Sage Journals: Discover world-class research

Abstract

Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia–induced memory deficit.

Keywords

High altitude hypoxia learning memory rats

Introduction

Hypoxia is defined as inadequate oxygen supply to the cells and tissues of the body. In this review, the term ‘hypoxia’ refers to ‘hypoxic hypoxia’, which is also the most common type of hypoxia and is due to low arterial oxygen concentration or hypoxemia. Low arterial oxygen concentration is first detected by sensory receptors in the carotid or aortic body and impulses are sent to cardiorespiratory centre in the medulla.¹ The body responds to normalize the decrease in the oxygen arterial concentration by activation of the sympathetic nervous system which leads to increased heart rate, blood pressure, ventilation and the production of stress hormones.^2
–4 However, in the case of very low arterial oxygen concentration, the body will fail to normalize.

Hypoxia has long been known to diminish brain function in humans and animals.^5
–7 In humans, the degree of hypoxia required to impair performance, and the task most sensitive to it, is controversial.⁷ It has been reported that the earliest cognitive signs and symptoms of hypoxia are typically experienced around 15–16% of oxygen concentration,⁸ and complex information processing and learning are among the most sensitive processes to be affected.⁹

Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure, for instance, during hypoxia-awareness training of aircrews or after an in-flight hypoxic incident.¹⁰ However, the effects of acute hypoxia on memory have only been sporadically studied in laboratory-controlled conditions, mainly for military aviation¹⁰ and even less for civilian aviation. With more severe hypoxia, critical judgement declines, and this proceeds to stupor, coma and, finally, death if the hypoxia is not reversed.¹¹

Materials and methods

All articles indexed to MEDLINE and books were searched using the following key words: hypoxia, hypobaric, normobaric, learning and memory. This review mainly aims to look into how different protocols of continuous hypoxia induced by hypobaric/normobaric hypoxic chamber affect the learning and memory of adult rats. Results from brain hypoxia induced by invasive procedures such as ligation of arterial supply to the brain¹² or by chemical induction such as carbon monoxide hypoxia¹³ are not included. The effects of different hypoxia protocols on learning and memory in rats are summarized in Table 1.

Table 1.

Comparison of hypoxic protocols and major cognitive findings from rat studies.^a

Authors	Hypobaric hypoxia (HH)/Normobaric hypoxia (NH)	Simulated altitude (m) and/or % O₂	Duration of exposure	Evaluation method	Major cognitive findings
Saligaut et al.¹⁴	HH	7180 m equivalent to 8% O₂	During behavioural test (days 1–5) ^b	Active avoidance	Impaired avoidance response
Groo et al. ¹⁵	NH	6% O₂	During behavioural test (days 1–3)^b	Active avoidance	Impaired avoidance response
Shukitt-Hale et al.¹⁶	HH	Sea level, 5500 m, 5950 m and 6400 m	2 and 6 h^b	MWM	Altitude exposures at 5950 or 6400 m decreased both spatial reference and working memory performance
Shukitt-Hale et al.¹⁷	HH	Sea level, 3500 m or 6400 m	3 and 6 days	MWM	Altitude exposures at 6400 m decreased both spatial reference and working memory performance
Barhwal et al.¹⁸	HH	6100 m	3 days	MWM	Impaired working memory but no change in the spatial reference memory
Titus et al.¹⁹	HH	6000 m	2 and 7 days	RAM	Impaired learning and memory
Jayalakshmi et al.²⁰	HH	6100 m	3 days	MWM	Impaired spatial working memory but not spatial reference memory
Hota et al.^21,22	HH	7600 m	3, 7 and 14 days	MWM	Impaired spatial working memory
Maiti et al.²³	HH	6100 m	3 and 7 days	MWM	Impaired spatial working memory
Maiti et al.^24,25	HH	6100 m	3, 7, 14 and 21 days	MWM	Impaired spatial working memory after 3 and 7 days of exposure but slight improvement was noted after 14 and 21 days of exposure
Barhwal et al.²⁶	HH	7600 m	3 and 7 days	MWM	Impaired spatial working memory
Barhwal et al.²⁷	HH	7620 m	14 days	MWM	Impaired spatial working memory
Muthuraju et al.^28,29	HH	6100 m	7 days	MWM	Impairment in relearning ability and spatial working memory retrieval
Xu et al.³⁰	NH	0.5 atm/10% O₂	21 days	T maze and NORT	Impaired memory and poor object recognition
Shi et al.³¹	HH	6000 m	5 days	MWM	Impaired spatial working memory
Jain et al.³²	HH	7620 m	7 days	MWM	Impaired spatial working memory
Prasad et al.³³	HH	7600 m	7 days	MWM	Impaired spatial working memory
Baitharu et al.^34,35	HH	7600 m	7 days	MWM	Impaired spatial working memory
Vornicescu et al.³⁶	HH	5500 m	3 days	MWM	Impaired spatial working memory
Kauser et al.^37,38	HH	4572 m for 24 h followed by 7620 m for 7 days	8 days	T maze	Impaired memory

MWM: Morris water maze; RAM: radial arm maze; NORT: novel object recognition test.

^aThe duration of hypoxic exposure was continuous for the stipulated period apart from a 10- to 30-min interval each day for replenishment of food and water, drug administration and changing the cages housing the animals except for entries marked with superscript alphabet ‘b’.

