Corollary Discharge in Genetic Mouse Models of Schizophrenia

该提案的目标是更深入地了解在精神分裂症患者中可靠观察到的感觉障碍，即区分自我产生的刺激和外部产生的刺激的障碍。许多冲击我们神经系统的刺激是由我们自己的行为直接引起的，需要与外部世界事件引起的刺激分开。长期以来，人们一直认为大脑通过必然放电来解决这个问题，即大脑信号，它代表了生物体行为的预期感官后果。有相当多的证据表明，这些必然的放电信号在精神分裂症患者中受损，这种干扰被假设为该疾病中观察到的幻觉和妄想的基础。本提案的目标是通过两种方式加深我们对精神分裂症的必然放电缺陷的理解：首先，详细检查这种缺陷背后的神经回路异常，其次，检查其与已知疾病风险因素的关系，特别是基因突变。为此，我们将检查两种小鼠系的必然放电，这两种小鼠系经过基因工程改造，携带代表精神分裂症主要危险因素的突变：22q11.2微缺失和DISC1突变。当这些小鼠通过按压杠杆触发听觉刺激时，将同时记录下来自听觉皮层和运动皮层多个部位的神经活动。因此，拟议的实验将有助于阐明易患精神分裂症的突变如何影响必然放电，以及它们的影响如何在单个神经元和神经回路的水平上表现出来。我们希望这一结果将进一步加深我们对大脑在健康和疾病状态下如何处理自我产生的刺激的理解。

The goal of the proposal is to gain a deeper understanding of a sensory disturbance that has been reliably observed in schizophrenia patients, namely an impairment in distinguishing self-generated from externally generated stimuli. Many of the stimuli that impinge on our nervous system are caused directly by our own actions and need to be separated from stimuli arising from events in the external world. It has long been assumed that the brain solves this problem using corollary discharge, brain signals that represent the expected sensory consequences of the organisms actions. There is considerable evidence suggesting that these corollary discharge signals are impaired in schizophrenia patients and this disturbance has been hypothesized to underlie the hallucinations and delusions that are observed in the disease. The goal of this proposal is to deepen our understanding of corollary discharge deficits in schizophrenia in two ways: first, to examine in detail the neural circuit abnormalities underlying this deficit and second, to examine its relationship to known risk factors for the disease, in particular genetic mutations. To this end, we will examine corollary discharge in two mouse lines that have been genetically engineered to carry mutations that represent major risk factors for schizophrenia: the 22q11.2 microdeletion and the DISC1 mutation. Neural activity will be recorded simultaneously in multiple sites from both the auditory cortex and motor cortex of these mice while they trigger auditory stimuli by pressing a lever. The proposed experiments will thus help shed light on how mutations that predispose to schizophrenia affect corollary discharge and how their effects manifest themselves at the level of individual neurons and neural circuits. We hope that the results will further our understanding of how the brain processes self-generated stimuli in both healthy and diseased states.