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.

项目总结