Hypoxia and memory impairment in human

Studies on the effects of hypoxia in life sciences are generally performed either by decreasing barometric pressure (PB), leading to hypobaric hypoxia as shown by Bert,³⁹ or by decreasing oxygen fraction (F_IO₂) without changing PB as shown by Barcroft⁴⁰ in his ‘Glass House’ experiment (normobaric hypoxia (NH)). It has been shown that exposure to hypobaric hypoxia (F_IO₂ < 20.9%; PB < 760 mmHg) and NH (F_IO₂ < 20.9%; PB = 760 mmHg) may or may not result in different physiological responses in human subjects.^41
–43

In a study by Shukitt-Hale et al.,⁴⁴ 23 non-acclimatized males were exposed to 500, 4200 or 4700 m in an altitude chamber for 4–5 h. The study demonstrated that the higher the altitude and the longer the duration of exposure, the more severe mood and memory impairment. A similar study was later conducted by Du et al.⁴⁵ involving 18 healthy young male subjects exposed to 300 m (control group), 2800, 3600 and 4400 m altitude in hypobaric chamber. Compared to control group, after exposure to 2800 m for 1 h, only the performance of continuous recognition memory decreased significantly. After exposure to 3600 m, total reaction time in all tests increased significantly and performance decreased, but the error rates in memory scanning and space memory test were unchanged. During exposure to 4400 m, performance of memory test decreased further and error rates also increased significantly. It was concluded that the performance of human short-term memory deteriorates after exposure to acute mild and moderate hypobaric hypoxia for 1 h, and these effects are aggravated with the increase in altitude as seen in another study.⁴⁶ In a study by Malle et al.¹⁰ involving a bigger number of participants, 28 subjects in the experimental group were exposed to a simulated altitude level of 10,000 m (31,000 ft) in a hypobaric chamber, while 29 subjects in the control group stayed at sea level. The short-term (working) memory assessed using paced auditory serial addition test (PASAT) showed that performance was strongly impaired in the hypoxic group with increased mean error frequency rate. While working memory performance decreased linearly with hypoxemia, peripheral oxygen saturation (SpO₂) was found to be a weak predictor of PASAT performance and vice versa.

Structural brain alterations following exposure to high altitude may include brain swelling,⁴⁷ increase in the number of white matter hyperintensities⁴⁸ and grey and white matter atrophy,^49
–51 contributing to a reduction in total brain volume. Hemosiderin deposits (microhaemorrhages) have also been reported in subjects who have experienced high-altitude cerebral edema.⁵² Cortical atrophy is linked to impaired cognitive function and has been suggested to occur with chronic high-altitude exposure.⁵³ However, human studies shed little light on the precise molecular mechanism(s) of hypoxia-induced memory impairment.

Animal studies related to hypoxia

It has been established that the brain is highly sensitive to hypoxia and that some areas, such as the hippocampus, are especially vulnerable to hypoxic damage.⁵⁴ Compared to human brain, the brain of smaller animal (such as rat) is more resistant to hypoxia because of its higher capillary density, that is, much more severe hypoxic condition must be applied to overtly damage its brain tissues relative to human.¹⁷ Male rats are more susceptible to hypoxia compared to female rats; hence, most hypobaric hypoxia studies were conducted on male rats to obtain better and more conclusive results.^55–56

Depending on the objectives of the study, smaller animals are either exposed to continuous or intermittent hypoxia. Continuous hypoxia with or without low PB rat model is commonly used to study the effect of acute mountain sickness, diseases associated with limited oxygen supply to the brain such as chronic obstructive pulmonary disease and acute respiratory distress syndrome, medication and drugs, concussion or changes in air quality, for example, in a nuclear power plant. Intermittent hypoxia rat model, on the other hand, is commonly used to study the effects of obstructive sleep apnoea. Furthermore, understanding how hypoxia alters brain function has implications for understanding other metabolic encephalopathies as well as aging and age-related disorders, such as Alzheimer’s disease.⁵⁷

Hypoxia and memory impairment in rats

Groo et al.¹⁵ used spontaneously hypertensive rats (SHRs) to study avoidance response to hypoxia as they were reported to be more sensitive to stressful stimuli^58,59 and showed greater hypoxic vulnerability than normotensive Wistar rats. The SHRs were exposed to either NH (6% oxygen) or normoxic conditions. Lowering the oxygen contents of inspired air to 6% impaired acquisition of the avoidance response, and the difference between the performance (in percentage of conditioned avoidance response) of animals kept under normoxic and hypoxic conditions was significant on day 3 (at 69.2% and 38.0%, respectively). Hypoxia was also found to increase the incidence of escape failures. These findings are in agreement with earlier study findings by Saligaut et al.,¹⁴ where the acquisition of a conditioned avoidance response was also impaired in hypobaric hypoxia at 300 Torr (7180 m; equivalent to 8% oxygen content).

