Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice

• Published in: The Journal of neuroscience Vol. 44; no. 7; p. e1665232023
• Main Authors: Pan, Yi-da, Zhang, Yuan, Zheng, Wen-Ying, Zhu, Min-Zhen, Li, Huan-Yu, Ouyang, Wen-Jie, Wen, Qin-Qing, Zhu, Xin-Hong
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 14.02.2024
• Subjects: Animal models; Animals; Atmospheric models; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - therapy; Autistic Disorder - genetics; Autistic Disorder - therapy; Cobalt; Cobalt chloride; Dorsal Raphe Nucleus; Down-regulation; Fragile X Mental Retardation Protein; Hypoxia; Male; Mice; Neurodevelopmental disorders; Neurons; Phenotype; Phenotypes; Raphe nuclei; Serotonergic Neurons - physiology; Serotonin; Social behavior; Stereotyped behavior; Training; dorsal raphe nucleus (DRN); autism spectrum disorder; serotonergic neurons; hypoxia inducible factor (HIF) 1α; intermittent hypobaric hypoxia (IHH)
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.1665-23.2023

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male and mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.