Molecular Mechanisms underlying Habituation in the Startle Reflex of Mammals

习惯化被认为是非联想学习的最基本形式。它描述了对重复的非威胁性感觉刺激的行为反应的减少，因此提供了一个重要的感觉过滤机制。精神分裂症或自闭症谱系障碍患者的习惯化受损，这会导致大脑高级区域的信息过载，从而导致认知缺陷。虽然习惯化在行为学上得到了很好的研究，但人们对其潜在的分子机制知之甚少。基于最近发现的一种进化高度保守的基本习惯机制，我将研究哺乳动物习惯化的分子机制。我将使用大鼠和转基因小鼠惊吓反应的习惯化作为模型。这使我能够将行为实验与一个成熟的体外脑切片模型结合起来，用于电生理单细胞记录。在提议的项目中，我将重点研究高压和钙激活的大电导钾通道（bk通道），它似乎是保守习惯机制的关键参与者。我将测试BK通道的激活是哺乳动物惊吓反应短期习惯化的原因，并研究其潜在机制。此外，我将探讨是否习惯可以通过各自的BK通道调制器增强。这些实验不仅将为非联想学习的潜在机制提供有价值的见解，而且将有助于确定治疗患者习惯缺陷的潜在药物。这种早期信息处理的药理学改善将有利于患有习惯性缺陷疾病（如精神分裂症和自闭症谱系障碍）的患者的认知功能。

Habituation is considered to be the most basic form of non-associative learning. It describes the decrease of behavioural response to repeated non-threatening sensory stimulation and therefore provides an important sensory filtering mechanism. Habituation is impaired in patients suffering from e.g. schizophrenia or autism spectrum disorders, which leads to information overload in higher brain areas causing cognitive deficits. While habituation is well studied behaviourally only little is known of the underlying molecular mechanisms. Based on a recent discovery of an evolutionary highly conserved fundamental habituation mechanism, I will investigate the molecular mechanisms underlying habituation of mammals. I will use habituation of the startle response in rats and transgenic mice as a model. This allows me to combine behavioural experiments with a well-established in vitro brain slice model for electrophysiological single cell recordings. In the proposed project I will focus on the high voltage- and calcium-activated, large-conductance potassium channel (BK-channel) that seems to be a key player in the conserved habituation mechanism. I will test the hypothesis that activation of BK channels is responsible for short-term habituation of the startle response in mammals and investigate the underlying mechanisms. Further, I will explore whether habituation can be enhanced by respective BK channel modulators. These experiments will not only give valuable insights into the mechanisms underlying non-associative learning but will help to identify potential drugs for a treatment of habituation deficits in patients. The pharmacological improvement of this early stage information processing will benefit cognitive functions in patients suffering from diseases involving habituation deficits, such as schizophrenia and autism spectrum disorders.