Hippocampal damage

Direct correlation between working memory impairment and level of altitude was evidenced in a study involving Fischer male rats exposed to various altitudes equivalent to sea levels 5500, 5950 and 6400 m, for 2 and 6 h.¹⁶ In a later study by the same group of researchers, two groups of rats were exposed to 6400 m altitude for either 72 or 144 h. It was found that the longer the time of exposure, the more noticeable the hippocampal damage (delayed neurotoxicity) as shown by 78% neuronal damage after 144 h compared to 50% after 72 h of exposure.⁵³ Titus et al.¹⁹ showed that hippocampal-dependent spatial learning in rats was affected marginally following 2 days of exposure to simulated hypobaric hypoxia at 6000 m, while 7 days of exposure severely affected learning of partially baited radial-arm maze (RAM) task. The study also found that exposure for 2 days to hypobaric hypoxia resulted in minimal deleterious effects on the CA1 pyramidal neurons, while exposure for 7 days caused a significant decrease in the number of branching points, intersections and dendritic length. Unlike the CA1 pyramidal neurons, CA3 neurons exhibited dendritic atrophy following both 2 and 7 days of hypobaric hypoxia exposure. Thus, CA3 neurons are more vulnerable to hypoxic insult compared to CA1 neurons.^23,60,61 Findings by Titus et al. are in agreement with the observation of neuronal degeneration in rat hippocampus exposed to hypobaric hypoxia in previous studies^23,53 as well as a later study by Prasad et al.³³

Maiti et al.²⁴ investigated spatial memory functions and dendritic changes in CA1, CA3 and entorhinal cortex of hippocampus, and layer II of prefrontal cortex (PFC) in rats exposed to simulated hypobaric hypoxia at 6100 m, but with different durations of hypobaric hypoxia exposure, that is, 3, 7, 14 and 21 days. There was impairment of spatial memory after 3 and 7 days, but slight improvement of spatial memory was noted after 14 and 21 days of exposure. The study suggested that hypobaric hypoxia induces dendritic plasticity of PFC and hippocampal pyramidal neurons of rat brain, which may be associated with improvement of spatial memory function after 21 days of hypobaric hypoxia exposure. These findings are in contrast with a recently published data on the adverse effects of hypobaric hypoxia on the brain which became more severe after 4 weeks compared to 2 days of exposure. The total brain weight and oxidative stress in all three brain regions (striatum, hippocampus and cortex) were significantly increased after 4 weeks compared to after 2 days of hypobaric hypoxia. The study, however, did not assess cognitive function.⁶² Further studies are necessary to attest to the possibility of compensatory stage after 2–3 weeks of hypobaric hypoxia exposure followed by a decompensated stage after 4 weeks.

Brain oxidative stress

Liu et al.⁶³ reported that oxidative damage to hippocampus impairs spatial memory of rats. Rats showed impairment of working memory but no change in reference memory after 3 days of exposure to simulated hypobaric hypoxia at 6100 m.^18,20 The study revealed a significant decrease in reduced glutathione (GSH) levels with concomitant increase in oxidized glutathione (GSSG) in the hypoxic rats. The increased generation of free radicals might have resulted in increased utilization of GSH, thus leading to increased GSSG synthesis. The increase in GSH utilization is further accompanied by decreased GSH synthesis as evidenced by decreased GSH reductase activity, thus depleting antioxidant status. This might have been triggered through low levels of NADPH, which is a cofactor for GSH reductase to convert GSSG to GSH. Increased generation of free radicals during hypobaric hypoxia is due to low oxygen availability, and this may be explained by leakage of free electrons triggering a chain reaction resulting in the formation of hydrogen peroxide and reactive hydroxyl radicals.⁶⁴ These reactive oxygen species (ROS) have a high affinity for membrane lipids,⁶⁵ especially in the brain, as it is rich in polyunsaturated fatty acids. The ROS leads to lipid peroxidation and membrane damage.⁶⁶ In addition, there is deterioration in the antioxidant defence mechanism that under normal physiological conditions scavenges the free radicals produced in the cell as by-products of various metabolic pathways. Similar findings were noted by Hota et al.^21,22 in studies on hypobaric hypoxia and oxidative stress. In these studies, however, acclimatization to oxidative stress occurred after prolonged hypobaric hypoxia exposure, that is, 14 days. The study also pointed towards the crucial role that glutamate might play in causing the hypobaric hypoxia–induced oxidative stress. Since numerous biochemical and molecular pathways are involved in the stress response of the cells, the precise mechanism responsible for the onset of acclimatization to oxidative stress still remains to be elucidated.

A study by Shi et al.³¹ supported earlier findings on the oxidative stress and apoptosis associated with memory impairment in rats exposed to hypobaric hypoxia. The study showed that exposure to simulated hypobaric hypoxia at 6000 m for 5 days caused spatial memory impairment as well as oxidative stress (increased lactate dehydrogenase activity, decreased GSH level, decreased superoxide dismutase (SOD) level, inhibition of GSH synthesis and greater utilization of GSH for detoxification of hypoxia-induced free radicals, thus leading to increased GSSG synthesis) and apoptosis in different regions of the brain in rats. They also found that the hippocampus is more susceptible to hypoxia when compared with the cortex.

A later study by Baitharu et al.^34,35 found that hypobaric hypoxia–induced memory impairment was associated with neurodegeneration along with alteration in nitric oxide (NO), glucocorticoid, corticosterone, oxidative stress and acetylcholinesterase (AChE) activity in the hippocampal region. In this study, rats were exposed to a simulated altitude of 7600 m in a specially designed animal decompression chamber for 7 days. Another study showed that a shorter and lower simulated altitude exposure also resulted in spatial memory impairment.³⁶ Exposure of rats to an altitude of 5500 m (375 mmHg) for 3 days was found to induce oxidative stress as evidenced by significant increase in malondialdehyde and reduction in GSH in serum and brain tissue, and neuronal death associated with reactive astrogliosis in hippocampus and superjacent cortex.

