Epilepsy Cognition and Development Group, Department of Neurological Sciences, University of Vermont, Larner College of Medicine, Burlington, Vermont, USA.
Epilepsia. 2024 Jul;65(7):2138-2151. doi: 10.1111/epi.18017. Epub 2024 May 23.
Sex determines cognitive outcome in animal models of early life seizure, where males exhibit impaired hippocampal-dependent learning and memory compared with females. The physiological underpinnings of this sex effect are unclear. Cholinergic signaling is essential for the generation of hippocampal oscillations, and supplementation of cholinergic precursors prior to status epilepticus in immature male rats prevents subsequent memory deficits. We hypothesized that there are sex differences in acetylcholine circuits and their response to experimental febrile status epilepticus (eFSE).
eFSE was induced in male and female rat pups. We transversed the hippocampus of postnatal day >60 control (CTL) and eFSE rats with a 64-channel laminar silicon probe to assay cholinergic-dependent theta oscillations under urethane anesthesia. Local field potential properties were compared during (1) baseline sensory stimulation, (2) pharmacological stimulation via acetylcholine reuptake blockade, and (3) sensory stimulation after muscarinic acetylcholine receptor block (atropine).
In all groups, a baseline tail pinch could elicit theta oscillations via corticohippocampal synaptic input. Following atropine, a tail pinch response could no longer be elicited in CTL male, CTL female, or eFSE female rats. In contrast, induced slow theta power in eFSE males after atropine was not decreased to spontaneous levels. Analysis of oscillation bandwidths revealed sex differences in acetylcholine modulation of theta frequency and slow gamma frequency and power. This study also identified significant effects of both sex and eFSE on baseline theta-gamma comodulation, indicating a loss of coupling in eFSE males and a potential gain of function in eFSE females.
There are differences in cholinergic modulation of theta and gamma signal coordination between male and female rats. These differences may underlie worse cognitive outcomes in males following eFSE. Promoting the efficacy of muscarinic acetylcholine signaling prior to or following early life seizures could elucidate a mechanism for the temporal discoordination of neural signals within and between hippocampus and neocortex and provide a novel therapeutic approach for improving cognitive outcomes.
在动物早期生活性癫痫模型中，性别决定认知结果，雄性表现出海马依赖性学习和记忆受损，而雌性则不受影响。这种性别效应的生理基础尚不清楚。胆碱能信号对海马振荡的产生至关重要，在未成熟雄性大鼠癫痫持续状态前补充胆碱能前体可预防随后的记忆缺陷。我们假设在乙酰胆碱回路及其对实验性发热性癫痫持续状态（eFSE）的反应中存在性别差异。
在雄性和雌性幼鼠中诱导 eFSE。我们用 64 通道层状硅探针横切出生后第 60 天以上的对照（CTL）和 eFSE 大鼠的海马，在尿烷麻醉下检测胆碱能依赖性θ振荡。在（1）基线感觉刺激、（2）通过乙酰胆碱再摄取阻断的药物刺激和（3）毒蕈碱乙酰胆碱受体阻断（阿托品）后的感觉刺激期间比较局部场电位特性。
在所有组中，基线尾巴刺痛可通过皮质-海马突触输入引起θ振荡。在阿托品后，CTL 雄性、CTL 雌性或 eFSE 雌性大鼠的尾巴刺痛反应都不能再被诱发。相比之下，在 eFSE 雄性大鼠中，在阿托品后诱导的慢θ功率不会降低到自发水平。振荡带宽分析显示，性别对乙酰胆碱调节θ频率和慢γ频率和功率有影响。这项研究还确定了性别和 eFSE 对基线θ-γ共调制的显著影响，表明 eFSE 雄性的耦合丧失和 eFSE 雌性的潜在功能增益。
雄性和雌性大鼠的乙酰胆碱对θ和γ信号协调的调节存在差异。这些差异可能是 eFSE 后雄性认知结果较差的原因。在生命早期癫痫发作前后增强毒蕈碱乙酰胆碱信号的效力可以阐明海马和新皮层内和之间神经信号时间失协调的机制，并为改善认知结果提供一种新的治疗方法。
