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.

项目摘要 视皮层可以根据上下文以不同的方式处理相同的刺激;行为状态， 运动或唤醒可以改变视觉反应的大小和特异性。神经调制器 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， 皮质电路，但它仍然不确定如何interneuron类有助于状态依赖。特别 围绕生长抑素阳性（SOM）细胞的作用存在争议，SOM细胞通过直接影响神经元的功能而形成回路输出。 抑制锥体细胞。一种模型认为ACh作用于上游中间神经元引发抑制， SOM细胞通过释放抑制性神经递质γ-氨基丁酸（GABA）。这会抑制金字塔 细胞在运动和潜在的其他状态下增加视觉回路的增益。然而，矛盾的 研究结果表明，SOM细胞，这可以直接促进乙酰胆碱通过毒蕈碱受体，实际上是 在运动过程中更活跃，表明去抑制模型不足以解释上下文依赖。 这一提议验证了毒蕈碱和GABA能对SOM细胞的作用具有 对调节视觉皮层回路和视觉辨别中的成形的互补作用。我假设 对SOM细胞的毒蕈碱作用有助于调节锥体细胞群，而GABA能作用 有助于锥体细胞增益。我将利用前所未有的交叉控制来剖析这一点 通过拴系药物急性限制（DART）方法在特定细胞类型上的特定受体 与小鼠初级视觉皮层的双光子钙成像相结合。 目的1：选择性地拮抗SOM细胞上的M受体，记录SOM细胞的活性 和附近的锥体细胞。我会评估视觉反应 运动和唤醒改变了反应，以揭示ACh对基础视觉中SOM细胞的直接影响。 通过行为状态进行加工和调节。在目标2中，我将选择性地阻断SOM细胞上的GABA受体， 再次记录在被动观察期间的SOM和锥体细胞活动。这将使我能够澄清抑制是如何 在运动和觉醒过程中，SOM细胞上的神经元参与基础视觉过程和电路调制。如果像 假设，毒蕈碱和GABA能控制影响锥体细胞的调谐和增益，这可能 有意义地影响视觉辨别力。为了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能受体 细胞，并记录SOM和锥体细胞的活动，而小鼠执行方向变化检测任务。 这些数据将共同解决长期存在的问题，即神经调节剂如何使视觉回路与 上下文特异性