Interneuron precursors and the ability to open new periods of cortical plasticity

中间神经元前体和开启皮质可塑性新时期的能力

• 批准号: 8805486
• 负责人: JUAN S ESPINOSA
• 金额: $ 9.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805486
• 关键词: Adolescent; Adult; Age; Amblyopia; Amygdaloid structure; Animal Model; Anxiety Disorders; Award; Biological Models; Brain; Career Transition Award; Cell Transplantation; Cells; Clinical; Corpus striatum structure; Data; Embryo; Embryonic Development; Epilepsy; Eye; Genetic; Hippocampus (Brain); Injury; Interneurons; Laboratories; Learning; Measures; Medial; Mentors; Methods; Microelectrodes; Modification; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Neonatal; Nervous System Trauma; Neuraxis; Neurons; Neurosciences Research; Ocular Dominance; Optics; Parkinson Disease; Parvalbumins; Phase; Phencyclidine; Phenotype; Photic Stimulation; Physiology; Play; Population; Positioning Attribute; Process; Prosencephalon; Recovery of Function; Research; Research Personnel; Role; Scientist; Seizures; Somatostatin; Spinal cord injury; Stem cell transplant; Synaptic Transmission; Synaptic Vesicles; System; Techniques; Testing; Therapeutic; Therapeutic Uses; Transplantation; Vision; Visual; Visual Cortex; Work; brain repair; calcium indicator; career; cell type; critical period; embryonic stem cell; excitatory neuron; experience; functional outcomes; gamma-Aminobutyric Acid; improved; induced pluripotent stem cell; interest; mature animal; migration; monocular deprivation; neonatal hypoxic-ischemic brain injury; nervous system disorder; neural circuit; novel; post-doctoral training; programs; public health relevance; research study; response; tool; transmission process

DESCRIPTION (provided by applicant): The NINDS Advanced Postdoctoral Career Transition Award to Promote Diversity in Neuroscience Research (K22) will significantly facilitate the candidate's ability to begin a career as an independent scientist, by extending and developing his postdoctoral training and expertise in stem cell transplantation methods and sophisticated methods to measure plasticity. Most forebrain interneurons originate in the developing medial ganglionic eminence (MGE), from where they migrate into cortex, hippocampus, striatum, and amygdala to form local inhibitory circuits. When transplanted into the juvenile or adult mouse cortex, MGE cells retain the ability for migration, functional integration, and differentiation primarily into parvalbumin (PV) and somatostatin (SOM) expressing GABAergic cortical interneurons. Previous work has shown that GABAergic inhibition is required for the induction of cortical plasticity and brain repair. Recent work in the laboratory showed that transplantation of MGE cells into the neonatal or juvenile mouse visual cortex can induce a new period of ocular dominance plasticity (ODP). The ability of these cells to induce plasticity de novo also offers a powerful tool to study the mechanisms and limits of cortical plasticity. The present proposal has four Aims. In Aim 1, we will determine which type of cortical interneuron is responsible for the induction of cortical plasticity. We have developed and validated genetic tools to ablate PV, SOM, or both cell types from the MGE grafts. Previous research suggests that PV cells may be responsible for the induction of ODP, but this hypothesis has not been formally tested. Surprisingly, our preliminary studies suggest that ODP can still be opened, even when most PV cells are eliminated from MGE grafts. We will determine if SOM interneuron depletion is sufficient for the elimination of ODP, or whether both populations have the capacity to induce ODP. In Aim 2, we will determine if the transplantation of cortical interneurons can be extended to the adult brain to induce ODP and contribute to recovery of function. We have developed and validated optical recording techniques to study ODP induction in adult mice. The laboratory also has preliminary evidence that MGE cells grafted into the adult mouse cortex migrate and integrate, suggesting that they could also modify cortical circuits and possibly induce ODP. The independent phase of the Award, will focus on the study of activity-dependent mechanisms of transplant- induced cortical plasticity. In Aim 3, we will explore whether potent GABAergic transmission from transplanted MGE cells is necessary for de novo cortical plasticity. We will use genetic tools to block synaptic transmission and reduce by half GABAergic transmission in specific transplanted MGE cells. In Aim 4, we will use genetically encoded calcium indicators to measure the changes in visual responses to the two eyes in transplanted and endogenous PV+ and SOM+ interneurons during de novo competitive cortical plasticity. The identification of cortical interneurons responsible for the induction of plasticity, the age range and types of cortical plasticity that can be induced, the role of GABAergic transmission, and how transplanted MGE cells change during plasticity will provide valuable new information for the therapeutic use of MGE cells in brain repair. In summary, the research proposed in this Career Transition Award will prepare the candidate to develop a fully independent research program capable of integrating a wide range of cellular and molecular and systems approaches in a technically advanced and high impact manner, including: (i) cell transplantation methods to open new periods of cortical plasticity in juvenile and adult mice, (ii) multisite microelectrode recordingsin vivo to measure neuronal responses and plasticity in all cortical layers, (iii) genetic methods to manipulate synaptic transmission of specific inhibitory microcircuits, and (iv) a model system to study the mechanisms of cortical plasticity and their therapeutic potential.

