在新生儿缺氧缺血后的成年小鼠中,TrkB介导的持续神经保护具有性别特异性和(text{ER}\alpha\)依赖性

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-01-04 DOI:10.1186/s13293-023-00573-0
Vishal Chanana, Margaret Hackett, Nazli Deveci, Nur Aycan, Burak Ozaydin, Nur Sena Cagatay, Damla Hanalioglu, Douglas B. Kintner, Karson Corcoran, Sefer Yapici, Furkan Camci, Jens Eickhoff, Karyn M. Frick, Peter Ferrazzano, Jon E. Levine, Pelin Cengiz
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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 $$\\text{ER}\\alpha$$ . These findings demonstrated that TrkB activation in the presence of $$\\text{ER}\\alpha$$ 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 $$\\text{ER}\\alpha$$ -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. $$\\text{ER}\\alpha$$ +/+ or $$\\text{ER}\\alpha$$ −/− 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 $$\\text{ER}\\alpha$$ . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$\\text{ER}\\alpha$$ -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$\\text{ER}\\alpha$$ . 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 $$\\text{ER}\\alpha$$ 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 $$\\text{ER}\\alpha$$ -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 ( $$\\text{ER}\\alpha$$ ). In this study, we extend these observations by subjecting mice either with or without $$\\text{ER}\\alpha$$ 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. 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引用次数: 0

摘要

与新生儿缺氧缺血(HI)相关的脑损伤是导致学习和记忆障碍的终生神经系统疾病的主要原因之一。有证据表明,男性新生儿更容易受到 HI 的有害影响,但人们对新生儿神经损伤的这些性别特异性反应的介导机制仍然知之甚少。我们之前测试了新生儿HI后使用酪氨酸激酶B受体(TrkB)的小分子激动剂--7,8-二羟基黄酮(DHF)治疗的效果,结果发现,雌性而非雄性海马中的TrkB磷酸化增加,细胞凋亡减少。此外,还发现TrkB激动剂对雌性的特异性作用依赖于$text{ER}\alpha$$的表达。这些研究结果表明,在$text{ER}\alpha$存在的情况下,TrkB的激活是以女性特异性方式提供神经保护的一种途径。本研究的目的是确定$\text{ER}\alpha$依赖的TrkB介导的神经保护在新生儿期暴露于HI的年轻成年小鼠的记忆和焦虑中的作用。在这项研究中,我们使用了单侧缺氧缺血(HI)小鼠模型。$$text{ER}\alpha$ +/+或$$\text{ER}\alpha$ -/-小鼠在出生后第9天(P)遭受HI,HI后小鼠接受车辆对照或TrkB激动剂DHF治疗7天。小鼠成年后,我们使用新物体识别、新物体定位和开阔地测试来评估长期记忆和焦虑样行为。然后用免疫组化方法评估小鼠大脑的组织损伤情况。新生儿DHF治疗可防止HI诱导的雌性小鼠成年后识别记忆和定位记忆的衰退,但雄性小鼠却没有这种效果。缺乏$\text{ER}\alpha$$的雌性小鼠没有这种保护作用。新生儿HI后,DHF疗法可改善雌性成年期的识别和定位记忆结果,但这两种结果分别倾向于或依赖于$text{ER}\alpha$。有趣的是,只有在缺乏$text{ER}\alpha$的小鼠中,DHF才会引发雌雄小鼠的焦虑样行为。当我们评估损伤的严重程度时,我们发现DHF疗法并没有降低组织损失的百分比与功能恢复的比例。此外,我们还观察到,$text{ER}\alpha$的存在显著降低了HI相关的男女总死亡率。这些观察结果为DHF的治疗作用提供了证据,其中TrkB介导的雌性识别记忆和位置记忆的持续恢复分别与$text{ER}\alpha$有关和依赖于$text{ER}\alpha$。然而,DHF疗法的有益效果并不包括减少组织的总损失,而可能来自于以细胞特异性方式增强残余组织的功能。众所周知,新生儿大脑的低氧输送和低血流量时期会对其成年后的认知能力造成终身损害。有趣的是,男性新生儿比女性更容易受到这种损伤。造成这种性别差异的机制尚不清楚。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中的作用。我们以前的研究表明,当小鼠在新生儿缺氧缺血后几天内接受 TrkB 激动剂 7,8-二羟基黄酮(DHF)治疗时,只有雌性小鼠能获得短期神经保护,而且这种保护依赖于雌激素受体 alpha 受体($$text\{ER}\alpha$$)的存在。在这项研究中,我们通过让有或没有雌激素受体α受体的小鼠接受HI来扩展这些观察结果。其中一些小鼠在HI后立即接受了DHF治疗。成年后,我们对小鼠的记忆力和焦虑行为进行了测试。测试结束后,我们对小鼠的大脑组织损失进行了评估。我们的研究结果表明,新生小鼠在HI后接受DHF治疗,成年后只有雌性小鼠的记忆力得到了保护,而且这种效果依赖于$text{ER}\alpha$$的存在。 此外,DHF治疗会引发缺乏$text{ER}\alpha$的小鼠的焦虑样行为。我们还发现,这种神经保护并不依赖于损伤后脑组织的保存。这些结果让我们对新生儿时期雌性对缺氧缺血性发作的抵抗力背后的机制有了更深入的了解。
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TrkB-mediated sustained neuroprotection is sex-specific and \(\text{ER}\alpha\)-dependent in adult mice following neonatal hypoxia ischemia
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 $$\text{ER}\alpha$$ . These findings demonstrated that TrkB activation in the presence of $$\text{ER}\alpha$$ 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 $$\text{ER}\alpha$$ -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. $$\text{ER}\alpha$$ +/+ or $$\text{ER}\alpha$$ −/− 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 $$\text{ER}\alpha$$ . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$\text{ER}\alpha$$ -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$\text{ER}\alpha$$ . 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 $$\text{ER}\alpha$$ 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 $$\text{ER}\alpha$$ -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 ( $$\text{ER}\alpha$$ ). In this study, we extend these observations by subjecting mice either with or without $$\text{ER}\alpha$$ 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 $$\text{ER}\alpha$$ . In addition, DHF therapy triggered anxiety-like behavior in mice lacking $$\text{ER}\alpha$$ . 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.
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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