Vigil Jose J, Tiemeier Erika, Orfila James E, Chalmers Nicholas E, Chang Victoria N, Mitchell Danae, Veitch Isobella, Falk Macy, Dietz Robert M, Herson Paco S, Quillinan Nidia
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Neurosurgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Neural Plast. 2025 May 9;2025:6103242. doi: 10.1155/np/6103242. eCollection 2025.
Cardiac arrest (CA)-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine CA and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal-dependent behavior to assess hippocampal function. LTP and contextual fear were impaired 7 days after GCI and endogenously recovered by 30 days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. This was confirmed with staining that revealed increased Cd68 expression in microglia within the hippocampus. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice, which differs mechanistically from juvenile males and does not occur in adults of either sex.
儿童期心脏骤停(CA)诱发的全脑缺血(GCI)常导致学习和记忆缺陷。我们之前在小鼠CA和心肺复苏(CA/CPR)模型中证明,学习和记忆的细胞机制——长时程增强(LTP),在幼年雄性小鼠海马体中急性受损,这与记忆任务缺陷相关。然而,关于幼年雌性小鼠可塑性损伤的情况知之甚少。我们对幼年(P21 - 25)雌性小鼠进行了CA/CPR,并使用脑片电生理学和海马体依赖行为来评估海马体功能。GCI后7天LTP和情境恐惧受损,30天时内源性恢复。卵巢切除的雌性小鼠在30天时LTP仍受损,表明青春期性腺性激素激增介导了内源性恢复。与幼年雄性不同,幼年雌性小鼠LTP的恢复与脑源性神经营养因子(BDNF)表达无关。NanoString转录分析揭示了神经炎症过程,特别是Cd68通路,在LTP损伤和激素依赖性恢复中的潜在作用。海马体内小胶质细胞中Cd68表达增加的染色证实了这一点。通过慢性和急性给予PPT,我们能够恢复卵巢切除雌性小鼠的LTP,这表明雌激素受体α参与了恢复机制。本研究支持幼年雌性小鼠GCI后内源性LTP恢复的机制,该机制在机制上与幼年雄性不同,且在任何性别的成年小鼠中均不发生。