How Inhibition Shapes Neuronal and Behavioral Responses to Auditory Stimuli

描述(由候选者提供)：这项建议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，不同的亚型在皮质加工中发挥着不同的作用。此外，异常的抑制回路可能是几种神经和精神疾病的基础，如癫痫、精神分裂症、自闭症和焦虑。然而，到目前为止，还很难具体地针对和操纵单个神经元间类。最近，细胞类型特异性启动子的使用使得在基因分隔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，来检查特定神经元间亚型的功能：表达小白蛋白(PV+)的和不表达小白蛋白(PV-)的。我的中心假设是，PV+中间神经元介导快速声诱发的突触抑制，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技术靶向视紫红质-2(ChR2)和卤视紫红质(Halo)的光敏蛋白质通道到听觉皮质中的PV+和PV-中间神经元，在不同的Cre转基因驱动鼠群体中，通过病毒传递loxP构建。ChR2将被用来在生理记录期间对PV+和PV-细胞进行光学标记，使我能够表征和比较它们的响应特性。在另一组实验中，我将使用Halo选择性地使PV+或PV-细胞沉默，并观察这如何影响清醒小鼠听觉皮质中的声音诱发活动。当PV+细胞被沉默时，我预计听觉反应会更持续，不那么稀疏，在时间上也不那么精确。PV中间神经元的沉默可能影响突触的总和和可塑性。最后，表达Halo的小鼠将接受听觉任务的训练，我将调查沉默PV+o PV-中间神经元如何影响听觉驱动行为。与公共健康相关：更好地理解不同类型的神经元是如何协同工作的，将有助于揭示当大脑电路不能正常工作时，会出现什么问题。特别是，癫痫、精神分裂症、自闭症和焦虑等疾病被认为涉及大脑皮层抑制网络的异常。探索神经活动、感知和行为之间的联系可能会指导各种大脑疾病的治疗策略的发展。

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.