The firing of theta state related septal cholinergic neurons disrupt hippocampal ripple oscillations via muscarinic receptors.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multi-channel in vivo recording and recorded MS cholinergic neurons' firings in freely behaving male mice for 5.5 - 72 hours. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration (AE) and rapid eye movement (REM) sleep, but almost silent during non-theta epochs, such as slow wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M2 or M4 receptor antagonists. These results suggest an important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine (ACh) level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.Significance StatementThe major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to the speculation of the septo-hippocampal cholinergic projection contributing to theta oscillation. In this paper, by long-term recording of MS cholinergic neurons, we found that they do show theta-state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during SWS could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M2 and M4 receptors.