As a role emerged for Hcrt neurons as critical regulators of arousal, further clarification of their input was progressing. The fascinating revelation that Hcrt neurons are predominantly controlled by local excitatory interneurons23 was made. Indeed, light microscopic observations revealed a robust interaction between vesicular glutamate transporter 2 (vGlut2)-containing, putative glutamatergic axon terminals and Hcrt perikarya.23 Some of this excitatory input appears to be regulated by Hcrt itself, as Hcrt is present in boutons on Hcrt perikarya,13 and, Hcrt administration has been shown to moderate presynaptic release of glutamate onto these neurons.23 Strikingly, it was also observed that perikaryal GABA input onto the Hcrt neurons is very minimal, approximately 1/10th that of the glutamatergic input.24 This makes these hypothalamic neurons unique in that there is no other example up till now, of long-projective, excitatory neurons being dominated by stimulatory input at the level of the perikaryon. Electron microscopic (see below) and electrophysiological analyses24 confirmed the above light microscopic observations. Electrophysiological results indicate, however, that other afferents, including brain stem noradrenergic and serotoninergic inputs as well as afferent cholinergic pathways also play direct roles in the regulation of Hcrt neuronal activity.23'25 Light microscopic evidence exists in support of serotoninergic innervation26 of Hcrt perikarya, while synaptic confirmation of these and other monoaminergic interactions is yet to be provided.
Of course, there are other peptide and amino acid transmitters and modulators that may play critical roles in affecting the output of Hcrt neurons. Ongoing anatomical research will continuously provide clues and help develop a better blue print of the organization of the input to the Hcrt system. However, this work needs to be complemented by ultrastructural evidence (see below).
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