Investigating a mammalian inhibitory circuit for distractor suppression

研究哺乳动物抑制干扰的抑制电路

• 批准号: 10507758
• 负责人: Ninad B Kothari
• 金额: $ 7.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507758
• 关键词: Adaptive Behaviors; Address; Animals; Area; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Behavioral Paradigm; Birds; Cell Nucleus; Complex; Coupled; Data; Disease; Distant; Electrophysiology (science); Environment; Functional disorder; Genetic; Head; Homologous Gene; Immunohistochemistry; Implant; Injections; Lateral; Light; Location; Mammals; Maps; Measures; Mental disorders; Midbrain structure; Modernization; Mus; Neural Inhibition; Neurons; Opsin; Parvalbumins; Peripheral; Primates; Process; Protocols documentation; Reporting; Resistance; Rewards; Role; Schizophrenia; Services; Silicon; Site; Source; Stimulus; Suggestion; Techniques; Tegmentum Mesencephali; Testing; Time; Touch sensation; Training; Visuospatial; Work; analog; base; cell type; extracellular; inhibitory neuron; insight; neural circuit; novel; optical fiber; optogenetics; receptive field; relating to nervous system; response; selective attention; superior colliculus Corpora quadrigemina; tool; touchscreen; visual stimulus

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.

项目摘要 在复杂的环境中，动物选择性地处理最重要（最高优先级）的刺激 引导行为，同时忽略所有其他空间位置的分散注意力的刺激。这种能力，称为空间 选择性注意力，对行为甚至生存都至关重要。来自灵长类动物和鸟类的证据 暗示中脑上级丘（哺乳动物的SC;鸟类的视顶盖- OT）2，3作为一个关键节点， 当存在多个竞争目标时对空间注意力的控制。研究还表明， 刺激之间的相互作用在SC的中间层和深层（SCid;鸟类的OTid）中编码， 刺激竞争表现为竞争刺激对每个刺激的反应的抑制。 此外，最近的鸟类研究（迈索尔实验室和其他人）表明，这种竞争性相互作用 在OTid内，由鸟类中脑中的一组小清蛋白阳性（PV+）抑制性神经元控制 被称为峡部大细胞核（Imc）。Imc以一种专门的方式与OT连接， 方式，并通过竞争刺激4-6驱动OTid反应的长距离抑制，导致暗示 在鸟类中，Imc可能有助于抑制干扰物并促进空间目标的选择， 注意力1，5，7.然而，不仅是抑制源，为类似的远程竞争相互作用，在 哺乳动物SCID未知，但也有具体的电路机制，潜在的干扰抑制和目标 在任何动物中，空间选择性注意的选择还有待发现11。在这里，我将解决这些 问题的小鼠通过调查的功能parabigeminal外侧被盖核（pLTN）， 被认为是哺乳动物的Imc同源物1，12，13。具体来说，在目标1中，我将使用特定于焦点细胞类型的 PV+ pLTN的光遗传学操作，结合头部固定、被动观察中的SCid电生理学 小鼠来测试pLTN神经元是否负责控制SCid中的竞争性相互作用。我预测 沉默pLTN神经元将消除SCid内的刺激竞争。接下来，在目标2中，我将利用新的 行为范式是在实验室中发展起来的，用于研究灵长类动物在自由状态下的视觉空间选择性注意。 行为小鼠14，并使用细胞类型特异性光遗传学操作，研究pLTN在 干扰抑制和目标选择。我预测pLTN编码区的光遗传学激活 靶点将引起高度注意（对分心的抵抗），而该部分的光遗传失活 pLTN编码的目标与原因过度分心。这些结果将首次揭示， 控制空间注意的干扰抑制的回路机制，并可以阐明回路 这是在精神疾病如多动症和精神分裂症中发现的使人衰弱的注意力功能障碍的基础。