NOVEL INTERNEURONS MEDIATING FEEDFORWARD THALAMOCORTICAL INHIBITION

描述（由申请人提供）：几乎我们所知道的关于世界的一切都是由丘脑通过丘脑皮质突触传递到我们新皮层的第4层。新皮层负责将这些感官输入转化为我们称之为感知的意识体验；因此，理解这些转变对于理解意识的正常和病理状态都是至关重要的。gaba释放抑制性中间神经元是这些转化的重要参与者。在初级感觉皮质区，丘脑皮质输入强烈激活抑制性中间神经元，这反过来又对邻近的兴奋性神经元提供失联抑制。这种“前馈”抑制使皮层反应处于强大但动态调节的控制之下，并将感觉输入转化为时空活动模式。两种最大和研究得最好的gaba能亚型是表达parvalbumin （PV+）的“快速尖峰”（FS）中间神经元和表达生长抑素（SOM+）中间神经元。目前，前馈丘脑皮质抑制被认为仅由PV+、FS中间神经元介导；然而，这种“一个中间神经元适合所有人”的模型很难与调节皮层对不同行为状态的反应的需要相协调。事实上，我们的初步结果表明，与之前的报道相反，PV+和SOM+中间神经元都接受直接的丘脑皮质兴奋，尽管具有非常不同的时间动态。因此，我们的中心假设是，PV+和SOM+中间神经元都介导前馈丘脑皮质抑制，但具有明显不同的空间和时间特性，因此可能对丘脑皮质转化有不同的贡献，可能参与不同的行为状态。为了验证这一假设，我们将使用我们已经产生的新型转基因小鼠，其中第4层SOM+中间神经元表达绿色荧光蛋白。该假设将通过记录丘脑皮质“三联体”的三条腿对应的电生理突触反应来验证——丘脑皮质输入到抑制性中间神经元，抑制性输入到第4层兴奋性神经元，以及丘脑皮质输入到第4层兴奋性神经元。这项研究的结果将促进我们对介导感觉知觉的神经元元件和突触回路的理解，以及它们在正常和异常行为状态下的运作方式。

DESCRIPTION (provided by applicant): Almost everything we know about the world is relayed to layer 4 of our neocortex by the thalamus, via the thalamocortical synapse. The neocortex is responsible for transforming these sensory inputs into the conscious experience we call perception; understanding these transformations is therefore essential for understanding both normal and pathological states of consciousness. GABA-releasing inhibitory interneurons are vital participants in these transformations. In primary sensory cortical areas, thalamocortical inputs strongly activate inhibitory interneurons, which in turn provide disynaptic inhibition to neighboring excitatory neurons. This "feedforward" inhibition holds the cortical response under a powerful but dynamically modulated control, and transforms sensory inputs into spatiotemporal activity patterns. The two largest and best studied GABAergic subtypes are parvalbumin-expressing (PV+), which are "fast spiking" (FS) interneurons, and somatostatin-expressing (SOM+) interneurons. Currently, feedforward thalamocortical inhibition is thought to be mediated solely by PV+, FS interneurons; however, this "one interneuron fits all" model is difficult to reconcile with the need to adjust cortical responses to different behavioral states. Indeed, our preliminary results indicate that, contrary to previous reports, both PV+ and SOM+ interneurons receive direct thalamocortical excitation, albeit with very different temporal dynamics. Our central hypothesis is therefore that both PV+ and SOM+ interneurons mediate feedforward thalamocortical inhibition, but with markedly different spatial and temporal properties, and are therefore likely to contribute differentially to thalamocortical transformations, possibly participating in different behavioral states. To test this hypothesis, we will use novel transgenic mice which we have generated, and in which layer 4 SOM+ interneurons express Green Fluorescent Protein. The hypothesis will be tested by recording electrophysiologically synaptic responses corresponding to the three legs of the thalamocortical "triad" - thalamocortical inputs onto inhibitory interneurons, inhibitory inputs onto layer 4 excitatory neurons, and thalamocortical inputs onto layer 4 excitatory neurons. The results of the proposed study will advance our understanding of the neuronal elements and synaptic circuits that mediate sensory perception, and how they operate during normal and abnormal behavioral states.