Signalling pathways involved in oxidative stress

Barhwal et al.^26,27 examined the signalling cascades involved in mediating oxidative stress neuronal damage in hypobaric hypoxia. The study revealed increased thioredoxin (Trx-1) expression and increased extracellular-signal-regulated kinase (ERK) phosphorylation in rats exposed to hypobaric hypoxia for 14 days.⁶⁷ Trx-1 increases hypoxia-inducible factor-1α (HIF-1α) expression in both normoxic and hypoxic conditions.⁶⁸ The HIF-1α activates many genes involved in erythropoiesis, angiogenesis, energy metabolism, proliferation/cell survival, apoptosis and generation of NO.^69
–71 Alteration of NO production plays an important role in brain injury in conditions of hypoxia/reoxygenation.⁶⁷ NO produced in excess in the brain under the action of hypoxia-induced neuronal nitric oxide synthases rapidly reacts with superoxide anion to form peroxynitrite (ONOO⁻), a more toxic metabolite that causes brain injury.⁷² The peroxynitrite is responsible for protein denaturation, lipid peroxidation, DNA damage and depletion of antioxidant defences.²⁵

On the other hand, ERK pathway contributes to nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein stabilization and may result in the increased translocation of Nrf2 into the nucleus.⁷³ Nrf2 is the central transcription factor involved in regulating the expression of antioxidant enzymes like GSH S-transferase and SOD that are important in protecting the cells against oxidative damage. However, despite increased nuclear translocation of Nrf2, there is increased free radical generation, protein oxidation and lipid peroxidation in hypobaric hypoxia rats.²⁷

Calcium overload-induced oxidative stress

Calcium overload in the neurons is previously reported to generate ROS by activating phospholipase A2, xanthine oxidase and monoamine oxidase. Release of cytochrome c from the mitochondria due to calcium sequesteration is also known to generate ROS and trigger apoptotic cell death.²⁶

The elevation of intracellular calcium concentrations and its L-type calcium channel expression, as well as increased calpain expression, have been demonstrated in rats exposed to hypobaric hypoxia.²⁶ Calpain and L-type calcium channel expressions are maximal on day 7 of hypobaric hypoxia exposure and decline on day 14. Calcium is known to activate calpain that mediates proteolysis of selective proteins and significantly contributes to neuronal damage⁷⁴ in several hypoxic and ischemic models.^75,76 Calcium is also known to be sequestered into the mitochondria in excitotoxic conditions, thus resulting in release of cytochrome c that triggers mitochondria-mediated apoptotic cascades.^77,78 Increased cytosolic cytochrome c on day 7 is also demonstrated followed by a marginal decline on day 14 of hypoxic exposure. Expression of active caspase 3, however, shows a different trend with its maximal level on day 14 of hypoxic exposure. This is, however, in accordance with another previous study that reported progressive increase in caspase 3 activity and neurodegeneration with increased duration of exposure.³³ This anomaly in caspase 3 activity may be due to existence of other signalling cascades on day 14 of chronic hypoxic exposure²¹ and warrants further investigation.

Glutamate excitotoxicity

The synthesis and release of neurotransmitters are particularly sensitive to hypoxia. Hypobaric hypoxia induces increased release of excitatory amino acid such as glutamate⁷⁹ and upregulation of N-methyl-d-aspartate (NMDA) receptors. In a study by Hota et al.,⁸⁰ male Sprague Dawley rats were exposed to simulated hypobaric hypoxia at 7600 m for 3, 7 and 14 days. Memory impairment in rats was maximal after 14 days of hypobaric hypoxia exposure. It was associated with significant increase in expression of NR1 subunit of NMDA receptor, indicating overstimulation of the NMDA receptor by hypobaric hypoxia. Binding of glutamate to NMDA receptors in hypoxic ischemia has also been reported to cause free radical production and robust influx of calcium ions into the cytosol leading to calcium overload.⁸¹ This excess calcium is sequestered by the mitochondria through the calcium uniporter in the inner mitochondrial membrane at the expense of mitochondrial membrane potential.^82

–86 This in turn causes generation of ROS by the mitochondria that may lead to mitochondrial membrane damage and may cause the release of cytochrome c from the mitochondria during hypoxia.^87,88 It is well known that cytochrome c is released from the mitochondria to the cytoplasm⁸⁹ as an outcome of mitochondrial dysfunction that may trigger apoptosis. This activates a plethora of proapoptotic proteins such as Bax, caspase-3, Smac/Diablo, Bid, Bad, Apaf-1 and many others.^90,91

Alteration in cholinergic and adrenergic systems

Apart from the crucial role of oxidative stress and glutamate excitotoxicity in mediating cognitive deficits following exposure to hypobaric hypoxia, cholinergic systems are also known to be involved.⁹² Previous reports have discussed that decreased choline acetyltransferase,⁹³ increased AChE and decreased α7 nicotinic and muscarinic M1 acetylcholine (ACh) receptors⁹⁴ are closely associated with cognitive deficits. Muthuraju et al.^28,29 revealed that impairment in relearning ability and memory retrieval in rats exposed to hypobaric hypoxia was associated with decreased ACh and increased AChE levels which then led to morphological damage in cortical and hippocampal neurons. Administration of AChE inhibitors, such as physostigmine and galantamine, resulted in amelioration of the hypobaric hypoxia-induced neuronal morphological damage in cortex and hippocampus. These AChE inhibitors improved ACh level, decreased AChE activity and increased ACh synthesis by increasing acetyltransferase activity.⁹⁵

The greatest amount of nerve growth factor (NGF) is produced in the cortex, hippocampus and pituitary gland, although significant quantities are also produced in other areas, including the basal ganglia, thalamus, spinal cord and in the retina.⁹⁶ The NGF plays a pivotal role in the survival and function of cholinergic neurons of the basal forebrain complex⁹⁷; such functions include attention, arousal, motivation, memory and consciousness.

