Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia

Abstract

Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes.

Hypobaric Hypoxia Induces Depression-like Behavior in Female Sprague-Dawley Rats, but not in Males

“…In 40 age-and gender-matched healthy individuals, those residing at 4500 ft (Salt Lake City, UT) were found to exhibit reduced total creatine levels (creatine + phosphocreatine) in the anterior cingulate cortex compared to those at sea level (20 ft, Belmont, MA, or Charleston, SC), implying that living at altitude alone can produce brain hypometabolism in healthy humans . In vivo 1 H-MRS scans of rodents prior to and after 1 week at an altitude simulation of 10,000 ft identified several changes in metabolic markers, including a similar forebrain deficit in total creatine after exposure to altitude (Bogdanova et al, 2014). Similarly, in vivo 1 H-MRS scans of Sprague Dawley rats prior to and after a shorter exposure to extreme hypobaric hypoxia (48 h at 21,976 ft) showed altered brain metabolites (including total creatine) in the hippocampus after hypoxia exposure, some of which persisted for 2 weeks after altitude exposure (Koundal et al, 2014).…”

An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor– or Serotonin-Norepinephrine Reuptake Inhibitor–Resistant Depression in Adult Women

“…Healthy individuals residing at 1370m (Salt Lake City, UT) show reduced inorganic phosphate levels and increased brain pH compared to those residing near sea level (Belmont, MA or Charleston, SC). 56 In rodents, hypobaric hypoxia increases the ratios of cellular metabolites like inositol to total creatine in the frontal cortex, 57 which is compatible with reductions in total creatine level. Accordingly, the women participating in this study may have been more likely than women residing at sea level to respond to the intervention, and, because of reduced basal serotonin synthesis, less likely to develop serotonin syndrome.…”

Cerebral bioenergetic differences measured by phosphorus‐31 magnetic resonance spectroscopy between bipolar disorder and healthy subjects living in two different regions suggesting possible effects of altitude

“…Although this observation was not replicated in some countries, it is intriguing that altitude may be a crucial factor affecting complex human behaviors, such as suicidal behavior, in line with reported alterations of various neurotransmitters due to hypobaric hypoxia . For example, rats exposed to a simulated altitude of 10 000 feet were more likely to display depression‐like behavior associated with neurochemical changes in the frontal lobe …”

“…11 For example, rats exposed to a simulated altitude of 10 000 feet were more likely to display depression-like behavior associated with neurochemical changes in the frontal lobe. 12,13 A growing body of literature has suggested that oxidative stress due to mitochondrial dysfunction may be a central pathophysiology of bipolar disorder (BD). 14 Magnetic resonance spectroscopic studies of the brain have noted abnormal lactate and phosphocreatine (PCr) in BD as well as alterations of intracellular pH and choline-containing metabolites.…”