Synchronous neuronal interactions in rat hypothalamic culture: a novel model for the study of network dynamics in metabolic disorders

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.