GABA deficit hypothesis of impaired visual inhibition in schizophrenia

描述（由申请人提供）：认知缺陷现在被认为是精神分裂症残疾的一个重要原因，精神分裂症是一种常见的使人衰弱的疾病。目前可用的治疗方法对认知缺陷的效果最好。这种情况要求阐明负责认知缺陷的神经机制，以便开发新的治疗方法。鉴于精神分裂症的复杂性，这一目标首先需要确定特定的受损认知过程，以便将其映射到特定的潜在神经通路和过程。由于普遍缺陷的存在和精神分裂症中一些最显著的认知缺陷的复杂性，这些目标已被证明是非常困难的。这个项目通过关注一个相对简单的信息处理途径来解决这些挑战，这个途径的功能神经解剖学是相对众所周知的。我们将运用视觉心理物理学中复杂的实验设计和方法来控制广义缺陷，并确定视觉加工中认知抑制的特定缺陷。我们将把这种方法与磁共振波谱相结合，以检验GABA缺乏与精神分裂症视觉加工的认知抑制之间的关联假设。这个项目的成功完成将代表一系列研究中的第一个，这些研究最终将导致精神分裂症认知过程受损的神经机制的首次展示。这项工作有望产生潜在的疾病生物标志物和信息处理缺陷的微电路水平模型。该模型系统将促进未来遗传学、分子和细胞研究，以充分了解精神分裂症认知缺陷的神经生物学基础，并开发针对它们的新治疗方法。

DESCRIPTION (provided by applicant): Cognitive deficits are now recognized as a significant source of disability in schizophrenia, which is a common, debilitating illness. Currently available treatments have, at best, modest effects on cognitive deficits. This situation calls for the elucidation of the neural mechanisms responsible for the cognitive deficits so that novel treatments can be developed. Given the complexity of schizophrenia, this goal requires first the identification of a specific impaired cognitive process so that it can be mapped onto specific underlying neural pathways and processes. These goals have proven very difficult due to the presence of generalized deficits and the complexity of some of the most notable cognitive deficits in schizophrenia. This project addresses these challenges by focusing on a relatively simple information process pathway whose functional neuroanatomy is relatively well known. We will apply the sophisticated experimental designs and methods utilized in visual psychophysics to control for generalized deficits and to identify a specific deficit in cognitive inhibition in visual processing. We will combine this approach with magnetic resonance spectroscopy to test the hypothesis of an association between GABA deficiency and cognitive inhibition of visual processing in schizophrenia. The successful completion of this project will represent the first in a series of studies that will eventually lead to one of the first demonstrations of a neural mechanism of an impaired cognitive process in schizophrenia. This work promises to yield potential disease biomarkers and a micro-circuit level model of information processing deficits. This model system will facilitate future genetics, molecular and cellular studies relevant to the full understanding of the neurobiological bases of cognitive deficits in schizophrenia, and to the development of new treatments targeting them. PUBLIC HEALTH RELEVANCE: The cognitive deficits in schizophrenia represent a tremendous public health burden yet we still know very little about their neural bases. This project will study the neural mechanism of a specific information processing pathway impaired in schizophrenia by testing the hypothesis that deficiencies in GABA is associated with abnormalities in visual inhibition. This and related future studies will lead to one of the first demonstrations of a neural mechanism of cognitive deficits in schizophrenia and may lead to the identification of new biomarkers and the development of targeted therapies for cognitive deficits in schizophrenia.