Other studies associate memory impairment with adrenergic dysregulation and neuronal damage in medial PFC. In these studies, rats were habituated at simulated altitude of 4572 m for 1 day followed by exposure to simulated altitude of 7620 m for a further 7 days.^37,38 It was suggested that norepinephrine (NE) dysregulation under hypobaric hypoxia might have been one of the possible underlying mechanisms leading to cognitive deficits and associated morphological damage. This is due to the fact that working memory is regulated by the PFC and is created by networks of PFC neurons engaged in recurrent excitation generating persistent activity.⁹⁸ If the PFC recurrent excitatory firing is profoundly altered by the NE dysfunction, working memory functions will also be affected.^98,99

Brain-derived neurotrophic factor

Jain et al.³² examined the cellular and molecular pathways related to hypobaric hypoxia–induced neuronal cell death. Adult male Sprague Dawley rats exposed to hypobaric hypoxia equivalent to 7620 m for 7 days resulted in spatial memory impairment and neurodegeneration that was related to low brain-derived neurotrophic factor (BDNF). The low BDNF inhibits PI3K/AKT pathway resulting in activation of GSK3β and caspase 3 which further augments neuronal apoptosis and memory impairment.

cAMP response element binding protein (CREB) is a key transcription factor involved in several critical functions of the brain including learning, neuronal plasticity and cell survival.¹⁰⁰ CREB has been shown to be the key mediator for BDNF-mediated cell survival as studies showed that silencing the transcriptional activity of CREB impaired BDNF protection.¹⁰¹ CREB can be activated by various kinases including ERK, AKT and GSK3β.¹⁰²

Although there was increased CREB phosphorylation in hypoxia as observed from the total CREB to phospho CREB ratio, total CREB was decreased when compared to the normoxic group, thus resulting in its decreased availability for phosphorylation. The decreased CREB expression in hypobaric hypoxia is probably due to the excitotoxic neuronal loss and free radical–mediated protein degradation as indicated by increased protein carbonyls.²²

Conclusion

Hypobaric hypoxia studies conducted in rats provide some insight into the underlying mechanism of hypobaric hypoxia–induced memory loss. Exposure to hypobaric hypoxia in rats induces glutamate excitotoxicity and increases influx of calcium ion by NR1 subunit of NMDA receptor and L-type calcium channel upregulation.^21,22,26 It also induces oxidative stress^{18,20
–22,34} via apoptotic signalling pathways leading to hippocampal cell apoptosis.^26,27,32 Hypobaric hypoxia exposure also impairs cholinergic^28,29 and adrenergic^37,38systems and lowers BDNF level which are important for memory function. All of these mechanisms may be related to learning and memory deficit in human exposed to hypobaric hypoxia.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research received funding from USM Short-term Grant (304/PPSP/61313086).

References

Kalia

Welles

. Brain stem projections of the aortic nerve in the cat: a study using tetramethyl benzidine as the substrate for horseradish peroxidase. Brain Res 1980; 188: 23–32.

Fishman

Fritts

Cournand

. Effects of acute hypoxia and exercise on the pulmonary circulation. Circulation 1960; 22: 204–215.

Buchheit

Richard

Doutreleau

. Effect of acute hypoxia on heart rate variability at rest and during exercise. Int J Sports Med 2004; 25: 264–269.

Richalet

Letournel

Souberbielle

. Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. Am J Physiol 2010; 299: 1685–1692.

Haldane

Kellas

Kennaway

. Experiments on acclimatization to reduced atmospheric pressure. J Physiol Cond 1919; 53:181.

Lutz

Schneider

. Alveolar air and respiratory volume at low oxygen tensions. Am J Physiol 1919; 50: 280–301.

Gibson

. Hypoxia. In: McCandless

(ed) Cerebral energy metabolism and metabolic encephalopathy. New York: Plenum, 1985, pp. 43–78.

Castor

Borgvall

Technical report: the effects of mild, acute hypoxia on cognitive performance. Report No. 2015:20 2015. SSM Available at: www.stralsakerhetsmyndigheten.se.

McFarland

. Stimuli primarily related to high altitude flight, in human factors in our transportation. Human Factors in Air Transportation, Occupational Health and Safety. New York: McGraw-Hill, 1953, pp. 153–169.

10.

Malle

Quinette

Laisney

. Working memory impairment in pilots exposed to acute hypobaric hypoxia. Aviat Space Environ Med 2013; 84: 773–779.

11.

Plum

Posner

. The diagnosis of stupor and coma. 3rd ed. Philadelphia: FA Davis Company, 1980.

12.

Rumajogee

Bregman

Miller

. Rodent hypoxia-ischemia models for cerebral palsy research: a systematic review. Front Neurol 2016; 7: 57.

13.

Zhang

Piantadosi

. Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 1992; 90(4): 1193–1199.

