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performance are not known. It is likely that the direct effects of mild transient hypoxia on the brain are variations in the level of specific neurotransmitters. Because the synthesis of several neurotransmitters is oxygen dependent, abnormalities of neurotransmitter metabolism may mediate the early functional changes due to acute hypoxia (Gibson and Duffy, 1981). It is likely that some of the behavioral decrements caused by hypoxia are attributable to changes in neurotransmitter utilization and concentration (Freeman and Gibson, 1988).

The cholinergic system is particularly vulnerable to hypoxia, and it appears that acetylcholine (ACh) is the neurotransmitter primarily affected (Gibson and Duffy, 1981). ACh is a neurotransmitter involved in the regulation of learning and memory processes (Freeman and Gibson, 1988). The rates of synthesis of other neurotransmitters (e.g., dopamine, serotonin, and the amino acids) are also sensitive to hypoxia, but perhaps less so than the rate of ACh synthesis (Freeman et al., 1986). To determine the effect and influence of acetylcholine on learning and memory performance at altitude, this laboratory undertook a variety of studies using the rat as an experimental model (Shukitt-Hale et al., 1991b, 1993a, 1993b, 1994, in press).

The first series of studies sought to determine the effects of various levels of hypobaric hypoxia on spatial memory in rats and to develop a model to test drug and nutrient interventions. Although deficits in human cognitive performance are well established, few studies have measured cognitive changes in animals exposed to hypoxia.

The Morris water maze (MWM) was used to assess behavior in these studies (Shukitt-Hale et al., 1993b, 1994). The MWM is a standardized test of spatial learning and memory that has been shown to be sensitive to decrements in hippocampal cholinergic function. The maze is a circular black pool filled with water, in which a circular black escape platform is located. The platform is kept below the surface of the water so that the rat must use distal cues to locate it. Numerous extramaze cues were located on the walls of the altitude chamber. Accurate navigation is rewarded with escape from the water onto the platform. The MWM does not rely on food as a reward like other tests of spatial memory (e.g., radial maze or T-maze). Because food consumption is suppressed under hypoxia (discussed below), this is an advantage of using the MWM to assess learning at altitude.

Rats were tested at 2 and 6 hours while exposed to a range of simulated altitudes: sea level, 5,500 m (18,045 ft); 5,950 m (19,521 ft); and 6,400 m (20,997 ft). At the beginning of each trial the rat was gently immersed in the water so that it was facing and touching the wall of the pool. Each rat was allowed 120 seconds to escape onto the platform (Trial 1: termed reference or long-term memory). If the rat failed to escape within this time, it was guided to the platform. Once the rat reached the platform, it remained there for 10 seconds. Trials were given in pairs, with the second trial using the same starting location as the first (Trial 2: termed working or short-term memory).

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