Experience-Dependent Plasticity of Neocortical Inhibitory Networks

新皮质抑制网络的经验依赖性可塑性

• 批准号: 7848596
• 负责人: Qian-Quan Sun
• 金额: $ 4.29万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848596
• 关键词: Address; Affect; Biological Models; Biological Neural Networks; Brain; Calcium; Cells; Cerebral cortex; Chemosensitization; Data; Development; Epilepsy; Equilibrium; Excitatory Synapse; Exhibits; Figs - dietary; Glutamate Receptor; Glutamates; Goals; Green Fluorescent Proteins; In Vitro; Individual; Inhibitory Synapse; Interneurons; Intervention; Label; Lead; Life; Literature; Measures; Mediating; Mental disorders; Metabotropic Glutamate Receptors; Modification; Molecular; Myoepithelial cell; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neocortex; Neurologic; Neurons; Pathway interactions; Pattern; Peripheral; Play; Preparation; Principal Investigator; Process; Research; Research Personnel; Rodent; Role; Sense Organs; Sensory; Sensory Deprivation; Shapes; Signal Transduction; Slice; Staging; Synapses; Synaptic Transmission; Synaptic plasticity; System; The Sun; Time; Transgenic Mice; Transgenic Organisms; Translating; Vibrissae; barrel cortex; critical period; excitatory neuron; experience; feeding; gamma-Aminobutyric Acid; in vivo; inhibitory neuron; neocortical; neuron development; novel; postnatal; programs; ranpirnase; receptive field; receptor; research study; sensory cortex; synaptic inhibition; transmission process; treatment strategy

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand mechanisms by which developing neocortical inhibitory circuits are able to adapt to sensory inputs from the peripheral sense organs, and to maintain their balance with the cortical excitatory circuits in the sensory cortex. During brain development, neurons in the cerebral cortex establish connections that are then fine tuned by experience-dependent mechanisms. Although much is now known regarding processes of glutamatergic maturation and activity-dependent modification of glutamatergic synapses for network formation, postnatal development of neocortical GABAergic synapses and their role in activity-dependent modification remains unclear. Mechanisms that match excitation and inhibition are central to attaining balanced function at the level of single neurons and brain circuits. Disturbances in the balance between excitation and inhibition in the neocortex provoke abnormal activities, such as epileptic seizures. The central hypothesis examined by this proposal is that the spike-timing dependent long-term plasticity of glutamatergic synapses in inhibitory interneurons plays an important role in experience-dependent refinement of interneuronal networks. The proposed research will utilize a combination of electrophysiological recording, pharmacological manipulations and quantitative immunohistological analysis to examine mechanisms underlying experience-dependent maturation of intracortical inhibitory networks. The synaptic strength underlying cortical plasticity will be measured from green-fluorescent protein labeled interneurons from brain slices prepared from transgenic mice, in which whisker experience was altered in the postnatal periods. This approach allows linkages to be made between amounts of intracortical synaptic plasticity recorded in vitro and previous sensory experiences in vivo. Successful completion of this study will provide a comprehensive view of the roles of sensory experiences in shaping inhibitory synaptic connectivity at early stages of life and mechanisms underlying excitation and inhibition balancing. This information could have implications for developing novel treatment strategies for developmental neurological and psychiatric disorders that result from aberrant connectivity among neocortical principal neurons and interneurons.

描述（由申请人提供）：本研究的长期目标是了解发育中的新皮层抑制回路能够适应来自周围感觉器官的感觉输入的机制，并保持它们与感觉皮层皮层兴奋回路的平衡。在大脑发育过程中，大脑皮层中的神经元建立连接，然后通过经验依赖机制进行微调。尽管目前对谷氨酸能成熟过程和谷氨酸能突触在网络形成过程中的活性依赖性修饰了解甚多，但新皮质gaba能突触的出生后发育及其在活性依赖性修饰中的作用仍不清楚。在单个神经元和脑回路的水平上，匹配兴奋和抑制的机制是实现平衡功能的核心。新皮层兴奋和抑制之间的平衡受到干扰会引起异常活动，如癫痫发作。本研究的中心假设是抑制性中间神经元中谷氨酸能突触的长时可塑性在神经元网络的经验依赖性细化中起重要作用。该研究将结合电生理记录、药理学操作和定量免疫组织学分析来研究皮层内抑制网络经验依赖成熟的机制。皮层可塑性的突触强度将通过绿色荧光蛋白标记的中间神经元来测量，这些中间神经元来自转基因小鼠制备的脑切片，其中须经历在出生后被改变。这种方法允许在体外记录的皮质内突触可塑性数量与体内先前的感觉体验之间建立联系。这项研究的成功完成将提供一个全面的观点，在形成抑制性突触连接的早期阶段的感觉经验的作用和机制背后的兴奋和抑制平衡。这一信息可能对新皮层主神经元和中间神经元之间异常连接导致的发育性神经和精神疾病的新治疗策略产生影响。