Sex differences in brain injury following pediatric cardiac arrest

家长奖 项目摘要 以下目标是根据以下已发表和未发表的研究结果制定的合乎逻辑的下一步 父母补助金（由已故的Traystman博士发起），以评估儿童性别特异性信号传导后， （幼年小鼠）心脏骤停和心肺复苏（CA/CPR）。小儿心脏骤停 令人惊讶的普遍，仍然知之甚少，研究不足。我们取得了重大进展， 上一个赠款周期的主要目标，并获得了构成基金会的重要的新的初步数据 为了当前的目标。我们利用我们新的幼年小鼠心脏骤停， 心肺复苏（CA/CPR）模型，以评估CA/CPR后的功能结局和恢复情况。 心肺复苏来自我们实验室和其他实验室的新证据表明， 功能网络导致认知缺陷。突触可塑性，以加强以下形式 生理刺激（长时程增强; LTP）是一种成熟的学习细胞模型， 记忆海马LTP缺陷与成年和幼年小鼠记忆障碍相关， 因此，我们专注于靶向逆转突触可塑性缺陷以增强功能性的治疗。 神经恢复（Neurorestoration）我们最近做了一个惊人的观察， 表现出内源性神经恢复; CA后14-30天恢复LTP和记忆功能， 心肺复苏术，我们没有观察到在成年人暴露于同样的伤害。 我们的数据表明，突触可塑性的损伤和内源性恢复， 幼年小鼠的记忆功能与脑源性神经营养因子（BDNF）的表达相关。 此外，我们表明，BDNF-TrkB信号的刺激促进海马功能的恢复。 我们在青少年中观察到海马功能的恢复与激素成熟相对应 发生在PND 28 -56之间。我们的初步资料表明，青少年男性性腺切除术（CAST） 雌性（OVX）小鼠阻止CA/CPR后LTP的恢复（和BDNF水平的恢复）。 此外，我们观察到性类固醇（女性雌激素和男性睾酮）的替代， 恢复CAST/OVX幼年小鼠的内源性神经恢复。重要的是，我们观察到雌激素 刺激BDNF在幼年雌性中的表达，而不是雄性，脑雌激素不促进 雄性LTP恢复。因此，我们的总体假设是：1）大脑中类固醇水平的增加 青春期通过性激活促进青少年CA/CPR后的内源性神经恢复- 特异性信号传导（Aim 2雄性特异性雄激素信号传导和Aim 3雌性特异性雌激素受体 信号传导），其会聚于BDNF和其他可塑性基因表达以增强突触可塑性。 这项研究将有助于我们了解功能性的机制， 儿童年龄组心脏骤停后的损伤和恢复，这是一个研究不足的人群。 特别是，这个项目扩展了我们长期以来的研究重点，关于性别特异性信号传导和 年龄、性别、性类固醇与脑损伤后结果之间的相互作用。此外，我们的研究将扩大 我们专注于开发治疗策略，以恢复幸存大脑网络中的突触功能， 而不是试图保护神经元免受缺血性损伤，这可能会影响所有患者的治疗。 年龄

From Parent Award Project Summary The following aims are developed as the logical next step based on published and unpublished findings from the parent grant (initiated by the late Dr.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.