14.

Saligaut

Moore

Boulu

. Hypobaric hypoxia: central catecholamine levels and cortical PO₂ and avoidance response in rats treated with apomorphine. Aviat Space Environ Med 1981; 52(3): 166–170.

15.

Groo

Palosi

Szporny

. Comparison of the effects of vinpocetine, vincamine, and nicergoline on the normal and hypoxia-damaged learning process in spontaneously hypertensive rats. Drug Dev Res 1988; 15(1): 75–85.

16.

Shukitt-Hale

Stillman

Welch

. Hypobaric hypoxia impairs spatial memory in an elevation-dependent fashion. Behav Neural Biol 1994; 62: 244–252.

17.

Shukitt-Hale

Kadar

Marlowe

. Morphological alterations in the hippocampus following hypobaric hypoxia. Hum Exp Toxicol 1996; 15: 312–319.

18.

Barhwal

Singh

Hota

. Acetyl-L-carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Eur J Pharmacol 2007; 570(1–3): 97–107.

19.

Titus

Shankaranarayana Rao

Harsha

. Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats. Neurosci 2007; 145(1): 265–278.

20.

Jayalakshmi

Singh

Kalpana

. N-acetyl cysteine supplementation prevents impairment of spatial working memory functions in rats following exposure to hypobaric hypoxia. Physiol Behav 2007; 92: 643–650.

21.

Hota

Barhwal

Singh

. Chronic hypobaric hypoxia induced apoptosis in CA1 region of hippocampus: a possible role of NMDAR mediated p75 NTR upregulation. Exp Neurol 2008; 212: 5–13.

22.

Hota

Barhwal

Baithar

. Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment. Neurobiol Dis 2009; 34: 23–39.

23.

Maiti

Singh

Muthuraju

. Hypobaric hypoxia damages the hippocampal pyramidal neurons in the rat brain. Brain Res 2007; 1175: 1–9.

24.

Maiti

Muthuraju

Ilavazhagan

. Hypobaric hypoxia induces dendritic plasticity in cortical and hippocampal pyramidal neurons in rat brain. Behav Brain Res 2008; 189: 233–243.

25.

Maiti

Singh

Ilavazhagan

. Nitric oxide system is involved in hypobaric hypoxia-induced oxidative stress in rat brain. Acta Histochem 2010; 112: 222–232.

26.

Barhwal

Hota

Baitharu

. Isradipine antagonizes hypobaric hypoxia induced CA1 damage and memory impairment: complementary roles of L-type calcium channel and NMDA receptors. Neurobiol Dis 2009; 34: 230–244.

27.

Barhwal

Hota

Jain

. Acetyl-l-carnitine (ALCAR) prevents hypobaric hypoxia-induced spatial memory impairment through extracellular related kinase-mediated nuclear factor erythroid 2-related factor 2 phosphorylation. Neurosci 2009; 161: 501–514.

28.

Muthuraju

Maiti

Solanki

. Acetylcholinesterase inhibitors enhance cognitive functions in rats following hypobaric hypoxia. Behav Brain Res, 2009; 203: 1–14.

29.

Muthuraju

Maiti

Solanki

. Cholinesterase inhibitors ameliorate spatial learning deficits in rats following hypobaric hypoxia. Exp Brain Res 2010; 203: 583–592.

30.

Sun

Eroku

. Diet-induced ketosis improves cognitive performance in aged rats. Adv Exp Med Biol 2010; 662: 71–75.

31.

Shi

. Huperzine A ameliorates cognitive deficits and oxidative stress in the hippocampus of rats exposed to acute hypobaric hypoxia. Neurochem Res 2012; 37: 2042–2052.

32.

Jain

Baitharu

Prasad

. Enriched environment prevents hypobaric hypoxia induced memory impairment and neurodegeneration: role of BDNF/PI3K/GSK3β pathway coupled with CREB activation. PloS One 2013; 8(5):e62235.

33.

Prasad

Baitharu

Sharma

. Quercetin reverses hypobaric hypoxia-induced hippocampal neurodegeneration and improves memory function in the rat. High Altitude Medicine & Biology 2013; 14: 383–394.

34.

Baitharu

Deep

Jain

. Inhibition of glucocorticoid receptors ameliorates hypobaric hypoxia induced memory impairment in rat. Behav Brain Res 2013; 240: 76–86.

35.

Baitharu

Jain

Deep

. Withania somnifera root extract ameliorates hypobaric hypoxia induced memory impairment in rats. J Ethnopharmacol 2013; 145: 431–441.

36.

Vornicescu

Boşca

Crişan

. Neuroprotective effect of melatonin in experimentally induced hypobaric hypoxia. Rom J Morphol Embryol 2013; 54(4): 1097–1106.

37.

Kauser

Sahu

Kumar

. Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline. Neuroscience 2013; 254: 110–119.

38.

Kauser

Sahu

Kumar

. Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits. Physiol Behav 2014; 123: 187–192.

39.

Bert

. La pression barométrique: recherches de physiologie expérimentale. Masson Paris 1878; 1168.

40.

Barcroft

. Respiratory function of the blood, Part I. New York: Cambridge University Press, 1925.

41.

Savourey

Launay

Besnard

. Normo- and hypobaric hypoxia: are there any physiological differences? Eur J Appl Physiol 2003; 89: 122–126.

42.

