Abstract
Orexinergic/hypocretinergic (Ox) neurotransmission plays an important role in regulating sleep, as well as in anxiety and depression, for which the serotonergic (5-HT) system is also involved in. However, little is known regarding the direct and indirect interactions between 5-HT in the dorsal raphe nucleus (DRN) and Ox neurons in the lateral hypothalamus (LHA). In this study, we report the additional presence of 5-HT1BR, 5-HT2AR, 5-HT2CR and fast ligand-gated 5-HT3AR subtypes on the Ox neurons of transgenic Ox-enhanced green fluorescent protein (Ox-EGFP) and wild type C57Bl/6 mice using single and double immunofluorescence (IF) staining, respectively, and quantify the colocalization for each 5-HT receptor subtype. We further reveal the presence of 5-HT3AR and 5-HT1AR on GABAergic neurons in LHA. We also identify NMDAR1, OX1R and OX2R on Ox neurons, but none on adjacent GABAergic neurons. This suggests a one-way relationship between LHA’s GABAergic and Ox neurons, wherein GABAergic neurons exerts an inhibitory effect on Ox neurons under partial DRN’s 5-HT control. We also show that Ox axonal projections receive glutamatergic (PSD-95 immunopositive) and GABAergic (Gephyrin immunopositive) inputs in the DRN. We consider these and other available findings into our computational model to explore possible effects of neural circuit connection types and timescales on the DRN-LHA system’s dynamics. We find that if the connections from 5-HT to LHA’s GABAergic neurons are weakly excitatory or inhibitory, the network exhibits slow oscillations; not observed when the connection is strongly excitatory. Furthermore, if Ox directly excites 5-HT neurons at a fast timescale, phasic Ox activation can lead to an increase in 5-HT activity; no significant effect with slower timescale. Overall, our experimental and computational approaches provide insights towards a more complete understanding of the complex relationship between 5-HT in the DRN and Ox in the LHA.
Highlights
Mood and neuropsychiatric disorders such as depression have a close relationship with sleep disturbances, and are instantiated by the overlap of emotional processing and the sleep-wake regulation neuronal circuitries [1]
It is interesting to note that Muraki et al (2004) has shown that the 5HT1A receptor antagonist WAY-100635 can completely block the 5-HT hyperpolarizing effect on orexin/ hypocretin (Ox) neurons
It could perhaps be that the 5-HT1A receptors have the highest affinity as compared to the other 5-HT receptor subtypes found in this study
Summary
Mood and neuropsychiatric disorders such as depression have a close relationship with sleep disturbances, and are instantiated by the overlap of emotional processing and the sleep-wake regulation neuronal circuitries [1]. Ox can have both direct and indirect influences on the DRN’s 5-HT neurons It remains unknown whether 5HT can reciprocally indirectly influence LHA’s Ox neurons by influencing the LHA’s GABAergic neurons, and whether this connection is effectively excitatory or inhibitory. Knowledge of direct and indirect circuit connections is important to provide a more complete understanding of diversified neural circuit dynamics and regulations within the DRN-LHA system [35,36]. It is not known how the interplay between fast synaptic transmission and slow currents induced by 5HT and Ox can affect the relay of information in these circuits. We show the importance of the timescale for the Ox-to-DRN connection during transient behaviour
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