Abstract：OBJECTIVE: To study long-term behavioral and ultrastructural alterations in a hypoxic-ischemic brain damage (HIBD) model of neonatal rats. METHODS: Sixty seven-day-old Sprague-Dawley rats were randomly subjected to unilateral carotid artery ligation followed by hypoxic exposure (HIBD group) or sham operation (n=30 each). A battery of behavioral tests, including Morris water maze test and sensorimotor tests, were performed at a postnatal age of 5 weeks. Nissl staining was used for counting neurons. Transmission electron microscopy was used for observing synapse structures and measuring the thickness of the postsynaptic density area and the length of the postsynaptic active area. The correlations of histological changes with the results of behavioral tests were evaluated. RESULTS: The HIBD group showed a significantly longer escape latency (P<0.05) and a lower frequency of original platform crossing (P <0.05) in the Morris water maze test compared with the sham operation group. The sensorimotor function test showed that the sensorimotor function in the HIBD group was worse than in the sham operation group. Nissl staining showed that the number of neurons in the HIBD group was significantly reduced (P <0.01) compared with the sham operation group. Transmission electron microscopy showed that synapses were significantly reduced in number, and that the thickness of the postsynaptic density area and the length of the postsynaptic active area were reduced in the HIBD group. The thickness of the postsynaptic density area was negatively correlated with escape latency in the Morris water maze test (r=-0.861, P<0.01), and also negatively correlated with the total score of sensorimotor function tests (r=-0.758, P<0.05) in the HIBD group. CONCLUSIONS: Hypoxia ischemia can lead to neuron loss and ultrastructure damage, resulting in long-term deficit of behavioral functions in neonatal rats.
［2］Johnston MV, Ishida A, Ishida WN, Matsushita HB,Nishimura A, Tsuji M. Plasticity and injury in the developing brain［J］. Brain Dev, 2009, 31(1): 1-10.
［3］Balduini W, De Angelis V, Mazzoni E, Cimino M. Simvastatin protects against long-lasting behavioral and morphological consequences of neonatal hypoxic/ischemic brain injury［J］. Stroke, 2001, 32(9): 2185-2191.
［4］Bona E, Johansson BB, Hagberg H. Sensorimotor function and neuropathology five to six weeks after hypoxia-ischemia in seven-day-old-rats［J］. Pediatr Res, 1997, 42(5): 678-683.
［9］Guldner FH, Ingham CA. Increase in postsynaptic density material in optic target neurous of the rat suprachiasmatic nucleus after bilateral enucleation［J］. Neurosci Lett, 1980, 17(1-2): 27-31.
［10］Kakizawa H, Matsui F, Tokita Y, Hirano K, Ida M, Nakanishi K, et al. Neuroprotective effect of nipradilol, an NO donor, on hypoxic-ischemic brain injury of neonatal rats［J］. Early Hum Dev, 2007, 83(8): 535-540.
［11］Kumral A, Uysal N, Tugyan K, Sonmez A, Yilmaz O, Gokmen N, et al. Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxiaischemia in rats［J］. Behav Brain Res, 2004, 153(1): 77-86.
［15］Chan KC, Khong P, Lau HF, Cheung PT, Wu EX. Late measures of microstructural alterations in severe neonatal hypoxic-ischemic encephalopathy by MR diffusion tensor imaging［J］. Int Devel Neurosci, 2009, 27(6): 607-615.
［16］Rutherford M, Malamateniou C, McGuinness A, Allsop J, Biarge MM, Counsell S. Magnetic resonance imaging in hypoxic-ischaemic encephalopathy［J］.Early Hum Dev, 2010, 86(6): 351-360.
［17］Jissendi Tchofo P, Christophe C, David P, Metens T, Soto Ares G, Balériaux D. Apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR) in pediatric hypoxicischemic brain injury［J］.J Neuroradiol, 2005, 32(1): 10-19.
［18］Ancora G, Soffritti S, Lodi R, Tonon C, Grandi S, Locatelli C, et al. A combined a-EEG and MR spectroscopy study in term newborns with hypoxic-ischemic encephalopathy［J］. Brain Dev, 2010, 32(10): 835-842.
［19］Kumar A, Chugani HT. PET in the assessment of pediatric brain development and developmental disorders［J］. PET Clin, 2008, 3(4): 487-515.
