Roles of neuronal integrative mechanisms in olivo-cerebellar networks and motor behaviour

大脑是人体最复杂的器官。大脑的一个重要功能是将大量信息组织或整合成一种连贯的形式，使我们能够以某种方式行事或行动，并对事件做出适当的反应。越来越多的证据表明，常见的精神疾病，如精神分裂症和自闭症，涉及大脑无法正确整合信息。然而，由于缺乏选择性地操纵神经元活动整合的工具，因此很难研究神经元整合机制在正常行为或疾病中的作用。这项研究建立在最近的工作基础上，我发现在小鼠中缺失HCN 1基因，该基因编码一种对神经元整合很重要的离子通道，导致行为发生微妙但深刻的变化。特别是，HCN 1离子通道的缺失会损害协调运动的学习，但会增强复杂空间导航问题的学习。这项工作表明，HCN 1基因缺失的小鼠可能是研究神经元整合机制如何影响学习和行为的重要模型。然而，删除HCN 1通道改变行为的具体机制尚不清楚。在本研究中，我们将开发两个新的研究方向。首先，我们将确定HCN 1通道如何影响下橄榄核神经元的整合，下橄榄核是一个对运动行为很重要的大脑区域，与包括自闭症在内的大脑疾病有关。其次，我们将探讨当HCN 1通道的基因缺失仅限于另一类重要的神经元（小脑浦肯野细胞）时，运动行为是如何受到影响的。浦肯野细胞是小脑皮质的输出神经元，它们的变性是许多常见形式的共济失调的基础。这项研究将为大脑中用于整合和编码信息的细胞机制提供新的见解，并将为研究和理解神经元整合机制在疾病中的作用建立原则。这可能会导致更好地了解大脑功能的基本机制，并可能为常见的精神和神经疾病提出新的治疗方法。

The brain is the most complex organ in the body. A vital function of the brain is to organize or integrate vast quantities of information into a coherent form that enables us to behave or act in certain ways and to respond to events appropriately. There is increasing evidence to suggest that common psychiatric disorders, such as schizophrenia and autism, involve failure of the brain to integrate information correctly. However, because of an absence of tools that selectively manipulate integration of neuronal activity, it has been difficult to study the roles of neuronal integrative mechanisms in normal behavior or in disease. This study builds on recent work in which I found that deletion in mice of the HCN1 gene, which encodes an ion channel important for neuronal integration, leads to subtle, but profound changes in behaviour. In particular, deletion of HCN1 ion channels impairs learning of coordinated movements, but enhances learning of complex spatial navigation problems. This work indicates that mice with deletion of the HCN1 gene may be an important model to study how neuronal integrative mechanisms influence learning and behavior. However, the specific mechanisms through which deletion of HCN1 channels modify behaviour are not yet clear. In the present study we will develop two new directions for investigation. First, we will determine how HCN1 channels influence integration by neurons in the inferior olive, a brain region important for motor behavior and implicated in brain disorders including autism. Second, we will ask how motor behavior is affected when genetic deletion of the HCN1 channel is restricted to another important class of neuron, the cerebellar Purkinje cell. Purkinje cells are the output neurons of the cerebellar cortex and their degeneration underlies many common forms of ataxia. This study will give new insights into the cellular mechanisms used for integration and encoding of information in the brain and will establish principles for investigating and understanding the roles of neuronal integrative mechanisms in disease. This could lead to a better understanding of the fundamental mechanisms of brain function and may suggest new therapeutic approaches for common psychiatric and neurological disorders.