，以改善脆弱情况下婴儿的诊断和治疗。
