Sonoda Masaki, Aimi Hisao, Kawasaki Keisuke, Toda Haruo, Hirai Shinobu, Horie Masao, Meguro Reiko, Asano Eishi, Okado Haruo, Kameyama Shigeki, Yamamoto Tetsuya, Hasegawa Isao
Department of Physiology, Niigata University School of Medicine, Niigata, Japan.
Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Epilepsia. 2025 Jun;66(6):2137-2152. doi: 10.1111/epi.18321. Epub 2025 Mar 11.
Clinical investigators have hypothesized that interictal epileptiform discharges (IEDs) generated by hypothalamic hamartoma (HH) lead to cognitive dysfunction in patients with drug-resistant gelastic seizures. Herein we provide causal evidence supporting this hypothesis by demonstrating that excitatory neural bursts, when propagating from the HH to the mediodorsal thalamus during the encoding period, impair working memory.
By employing channelrhodopsin-2 photostimulation, we induced excessive neural excitation in Long-Evans rats, resembling IEDs, at the axon terminals of the lateral hypothalamus projecting toward the mediodorsal thalamus and prelimbic cortex. We recorded local field potentials (LFPs) at these sites and assessed the performance of working memory tasks with and without photostimulation. Utilizing support vector machine analysis on LFP trials under sham photostimulation, we identified the neural correlates of successful task performance. Through mixed model analyses, we evaluated the impacts of photostimulation timing and the alteration in LFP amplitude induced by photostimulation on task performance.
Ten rats completed operant conditioning using a spout lever system after receiving an average of 70.7 days of training, at a rate of 135.2 trials per day. During sham photostimulation, successful trials were associated with a shorter duration of the working memory maintenance period, as well as an augmentation in the 10- to 14-Hz LFP amplitude at the mediodorsal thalamus and prelimbic cortex during the memory encoding phase. Photostimulation at the mediodorsal thalamus during encoding reduced the odds of a trial being successful by 0.19. Conversely, excessive mediodorsal thalamus LFP augmentation induced by photostimulation during encoding increased the odds of a trial being unsuccessful by 1.04.
Excessive neural excitation, specifically propagating from the lateral hypothalamus to the mediodorsal thalamus during encoding, alters physiological neural activity and transiently impairs working memory. This study clarifies the pathophysiological mechanism underlying cognitive disabilities associated with working memory impairment in HH-related epileptic encephalopathy.
临床研究人员推测，下丘脑错构瘤（HH）产生的发作间期癫痫样放电（IEDs）会导致药物难治性痴笑发作患者出现认知功能障碍。在此，我们通过证明兴奋性神经冲动在编码期从HH传播至丘脑背内侧核时会损害工作记忆，从而提供支持这一假设的因果证据。
通过使用通道视紫红质-2光刺激，我们在向丘脑背内侧核和前边缘皮层投射的下丘脑外侧轴突末端诱导Long-Evans大鼠出现类似于IEDs的过度神经兴奋。我们在这些部位记录局部场电位（LFPs），并评估有无光刺激时工作记忆任务的表现。利用对假光刺激下LFP试验的支持向量机分析，我们确定了成功完成任务的神经关联因素。通过混合模型分析，我们评估了光刺激时机以及光刺激引起的LFP振幅变化对任务表现的影响。
10只大鼠在平均接受70.7天训练后，以每天135.2次试验的速度使用喷口杠杆系统完成了操作性条件反射。在假光刺激期间，成功的试验与工作记忆维持期较短有关，同时在记忆编码阶段丘脑背内侧核和前边缘皮层的10至14赫兹LFP振幅增加。编码期在丘脑背内侧核进行光刺激使试验成功的几率降低了0.19。相反，编码期光刺激引起的丘脑背内侧核LFP过度增强使试验不成功的几率增加了1.04。
过度的神经兴奋，特别是在编码期从下丘脑外侧传播至丘脑背内侧核，会改变生理神经活动并短暂损害工作记忆。本研究阐明了HH相关癫痫性脑病中与工作记忆损害相关的认知障碍的病理生理机制。
