Optogenetic activation of medial septal cholinergic neurons during slow-wave sleep disrupts hippocampal ripple oscillations

【作者】 林龙年；

【Author】 Longnian Lin;Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Brain Functional Genomics, School of Life Science, East China Normal University;

【机构】 Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Brain Functional Genomics, School of Life Science, East China Normal University；

【摘要】 Existing pharmacological and lesion data indicate that acetylcholine(ACh) plays a crucial role in memory acquisition and consolidation. Elevated ACh release from the cholinergic basal forebrain enhances memory acquisition during waking, while low levels of ACh mediates memory consolidation during slow-wave sleep(SWS). We identified firing patterns of medial septal(MS) cholinergic neurons and thire physiological functions in freely behaving Ch AT-Ch R2-EYFP transgenic mice with multichannel in vivo recording and optogenetic techniques. In the medial septum of Ch AT-Ch R2-EYFP transgenic mice, confocal microscope immunohistochemistry showed that Ch R2-YFP-labeled somata were almost all cholinergic: 98.5 ± 3.4% of Ch R2-YFP-labeled somata were Ch AT-positive, and of Ch AT-activity of positive somata, 75.4 ± 14.9% were labeled with Ch R2-YFP. We recorded the activities of the MS cholinergic neurons that responded to blue light stimulation. Most of the MS cholinergic neurons showed high theta-related activity. It is because these cells fired more spikes during the theta states of exploration and rapid eye movement sleep. On the other hand, their activity level stayed low during the non-theta states of quiet waking and slow-wave sleep. Interestingly, optogenetic activation of MS cholinergic neurons during slow-wave sleep could completely disrupt ripple oscillations in hippocampal CA1 region. Pharmacology revealed that this inhibitory effect of MS cholinergic neurons on ripple could be blocked by atropine, an antagonist of muscarinic cholinergic receptors. These results suggest that the reason why Ach can block SWS-related consolidation of memory is that high levels of hippocampal Ach during SWS can suppress hippocampal sharp-wave ripple via muscarinic receptors.更多还原

【Abstract】 Existing pharmacological and lesion data indicate that acetylcholine(ACh) plays a crucial role in memory acquisition and consolidation. Elevated ACh release from the cholinergic basal forebrain enhances memory acquisition during waking, while low levels of ACh mediates memory consolidation during slow-wave sleep(SWS). We identified firing patterns of medial septal(MS) cholinergic neurons and thire physiological functions in freely behaving Ch AT-Ch R2-EYFP transgenic mice with multichannel in vivo recording and optogenetic techniques. In the medial septum of Ch AT-Ch R2-EYFP transgenic mice, confocal microscope immunohistochemistry showed that Ch R2-YFP-labeled somata were almost all cholinergic: 98.5 ± 3.4% of Ch R2-YFP-labeled somata were Ch AT-positive, and of Ch AT-activity of positive somata, 75.4 ± 14.9% were labeled with Ch R2-YFP. We recorded the activities of the MS cholinergic neurons that responded to blue light stimulation. Most of the MS cholinergic neurons showed high theta-related activity. It is because these cells fired more spikes during the theta states of exploration and rapid eye movement sleep. On the other hand, their activity level stayed low during the non-theta states of quiet waking and slow-wave sleep. Interestingly, optogenetic activation of MS cholinergic neurons during slow-wave sleep could completely disrupt ripple oscillations in hippocampal CA1 region. Pharmacology revealed that this inhibitory effect of MS cholinergic neurons on ripple could be blocked by atropine, an antagonist of muscarinic cholinergic receptors. These results suggest that the reason why Ach can block SWS-related consolidation of memory is that high levels of hippocampal Ach during SWS can suppress hippocampal sharp-wave ripple via muscarinic receptors.更多还原