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

解开精神分裂症小鼠模型皮质异常的遗传和经验危险因素

• 批准号: MR/Y014693/1
• 负责人: Jennifer Linden
• 金额: $ 78.21万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY014693%2F1
• 关键词: Disentangling; Genetic; Experiential; Risk; Factors

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.

基因和经验如何相互作用导致精神疾病？解决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中建立的独特实验系统来解开精神分裂症的遗传和经验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，导致皮层功能异常。听力障碍被称为“被忽视的精神病风险因素”。纵向研究已经将早期听力损伤与后来的精神分裂症诊断联系起来，并将成年听力损伤与随后的精神病经历（包括幻听）联系起来。这些纵向关联的机制尚不清楚，但可能包括听力障碍和精神病的共同原因，或听力障碍对大脑的因果影响。听觉障碍在幻听出现中的因果作用在机制上是合理的，因为已知听觉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，听觉障碍引起的皮层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观察到的皮层兴奋和抑制的破坏。听觉障碍的经历是否会加剧精神分裂症遗传易感性引起的皮层异常，从而成为精神疾病的"第二次打击"？或者精神分裂症的遗传易感性和听力受损的经历对皮层功能有很大程度上独立的、非重叠的影响？我们建议使用人类22q11.2缺失综合征（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，也会导致中耳问题，降低听力。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模型小鼠可以具有正常的听力或中耳问题引起的轻度至中度听力障碍。在这里，我们将研究如何测量皮质功能的不同与听力能力在各个22q11.2DS模型小鼠，以确定大脑异常和听力障碍之间的关系，在精神分裂症的遗传易感性的存在。我们还将研究相同的皮质功能测量如何随着听力正常的遗传正常（野生型）小鼠的听力或实验诱导的轻度至中度听力障碍而变化。22q11.2DS模型小鼠和野生型小鼠之间的比较结果将使我们能够区分基因型和听力障碍之间的独立和协同作用，该项目的主要预期成果是在理解精神分裂症的遗传和经验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层功能有独立的、非重叠的影响，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）遗传风险的皮层后果。相反，如果听力障碍的经历加剧了由精神分裂症的遗传易感性引起的皮质异常，那么实验将提供听力障碍可能是精神疾病的因果贡献者的机械证据。