Orexin‐A increases the firing activity of hippocampal CA1 neurons through orexin‐1 receptors

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Orexins, generally known as hypocretin, were first reported in the hypothalamus. Orexins including orexin‐A and orexin‐B are produced from prepro‐orexin precursor in the lateral hypothalamus (de Lecea et al., 1998). Orexinergic neurons extend ascending and descending projections to almost all brain areas (Peyron et al., 1998). There are two types of orexin receptors, orexin‐1 (OX1) and orexin‐2 (OX2) receptors, which belong to G‐protein–coupled receptors. Orexin‐A combines with both OX1 and OX2 receptors with similar affinity, while orexin‐B mainly combines with OX2 receptors (Marcus et al., 2001; Langmead et al., 2004). Much evidence has suggested that the orexinergic system is involved in several physiological functions (Li et al., 2014; Sakurai, 2014), including regulation of arousal state (Sutcliffe and de Lecea, 2002; Ohno and Sakurai, 2008; Tsujino and Sakurai, 2013); energy metabolism and feeding behavior (Ganjavi and Shapiro, 2007; Girault et al., 2012); neuroendocrine, natural, and drug rewards (Sadeghi et al., 2016); and motor regulation (Hara et al., 2001; Zhang et al., 2013; Hu et al., 2015).
Hippocampus, as a major component of the limbic system in the brain, plays important roles in learning and memory, cognition, and so on, especially in the consolidation of information from short‐term memory to long‐term memory. According to the cellular morphology and nerve fiber formation of different regions, the hippocampus is separated into the CA1, CA2, CA3, and CA4 regions. It is well known that the degenerations of hippocampal neurons are closely related to Alzheimer disease, which is generally acknowledged as a chronic neurodegenerative disease. Several studies have demonstrated that central orexins might be implicated in the pathophysiology of Alzheimer disease (Kang et al., 2009; Fronczek et al., 2012; Ferini‐Strambi, 2014). The Aβ‐plaque formation and tau hyperphosphorylation lead to down‐regulation of hippocampal orexin receptors (Davies et al., 2015). Furthermore, the number of hypocretin‐1 immunoreactive neurons in the lateral hypothalamus and the cerebrospinal fluid hypocretin‐1 level decrease significantly in patients with Alzheimer disease (Fronczek et al., 2012; Kasanuki et al., 2014).
Morphological studies have revealed that the hippocampus receives orexinergic innervations arising from the lateral hypothalamus (Peyron et al., 1998; Cutler et al., 1999; Nambu et al., 1999; Baldo et al., 2003; Dell et al., 2013). Both OX1 and OX2 receptors are expressed in the hippocampus, with OX1 receptors expressed in CA1 and CA2, while OX2 receptors are expressed in CA3 (Trivedi et al., 1998; Lu et al., 2000; Hervieu et al., 2001; Marcus et al., 2001). Early functional studies have shown that intracerebroventricular (i.c.v.) administration of orexin‐A modulates learning and memory in rats (Jaeger et al., 2002; Telegdy and Adamik, 2002; Aou et al., 2003). Furthermore, blockade of OX1 receptors in hippocampal CA1 regions impairs acquisition, consolidation, and retrieval in the Morris water maze task (Akbari et al., 2006). Recently, studies by Riahi et al. (2015) have revealed that i.c.v. application of orexin‐A modulates the spontaneous firing rate of hippocampal CA1 neurons. However, the direct electrophysiological effects of orexin‐A on spontaneous firing of hippocampal CA1 neurons remain unclear. In present study, in vivo multibarrel single‐unit electrophysiological recordings were performed to investigate the effects and possible receptor mechanisms of orexin‐A on hippocampal CA1 neurons of rats.
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