Cellular Physiology of Neuronal Circuits in Neocortex

描述（由申请人提供）：丘脑和新皮层对于正常的感觉、运动和认知是必不可少的，它们之间有着密切的、不可分割的联系。丘脑是几乎所有进入新皮层的特定信息的来源，而新皮层反过来又向丘脑发送大量反馈。丘脑和新皮层中的特异性抑制神经元是丘脑皮质系统信息流的关键调节器。我的建议的中心目标是了解这些抑制性神经元及其突触的不同功能。主要有四个方面：1)研究两种不同类型的新皮层抑制性中间神经元及其在丘脑皮质加工早期阶段的作用；2)研究这些中间神经元在大脑皮层局部回路中的作用；3)检测抑制功能的活性依赖性和状态依赖性；4)表征丘脑网状核之间、之间和内部的突触连接。我们将使用转基因小鼠系来鉴定和选择感兴趣的神经元，各种体外方法来记录鉴定的中间神经元，解剖学方法来验证和表征神经元类型，以及药理学和分子工具来操纵细胞和突触。提出的实验将为丘脑皮质系统中抑制的细胞机制提供新颖而重要的见解。这一信息将对我们理解感觉、运动和认知加工及其障碍的机制至关重要。描述：大脑皮层和它的伙伴丘脑，是对最复杂和独特的人类行为至关重要的大脑区域。皮层和丘脑中抑制性神经细胞的异常与癫痫、精神分裂症、焦虑和其他神经和精神疾病有关。本文提出的实验将表征抑制细胞的正常功能，以便更合理地评估其在疾病中的作用。

DESCRIPTION (provided by applicant): The thalamus and neocortex are essential for normal sensation, movement, and cognition, and they work in intimate, inextricable association. The thalamus is the origin of virtually all specific information entering the neocortex, and the neocortex in turn sends massive feedback to the thalamus. Specific inhibitory neurons in both the thalamus and neocortex are critical regulators of information flow through the thalamocortical system. The central goal of my proposal is to understand the diverse functions of some of these inhibitory neurons and their synapses. There are four specific aims: 1) To characterize two distinctly different types of neocortical inhibitory interneurons and their roles in the earliest stages of thalamocortical processing; 2) To characterize the roles of these interneurons in local circuits in the neocortex; 3) To test the activity- and state-dependence of inhibitory functions; 4) To characterize synaptic connections to, from, and within the thalamic reticular nucleus. We will use transgenic lines of mice to identify and select the neurons of interest, a variety of in vitro methods to record from identified interneurons, anatomical methods to verify and characterize neuron types, and pharmacological and molecular tools to manipulate cells and synapses. The proposed experiments will provide novel and important insight into the cellular mechanisms of inhibition in the thalamocortical system. This information will be of central importance to our understanding of the mechanisms of sensory, motor, and cognitive processing and their disorders. Description: The cerebral cortex and its partner, the thalamus, are brain regions critical for the most complex and uniquely human behaviors. Abnormalities of inhibitory nerve cells in the cortex and thalamus have been implicated in epilepsy, schizophrenia, anxiety, and other neurological and psychiatric diseases. The experiments proposed here will characterize the normal functions of inhibitory cells, so that their roles in disease can be more rationally evaluated.