**1. Introduction**

Hypoxia is a condition in which some organ(s) or a whole organism is deprived of adequate oxygen supply. Except in very short or static exercises [1–3], hypoxia negatively affects exercise performance [4,5]. In particular, the maximal aerobic workload that can be sustained during exercise involving large muscle groups (e.g., cycling, running) is considerably lower in hypoxia compared with normoxia. The origin of human performance limitation in hypoxia is attributed to a decrease in maximal oxygen uptake (VO2max). Dempsey and Wagner [6] observed that each 1% decrement in SaO2% below the 95% level approximates to a 1–2% decrement in VO2max. Diminished VO2max in hypoxia is accompanied by a lowered O2 partial pressure in arterial blood (PaO2), which reduces O2 delivery to tissues and negatively affects muscle metabolism and contraction [7,8], leading to so-called peripheral fatigue. There is also evidence that maximal cardiac output and maximal heart rate (HRmax) during maximal exercise in hypoxia are decreased [9] and the decrease in HRmax is linearly related to the decrease in SaO2% [10]. This effect can be reversed by oxygen administration during hypoxia exposure in both acute [11] and chronic hypoxia [9,11–13].

The aforementioned factors do not fully explain the hypoxia-induced reduction in exercise performance. As biochemical, electromyographic and mechanical signs of muscle fatigue are reduced in severe hypoxia compared with normoxia, peripheral (muscle) fatigue may not be the main factor responsible for impaired exercise performance [12,14]. It is well recognized that metabolites produced in working muscles can directly modulate central nervous system (CNS) functions by changes in sensory nerve impulses. Moreover, chemical messengers originating from working muscle are released into the circulation [15] and can affect brain function after their translocation to the CNS. An alternative hypothesis that may, at least partially, explain reduced exercise performance in hypoxic condition attributes it to so-called central fatigue [16]. This assumption is supported by studies showing impairment of cognitive performance [17] by reduced O2 delivery. Several studies [18,19] have reported that moderate levels of hypoxia degraded the ability to perform psychomotor tasks, and the main cause of cognitive impairment is the low PaO2 regardless of the type of hypoxia (normobaric vs. hypobaric) [20].

The negative impact of hypoxia on cognitive functions is manifested by memory deterioration, reduced learning ability, decreased concentration, and psychomotor performance [21]. One of the best indicators of the speed and efficiency of mental processes is choice reaction time (CRT) and the number of correct reactions (NCR), especially if these variables are used to assess the cognitive function within the same group of participants [22,23]. However, in previous studies, the effect of hypoxia on CRT was ambiguous and most likely depended on the time of exposure [24,25] and level of hypoxia: moderate vs. severe [24,26,27]. Some studies show that acute exposure to severe hypoxia led to an increase in CRT [24,27]. However, prolonged exposure to moderate hypoxia did not disturb CRT [24,27]. Animal studies reveal that hypoxia causes neuronal injuries in the hippocampus and cortex, leading to functional and behavioral deficits [28–30]. Likewise, data obtained from neuroimaging proved that intermittent hypoxia may result in a decrease in the volume of the hippocampus in humans [31].

Some previous studies performed in normoxia indicated that exercise of low or moderate intensity improves psychomotor performance [32–37], while other studies showed a significant decrease in psychomotor performance during heavy exhaustive exercise [34,37,38]. It is not known if these aforementioned effects can be modulated by a hypoxia-induced deleterious influence on the CNS. Most recent data suggest that an essential role in these phenomena is played by brain-derived neurotrophic factor (BDNF) (for review, see [39,40]).

BDNF plays a key role in the physiology of the developing and mature CNS, showing a high affinity for the TrkB receptor. Consequently, it is responsible for neurogenesis, differentiation, survival, and remodeling of neurons, and it also positively affects synaptogenesis, synaptic plasticity, and long-term potentiation [41–43]. The upregulation of BDNF may influence brain functions including learning and memory [44].

Several lines of evidence suggest a link between BDNF and physical activity. Both acute and chronic aerobic activity were effective for increasing peripheral BDNF concentrations [45]. An elevated level of BDNF was also seen in active sportsman compared to sedentary individuals [46,47]. Another factor that can be considered a stimulator of BDNF production within the brain is nitric oxide (NO). A role for NO in increased BDNF production in response to exercise has been recently evidenced [48,49]. Exercises of extreme intensity or duration are known to greatly elevate blood cortisol (C) [50,51], while high circulating corticosterone has been shown to suppress brain production of BDNF in rats [52]. Of importance, BDNF induces expression of the monocarboxylate transporter that enables the use of lactate as an alternative energy source [53].

There are also very limited data about the efficacy of hypoxia exposure on psychomotor performance where subjects performed exercise with low and high intensity. Some data suggest that exposure to hypoxia reduces cognitive functions [17]. Also, mechanisms of hypoxia's effect on the CNS are still poorly understood. One possible candidate which might take part in this phenomenon is BDNF. It has been shown that cognitive impairment is noticeable in neurodegenerative diseases, which is associated with a lower serum BDNF level as compared to healthy individuals [54]. Moreover, the level of this decrease depends on the degree of cognitive impairment [54]. On the other hand, BDNF is thought to be responsible for improving cognitive function as a result of exercise effort [55]. Moreover, it has been proven that both resting and post-exercise peripheral BDNF levels correspond to its brain production [45,56] and its level is elevated in response to exercise effort [46].

Therefore, the aim of this study was to examine the impact of a single bout of exercise to volitional exhaustion during acute exposure of well-trained endurance athletes to moderate hypoxia on psychomotor performance. For this purpose, we measured a peripheral level of BDNF and CRT and NCR as indices of psychomotor performance during graded cycloergometer exercise test. Furthermore, we examined a level of selected circulating biochemical factors, such as C, NO pathway-related metabolites (nitrite, endothelin-1(ET-1), catecholamines), because they are known to affect BDNF expression/production [48,49,52,57–60] and their expression can be influenced by both exercise and hypoxia [34,48–51,61–68].
