Orexin Neurons Project Diffusely

From a hypothalamic point of origin, orexin fibers project across the entire neuraxis from the cortex to the spinal cord (Fig. 1). The diffuse nature of orexin efferents has implicated the orexin neurons in a wide variety of physiological systems (5). The lateral hypothalamic area, the origin of orexin projections, has long been considered a master integration and command center for numerous homeostatic, autonomic, endocrine, and behavioral systems (25). For example, retrograde and anterograde tracing studies have shown that the LHA is a primary recipient of projections, presumably containing visceral sensory information, from the brain-stem (30) and provides a reciprocal descending projection to these brainstem regions (30). Similarly, the LHA both innervates and is innervated by the cortex (31,32). The LHA also innervates neuroendocrine control regions in the hypothalamus such as the arcuate nucleus (ARC) and the paraventricular hypothalamic nucleus (PVH) (33).

Not surprisingly, the orexin fibers that exit the LHA innervate many if not all of the regions shown previously to be innervated by the LHA. Numerous studies have reported the locations of orexin fibers (5,8,34-39) using immunohistochemical techniques. Several studies detailing orexin receptor mRNA expression using in situ hybridization (40-42) and immunohistochem-istry (43-46) have also been performed. In general, these studies are consistent with each other. For example, areas receiving dense innervation of orexin fibers also express high levels of receptor mRNA. In addition, all central areas innervated by fibers express mRNA for either of the two orexin receptors or both of them. The results of these distribution studies are summarized in Figs. 1-7 and Table 1, and within the text below in a survey of the central nervous system.

4.1. Hypothalamic Innervation and Receptor Distribution 4.1.1. Orexin Fibers

Orexin fiber innervation of the hypothalamus is extremely robust. Fiber innervation is present at all levels of the hypothalamus, from the preoptic level to the level of the mammil-lary bodies. Not surprisingly, the densest concentrations of fibers are seen in the lateral and posterior hypothalamus. Many if not most of these fibers are exiting the orexin neuronal field, but some of these fibers probably terminate on neurons within the LHA itself, including on orexin neurons (13,29) and MCH neurons (47). Large numbers of fibers are present in the parvocellular portions of the paraventricular nucleus, whereas few fibers enter the magnocel-lular portion (Fig. 2B). Innervation of the dorsomedial nucleus is moderate, as is innervation of the ventromedial nucleus (VMH), especially the region anterior to the VMH. More ros-trally, the preoptic nuclei are innervated by a moderate number of fibers. Orexin fibers are seen around the supraoptic nucleus and suprachiamatic nucleus, but few fibers enter these areas (8). The ARC is densely innervated throughout its extent, and fibers extend into the median eminence (29,36). Fibers are also seen in the periventricular nucleus, with some fibers appearing to extend into the third ventricle (38). In the caudal hypothalamus, the tuberomam-millary and suprammamillary nuclei are densely innervated (Fig. 2C).

Fig. 1. Schematic depiction of the rat brain showing widespread distribution of orexin-containing fibers (arrows) originating from the lateral hypothalamus. AP, area postrema; LC, locus ceruleus; SFC, subfornical organ; V, fourth ventricle; (Modified from ref. 34.)

4.1.2. Hypothalamic OX1R Distribution

OX1R mRNA is expressed in a subset of the hypothalamic nuclei described above. For example, low levels of expression are present in the preoptic nuclei, with more moderate levels in the medial preoptic nucleus. Robust expression is seen in the anterior hypothalamic nucleus (Fig. 3C) and the dorsomedial portion of the VMH (Fig. 3E and F). Moderate levels of OX1R mRNA are seen in the dorsal hypothalamus, ventral premammillary nucleus (Fig. 3G), posterior hypothalamus, and supramammillary nucleus. Diffuse expression is present in the LHA (Fig. 3F). Messenger RNA expression is absent in the paraventricular, arcuate, suprachiasmatic, and tuberomammillary nuclei (Fig. 5).

4.1.3. Hypothalamic OX2R Distribution

OX2R mRNA expression is present in many hypothalamic nuclei. For example, the tuberomammillary nucleus contains the most robust OX2R expression in the hypothalamus (Fig. 4G). These tuberomammillary neurons are histaminergic (48,49). As with OX1R, the preoptic nuclei (Fig. 4C), supramammillary nucleus, and posterior hypothalamus express OX2R mRNA. OX2R mRNA is less robust than OX1R mRNA in the ventromedial nucleus and dorsal hypothalamus (Fig. 4F). However, many hypothalamic nuclei show preferential expression of OX2R. These include the arcuate (Fig. 4E), dorsomedial (Fig. 4F), parvocellular paraventricular (Fig. 4D), medial mammillary (Fig. 4G), lateral mammillary (Fig. 4G), and tubermammillary nuclei (Fig. 5). Diffuse OX2R mRNA is also present in the lateral hypothalamic area (Fig. 4F).

4.2. Ascending Projections From the Hypothalamus 4.2.1. Ascending Orexin Fibers

The ascending projections of orexin neurons are extremely widespread and extend to cortical and subcortical regions. In the cortex, fibers are widespread and present in low but diffuse concentrations across all cortical levels. Moderate amounts of cortical innervation are

Fig. 2. Photomicrographs depicting the orexin-fiber innervation of the (A) basal forebrain, (B) paraventricular hypothalamic nucleus, (C) tuberomammillary hypothalamic nucleus, (D) dorsal raphe nucleus, (E) locus coeruleus, and (F) dorsal vagal complex. Orexin fibers are visualized as the dark DAB precipitate. Abbreviations: BFB, basal forebrain, PVHpm, paraventricular hypothalamic nucleus, posterior magnocel-lular, 3v, third ventricle, TMN, tubermammillary hypothalamic nucleus, DR, dorsal raphe nucleus, mlf, medial longitudinal fasiculus, LC, locus coeruleus, 4v, fourth ventricle, AP, area postrema, NTS, nucleus of the solitary tract, DMX, dorsal motor nucleus of the vagus nerve, cc, central canal.

Fig. 2. Photomicrographs depicting the orexin-fiber innervation of the (A) basal forebrain, (B) paraventricular hypothalamic nucleus, (C) tuberomammillary hypothalamic nucleus, (D) dorsal raphe nucleus, (E) locus coeruleus, and (F) dorsal vagal complex. Orexin fibers are visualized as the dark DAB precipitate. Abbreviations: BFB, basal forebrain, PVHpm, paraventricular hypothalamic nucleus, posterior magnocel-lular, 3v, third ventricle, TMN, tubermammillary hypothalamic nucleus, DR, dorsal raphe nucleus, mlf, medial longitudinal fasiculus, LC, locus coeruleus, 4v, fourth ventricle, AP, area postrema, NTS, nucleus of the solitary tract, DMX, dorsal motor nucleus of the vagus nerve, cc, central canal.

seen in the insular, prelimbic, piriform, and infralimbic cortices, with fewer fibers in the sensory and motor cortices (5). In the olfactory system, fibers are seen in the anterior olfactory bulb. Orexin fibers avoid the caudate putamen and globus pallidus, but a moderate number of fibers exist in the medial nucleus accumbens. Within the basal forebrain, orexin fibers

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