The Development and Integration of Early Born SST-Expressing

早期出生 SST 表达的发展和整合

• 批准号: 10176605
• 负责人: GORDON J FISHELL
• 金额: $ 53.57万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176605
• 关键词: Affective; Area; Award; Behavioral; Brain Diseases; Cells; Cerebral cortex; Development; Disease; Epigenetic Process; Epilepsy; Etiology; Event; Excision; Funding; Genetic; Goals; Grant; Hindlimb; Interneurons; Knockout Mice; Laboratories; Mediating; Metabotropic Glutamate Receptors; Minority; Molecular; Morphology; Mutation; Nature; Paper; Parvalbumins; Perception; Perinatal; Physiological; Population; Publishing; Reflex action; Role; Schizophrenia; Seizures; Sensory; Signal Transduction; Sleep; Somatosensory Cortex; Somatostatin; Structure; Testing; Thalamic structure; Visual; Work; area striata; barrel cortex; critical period; executive function; experimental study; glutamatergic signaling; hippocampal pyramidal neuron; nervous system disorder; progenitor; risk variant; somatosensory; transcription factor

In the studies supported during the previous funding period we discovered that perinatally deep layer SST-cINs but not PV-cINs within the barrel cortex receive strong but transient input from the ventrobasal thalamus. In addition, perturbations to the connectivity of early born deep layer SST-cIN within the somatosensory cortex have a lasting impact on the subsequent establishment of the feedforward inhibitory circuits formed between PV cINs and deep layer pyramidal neurons. Our goals within the present proposal are two-fold. First, we wish to determine whether our previous findings reflect a general principle underlying the establishment of inhibitory cortical circuitry (Aim 1) by examining the interactions between thalamus, SST and PV cINs within regions of the cortex that either subserve a similar sensory role in perception (i.e. visual) or markedly different executive functions (i.e. prefrontal). Moreover, we will leverage our previous findings to explore the physiological and molecular mechanisms underlying these events in the somatosensory cortex. Preliminary findings presented here demonstrate a requirement for activity for the maturation of both SST and PV cINs. In Aim 2, we will explore the hypothesis that the mode of glutamate- signaling within developing SST cINs controls their connectivity. Specifically, we will test the hypothesis that ionotropic AMPA-mediated signaling promotes maturation and connectivity of SST cINs, while mGluR1/5 metabotropic-mediated signaling acts to limit this connectivity. Finally, in Aim 3, we will examine the molecular changes that occur within SST and PV cINs during the periods when these events occur. We will also explore the requirement for the NURD-associated transcription factor SatB1, which is activity- dependent and is required for the maturation of SST and PV cINs both in the establishment of L5/6 inhibitory circuitry.

在上一个资助期间支持的研究中，我们发现围产期深层 桶状皮层内的 SST-cIN 而不是 PV-cIN 接收来自腹基底层的强烈但短暂的输入 丘脑。此外，对早期出生的深层 SST-cIN 的连接性的干扰 体感皮层对前馈抑制的后续建立有持久的影响 PV cIN 和深层锥体神经元之间形成的电路。我们在当前提案中的目标 有两重。首先，我们希望确定我们之前的发现是否反映了潜在的一般原则 通过检查丘脑之间的相互作用来建立抑制性皮质回路（目标 1）， 皮质区域内的 SST 和 PV cIN 在感知中发挥类似的感觉作用（即 视觉）或明显不同的执行功能（即前额叶）。此外，我们将利用我们之前的 研究结果旨在探索这些事件背后的生理和分子机制 体感皮层。这里提出的初步结果表明了对活动的要求 SST 和 PV cIN 的成熟。在目标 2 中，我们将探讨谷氨酸模式的假设 发育中的 SST cIN 内的信号传导控制着它们的连接。具体来说，我们将检验假设 离子型 AMPA 介导的信号传导促进 SST cIN 的成熟和连接，同时 mGluR1/5 代谢介导的信号传导可限制这种连接。最后，在目标 3 中，我们将检查 在这些事件发生期间，SST 和 PV cIN 内发生的分子变化。我们 还将探索 NURD 相关转录因子 SatB1 的需求，该因子的活性是 依赖，并且是 L5/6 建立过程中 SST 和 PV cIN 成熟所必需的 抑制电路。