Neural circuit architecture and dynamics of the serotonin-orexin/hypocretin system

Serotonin (5-HT) and orexin/hypocretin (Ox) systems are known to have a bi-directional relationship. Using immunofluorescence staining on Ox-enhanced green fluorescent protein (Ox-EGFP) transgenic mice brains, we have previously successfully mapped out the direct and indirect connections between the dorsal raphe nucleus (DRN, a source of 5-HT) and the lateral hypothalamus (LHA, a source of Ox). We have found that direct connection from DRN to Ox neurons in LHA consists of fast ligand-gated 5-HT3A receptors and slower non-5-HT3 (e.g. 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C) receptors. We also found 5-HT3A and 5-HT1A receptors on GABAergic inhibitory neurons in the LHA. Other experimental work has further demonstrated Ox1 and Ox2 receptor-mediated excitation on 5-HT and GABAergic inhibitory neurons in the DRN. Self-regulation of 5-HT (Ox) activity within the DRN (LHA) arises from the inhibitory feedback of their local inhibitory neurons, and additionally, inhibitory autoreceptors for 5-HT neurons (Ox autoreceptors are excitatory). We incorporate these findings into a neuronal circuit model of the DRN-LHA system consisting of 5-HT, Ox and inhibitory neuronal populations to elucidate its possible neural circuit dynamics, which has till now remains unknown. By constraining the relative connection strengths and relative baseline activities of the model to experimental data, our model demonstrates that the system’s baseline activities are more stable with respect to connection strength changes if the DRN’s 5-HT to LHA’s GABAergic neurons connection is excitatory as compared to inhibitory. If 5-HT inhibits LHA’s GABAergic neurons, the system’s baseline activities can vary substantially with its increasing connection strength, and can even lead to slow oscillations. Furthermore, a faster phasic influence of 5-HT on Ox neurons (e.g. fast 5-HT3A as compared to slow 5-HT1A receptors) can lead to a larger effect on Ox activity. 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. Current work includes investigating how this neuronal circuit and behaviour can be altered in stress-induced mouse model of depression.