Distribution Of Hcrt Efferent Axons

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The morphology of Hcrt-immunoreactive axons is heterogeneous and varies from thick, densely-varicose to fine, lightly-varicose.10 Hcrt-immunoreactive axons are found throughout the brain, with the highest density of terminal fields seen in the hypothalamus (Fig. 1).5,7,8

Hypocretin Projections
Figure 1. Schematic diagram of the pathways taken by Hcrt/orexin axons, which widely innervate the rat brain through both ascending and descending projections.6 Copyright 1998 by the Society for Neuroscience.

Hypothalamic regions receiving Hcrt innervation include the LHA and posterior hypothalamic area (regions of Hcrt and MCH neuronal populations), the DMH, the paraventricular hypothalamic nucleus (parvocellular division), arcuate nucleus, and supramammillary nucleus. High Hcrt terminal densities were seen in the locus coeruleus (LC) and moderate-to-high densities in the septum, bed nucleus of the stria terminalis, thalamic paraventricular and reuniens nuclei, periaqueductal gray, substantia nigra, raphe, peribrachial pontine region, medullary reticular formation, and nucleus of the solitary tract, with lesser projections to the cortex, amygdala, hippocampus, and olfactory bulb.5-7 Similar patterns were seen with antisera to Hcrt1 or Hcrt2.7 Juxtaventricular (lateral and third ventricular) axon varicosities were noted in Hcrt1-immunostained material6 and varicose terminals were seen in the circumventricular organs (subfornical organ and area postrema).8 At the EM level, Hcrt-immunoreactive boutons in the periaqueductal gray contain densely-stained granular vesicles and make asymmetric contacts.1 Similarly, Hcrt-immunoreactive axons in the LC make asymmetric, presumably excitatory, synapses with tyrosine hydroxylase-positive noradrenergic dendrites.38

Hcrt innervation is strongly targeted to ascending arousal systems including the noradrenergic LC, the cholinergic pedunculopontine and laterodorsal tegmental nuclei, the serotonergic dorsal and median raphe nuclei, and the histaminergic tuberomammillary nucleus.5 Similarly, Hcrt1- and Hcrt2-immunoreactive axons in the cat brainstem were found at high density in the LC, raphe nuclei, and laterodorsal tegmental nucleus, as well as other brainstem regions.69

Hcrt innervation was found to strongly overlap with noradrenergic, dopamine beta-hydroxylase-immunoreactive fibers in several brain regions including the paraventricular thalamic nucleus, hypothalamus (mainly the region of Hcrt cell bodies), medial and central amygdala, the dorsal raphe nucleus (DR), and pedunculopontine tegmental nucleus.70 Hcrt-immunoreactive axons were seen forming putative synaptic contacts with parvalbumin-immunoreactive neurons in the medial septum.71 Hcrt varicose axons in the DR form putative synaptic contact with both serotonergic and GABAergic neurons as shown using double immunohistochemistry.72 EM analysis of Hcrt-immunoreactive axons in the DR revealed axon terminals containing immunolabeled large dense core vesicles that made asymmetric contact with unlabeled raphe dendrites and rarely made synaptic contact with perikarya.73

Hcrt neurons also have connections with feeding-related hypothalamic regions. Hcrt is reciprocally connected with NPY and leptin receptor-positive neurons in the arcuate nucleus.44 At the EM level, Hcrt axons in the arcuate nucleus also display axo-axonic synaptic contacts with both Hcrt and other unlabeled terminals.44,74 Hcrt axons were also found to make synaptic contact with neighboring MCH neurons.75

Hcrt axon projections to the dopaminergic ventral tegmental area (VTA) were studied with retrograde and anterograde tracing, which demonstrated numerous retrogradely labeled neurons from the VTA but not from the adjacent medial substantia nigra.76 Another retrograde labeling study determined that approximately 10% of Hcrt neurons project to the dorsal vagal complex.9 Retrograde tracing from the nucleus of the solitary tract and nucleus ambiguous revealed that the percentage of Hcrt neurons that project to those sites comprise approximately 8% and 16%, respectively.77

In addition, Hcrt innervation of the spinal cord was seen in several studies using immunohistochemistry against Hcrt1,78 Hcrt2,10 or both.79 Several immunoreactive fibers were seen in the dorsal horn of the spinal cord78 and, at the EM level, these fibers were found to make both symmetric and asymmetric synapses on dendritic elements. Large dense-core vesicles seen in Hcrt axons were intensely immunoreactive.78 Another study using antisera against Hcrt2 showed dense Hcrt fibers in the dorsal horn (marginal zone, lamina 1), intermediolateral column, and lamina 10, and strong innervation of the sacral spinal cord.10 These projections were found to arise from the perifornical Hcrt neurons, as determined by retrograde tracing from the spinal cord.10 Hcrt may also have effects on non-neural tissue in the brain, as Hcrt-immunoreactive fibers are seen in the region of the median eminence, ventricular ependymal lining,5 and the pineal stalk of the rat80 and pig.50 Hcrt has also been found to project indirectly to brown adipose tissue, as shown using transsynaptic retrograde tracing with pseudorabies virus.81

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