描述（由申请人提供）：NINDS高级博士后职业过渡奖，以促进神经科学研究的多样性（K22）将显着促进候选人的能力，开始职业生涯作为一个独立的科学家，通过扩展和发展他的博士后培训和专业知识在干细胞移植方法和复杂的方法来测量可塑性。大多数前脑中间神经元起源于发育中的内侧神经节隆起（MGE），从那里它们迁移到皮质、海马、纹状体和杏仁核以形成局部抑制回路。当移植到幼年或成年小鼠皮质中时，MGE细胞保留迁移、功能整合和分化的能力，主要分化为表达GABA能皮质中间神经元的小清蛋白（PV）和生长抑素（SOM）。先前的工作表明，GABA能抑制是诱导皮质可塑性和脑修复所必需的。最近的实验室工作表明，将MGE细胞移植到新生或幼年小鼠的视皮层中可以诱导新的眼优势可塑性（ODP）时期。这些细胞重新诱导可塑性的能力也为研究皮质可塑性的机制和限制提供了有力的工具。目前的建议有四个目标。在目标1中，我们将确定哪种类型的皮质中间神经元负责诱导皮质可塑性。我们已经开发并验证了遗传工具，以消融PV，SOM，或两种细胞类型的MGE移植物。以前的研究表明，光伏电池可能是负责诱导ODP，但这一假设尚未得到正式验证。令人惊讶的是，我们的初步研究表明，ODP仍然可以打开，即使大多数PV细胞从MGE移植物中消除。我们将确定SOM中间神经元耗竭是否足以消除ODP，或者两个群体是否有能力诱导ODP。在目标2中，我们将确定皮质中间神经元的移植是否可以扩展到成年大脑以诱导ODP并有助于功能恢复。我们已经开发并验证了光学记录技术，以研究ODP诱导成年小鼠。该实验室也有初步证据表明，移植到成年小鼠皮层的MGE细胞迁移和整合，这表明它们也可以修改皮层回路，并可能诱导ODP。该奖项的独立阶段，将集中在移植诱导的皮层可塑性的活动依赖性机制的研究。在目标3中，我们将探讨是否从移植的MGE细胞有效的GABA能传输是必要的从头皮质可塑性。我们将使用遗传工具来阻断突触传递，并将特定移植的MGE细胞中的GABA能传递减少一半。在目标4中，我们将使用遗传编码的钙指标来测量在从头竞争性皮层可塑性过程中移植的和内源性PV+和SOM+中间神经元对双眼的视觉反应的变化。鉴定负责诱导可塑性的皮层中间神经元，可以诱导的皮层可塑性的年龄范围和类型，GABA能传递的作用，以及移植的MGE细胞在可塑性过程中如何变化，将为MGE细胞在脑修复中的治疗用途提供有价值的新信息。总之，在这个职业过渡奖提出的研究将准备候选人开发一个完全独立的研究计划，能够整合广泛的细胞和分子和系统的方法在技术先进和高影响力的方式，包括：（i）在幼年和成年小鼠中开启皮质可塑性的新时期的细胞移植方法，（ii）多位点微电极记录在体内测量所有皮层神经元的反应和可塑性，（iii）遗传方法来操纵特定抑制性微电路的突触传递，和（iv）模型系统来研究皮层可塑性的机制及其治疗潜力。