Department of Pediatrics, University of Wisconsin-Madison, 1500 Highland Ave-T503, Madison, WI, 53705-9345, USA.
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
Biol Sex Differ. 2024 Jan 4;15(1):1. doi: 10.1186/s13293-023-00573-0.
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.
新生儿缺氧缺血（HI）相关脑损伤是导致终身神经发育障碍的主要原因之一，导致学习和记忆障碍。有证据表明，雄性新生儿更容易受到 HI 的不利影响，但介导新生儿神经损伤的这些性别特异性反应的机制仍知之甚少。我们之前测试了用酪氨酸激酶 B 受体（TrkB）的小分子激动剂 7,8-二羟基黄酮（DHF）治疗新生 HI 后的效果，并确定只有雌性而不是雄性的海马体 TrkB 磷酸化增加，细胞凋亡减少。此外，发现这种 TrkB 激动剂的雌性特异性作用取决于 Erα 的表达。这些发现表明，TrkB 在 Erα 存在的情况下的激活构成了以雌性特异性方式赋予神经保护的一种途径。本研究的目的是确定在新生期暴露于 HI 的年轻成年小鼠中，依赖 Erα 的 TrkB 介导的神经保护在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。在出生后第 9 天（P），用 Erα 或 Erα 小鼠进行 HI，并用 DHF 或 vehicle 处理 7 天。当小鼠进入成年期时，我们使用新物体识别、新物体位置和旷场测试来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。
新生期 DHF 治疗可预防成年雌性 HI 诱导的识别和位置记忆减退，但对雄性无影响。在缺乏 Erα 的雌性小鼠中，这种保护作用不存在。在新生 HI 后，DHF 治疗可改善成年雌性的识别和位置记忆，这种作用分别依赖于 Erα。有趣的是，DHF 仅在缺乏 Erα 的雄性小鼠中引发焦虑样行为。当我们评估损伤的严重程度时，我们发现 DHF 治疗并未按功能恢复的比例减少组织损失的百分比。我们还发现，Erα 的存在显著降低了两性 HI 相关的死亡率。
这些观察结果为 DHF 的治疗作用提供了证据，即 TrkB 介导的识别和位置记忆的持续恢复在雌性中与 Erα 相关，并且分别依赖于 Erα。然而，DHF 治疗的有益效果不包括减少大体组织损失，但可能源于以细胞特异性方式增强剩余组织的功能。
