The Medial Septum-hippocampus Cholinergic Neural Circuit Is Critical For The Regulation Of Negative Emotion In Mice

Stress response is an important cause of cognitive impairment and emotional disorders such as anxiety and depression.Recent studies have found that the central cholinergic system is involved in the regulation of stress response.However the cellular and circuit mechanisms remain largely unclear.Several studies have found that the levels of acetylcholine in the hippocampus are increased significantly in response to acute stress.Increased levels of acetylcholine in the hippocampus lead to depress-and anxiet-like behaviors in mice.Although the medial septal nucleus is the main source of acetylcholine in the hippocampus,the role of cholinergic neurons in the medial septal nucleus in stress response is not fully understood.Therefore,this study aimed to investigat how the neural circuits from the medial septal nuclear cholinergic neurons to the hippocampus participate in the stress response in mice.Firstly,we recorded the responses of medial septum cholinergic neurons to different stimuli using in vivo fiber photometry recording.We found that footshock,tail restrain,and quinine stimuli activated cholinergic neurons in the medial septum,while reward stimuli inhibited these neurons.In social experiments,normal social interactions did not affect the activation of the medial septum cholinergic neurons,however,aversive social attacks activated these neurons.Secondly,we optogenetically and chemogenetically manipulated the activity of medial septum cholinergic neurons and found that optogenetic activation of these neurons caused avoidance behavior in mice.Further studies indicated that activation of these neurons resulted in increased plasma corticosterone levels in mice.However,suppression of these neurons did not produce place preference.Our circuit tracing results demonstrated that different subsets of cholinergic cells in the medial septum innervated the dorsal and ventral hippocampus,respectively.We further demonstrated that the medial septal nucleus mainly regulated avoidance,anxiety-like and social behaviors of mice through cholinergic projection to the ventral hippocampus.Thirdly,we found that chronic restraint stress(CRS)could increase the amplitude,but not the frequency of spontaneous excitatory postsynaptic current(sEPSCs)of ventral hippocampal projection medial septal cholinergic neurons in mice.Meanwhile,CRS decreased the amplitude and frequency of sEPSCs in dorsal hippocampal projection medial septal cholinergic neurons and reduced the their intrinsic excitability.Inhibition of cholinergic projection from the medial septum to the ventral hippocampus could alleviate anxiety-like behavior of mice caused by chronic restrain stress.In summary,our study suggests that the cholinergic neural circuits from the medial septum to the ventral hippocampus can rapidly regulate avoidance and anxiet-like behaviors in mice.Chronic stress can lead to changes in synaptic transmission of septal cholinergic neurons projecting to the ventral hippocampus,and enhance spontaneous firing of these neurons.Inhibition the excitability of this circuit alleviates stress-induced anxiety-like behavior in mice.This study provides a new perspetive for understanding the involvement of cholinergic system in emotional regulation and provides new ideas for the development of novel treatments for mental diseases such as PTSD and depression caused by stress.