Disentangling Genetic and Experiential Risk Factors for Cortical Abnormalities in a Mouse Model of Schizophrenia

基因和经验是如何相互作用而导致精神疾病的？回答这个问题是神经科学和心理健康研究面临的最大挑战之一。在这里，我们将利用我们在小鼠身上建立的一个独特的实验系统来分离精神分裂症的遗传和经验性风险因素对大脑的影响。更具体地说，我们的目标是了解精神分裂症的遗传易感性和听力障碍的经历如何相互作用，导致皮质功能异常。听力障碍被称为“被忽视的精神病风险因素”。纵向研究已将早期听力障碍与后来的精神分裂症诊断联系起来，并将成年听力障碍与随后的精神病经历(包括幻听)联系起来。这些纵向联系背后的机制尚不清楚，但可能包括听力障碍和精神病的共同原因，或听力障碍经历对大脑的因果影响。听力障碍在幻听出现中的因果作用在机制上是可信的，因为众所周知，听力障碍的经历会增加听觉大脑中神经元的自发和相关活动。此外，听力障碍经历引起的皮质功能变化类似于在精神分裂症患者和精神分裂症动物模型中也观察到的皮质兴奋和抑制障碍。听力障碍经历是否会加剧精神分裂症遗传易感性引起的皮质异常，成为精神疾病的第二次打击？或者精神分裂症的遗传易感性和听力障碍的经历在很大程度上是独立的、不重叠的对皮质功能的影响？我们建议使用人类22q11.2缺失综合症(22q11.2DS)的小鼠模型对这两种可能性进行第一次严格的实验测试。22q11.2染色体微缺失是精神分裂症最重要的已知遗传风险因素之一，在某些情况下，还会导致听力下降的中耳问题。因此，一些22q11.2DS患者听力正常，而另一些患者则有轻度至中度听力障碍。我们之前已经证明，就像22q11.2DS患者一样，22q11.2DS模型鼠可以有正常的听力，也可以有由于中耳问题而造成的轻度到中度听力障碍。在这里，我们将研究22q11.2DS模型小鼠的皮质功能指标如何随着听力的变化而变化，以确定在精神分裂症遗传易感性存在的情况下，大脑异常和听力障碍之间的关系。我们还将研究在听力正常或实验诱导的轻度至中度听力障碍的遗传正常(野生型)小鼠中，皮质功能的相同指标如何随听力能力的变化而变化。比较22q11.2DS模型小鼠和野生型小鼠的结果将使我们能够区分基因和听力障碍的独立和协同效应。该项目的主要预期结果是在理解精神分裂症的遗传和经验性危险因素如何引起皮质功能障碍方面取得突破。如果精神分裂症的遗传易感性和听力障碍的经历在很大程度上对皮质功能有独立、不重叠的影响，那么这两种影响之间的对比将有助于更清楚地定义精神分裂症(和听力障碍的经历)遗传风险的皮质后果。相反，如果听力障碍的经历加剧了由于精神分裂症的遗传脆弱性而引起的皮质异常，那么这些实验将提供机制证据，证明听力障碍可能是精神疾病的原因之一。

How do genes and experience interact to cause psychiatric disease? Answering this question is one of the greatest challenges for neuroscience and mental health research. Here, we will leverage a unique experimental system we have established in mice to disentangle effects of genetic and experiential risk factors for schizophrenia on the brain. More specifically, we aim to understand how genetic vulnerability to schizophrenia and experience of hearing impairment interact to cause abnormalities in cortical function.Hearing impairment has been called the "neglected risk factor for psychosis". Longitudinal studies have linked early hearing impairment with later schizophrenia diagnosis, and adulthood hearing impairment with subsequent psychotic experiences including auditory hallucinations. The mechanisms underlying these longitudinal associations are unknown, but could include common causes of both hearing impairment and psychosis, or causal effects of experience of hearing impairment on the brain. A causal role for hearing impairment in emergence of auditory hallucinations is mechanistically plausible, because the experience of hearing impairment is known to increase spontaneous and correlated activity of neurons in the auditory brain. Moreover, changes in cortical function caused by experience of hearing impairment resemble disruptions of cortical excitation and inhibition that have also been observed in schizophrenia patients and in animal models of schizophrenia.Could experience of hearing impairment exacerbate cortical abnormalities arising from genetic vulnerability to schizophrenia, acting as a "second hit" for psychiatric disease? Or do genetic vulnerability to schizophrenia and experience of hearing impairment have largely independent, non-overlapping effects on cortical function? We propose to perform the first rigorous experimental test of these two possibilities, using a mouse model of human 22q11.2 Deletion Syndrome (22q11.2DS). The 22q11.2 chromosomal microdeletion is one of the most significant known genetic risk factors for schizophrenia, and in some cases, also causes middle-ear problems that reduce hearing ability. Thus, some 22q11.2DS patients have normal hearing while others have mild to moderate hearing impairment. We have previously shown that just like 22q11.2DS patients, 22q11.2DS model mice can have either normal hearing or mild to moderate hearing impairment from middle-ear problems. Here, we will examine how measures of cortical function vary with hearing ability across individual 22q11.2DS model mice, to determine the relationship between brain abnormalities and hearing impairment in the presence of genetic vulnerability to schizophrenia. We will also examine how the same measures of cortical function vary with hearing ability across genetically normal (wildtype) mice with normal hearing or experimentally induced mild to moderate hearing impairment. Comparing results between 22q11.2DS model mice and wildtype mice will enable us to distinguish between independent and synergistic effects of genotype and hearing impairment.The main expected outcome of this project is a breakthrough in understanding how cortical dysfunction arises from genetic and experiential risk factors for schizophrenia. If genetic vulnerability to schizophrenia and experience of hearing impairment have largely independent, non-overlapping effects on cortical function, then the contrast between the two effects will help to define the cortical consequences of genetic risk for schizophrenia (and experience of hearing impairment) more clearly. Conversely, if experience of hearing impairment exacerbates cortical abnormalities arising from genetic vulnerability to schizophrenia, then the experiments will provide mechanistic evidence that hearing impairment may be a causal contributor to psychiatric disease.