Sex differences in brain injury following pediatric cardiac arrest

项目摘要 以下目标是根据已发表和未发表的调查结果制定的， 父母补助金（由已故的Traystman博士发起），以评估儿童（青少年） 小鼠）心脏骤停和心肺复苏（CA/CPR）。小儿心脏骤停 这是一个普遍的现象，人们对它的了解和研究仍然很少。我们在主要目标方面取得了重大进展， 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赠款周期的基础。 目标。我们利用我们的新的幼年小鼠心脏骤停和心肺复苏 (CA/CPR）模型，以评估CA/CPR后的功能结局和恢复。来自我们的新证据 实验室和其他研究表明，存活功能网络的改变有助于认知功能的恢复。 赤字突触可塑性，以生理刺激后加强的形式（长时程增强; LTP）是一种成熟的学习和记忆细胞模型。海马LTP缺陷与 成年和幼年小鼠的记忆障碍，因此，我们专注于靶向逆转 突触可塑性缺陷，以增强功能恢复（神经恢复）。我们最近做了 幼年小鼠表现出内源性神经恢复的显著观察;恢复LTP CA/CPR后14-30天的记忆功能，我们在暴露于 同样的伤。 我们的数据表明，突触可塑性和记忆的损伤和内源性恢复 幼年小鼠的功能与脑源性神经营养因子（BDNF）的表达相关。我们还 显示BDNF-TrkB信号传导刺激促进海马功能的恢复。的复苏 我们在青少年中观察到的海马功能与发生在 PND 28 -56。我们的初步数据表明，幼年雄性（CAST）和雌性（OVX）小鼠的性腺切除术 阻止CA/CPR后LTP的恢复（和BDNF水平的恢复）。此外，我们观察到， 替代性类固醇（女性的雌激素和男性的睾酮）恢复内源性神经元， 在CAST/OVX幼年小鼠中恢复。重要的是，我们观察到雌激素刺激BDNF的表达， 幼年雌性而非雄性，脑雌激素不促进雄性LTP恢复。因此，我们认为， 我们的首要假设是：1）青春期大脑中类固醇水平的增加促进了内源性 通过激活性别特异性信号（Aim 2雄性特异性），在幼年CA/CPR后的神经恢复 雄激素信号传导和aim 3女性特异性雌激素受体信号传导），其在BDNF和其他 可塑性基因表达增强突触可塑性。这项研究将有助于我们 了解心脏骤停后功能障碍和恢复的机制， 儿童年龄组，一个未被充分研究的人群。特别是，这个项目扩展了我们长期的研究， 重点关注性别特异性信号和年龄之间的相互作用，性别，性类固醇和以下结果 脑损伤此外，我们的研究将扩大我们的重点，开发治疗策略，以恢复突触 在存活的大脑网络中发挥作用，而不是试图保护神经元免受缺血性损伤， 可能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Project Summary The following aims are developed as the logical next step based on published and unpublished findings from the parent grant (initiated by the late Dr.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.