Investigating a mammalian inhibitory circuit for distractor suppression

项目摘要 在复杂的环境中运作，动物有选择地处理最重要(最优先)的刺激 以指导行为，同时忽略所有其他空间位置的分心刺激。这种能力被称为空间 选择性注意，对行为甚至生存都至关重要。来自灵长类和鸟类的证据汇聚在一起 牵涉到中脑上丘(哺乳动物的SC；鸟类的视顶盖-OT)2，3作为 当存在多个相互竞争的目标时，空间注意力的控制。研究还表明，具有竞争力的 刺激之间的相互作用编码在SC的中层和深层(SCID；鸟类的OTID)，与 刺激竞争表现为相互竞争的刺激对每个刺激的反应的抑制。 此外，最近在鸟类上的研究(由迈索尔实验室和其他机构)揭示了这种竞争性的相互作用 在OTid内，由鸟类中脑中的一组小白蛋白阳性(PV+)抑制神经元控制 被盖又称峡部大细胞核(IMC)。IMC与OT在专业的 通过竞争刺激4-6的方式和驱动对OTid反应的远程抑制，导致了这一建议 在鸟类中，IMC可能起到抑制干扰和促进空间目标选择的作用 注意1，5，7。然而，不仅是类似的长距离竞争性相互作用的抑制源 哺乳动物的SCID未知，但也有特定的电路机制潜在的干扰物抑制和靶点 对于任何动物来说，空间选择性注意的选择还没有被发现。在这里，我将谈到这些 小鼠双侧束旁外侧被盖核(PLTN)的功能 被认为是Imc1，12，13的哺乳动物同源物。具体地说，在目标1中，我将使用特定于焦点细胞类型 头固定被动观察中PV+pLTN的光遗传操作与SCID电生理学 小鼠测试pLTN神经元是否负责控制SCID中的竞争性相互作用。我预测 使pLTN神经元沉默将消除SCID内的刺激竞争。接下来，在Aim 2中，我将利用一个新的 实验室开发的研究灵长类视觉空间选择性注意的行为范式 表现为小鼠14，并使用细胞类型特异性光遗传操作，研究pLTN在 干扰抑制和目标选择。我预测pLTN编码部分的光遗传激活 目标会引起高度注意(对分心的抵抗力)，而该部分的光遗传失活 导致过度分心的pLTN编码目标。这些结果将第一次揭示神经 用于控制分心抑制空间注意的电路机制，并可以阐明电路 精神疾病如多动症和精神分裂症导致注意力减退的基础。

Project Summary Operating in complex environments, animals selectively process the most important (highest ‘priority’) stimulus to guide behavior, while ignoring distracting stimuli at all other spatial locations. This ability, called spatial selective attention, is critical for behavior and even survival. Converging evidence from primates and birds has implicated the midbrain superior colliculus (SC in mammals; optic tectum – OT in birds)2,3 as a critical node for the control of spatial attention when multiple competing targets are present. Studies also show that competitive interactions among stimuli are encoded in the intermediate and deep layers of the SC (SCid; OTid in birds), with stimulus competition manifesting as the suppression of the responses of each stimulus by competing stimuli. Additionally, recent work in birds (by the Mysore Lab and others) has revealed that such competitive interactions within the OTid are controlled by a group of parvalbumin positive (PV+) inhibitory neurons in the avian midbrain tegmentum called nucleus isthmi pars magnocellularis (Imc). The Imc connects with the OT in a specialized manner and drives long-range suppression of OTid responses by competing stimuli 4-6, leading to the suggestion that, in birds, the Imc may serve to suppress distracters and facilitate the selection of the target of spatial attention1,5,7. However, not only is the inhibitory source for similar long-range competitive interactions in the mammalian SCid unknown, but also the specific circuit mechanisms underlying distractor suppression and target selection for spatial selective attention in any animal are yet to be discovered11. Here, I will address these questions in mice by investigating the function of the peri-parabigeminal lateral tegmental nucleus (pLTN), which is thought to be mammalian homolog of the Imc1,12,13. Specifically, in Aim 1, I will use focal cell type-specific optogenetic manipulations of the PV+ pLTN, coupled with SCid electrophysiology in head-fixed, passive-viewing mice to test if pLTN neurons are responsible for controlling competitive interactions in the SCid. I predict that silencing pLTN neurons will abolish stimulus competition within SCid. Next, in Aim 2, I will leverage a new behavioral paradigm developed in the lab for the study of primate-like visuospatial selective attention in freely behaving mice14, and using cell-type specific optogenetic manipulation, investigate the causal role of pLTN in distractor suppression and target selection. I predict that optogenetic activation of the portion of pLTN encoding the target will cause hyper-attention (resistance to distractibility), whereas optogenetic inactivation of the portion of the pLTN encoding the target with cause hyper-distractibility. These results will reveal, for the first time, neural circuit mechanisms for the control of distracter suppression for spatial attention, and can shed light on the circuit basis of the debilitating attentional dysfunction found in psychiatric conditions such as ADHD and schizophrenia.