Effects Of The Excitation Or Inhibition Of Basal Forebrain Cholinergic Neurons On Cognitive Ability In Mice Exposed To Chronic Intermittent Hypoxia

Objective To investigate the effect of the excitation or inhibition of basal forebrain(BF)cholinergic neurons on cognitive ability in mice exposed to chronic intermittent hypoxia(CIH).Methods Initially,microinjection cannulas were implanted in the BFs of adult C57BL/6mice.The mice were randomly divided into the normoxic group(control group),CIH group,CIH-acetylcholine group(CIH-ACH group),CIH-carbachol group(CIH-CCH group)and CIH-atropine group(CIH-Atr group),CIH-ibotenic acid damage group(CIH-IBO)and CIH-ibotenic acid damage + acetylcholine compensation group(CIH-IBO-ACH group),CIH-adenosine group(CIH-A group)and CIH-caffeine group(CIH-C group).The mice in the control group were exposed to atmospheric normoxia,while the mice in the CIH group were exposed to intermittent hypoxia at atmospheric pressure for 8 h per day for 4 consecutive weeks.Behavioral experiments were then performed to test the cognitive ability of the mice.The mice in the IBO groups were microinjected with ibotenic acid to induced damage to the BF before being exposed to CIH,while the mice in the other groups were microinjected with the corresponding reagents before the behavioral experiments.Finally,BF tissues were collected and stored.Immunofluorescence was utilized to detect c-fos expression in cholinergic neurons.TUNEL staining was utilized to detect BF apoptosis.Western blotting was used to detect BIP and XBP-1 to evaluate endoplasmic reticulum stress.The oxidative stress indicators SOD,CAT and MDA were detected by biochemical detection kits.Western blotting and RT-PCR were used to detect L-PGDS expression,and ELISA was used to detect the inflammatory factors IL-1,IL-6 and TNF-α.Results(1)CIH induced cognitive decline in mice.(2)The excitation of BF cholinergic neurons attenuated cognitive decline,while the inhibition of these neurons aggravated cognitive impairment.(3)Microinjection of adenosine into the BF aggravated cognitive decline,while caffeine improved cognitive ability.(4)CIH induced BF cholinergic neuron injury in mice.(5)The excitation of BF cholinergic neurons alleviated cholinergic neuron injury,while the inhibition of these neurons aggravated this injury.(6)Microinjection of adenosine into the BF aggravated cholinergic neuron injury,while caffeine alleviated this injury.(7)CIH induced endoplasmic reticulum stress,oxidative stress and inflammatory responses in the BFs of mice.(8)The excitation of BF cholinergic neurons mitigated endoplasmic reticulum stress,oxidative stress and inflammatory responses in the BF in mice,while the inhibition of BF cholinergic neurons worsened these responses in the BF.(9)Microinjection of adenosine into the BF aggravated endoplasmic reticulum stress,oxidative stress and the inflammatory response,while caffeine alleviated these responses.Conclusions CIH induces BF cholinergic neuron injury through multiple pathways,including endoplasmic reticulum stress,oxidative stress and the inflammatory response,thereby leading to cognitive dysfunction in mice.BF cholinergic neurons play a vital role in these pathways,thus reducing cholinergic neuron injury and restoring cognitive function in mice.Adenosine,which is an upstream modifier of acetylcholine,also plays an important role in altering cognitive ability.