Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor.
Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor.
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DOI：
10.1159/000454949
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发表时间：
2017
影响因子：
2.9
通讯作者：
Chavez-Valdez R
中科院分区：
文献类型：
--
作者：
Diaz J;Abiola S;Kim N;Avaritt O;Flock D;Yu J;Northington FJ;Chavez-Valdez R
尽管接受了治疗性低温(TH)治疗，但在缺氧缺血性脑病(HIE)中幸存下来的婴儿在学龄期仍有持续性的神经异常。在人类和动物模型中，TH对HI脑损伤的保护作用是不同的。我们目前的HI和TH的临床前模型显示了神经病理和神经成像终点的这种结果的变异性，并具有一定的性别二型性。该模型的具体行为表型以及某些行为领域是否存在性别二型性尚不清楚。脑源性神经营养因子(BDNF)支持神经细胞的存活和修复，但也可能是损伤的标志。在这里，我们描述了HI和TH后按性别分层的行为缺陷，以及脑源性神经营养因子的晚期变化及其与记忆障碍的相关性。C57BL6小鼠在p10(改良的Vannucci模型)诱发Hi。小鼠随机分为TH(31°C)和常温(NT，36°C)两组，每组4 h。对照组为假麻醉暴露的胎鼠，年龄和性别匹配。在P16~P39期间进行生长跟踪和行为测试，包括：反射(空中翻正、前肢抓握和负向趋地性)、感觉运动、学习和记忆技能(开阔视野、平衡木、粘合剂去除、Y迷宫测试和物体定位任务[OLT])。研究P42记忆结果时前脑内成熟BDNF水平之间的相关性。雄性和雌性HI小鼠的生长率(GR/天)都比Shams(p≤0.01)低约8%到12%。TH可以改善雌性小鼠的这种生长障碍，但不能改善雄性小鼠的这种生长障碍。在雌性小鼠中，无论治疗方法如何，HI损伤都延长了P36在外围(开阔场地)停留的时间(p=0.004)。在雄性和雌性小鼠的平衡木和粘合剂去除试验中，TH分别防止了运动损伤(p≤005)。雄性和雌性HI小鼠访问Y迷宫新臂的频率分别比假手术组低12.5%(p≤0.05)和10%(p=0.03)。在原位肝移植中，雄性HI小鼠的探索偏好得分也比Sham低35%(p≤0.001)。在P26，TH不能预防Y迷宫测试或OLT中发现的记忆损害(p=0.01)。在P42，Hi损伤同侧前脑的BDNF水平是假手术前脑的1.7-2倍，TH不能阻止这种增加。无论性别还是雄性小鼠，在Y迷宫和原位肝移植中，侮辱侧同侧前脑中BDNF水平较高与表现较差相关(p=0.01)。TH在新生儿HI后的特定行为领域提供了益处。一般来说，这些福利对男性和女性都有，但并不是在所有领域都是如此。在某些领域，例如记忆，没有发现TH的好处。个体脑源性神经营养因子水平的后期差异可能解释了其中一些发现。
Despite treatment with therapeutic hypothermia (TH), infants who survive hypoxic ischemic (HI) encephalopathy (HIE) have persistent neurologic abnormalities at school age. Protection by TH against HI brain injury is variable in both humans and animal models. Our current pre-clinical model of HI and TH displays this variability of outcomes in neuropathological and neuroimaging endpoints with some sexual-dimorphism. The detailed behavioral phenotype of this model is unknown as well as whether there is sexual-dimorphism in certain behavioral domains. Brain derived neurotrophic factor (BDNF) supports neuronal cell survival and repair but may also be a marker of injury. Here, we characterize behavioral deficits after HI and TH stratified by sex, as well as late changes in BDNF and its correlation with memory impairment. HI was induced in C57BL6 mice at p10 (modified Vannucci model). Mice were randomized to TH (31 °C) or normothermia (NT, 36 °C) for 4 h after HI. Controls were sham anesthesia-exposed age and sex-matched littermates. Between p16 and p39, growth was followed and behavioral testing was performed including: reflexes (air righting, forelimb grasp and negative geotaxis), sensorimotor, learning and memory skills (open field, balance beam, adhesive removal, Y-maze tests and object location task [OLT]). Correlations between mature BDNF levels in forebrain at p42 memory outcomes were studied. Both male and female HI mice had a ~8 to 12% lower growth rate (gr/day) than shams (p≤0.01) by p39. TH ameliorated this growth failure in female but not in male mice. In female mice HI injury prolonged the time spent in the periphery (open field) at p36 (p=0.004), regardless of treatment. TH prevented motor impairments on the balance beam and in adhesive removal tests in male and female mice, respectively (p≤0.05). Male and female HI mice visited the new arm of the Y-maze 12.5% (p≤0.05) and 10% (p=0.03) less often than shams, respectively. Male HI mice also had 35% lower exploratory preference score than sham (p≤0.001) in OLT. TH did not prevent memory impairments found with Y maze testing or OLT in either sex (p=0.01) at p26. At p42, BDNF levels in the forebrain ipsilateral to the HI insult were 1.7 to 2 fold higher than BDNF levels in sham forebrain and TH did not prevent this increase. Higher BDNF levels in the forebrain ipsilateral to the insult correlated with worse performance in the Y-maze in both sexes and in OLT in male mice (p=0.01). TH provides benefit in specific domains of behavior following neonatal HI. In general, these benefits accrued to both males and females but not in all areas. In some domains, such as memory, no benefit of TH was found. Late differences in individual BDNF levels may explain some of these findings.
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DOI：
10.1083/jcb.201504092
发表时间：
2015-09-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Briz V;Liu Y;Zhu G;Bi X;Baudry M
通讯作者：
Baudry M
晶须在C57BL/6小鼠的感觉运动发展中的作用。
影响因子：
2.7
作者：
Arakawa, Hiroyuki;Erzurumlu, Reha S.
通讯作者：
Erzurumlu, Reha S.
影响因子：
3.5
作者：
Aarse, Janna;Herlitze, Stefan;Manahan-Vaughan, Denise
通讯作者：
Manahan-Vaughan, Denise
影响因子：
3.6
作者：
Dalen, Marit L.;Liu, Xun;Thoresen, Marianne
通讯作者：
Thoresen, Marianne
影响因子：
2.4
作者：
Azzopardi D;Brocklehurst P;Edwards D;Halliday H;Levene M;Thoresen M;Whitelaw A;TOBY Study Group
通讯作者：
TOBY Study Group