Degache

Larghi

Faiss

. Hypobaric versus normobaric hypoxia: same effects on postural stability? High Alt Med Biol 2012; 13: 40–45.

43.

Neuhaus

Hinkelbein J. Cognitive responses to hypobaric hypoxia: implications for aviation training Psychol Res Behav Manag 2014; 7: 297–302.

44.

Shukitt-Hale

Banderet

Lieberman

. Elevation-dependent symptom, mood, and performance changes produced by exposure to hypobaric hypoxia. Int J Aviat Psychol 1998; 8: 319–334.

45.

Zhuang

. Effects of acute mild and moderate hypoxia on human short memory. Space Med Eng (Beijing) 1999; 12: 270–273.

46.

Virués-Ortega

Buela-Casal

Garrido

. Neuropsychological functioning associated with high-altitude exposure. Neuropsychol Rev 2004; 14: 197–224.

47.

Rupp

Jubeau

Lamalle

. Cerebral volumetric changes induced by prolonged hypoxic exposure and whole-body exercise. J Cereb Blood Flow Metab 2014; 34: 1802–1809.

48.

McGuire

Sherman

Wijtenburg

. White matter hyperintensities and hypobaric exposure. Ann Neurol 2014; 76: 719–726.

49.

Garrido

Segura

Capdevila

. New evidence from magnetic resonance imaging of brain changes after climbs at extreme altitude. Eur J Appl Physiol Occup Physiol 1995; 70: 477–481.

50.

Paola

Bozzali

Fadda

. Reduced oxygen due to high-altitude exposure relates to atrophy in motor-function brain areas. Eur J Neurol 2008; 15: 1050–1057.

51.

Foster

Davies-Thompson

Dominelli

. Changes in cerebral vascular reactivity and structure following prolonged exposure to high altitude in humans. Physiol Rep 2015; 3: e12647.

52.

Schommer

Kallenberg

Lutz

. Hemosiderin deposition in the brain as footprint of high-altitude cerebral edema. Neurology 2013; 81: 1776–1779.

53.

Fayed

Modrego

Morales

. Evidence of brain damage after high-altitude climbing by means of magnetic resonance imaging. Am J Med 2006; 119(2): 168.e1–6.

54.

Pulsinelli

. Selective neuronal vulnerability: morphological and molecular characteristics. Prog Brain Res 1985; 63: 29–37.

55.

Hurn

Vannucci

Hagberg

. Adult or perinatal brain injury does sex matter? Stroke 2005; 36: 193–195.

56.

Mayoral

Omar

Penn

. Sex differences in a hypoxia model of preterm brain damage. Pediatr Res 2009; 66: 248–253.

57.

Gibson

Huang

. Animal models of brain hypoxia. In: Boulton

Baker

Roger

(eds) Animal models of neurological disease. Totowa NJ: The Humana Press Inc, 1992, pp. 51–93.

58.

McCarty

Kopin

. Patterns of behavioral development in spontaneously hypertensive rats to inescapable footshock. Dev Psychobiol 1979; 12: 239–243.

59.

Krauchi

Witz-Justice

Willener

. Spontaneous hypertensive rats: behavioral and corticosterone response depend on circadian phase. Physiol Behav 1983; 30: 35–40.

60.

Rybnikova

Sitnik

Gluschenko

. The preconditioning modified neuronal expression of apoptosis-related proteins of Bcl-2 superfamily following severe hypobaric hypoxia in rats. Brain Res 2006; 1089(1): 195–202.

61.

Hota

Srivastava

. Neuroglobin regulates hypoxic response of neuronal cells through Hif-1α- and Nrf2-mediated mechanism. J Cereb Blood Flow Metab 2012; 32(6): 1046–1060.

62.

Chiş

Baltaru

Dumitrovici

. Quercetin ameliorate oxidative/nitrosative stress in the brain of rats exposed to intermittent hypobaric hypoxia. Rev Virtual Quim 2016; 8(2): 369–383.

63.

Liu

Head

Gharib

. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation; partial reversal by feeding acetyl-l-carnitine and/or R-alpha lipoic acid. Proc Natl Acad Sci 2002; 99(4): 2356–2361.

64.

Martilla

Roytta

Lorentz

. Oxygen toxicity protecting enzymes in the human brain. J Neural Transm 1988; 74: 87–90.

65.

Watson

. Effect of concomitance of lipid peroxidation in experimental models of cerebral ischemia and stroke. Prog Brain Res 1996; 96: 69–90.

66.

. Nitric oxide synthase and intermittent hypoxia-induced spatial learning deficit in the rat. Neurobiol Dis 2004; 17: 44–53.

67.

Matsui

Nagafuji

Kumanishi

. Role of nitric oxide pathogenesis underlying ischemic cerebral damage. Cell Mol Neurobiol 1999; 19: 177.

68.

Welsh

Bellamy

Briehl

. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 2002; 62(17): 5089–5095.

69.

Chandel

Maltepe

Goldwasser

. Mitchondrial reactive species triggerhypoxia induced transcription. Proc Natl Acad Sci USA 1998; 95: 11715–11720.

70.

Kaluz

Kaluzova

Stanbridge

. Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element. Clin Chim Acta 2008; 395(1–2): 6–13.

71.

Romero

Canuelo

Siles

. Nitric oxide modulates hypoxia-inducible factor-1 and poly (ADPribose) polymerase-1 cross talk in response to hypobaric hypoxia. J Appl Physiol 2012; 112(5): 816–823.

