title: Neural circuit interactions between the dorsal raphe nucleus and the lateral hypothalamus: an experimental and computational study.
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.
authors: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors: Jaishree
authors: J
authors: Jalewa
authors: Intelligent Systems Research Centre, University of Ulster, Magee Campus, Londonderry, Northern Ireland, United Kingdom.
authors: Alok
authors: A
authors: Joshi
authors: Intelligent Systems Research Centre, University of Ulster, Magee Campus, Londonderry, Northern Ireland, United Kingdom.
authors: T Martin
authors: TM
authors: McGinnity
authors: Intelligent Systems Research Centre, University of Ulster, Magee Campus, Londonderry, Northern Ireland, United Kingdom.
authors: Girijesh
authors: G
authors: Prasad
authors: Intelligent Systems Research Centre, University of Ulster, Magee Campus, Londonderry, Northern Ireland, United Kingdom.
authors: KongFatt
authors: K
authors: Wong-Lin
authors: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom.
authors: Christian
authors: C
authors: Hölscher
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D003198:Computer Simulation; D065847:Dorsal Raphe Nucleus / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D059330:GABAergic Neurons / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000502:physiology*; D007395:Interneurons / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009415:Nerve Net / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013997:Time Factors
chemical_list: D005971:Glutamates; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012701:Serotonin