Dissecting cholinergic modulation of interneurons underlying state-dependent processing in mouse visual cortex

剖析小鼠视觉皮层状态依赖性处理背后的中间神经元的胆碱能调节

• 批准号: 10748259
• 负责人: Celine Cammarata
• 金额: $ 6.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748259
• 关键词: Acetylcholine; Acute; Alzheimer' s Disease; Animals; Arousal; Behavior; Behavioral; Calcium; Cells; Cognitive; Conflict (Psychology); Coupled; D Cells; Data; Dependence; Detection; Diameter; Discrimination; Disease; Disinhibition; GABA Receptor; Goals; Image; Interneurons; Locomotion; Measures; Methodology; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Neuromodulator; Neurotransmitters; Output; Pathway interactions; Pharmaceutical Preparations; Population; Process; Pupil; Pyramidal Cells; Role; Schizophrenia; Shapes; Signal Transduction; Somatostatin; Specificity; Stimulus; Techniques; Testing; Vasoactive Intestinal Peptide; Visual; Visual Cortex; area striata; cell type; cholinergic; experimental study; gamma-Aminobutyric Acid; neural; neuroregulation; prevent; receptor; recruit; response; therapy development; two-photon; visual information; visual process; visual processing; visual stimulus

PROJECT SUMMARY The visual cortex can process identical stimuli differently depending on context; behavioral states such as locomotion or arousal can alter the magnitude and the specificity of visual responses. The neuromodulator acetylcholine (ACh) is implicated in state-dependent processing and acts on diverse inhibitory interneurons in cortical circuits, but it remains uncertain how interneuron classes contribute to state-dependence. Particular controversy surrounds the role of the somatostatin-positive (SOM) cells, which shape circuit output by directly inhibiting pyramidal cells. One model suggests that ACh action on upstream interneurons triggers suppression of SOM cells via release of the inhibitory neurotransmitter γ-Aminobutyric acid (GABA). This disinhibits pyramidal cells to increase gain in visual circuits during locomotion and potentially other states. However, contradictory findings reveal that SOM cells, which can be directly facilitated by ACh through muscarinic receptors, are actually more active during locomotion, indicating the disinhibitory model is not sufficient to explain context dependence. This proposal tests the hypothesis that muscarinic and GABAergic action on SOM cells have complementary effects on modulating visual cortex circuits and shaping in visual discrimination. I hypothesize that muscarinic action on SOM cells contributes to tuning of the pyramidal population, while GABAergic action on SOM cells contributes to pyramidal cell gain. I will dissect this utilizing unprecedented intersectional control of specific receptors on specific cell types via the Drugs Acutely Restricted by Tethering (DART) methodology coupled with 2-photon calcium imaging of mouse primary visual cortex. In Aim 1, I will selectively antagonize muscarinic receptors on SOM cells and record activity of SOM cells and nearby pyramidal cells as mice passively view visual stimuli. I will assess visual responses and how responses are altered by locomotion and arousal, to reveal the direct impact of ACh on SOM cells in basal visual processing and modulation by behavioral state. In Aim 2, I will selectively block GABA receptors on SOM cells, again recording SOM and pyramidal cell activity during passive viewing. This will allow me to clarify how inhibition onto SOM cells contributes to basal visual process and circuit modulation during locomotion and arousal. If, as hypothesized, muscarinic and GABAergic control impact tuning and gain of pyramidal cells, this could meaningfully impact visual discrimination. To assess how these two pathways act on animals' ability to perceive and use visual information, in Aim 3 I will selectively antagonize muscarinic or GABAergic receptors on SOM cells, and record activity of SOM and pyramidal cells, while mice perform an orientation change detection task. Together these data will resolve longstanding questions around how neuromodulators imbue visual circuits with context specificity.

项目概要 视觉皮层可以根据不同的行为状态对相同的刺激进行不同的处理，例如： 运动或唤醒可以改变视觉反应的幅度和特异性。 乙酰胆碱（ACh）参与状态依赖性加工，并作用于多种抑制性中间神经元 皮层回路，但仍不确定中间神经元类别如何促进特定的状态依赖性。 围绕生长抑素阳性（SOM）细胞的作用存在争议，该细胞通过直接影响电路输出 一种模型表明，乙酰胆碱对上游中间神经元的作用会引发抑制。 SOM 细胞通过释放抑制性神经递质 γ-氨基丁酸 (GABA) 来抑制锥体细胞。 然而，这是矛盾的。 研究结果表明，SOM 细胞实际上可以通过乙酰胆碱通过毒蕈碱受体直接促进 在运动过程中更加活跃，表明去抑制模型不足以解释上下文依赖性。 该提案检验了毒蕈碱和 GABA 能对 SOM 细胞的作用的假设 对调节视觉皮层回路和视觉辨别塑造的互补作用。 对 SOM 细胞的毒蕈碱作用有助于调节锥体细胞群，而 GABA 作用 我将利用这种前所未有的交叉控制来剖析 SOM 细胞对锥体细胞增益的贡献。 通过药物束缚 (DART) 方法急性限制特定细胞类型上的特定受体 结合小鼠初级视觉皮层的 2 光子钙成像。 在目标1中，我将选择性地拮抗SOM细胞上的毒蕈碱受体并记录SOM细胞的活性 当小鼠被动地观察视觉刺激时，我将评估视觉反应以及如何评估附近的锥体细胞。 反应因运动和唤醒而改变，以揭示 ACh 对基础视觉中 SOM 细胞的直接影响 在目标 2 中，我将选择性地阻断 SOM 细胞上的 GABA 受体， 再次记录被动观察期间的 SOM 和锥体细胞活动，这将使我能够阐明抑制的方式。 SOM 细胞有助于运动和唤醒过程中的基础视觉过程和电路调节。 轻敲、毒蕈碱和 GABA 能控制影响锥体细胞的调谐和增益，这可以 评估这两种途径如何影响动物的感知能力。 并使用视觉信息，在目标 3 中，我将选择性地拮抗 SOM 上的毒蕈碱或 GABA 受体 细胞，并记录 SOM 和锥体细胞的活动，同时小鼠执行方向变化检测任务。 这些数据将共同解决有关神经调节剂如何向视觉回路注入神经调节剂的长期存在的问题。 上下文的特殊性。