Mavanji Vijayakumar, Georgopoulos Apostolos P, Kotz Catherine M
Research Service, Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA.
Research Service (151), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA.
Exp Brain Res. 2021 Mar;239(3):755-764. doi: 10.1007/s00221-020-05977-7. Epub 2021 Jan 3.
Synchronous neural activity is a feature of normal brain function, and altered synchronization is observed in several neurological diseases. Dysfunction in hypothalamic pathways leads to obesity, suggesting that hypothalamic neural synchrony is critical for energy homeostasis. The lateral hypothalamic orexin neurons are extensively interconnected with other brain structures and are important for energy balance. Earlier studies show that rats with higher orexin sensitivity are obesity resistant. Similarly, topiramate, an anti-epileptic drug, has been shown to reduce weight in humans. Since orexin enhances neuronal excitation, we hypothesized that obesity-resistant rats with higher orexin sensitivity may exhibit enhanced hypothalamic synchronization. We further hypothesized that anti-obesity agents such as orexin and topiramate will enhance hypothalamic synchronization. To test this, we examined neural synchronicity in primary embryonic hypothalamic cell cultures, obtained from embryonic day 18 (E18) obesity-susceptible Sprague-Dawley (SD) and obesity-resistant rats. Hypothalamic tissue was cultured in multielectrode array (MEA), and recordings were performed twice weekly, from 4th to 32nd day in vitro (DIV). Next, we tested the effects of orexin and topiramate application on neural synchronicity of hypothalamic cultures obtained from SD rat embryos. Signals were analyzed for synchronization using cross correlation. Our results showed that (1) obesity-resistant hypothalamus exhibits significantly higher synchronization compared to obesity-sensitive hypothalamus; and (2) orexin and topiramate enhance hypothalamic synchronization. These results support that enhanced orexin sensitivity is associated with greater neural synchronization, and that anti-obesity treatments enhance network synchronization, thus constrain variability in hypothalamic output signals, to extrahypothalamic structures involved in energy homeostasis.
同步神经活动是正常脑功能的一个特征，并且在几种神经疾病中观察到同步性改变。下丘脑通路功能障碍会导致肥胖，这表明下丘脑神经同步性对于能量稳态至关重要。下丘脑外侧的食欲素神经元与其他脑结构广泛相互连接，并且对能量平衡很重要。早期研究表明，食欲素敏感性较高的大鼠具有抗肥胖能力。同样，抗癫痫药物托吡酯已被证明可减轻人体体重。由于食欲素增强神经元兴奋，我们假设食欲素敏感性较高的抗肥胖大鼠可能表现出增强的下丘脑同步性。我们进一步假设，诸如食欲素和托吡酯之类的抗肥胖药物将增强下丘脑同步性。为了验证这一点，我们检查了从胚胎第18天（E18）的易肥胖斯普拉格-道利（SD）大鼠和抗肥胖大鼠获得的原代胚胎下丘脑细胞培养物中的神经同步性。下丘脑组织在多电极阵列（MEA）中培养，并且在体外培养的第4天至第32天每周进行两次记录。接下来，我们测试了应用食欲素和托吡酯对从SD大鼠胚胎获得的下丘脑培养物神经同步性的影响。使用互相关分析信号的同步性。我们的结果表明：（1）与肥胖敏感的下丘脑相比，抗肥胖的下丘脑表现出明显更高的同步性；（2）食欲素和托吡酯增强下丘脑同步性。这些结果支持，增强的食欲素敏感性与更大的神经同步性相关，并且抗肥胖治疗增强网络同步性，从而限制下丘脑输出信号到参与能量稳态的下丘脑外结构的变异性。
