Acetylcholine Modulates Anxiety- And Depression-like Behaviors Via Ms/DBB-hippocampal Circuit

BackgroundDepression is a mental disorder that affects people all over the world.Patients with depression are usually accompanied by anxiety-like symptoms.It has been reported that part of anxiety and major depressive disorder(MDD)patients displayed similar effective response to the same treatment.However,the pathogenesis of depression is not completely understood.The cholinergic hypothesis of depression can explain part of the causes.Previous studies majorly focused on the effects of systemically or locally altered ACh levels on depression,but didn’t explained the mechanism of anxiety and depression on the circuit level.Cholinergic neurons are distributed in MS/DBB nucleus of basal forebrain;its mechanism of regulating anxiety and depression is currently unknown.Cholinergic fibers derived from MS/DBB are widely distributed in the ventral hippocampus.It is unclear whether this septo-hippocampal cholinergic system is involved in regulating anxiety-and depression-like symptoms.This study,therefore,focuses on the mechanism of septo-hippocampal cholinergic system in the anxiety and depression.Objective1)To investigate the excitability of the pyramidal neurons in the ventral subiculum that affected by anxiety and depression;2)To ascertain the role of cholinergic neurons in the MS/DBB on anxiety and depression;3)To clarify,at the circuit level,the mechanism of the septo-hippocampal cholinergic system on anxiety and depression.MethodsThis project took the advantage of transgenic mouse line and chemogenetic technique to precisely manipulate the cholinergic system.Immunofluorescence and multichannel in vivo electrophysiological recordings were used to determine the success of the system.CNO intraperitoneally and locally microinjection technologies were used to precisely manipulate the cholinergic system.Chronic unpredictable mildstress(CUMS)was used to develop the depression model,and electrophysiological techniques in vitro were used to detect the excitability of the pyramidal neurons in the ventral subiculum that affected by anxiety and depression.Finally,behavioral tests such as open-field test,forced swimming test,and tail suspension test were used to evaluate the degree of anxiety-and depression-like symptoms.ResultsWe found that: the excitability of neurons in depressive group in the ventral subiculum was increased.Altering the excitability of cholinergic neurons of the MS/DBB could induced anxiety-and depression-like symptoms.Precisely manipulating septo-hippocampal cholinergic system could activate pyramidal neurons in the ventral subiculum.Stimulating cholinergic fibers that distributed in both sides of ventral subiculum was enough to induce anxiety-and depression-like behaviors.Microinjecting of mAChRs antagonist,atropine,in ventral subiculum could reverse anxiety-and depression-like behaviors.ConclusionThis project explored,for the first time,the mechanism of anxiety-and depression-like behaviors on septo-hippocampal cholinergic system.This provides a new basis for the cholinergic hypothesis of depression,and provides a new idea for the treatment of anxiety and depression.