Hcrt Autoregulation

Local administration of Hcrt into the LHA itself results in increased feeding.89 In addition to what has been described above concerning Hcrt-MCH interactions, this result may partly be explained by a positive feedback loop driving Hcrt neurons. This possibility is supported by the observation that at the light microscope level, a dense network of Hcrt-ir terminals can be seen surrounding, and often contacting, Hcrt-ir cell bodies in the LHA.909192 have recently described a local circuit providing feedback excitation of the Hcrt population, which may, however, involve an intermediary glutamatergic interneurons rather than direct autoinnervation. Specifically, it was shown that the depolarisation and increased firing rate observed in Hcrt neurons following application of Hcrt1 or 2 requires intact synaptic activity as well as intact ionotropic glutamatergic transmission. Furthermore, glutamatergic terminals were also shown to form close appositions suggestive of synaptic specializations onto Hcrt-expressing perikarya and dendrites. Since the evidence suggests that the Hcrt neurons are glutamatergic, a likely explanation for these findings is that Hcrt presynaptically facilitates release of glutamate onto the Hcrt neurons themselves. Indeed, as mentioned, Hcrt1R-LI has been observed in Hcrt neurons.81 Yet, it cannot be excluded that these effects are mediated via local glutamatergic interneurons. The concept of interneurons modulating neurotransmission is well established in e.g. neocortical circuits but has been only scantily investigated in hypothalamic nuclei. Such putative interneurons also remain to be identified histochemically. Regardless of the mechanism, feedback excitation provides a powerful mechanism for amplifying the Hcrt tone. This mechanism may be of importance in stabilizing the behavioural state towards sleep or arousal by serving as a "flip-flop" device, which prevents the animal from drifting into intermediate states.93

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