Novel Interneurons Mediating Feedforward Inhibition

描述(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，在清醒时，大脑皮层负责将这些感觉输入转化为神经活动的时空模式，从而产生外部世界的内部表征。这些表征是我们有意识体验的重要组成部分。因此，了解丘脑传入的信息如何引起皮质活动，对于理解意识的正常和病理状态，如精神分裂症或自闭症，当内部表征似乎出现错误时，都是至关重要的。虽然它们只是所有皮质神经元中的一小部分，但GABA释放抑制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的电活动限制在时间和空间上的精确调谐反应。因此，要理解感觉表征是如何产生的，需要详细了解介导前馈和反馈抑制的GABA能神经元和突触的身份和特性，以及它们对传入感觉信息的反应，但这种知识仍然缺乏。两种最大、研究最深入的抑制亚型是“快速放电”中间神经元和含有生长抑素的中间神经元。以前的研究表明，前馈抑制完全是由快脉冲细胞介导的。相反，我们在之前的授权期显示，两种亚型的中间神经元都介导了前馈抑制，但在非常不同的刺激机制下做到了这一点：快速放电的中间神经元将对瞬时刺激做出反应，而含有生长抑素的中间神经元将对持续的输入做出反应。在目前的资助期间，我们将使用电生理和药理学方法来阐明这些显著反应特性差异的生物物理基础，并将使用新的转基因小鼠品系来测试每种中间神经元亚型在塑造皮质神经元对来自丘脑的传入感觉信息的反应中所起的作用。

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.