Sex differences in brain injury following pediatric cardiac arrest

项目摘要 以下目标是根据已公布和未公布的调查结果制定的合乎逻辑的下一步行动 父母赠款(由已故的特雷斯特曼博士发起)，用于评估儿童(青少年)后的性别信号 小鼠)心脏骤停和心肺复苏(CA/CPR)。儿童心脏骤停令人惊讶 这种现象很常见，但人们对它的了解和研究仍然很少。我们在以下主要目标上取得了重大进展 上一个赠款周期，并获得了重要的新的初步数据，这些数据构成了当前 目标。我们利用我们的新型幼年小鼠心脏骤停和心肺复苏 (CA/CPR)模型用于评估CA/CPR后的功能结果和恢复情况。新出现的证据来自我们的 实验室和其他研究人员指出，幸存的功能网络的改变有助于认知 赤字。突触可塑性，在生理刺激后强化的形式(长时程增强； LTP)是一个成熟的学习和记忆细胞模型。海马区LTP缺陷与 成年和幼年小鼠的记忆障碍，因此，我们专注于针对逆转的治疗 突触可塑性缺陷，以促进功能恢复(神经恢复)。我们最近制作了 幼鼠内源性神经修复的显著观察：恢复LTP 和记忆功能，在CA/CPR后14-30天，我们在暴露于 同样的伤痕。 我们的数据表明，突触可塑性和记忆的损伤和内源性恢复 幼鼠的功能与脑源性神经营养因子(BDNF)的表达有关。此外，我们 提示刺激BDNF-TrkB信号可促进海马区功能的恢复。年的复苏 我们在青少年中观察到的海马体功能与荷尔蒙成熟相对应 PND28-56。我们的初步数据表明，幼年雄性(CAST)和雌性(OVX)小鼠的性腺切除 防止CA/CPR后LTP的恢复(和BDNF水平的恢复)。此外，我们观察到， 更替性类固醇(女性为雌激素，男性为睾酮)可恢复内源性神经功能-- CAST/OVX幼鼠的修复。重要的是，我们观察到雌激素刺激脑源性神经营养因子的表达。 青少年女性，而不是男性，脑雌激素不利于男性LTP的恢复。因此， 我们的主要假设是：1)青春期大脑中类固醇水平的增加促进了内源性 青少年CA/CPR后通过激活性别特异性信号来恢复神经功能(目标2-男性特异性 雄激素信号和AIM 3女性特异性雌激素受体信号)，汇聚在BDNF和其他 可塑性基因表达增强突触可塑性。拟议的研究将有助于我们的 心脏骤停后功能损害及恢复机制的研究进展 儿科年龄组，研究不足的人群。特别是，这个项目扩展了我们长期的研究 关注性别特有的信号传递以及年龄、性别、性激素和以下结果之间的相互作用 脑部受伤。此外，我们的研究将扩展我们对开发恢复突触的治疗策略的关注 在存活的大脑网络中的功能，而不是试图保护神经元免受缺血损伤，这 可能会影响所有年龄段患者的治疗。

Project Summary The following aims are developed as the logical next step based on published and unpublished findings from the parent grant (initiated by the late Dr. Traystman) to assess sex-specific signaling following pediatric (juvenile mice) cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Pediatric cardiac arrest is surprisingly common and remains poorly understood and understudied. We made significant progress on the major aims of the previous grant cycle and obtained important new preliminary data that form the foundation for the current aims. We take advantage of our novel juvenile mouse cardiac arrest and cardiopulmonary resuscitation (CA/CPR) model to assess functional outcomes and recovery following CA/CPR. Emerging evidence from our laboratory, and others, indicate that alterations in the surviving functional networks contribute to cognitive deficits. Synaptic plasticity, in the form of strengthening following physiological stimuli (long-term potentiation; LTP) is a well-established cellular model of learning and memory. Deficits in hippocampal LTP correlate with memory impairments in adult and juvenile mice and therefore, we focus on therapies that target reversing synaptic plasticity deficit to enhance functional recovery (neuro-restoration). We recently made the remarkable observation that juvenile mice exhibit endogenous neuro-restoration; recovery LTP and memory function 14-30 days after CA/CPR, which we do not observe in adults exposed to the same injury. Our data indicates that the impairments and endogenous recovery of synaptic plasticity and memory function in juvenile mice correlates with expression of brain derived neurotrophic factor (BDNF). Further, we show that stimulation of BDNF-TrkB signaling facilitates recovery of hippocampal function. The recovery in hippocampal function we observed in juveniles corresponds with hormonal maturation that occurs between PND28-56. Our preliminary data indicates that gonadectomy of juvenile male (CAST) and female (OVX) mice prevents recovery of LTP (and recovery of BDNF levels) following CA/CPR. Further, we observed that replacement of sex steroids (estrogen in females and testosterone in males) restores endogenous neuro- restoration in CAST/OVX juvenile mice. Importantly, we observe that estrogen stimulates BDNF expression in juvenile females but not males and that brain estrogen does not facilitate recovery of LTP in males. Therefore, our overarching hypothesis is that 1) increased steroid levels in the brain during puberty facilitate endogenous neuro-restoration following juvenile CA/CPR through activation of sex-specific signaling (Aim 2 male-specific androgen signaling and aim 3 female-specific estrogen receptor signaling) that converges on BDNF and other plasticity gene expression to enhance synaptic plasticity. The proposed research will contribute to our understanding of the mechanisms of functional impairments and recovery following cardiac arrest in the pediatric age group, an understudied population. In particular, this project extends our long-standing research focus regarding sex-specific signaling and the interaction between age, sex, sex steroids and outcomes following brain injury. Further, our studies will extend our focus on developing therapeutic strategies to restore synaptic function within surviving brain networks, rather than attempting to protect neurons from ischemic injury, which may impact treatments of patients of all ages.