Effects of the excitation or inhibition of basal forebrain cholinergic neurons on cognitive ability in mice exposed to chronic intermittent hypoxia
Introduction
Obstructive sleep apnea syndrome (OSAS) is a common disease characterized by recurrent upper airway obstruction and interrupted breathing during sleep, which is associated with potential severe effects. Previously, the incidence of OSAS was estimated to be 4%, but recent studies have suggested that the incidence may be much higher (Mirrakhimov et al., 2013). Chronic intermittent hypoxia (CIH) and structural disturbances of sleep manifested by fragmented sleep and frequent awakening are the main pathophysiological characteristics of OSAS and cause multiple complications and comorbidities, such as hypertension (Marin et al., 2012), metabolic diseases such as diabetes (Aurora and Punjabi, 2013), and various cardiovascular and cerebrovascular diseases (Javaheri et al., 2019). OSAS comprises a variety of atypical symptoms, such as excessive daytime sleepiness (Marklund et al., 2015), cognitive impairment (Andrade et al., 2018; Steiropoulos et al., 2019), depression and neurological impairment (Jackson et al., 2018). Cognitive impairment in patients with OSAS not only affects quality of life but also increases the risk of work and traffic accidents (Garbarino et al., 2016). An increasing number of studies have shown that cognitive impairment is related to OSAS (Bucks et al., 2013; Kerner and Roose, 2016); however, OSAS patients are usually subjectively unaware of cognitive impairments that are objectively already present (Gagnon et al., 2018). In addition, the mechanism of cognitive impairment in OSAS patients is unclear.
The basal forebrain (BF), which includes the medial septum (MS), substantia innominata (SI), nucleus of the horizontal limb of the diagonal band (HDB), magnocellular preoptic nucleus (MCPO) and large cellular basal nucleus (MBN), sends cholinergic projections to the cortex, limbic system and hippocampus, and the MS and HDB are the main sources of the cholinergic system. Although the hippocampus has been proven to be related to cognitive function, the role of BF cholinergic neurons in cognitive function cannot be ignored, as the BF is the main source of acetylcholine in the hippocampus and cortex. A reduction in the number of BF cholinergic neurons is related to cognitive impairment in diseases such as normal aging and Alzheimer's disease (Schliebs and Arendt, 2006). Therefore, we speculate that the cognitive impairment of OSAS patients is also related to BF cholinergic neurons.
Multiple studies have examined cholinergic neurons and cognitive ability, and some studies have explored the relationship between hypoxia and cognitive ability, but research regarding the influence of BF cholinergic neurons on cognitive ability in a CIH model is still lacking, and the pathophysiology underlying the effect of BF cholinergic neurons on cognitive function is unknown. In the present study, we analyzed the influence of BF cholinergic neurons on the cognitive ability of CIH mice and the pathways by which CIH may induce cognitive decline from multiple angles.
Section snippets
Animals and reagents
A total of 108 10-week-old male SPF C57BL/6 mice weighing 24−26 g were purchased from the Animal Experiment Center of Hubei Province. The mice were raised in pathogen-free barrier animal breeding cages on a 12:12-h light-dark cycle at a constant temperature of 25 °C and were provided free access to food and water. The work in our article have been carried out in accordance with EC Directive 86/609/EEC for animal experiments, and were subject to approval by the Ethics Committee of Renmin
Statistical analysis
Statistical analysis was performed using IBM SPSS 22.0 statistical software. All data in this study are expressed as the mean ± SD. One-way ANOVA was used to compare the data between multiple samples. The water maze data were compared by repeated-measures ANOVA. Post hoc multivariate ANOVA was used to determine differences between groups. An LSD t-test was performed when the variance was the same; otherwise, Dunnett’s C test was used. P values < 0.05 were considered statistically significant.
CIH induced cognitive decline in mice
As presented in Fig. 1, Fig. 2, compared with the control group, the CIH group exhibited a significantly longer escape latency (F = 20.18, P < 0.001) and time required to reach the platform location (t = 4.580, P < 0.001) as well as a deceased number of platform crossings (t = 6.641, P < 0.001). This result indicated that the spatial memory ability of the CIH mice was remarkably decreased. As shown in Fig. 3, Fig. 4, the average speed, total distance traveled and time spent in the center area
Discussion
The behavioral results indicated that exposure to CIH for 4 weeks induced cognitive decline in mice. Besides, CIH can induce BF cholinergic neuron injury. Our experiment also found that CIH promoted endoplasmic reticulum stress, oxidative stress and inflammation in the BF. The results indicate that CIH may induce BF cholinergic neuron injury through endoplasmic reticulum stress, oxidative stress and inflammatory response, thereby leading to cognitive dysfunction in mice.
In recent years,
Conclusions
In this study, we found that CIH in OSAS leads to cognitive impairment in mice, that the excitation of BF cholinergic neurons improves cognitive decline induced by CIH, and that the inhibition of these neurons impairs cognitive ability. CIH induces BF cholinergic neuron injury through multiple pathways, such as endoplasmic reticulum stress, oxidative stress and the inflammatory response, thereby resulting in cognitive dysfunction. The excitation of BF cholinergic neurons affects these
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 81770089).
CRediT authorship contribution statement
Si Tang: Methodology, Investigation, Writing - original draft, Writing - review & editing. Jing Zhu: Data curation, Visualization, Investigation. Dong Zhao: Data curation, Visualization. Huaheng Mo: Formal analysis. Zhaofu Zeng: Formal analysis. Mengqing Xiong: Software, Validation. Minglin Dong: Software, Validation. Ke Hu: Conceptualization, Supervision, Validation.
Declaration of Competing Interest
The authors report no declarations of interest.
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