背景:新生儿缺氧缺血(HI)相关脑损伤是导致学习和记忆障碍的终身神经系统疾病的主要原因之一。证据表明,男性新生儿更容易受到HI的有害影响,然而,新生儿对这些性别特异性神经损伤的调节机制仍知之甚少.我们之前测试了用酪氨酸激酶B受体(TrkB)的小分子激动剂治疗的效果,新生儿HI后的7,8-二羟基黄酮(DHF),并确定女性,但是雄性海马中TrkB的磷酸化增加和凋亡减少。此外,发现TrkB激动剂的这些女性特异性作用依赖于[式:见正文]的表达。这些发现证明在[式:参见正文]的存在下的TrkB活化包括一个途径,通过该途径可以以女性特异性方式赋予神经保护。这项研究的目的是确定[公式:参见正文]依赖性TrkB介导的神经保护在新生期暴露于HI的年轻成年小鼠的记忆和焦虑中的作用。
方法:在本研究中,我们使用单侧缺氧缺血(HI)小鼠模型。[配方:见正文]+/+或[配方:见正文]-/-小鼠在出生后第(P)9天接受HI治疗,小鼠用载体对照或TrkB激动剂治疗,DHF,在HI之后的7天。当老鼠成年时,我们使用了新的物体识别,新颖的对象位置和野外测试,以评估长期记忆和焦虑样行为。然后使用免疫组织化学评估大脑的组织损伤。
结果:新生儿DHF治疗可防止HI引起的女性成年期识别和位置记忆下降,但不是男性。这种保护作用在缺乏[配方:见正文]的雌性小鼠中不存在。新生儿HI后DHF治疗赋予的成年期女性特异性识别和位置记忆结果改善倾向于或为[公式:见正文]依赖,分别。有趣的是,DHF仅在缺乏[公式:见文本]的小鼠中触发了两性的焦虑样行为。当我们评估受伤的严重程度时,我们发现,DHF治疗并没有降低与功能恢复成比例的组织丢失百分比.我们还观察到[式:见正文]的存在显著降低了男女的总体HI相关死亡率。
结论:这些观察结果为DHF的治疗作用提供了证据,其中TrkB介导的女性识别和位置记忆的持续恢复是[公式:见正文]相关和依赖的,分别。然而,DHF治疗的有益效果不包括减少组织的总体损失,但可能源于以细胞特异性方式增强残留组织的功能.
众所周知,新生儿大脑的低氧输送和血流量会导致成年后的认知能力终身受损。有趣的是,男性新生儿比女性更容易受到这种伤害。导致这种性别差异的机制知之甚少。在这里,我们测试了神经生长因子受体酪氨酸激酶B(TrkB)在小鼠新生儿缺氧缺血(HI)后提供长期神经保护的作用。我们以前已经表明,当小鼠在新生儿HI后的几天内用TrkB激动剂7,8-二羟基黄酮(DHF)治疗时,结果是仅在女性中的短期神经保护,这种保护取决于雌激素受体α受体的存在([公式:见正文])。在这项研究中,我们通过对具有或不具有[公式:见文本]的小鼠进行HI来扩展这些观察。然后在HI后立即用DHF处理一些小鼠。作为成年人,我们进行了测试,以评估小鼠的记忆和焦虑样行为.在这些测试结束时,我们评估了大脑的组织损失。我们的结果表明,作为成年人,新生小鼠HI后的DHF治疗仅在雌性中保留了记忆,这种作用取决于[公式:见正文]的存在。此外,DHF治疗在缺乏[公式:见文本]的小鼠中引发焦虑样行为。我们还表明,这种神经保护作用不依赖于损伤后脑组织的保存。这些结果提供了对女性抵抗新生儿缺氧缺血性发作背后的机制的见解。
Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of Erα. These findings demonstrated that TrkB activation in the presence of Erα comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of Erα-dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period.
In this study, we used a unilateral hypoxic ischemic (HI) mouse model. Erα+/+ or Erα-/- mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry.
Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking Erα. The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were Erα-dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked Erα. When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of Erα significantly reduced overall HI-associated mortality in both sexes.
These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are Erα-associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner.
Periods of low oxygen delivery and blood flow to the brains of newborns are known to cause life-long impairments to their cognitive ability as adults. Interestingly, male newborns are more susceptible to this injury than females. The mechanisms causing this sex difference are poorly understood. Here we test the role of the nerve growth factor receptor tyrosine kinase B (TrkB) in providing long-term neuroprotection following neonatal hypoxia–ischemia (HI) in mice. We have previously shown that when mice are treated with the TrkB agonist 7,8-dihydroxyflavone (DHF) in the days following neonatal HI, the result is short-term neuroprotection only in females and this protection is dependent on the presence of the estrogen receptor alpha receptor ([Formula: see text]). In this study, we extend these observations by subjecting mice either with or without [Formula: see text] to HI. Some of the mice were then treated with DHF immediately after HI. As adults, we performed tests to assess the mice’s memory and anxiety-like behavior. At the end of these tests, we assessed the brains for tissue loss. Our results show that as adults the DHF treatment following HI in neonatal mice preserved memory only in females and this effect was dependent on the presence of [Formula: see text]. In addition, DHF therapy triggered anxiety-like behavior in mice lacking [Formula: see text]. We also show that this neuroprotection is not dependent on preservation of brain tissue following the injury. These results provide insight into the mechanisms behind the female resistance to hypoxic ischemic episodes as newborns.