How Inhibition Shapes Neuronal and Behavioral Responses to Auditory Stimuli

抑制如何塑造神经元和行为对听觉刺激的反应

• 批准号: 7674943
• 负责人: KATHARINE BORGES
• 金额: $ 5.01万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-16 至 2012-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674943
• 关键词: Accounting; Affect; Albumins; Animals; Anxiety; Auditory; Auditory area; Autistic Disorder; Behavior; Behavioral; Brain; Brain Diseases; Calcium-Binding Proteins; Cells; Cerebral cortex; Complex; Dendrites; Development; Disease; Distal; Epilepsy; Fire - disasters; Frequencies; Genes; Goals; Halorhodopsins; Hand; Individual; Injection of therapeutic agent; Interneurons; Ion Channel; Light; Link; Mediating; Mental disorders; Mus; Neurologic; Neurons; Optics; Pan Genus; Parvalbumins; Pattern; Perception; Physiological; Play; Population; Process; Property; Proteins; Pump; Research; Role; Schizophrenia; Shapes; Stimulus; Synapses; System; Technology; Testing; Training; Transgenic Mice; Transgenic Organisms; Viral; Virus; Work; auditory stimulus; awake; cell type; driving behavior; interest; millisecond; neurophysiology; neuroregulation; postsynaptic; promoter; public health relevance; receptive field; recombinase; relating to nervous system; research study; response; sound; synaptic inhibition; therapeutic development

DESCRIPTION (provided by candidate): The goal of this proposal is to investigate how inhibitory interneurons shape the response properties of cortical projection neurons. The great diversity of interneurons suggests that different subtypes play distinct roles in cortical processing. In addition, abnormal inhibitory circuitry may underlie several neurological and psychiatric disorders, such as epilepsy, schizophrenia, autism, and anxiety. However, thus far it has been difficult to specifically target and manipulate individual interneuronal classes. Recently, the use of cell-type-specific promoters has made it possible to express genes of interest in genetically-delimited groups of cells. I propose to use this technology, in conjunction with optical control of neural activity, to examine the function of specific interneuronal subtypes: those that express parvalbumin (PV+), and those that do not (PV-). My central hypothesis is that PV+ interneurons mediate fast sound-evoked synaptic inhibition, whereas PV- interneurons play a role in dendritic integration and plasticity. I will use Cre/LoxP technology to target the light-sensitive proteins channelrhodopsin-2 (ChR2) and halorhodopsin (Halo) to PV+ and PV- interneurons in auditory cortex, in separate populations of transgenic Cre driver mice, with viral delivery of loxP constructs. ChR2 will be used to optically "tag" PV+ and PV- cells during physiological recordings, allowing me to characterize and compare their response properties. In a separate set of experiments, I will use Halo to selectively silence either PV+ or PV- cells, and observe how this affects sound-evoked activity in auditory cortex in awake mice. When PV+ cells are silenced, I expect auditory responses to be more sustained, less sparse, and less temporally precise. The silencing of PV- interneurons may affect synaptic summation and plasticity. Finally, mice expressing Halo will be trained on auditory tasks, and I will investigate how silencing PV+ o PV- interneurons affects auditory-driven behaviors. PUBLIC HEALTH RELEVANCE: better understanding of how different types of neurons work together will shed light on what can go wrong when brain circuits do not function properly. In particular, disorders such as epilepsy, schizophrenia, autism, and anxiety are thought to involve abnormalities of inhibitory networks in the cerebral cortex. Exploring the link between neural activity, perception, and behavior may guide the development of therapeutic strategies for a variety of brain disorders.

描述（由候选人提供）：该提案的目标是研究抑制性中间神经元如何塑造皮质投射神经元的反应特性。中间神经元的巨大多样性表明不同的亚型在皮质处理中发挥着不同的作用。此外，异常的抑制回路可能是多种神经和精神疾病的基础，例如癫痫、精神分裂症、自闭症和焦虑症。然而，到目前为止，还很难专门针对和操纵单个中间神经元类别。最近，细胞类型特异性启动子的使用使得在遗传限定的细胞群中表达感兴趣的基因成为可能。我建议使用这项技术，结合神经活动的光学控制，来检查特定中间神经元亚型的功能：表达小清蛋白的亚型 (PV+) 和不表达小清蛋白的亚型 (PV-)。我的中心假设是 PV+ 中间神经元介导快速声音诱发的突触抑制，而 PV- 中间神经元在树突整合和可塑性中发挥作用。我将使用 Cre/LoxP 技术，在单独的转基因 Cre 驱动小鼠群体中，通过病毒传递 loxP 构建体，将光敏蛋白通道视紫红质-2 (ChR2) 和盐视紫红质 (Halo) 靶向听觉皮层中的 PV+ 和 PV- 中间神经元。 ChR2 将用于在生理记录期间光学“标记”PV+ 和 PV- 细胞，使我能够表征和比较它们的响应特性。在一组单独的实验中，我将使用 Halo 选择性地沉默 PV+ 或 PV- 细胞，并观察这如何影响清醒小鼠听觉皮层的声音诱发活动。当 PV+ 细胞沉默时，我预计听觉反应会更加持续、不那么稀疏，并且在时间上不那么精确。 PV-中间神经元的沉默可能影响突触总和和可塑性。最后，表达 Halo 的小鼠将接受听觉任务训练，我将研究沉默 PV+ 或 PV- 中间神经元如何影响听觉驱动的行为。公共健康相关性：更好地了解不同类型的神经元如何协同工作将有助于揭示当大脑回路无法正常运行时可能出现的问题。特别是，癫痫、精神分裂症、自闭症和焦虑症等疾病被认为与大脑皮层抑制网络的异常有关。探索神经活动、感知和行为之间的联系可以指导各种脑部疾病治疗策略的制定。