Novel Interneurons Mediating Feedforward Inhibition

描述（由申请人提供）：所有传入的听觉、视觉和躯体感觉信息都通过丘脑传递到大脑皮层，在清醒期间，大脑皮层负责将这些感觉输入转化为神经元活动的时空模式，从而产生外部世界的内部表征。这些表征是我们意识体验的重要组成部分。因此，了解来自丘脑的信息是如何引起皮层活动的，对于理解正常和病态的意识状态（如精神分裂症或自闭症）是至关重要的，当内部表征出现错误时。虽然它们只是所有皮层神经元中的少数，但释放GABA的抑制性中间神经元在这些转化中起着至关重要的作用。通过提供前馈和反馈抑制，抑制性中间神经元将大多数兴奋性神经元中的电活动限制为在时间和空间上精确调谐的响应。因此，了解感觉表征是如何产生的，需要对介导前馈和反馈抑制的GABA能神经元和突触的身份和性质以及它们对传入感觉信息的反应有详细的了解，但这些知识仍然缺乏。两个最大和最好的研究抑制亚型是“快速尖峰”的中间神经元和生长抑素含有中间神经元。以前的研究表明，前馈抑制是由快速尖峰细胞介导的。相比之下，我们在前一个资助期表明，两种亚型的中间神经元都介导前馈抑制，但在非常不同的刺激机制下这样做：快速尖峰的中间神经元将响应于瞬时刺激而激发，而含有生长抑素的中间神经元将响应于持续输入而激发。在目前的资助期间，我们将使用电生理学和药理学方法来阐明这些反应特性显著差异的生物物理学基础，我们将使用新的转基因小鼠品系来测试每个中间神经元亚型在塑造皮层神经元对丘脑传入感觉信息的反应中的作用。

DESCRIPTION (provided by applicant): All incoming auditory, visual and somatosensory information is relayed through the thalamus to the cerebral cortex, which, during wakefulness, is responsible for transforming these sensory inputs into a spatio-temporal pattern of neuronal activity that gives rise to an internal representation of the external world. These representations are a crucial component of our conscious experience. Understanding how incoming information from the thalamus gives rise to cortical activity is therefore essential for understanding both normal and pathological states of consciousness, such as schizophrenia or autism, when internal representations appear to go awry. Although they are only a minority of all cortical neurons, GABA-releasing inhibitory interneurons play a crucial role in these transformations. By providing both feedforward and feedback inhibition, inhibitory interneurons restrict electrical activity in the majority excitatory neurons to a precisely tuned response in time and in space. Therefore, understanding how sensory representations are generated requires a detailed knowledge of the identity and properties of the GABAergic neurons and synapses which mediate feedforward and feedback inhibition, and of their responses to incoming sensory information, but such knowledge is still lacking. The two largest and best studied inhibitory subtypes are "fast spiking" interneurons and somatostatin-containing interneurons. Previous studies suggested that feedforward inhibition is mediated exclusively by fast-spiking cells. In contrast, we showed in the previous grant period that both subtypes of interneurons mediate feedforward inhibition, but do so under very different stimulation regimes: fast- spiking interneurons will fire in response to a transient stimulus, while somatostatin- containing interneurons will fire in response to a sustained input. During the current grant period, we will use electrophysiological and pharmacological methods to elucidate the biophysical basis for these striking differences in response properties, and we will use novel genetically modified strains of mice to test the roles of each interneuron subtype in shaping responses of cortical neurons to incoming sensory information from the thalamus.