How Inhibition Shapes Neuronal and Behavioral Responses to Auditory Stimuli

描述（由候选人提供）：本提案的目的是研究抑制性中间神经元如何塑造皮层投射神经元的反应特性。中间神经元的多样性表明不同的亚型在皮层加工中起着不同的作用。此外，异常抑制回路可能是一些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，很难明确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划分的细胞群中表达感兴趣的基因成为可能。我建议使用这种技术，结合神经活动的光学控制，来检查特定的神经元间亚型的功能：那些表达小白蛋白的（PV+）和那些不表达的（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技术将光敏蛋白通道视紫红质-2 （ChR2）和halorhodopsin （Halo）靶向于听觉皮层的PV+和PV-中间神经元，在不同的转基因Cre驱动小鼠群体中，通过LoxP构建物的病毒传递。在生理记录期间，ChR2将用于光学“标记”PV+和PV-细胞，使我能够表征和比较它们的响应特性。在另一组实验中，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中声音诱发的活动。当PV+电池沉默时，我期望听觉反应更持久，更少稀疏，更少时间上的精确。PV-中间神经元的沉默可能影响突触的聚合和可塑性。最后，表达Halo的小鼠将接受听觉任务训练，我将研究沉默PV+ o PV-中间神经元如何影响听觉驱动行为。公共卫生相关性：更好地了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回路功能不正常时可能出现的问题。特别是，癫痫、精神分裂症、自闭症和焦虑等疾病被认为与大脑皮层中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能会指导各种脑部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.