72.

McCord

. The evolution of free radicals and oxidative stress. Am J Med 2000; 198: 652.

73.

Nguyen

Sherratt

Nioi

. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem 2005; 280: 32485–32492.

74.

Saido

Nagao

Shiramine

. Distinct kinetics of subunit autolysis in mammalian m-calpain activation. FEBS Lett 1994; 346: 263–267.

75.

Villa

Henzel

Sensenbrenner

. Calpain inhibitors, but not caspase inhibitors, prevent actin proteolysis and DNA fragmentation during apoptosis. J Cell Sci 1998; 111: 713–722.

76.

Lankiewicz

Luetjens

Bui

. Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death. J Biol Chem 2000; 275: 17064–17071.

77.

Gorman

Ceccatelli

Orrenius

. Role of mitochondria in neuronal apoptosis. Dev Neurosci 2000; 22: 348–358.

78.

Kroemer

Reed

. Mitochondrial control of cell death. Nat Med 2000; 6: 513–519.

79.

Nicholls

Attwell

. The release and uptake of excitatory amino acids. Trends Pharmacol Sci 1990; 11: 462–468.

80.

Hota

Prasad

. Oxidative-stress-induced alterations in Sp factors mediate transcriptional regulation of the NR1 subunit in hippocampus during hypoxia. Free Radic Biol Med 2010; 49: 178–191.

81.

Sattler

Tymianski

. Molecular mechanisms of calcium dependent excitotoxicity. J Mol Med 2000; 78: 3–13.

82.

Dugan

Sensi

Canzoniero

. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 1995; 15: 6377–6388.

83.

Reynolds

Hastings

. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci 1995; 15: 3318–3327.

84.

Gunter

Buntinas

Sparagna

. The Ca²⁺ transport mechanisms of mitochondria and Ca²⁺ uptake from physiological type Ca²⁺ transients. Biochim Biophys Acta 1998; 1366: 5–15.

85.

Stout

Raphael

Kanterewicz

. Glutamate induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1998; 1: 366–373.

86.

Luetjens

Bui

Sengpiel

. Delayed mitochondrial dysfunction in excitotoxic neuron death: cytochrome c release and a secondary increase in superoxide production. J Neurosci 2000; 20: 5715–5723.

87.

Sengpiel

Preis

Krieglstein

. NMDA-induced superoxide production and neurotoxicity in cultured rat hippocampal neurons: role of mitochondria. Eur J Neurosci 1998; 10: 1903–1910.

88.

Carriedo

Sensi

Yin

. AMPA exposures induce mitochondrial Ca2⁺ overload and ROS generation in spinal motor neurons in vitro. J Neurosci 2000; 20: 240–250.

89.

Kluck

Bossy-Wetzel

Green

. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997; 275: 1132–1136.

90.

Green

Reed

. Mitochondria and apoptosis. Science 1998; 281: 1309–1312.

91.

Shimizu

Narita

Tsujimoto

. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 1999; 399: 483–487.

92.

Tsai

Peng

Wang

. Effects of luteolin on learning acquisition in rats: involvement of the central cholinergic system. Life Sci 2007; 80: 1692–1698.

93.

Gericke

Lang

Steckler

. Nerve growth factor response to excitotoxic lesion of the cholinergic basal forebrain is slightly impaired in aged rats. J Neural Transm 2003; 110: 627–639.

94.

Arneric

Wiliams

. Nicotinic agonists in Alzheimer’s disease: does the molecular diversity of nicotine receptors offer the opportunity for developing CNS selective cholinergic channel activators? In: Racagni

Brunello

Langer

(eds) Recent advances in the treatment of neurodegenerative disorders and cognitive dysfunction. Basel: Darger, 1994, pp. 58–70.

95.

Muthuraju

Maiti

Solanki

. Possible role of cholinesterase inhibitors on memory consolidation following hypobaric hypoxia of rats. Int J Neurosci 2011; 121: 279–288.

96.

McAllister

. Neurotrophins and neuronal differentiation in the central nervous system. Cell Mol Life Sci 2001; 58: 1054–1060.

97.

Dreyfus

. Effects of nerve growth factor on cholinergic brain neurons. Trends Pharmacol Sci 1989, 10: 145–149.

98.

Goldman-Rakic

. Cellular basis of working memory. Neuron 1995; 14: 477–485.

99.

Arnsten

AFT

. Through the looking glass: differential noradrenergic modulation of prefrontal cortical function. Neural Plast 2000; 7: 1–2.

100.

Sakamoto

Karelina

Obrietan

. CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 2011; 116: 1–9.

101.

Bonni

Brunet

West

. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and independent mechanisms. Science 1999; 286: 1358–1362.

102.

Montminy

. CREB is a regulatory target for the protein kinase AKT/PKB. J Biol Chem 1998; 273: 32377–32379.

Insight into potential mechanisms of hypobaric hypoxia–induced learning and memory deficit – Lessons from rat studies

Abstract

Keywords

Introduction

Materials and methods

Hypoxia and memory impairment in human

Animal studies related to hypoxia

Hypoxia and memory impairment in rats

Hippocampal damage

Brain oxidative stress

Signalling pathways involved in oxidative stress

Calcium overload-induced oxidative stress

Glutamate excitotoxicity

Alteration in cholinergic and adrenergic systems

Brain-derived neurotrophic factor

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References