Simulated High Altitude Intermittent Hypoxia Learning And Memory Function In Mice

Hypoxia has close relations with people. It can change physiological function and in some cases it may be helpful to our body, however, sever hypoxia may cause phathyological changes. Nervous system is high sensitive to hypoxia; so, the effects of hypoxia on cognitions may be the best concern to people. Recently, scientists make great progresses in the research on memory, reflecting people long for interpret the work of our brain. Memories can be clarified to many types. The present study is designed to detect how intermittent hypoxia (IH) affects mice learning and memory when mice were exposed to IH at adult, neonatal or prenatal, respectively. Mice were exposed to a simulated hypobaric hypoxia, by the way of 4h/day, and set at altitude of 2 km (16.0% O₂; PaO₂, 60mmHg) or 5 km (10.8% O₂; PaO₂, 41mmHg). Spatial learning and memory ability was tested in the Morris water maze (MWM), and associative learning and memory was tested in the shuttle box. Results1. Compared with controls (set at sea level, 21% O₂), postnatal IH-3w and IH-4w at 2 km and 5 km significantly reduced the escape latencies of male mice at postnatal day (P) 36 (P36) -P40 in MWM task with significantly enhanced retention, and this spatial enhancement was further confirmed by 8-arm maze test in IH-3w (or 4w) male and female mice at P60-68. The improvement in MWM induced by IH-4w at 2 km was still maintained in mice at P85-89. The IH-4w mice at P36 were used to clarify the mechanism involved in behavior tests. Compared with controls, electron microscopy revealed that IH-4w at 2 km or 5 km significantly increased the number of synapse in CA3. In CA1, significant increased fEPSP amplitudes were recorded in IH mice at 5 km. Western blot detected an marked increased phosphorylated cAMP response element binding protein(p-CREB) level in hippocampus, and immunohistochemistry research found this increase was in CA3. Significantly enhanced expressions of polysialylated neural cell adhesion molecule(PSA-NCAM) were found in stratum radiatum, stratum lucidum and molecular layer of CA1, CA3, DG and hilus by immunofluorescence. Immunofluorescence also detected intensive expressions of homeobox gene Pax6 intaenia tecta and anterior olfactory nucleus. Glial fibrillary acidic protein(GFAP) immunoreactive(IR) astrocytes decreased in all subfields of hippocampus, RT-PCR analysis found weak fibroblast growth factor-2(FGF2) mRNA transcripition may be contribute to the decreasing. In addition, IH-4w at 2 km or 5 km induced an intensive expression of PSA-NCAM in striatrum. Microdialysis in CA3 of hippocampus in adult mice for real-time monitoring of extracellular excitatory amino acids EAAs (GLU and aspartate) and GABA dynamics showed that 4-hour hypoxia both of 2 km and 5 km enhanced concentration of GLU and ASP and reduced extracellular GABA. 2. Two-way active avoidance tested in postnatal hypoxic males and females (P36-43) revealed that, IH-2w(or 4w) at 5 km impaired male learning or memory, while IH-lw at 5 km impaired female learning. When mice were tested in shuttle box at P96-103, IH-lw(or 2w) at 5 km markedly decreased the number of active avoidance of both male and female in training. The IH-4w mice at P36 were used to clarify the mechanism involved in behavior tests. Compared with controls, radioimmunoassay analysis showed that IH-4w at 2 km decreased somatostatin in amygdala. Both 2 km and 5 km increased the expression of p-CREB in baselateral amygdala (BLA), but suppressed Pax6 expression in amygdala and .hypothalamus. The opposite changes of GLU, ASP, and GABA were found in BLA of adult mice by microdialysis, compared with in CA3 of hippocampus.4. Compared with controls, adult male mice exposed to IH-2, 5,10,15, or 25d at both 2 km and 5 km and male offspring prenatal exposed to IH at both 2 km and 5 km spent no significant difference time in finding submerged platform during water maze training, and no marked retention difference in probe test. However, two-way active avoidance tested in IH-2, 10, or 25d adult male mice revealed significant lower number of active avoidance in training and retention test compared with controls. Conclusions1. Neonatal exposure to intermittent hypoxia enhanced mice spatial learning and memory, which may be associated with neural plasticity at the synapse or neurocircuits in hippocampus, stritum, and endorihnal cortex, and then established a new 'hypoxia-enhanced model' in mice in the present study. In this model, IH (4h/d)exposure at 2 km during the first three or four week's developing stages of life enhances mice spatial learning and memory.2. Neonatal exposures to IH impaired mice associative learning and memory, which may be related to hypoxia-inhibited cell proliferation or cell apoptosis.3. Intermittent hypoxia discriminately affect on spatial learning and memory and associative learning and memory. The development stage when animals were exposed to hypoxia, hypoxic mode (intensity, pattern, and duration), and sex may be critical.4. The present study suggests competitive relations between hippocampus and amygdala in the two memory systems.