Localization Of Hcrt Receptors

The distribution of Hcrt receptors is largely consistent with Hcrt axon innervation patterns (Fig. 2). However, a differential distribution of the two Hcrt receptors, HcrtR1 and HcrtR2, has been demonstrated in several brain regions in both in situ hybridization82-84 and immunohistochemical85,86 studies. In the cerebral cortex, hcrtrl mRNA is expressed primarily in layers II, III and V, whereas hcrtr2 mRNA is found at higher density in layers II and VI and more diffusely in other layers (Fig. 2). In the hippocampus, hcrtrl is expressed mainly in the CA2 region and medial dentate gyrus, while hcrtr2 was most abundant in CA3. However, HcrtR1-immunoreactivity was found only in the dentate gyrus and not in CA2.85 Other forebrain regions expressing moderate to high levels of hcrtrl mRNA are the tenia tecta, bed nucleus of the stria terminalis, horizontal limb of the diagonal band of Broca, and medial amygdala. In contrast, hcrtr2 mRNA was prominent is the medial septum, vertical and horizontal limbs of the diagonal band of Broca, substantia innominata, and cortical amygdala.

Figure 2. Distribution of Hcrt receptor 1 (HcrtR1) and receptor 2 (HcrtR2) mRNAs as described in Marcus et a/.84 for brain regions involved in arousal state regulation. Abbreviations: DRN, dorsal raphe nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MS, medial septal nucleus; NDB, nuclei of the diagonal band of Broca; PPT, pedunculopontine nucleus; TMN, tuberomammillary nucleus; VTA, ventral tegmental area. I, III, V and VI represent cortical laminae. Modified from Ref 92.

Intergeniculate Leaflet

Figure 2. Distribution of Hcrt receptor 1 (HcrtR1) and receptor 2 (HcrtR2) mRNAs as described in Marcus et a/.84 for brain regions involved in arousal state regulation. Abbreviations: DRN, dorsal raphe nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MS, medial septal nucleus; NDB, nuclei of the diagonal band of Broca; PPT, pedunculopontine nucleus; TMN, tuberomammillary nucleus; VTA, ventral tegmental area. I, III, V and VI represent cortical laminae. Modified from Ref 92.

In the hypothalamus, little or no hcrtrl mRNA expression was seen in the arcuate nucleus, paraventricular hypothalamic nucleus, LHA, or tuberomammillary nucleus, regions that prominently express hcrtr2 mRNA. Hypothalamic regions with high expression of hcrtrl include the ventromedial hypothalamic nucleus and a specific region of anterior hypothalamic nucleus dorsolateral to the SCN.83 In the thalamus, moderately dense levels of hcrtrl and hcrtr2 mRNAs were detected in the paraventricular thalamic nucleus and the intergeniculate leaflet, with lesser density in the rhomboid, reuniens, and other midline nuclei.

The subthalamic nucleus expressed both receptors, but preferentially hcrtrl. In the brainstem, the highest density of hcrtrl mRNA was found in the LC, which did not express hcrtr2. Other brainstem noradrenergic groups were noted as expressing hcrtrl. The cholinergic brainstem nuclei, the laterodorsal and pedunculopontine tegmental nuclei, expressed both receptors but expressed hcrtrlat a higher level.

The VTA, containing dopaminergic neurons, and the DR, containing serotonin neurons, expressed both receptors, although there was a medial-lateral preference in the DR, with hcrtrl medial and hcrtr2 lateral. Moderate hcrtrl mRNA expression was seen in the pontine raphe, raphe magnus, raphe obscurus, and dorsal motor vagal complex. Moderate density of hcrtr2 mRNA expression was described in ventral periaqueductal gray, midbrain reticular formation, dorsal interpeducular nucleus, Barrington's nucleus, the sensory trigeminal nucleus, ventrolateral medulla, and the dorsal vagal nucleus. Low levels of hcrtr2 were seen in the facial motor nucleus, hypoglossal nucleus, and the external cuneate and gracile nuclei.83,85,86 In addition, hcrtrlmRNA and HcrtRl protein were identified within the spinal cord in all subdivisions of the gray matter.85

Immunohistochemical studies show HcrtRl and HcrtR2 protein distribution in similar regions shown to express the mRNA for those receptors,85,86 although some discrepancies were seen. Regions that were immunoreactive for HcrtRl protein that were not reported in in situ hybridization studies include the olfactory tubercle, paraventricular hypothalamic nucleus, caudate-putamen, globus pallidus, anteroventral nucleus and ventroposterior lateral and ventroposterior medial thalamic nuclei.85 Regions that were immunoreactive for HcrtR2 protein that were not reported in in situ hybridization studies include the caudate-putamen, globus pallidus, nucleus accumbens, and the superior olivary complex.86 These differences may be due to low level mRNA that is translated into protein at a high rate or to immunoreactivity localized in HcrtR protein transported away from the cell body, as some staining seen in these studies is diffuse and not contained within neuronal cell bodies.

A number of other studies confirmed receptor localization in specific brain regions and, additionally, describe HcrtR localization in specific neurochemically-identified populations. Double-immunohistochemistry showed colocalization of HcrtRl in NPY-and alpha-melanocyte-stimulating hormone (alpha-MSH)-immunoreactive neurons in the arcuate nucleus.74,87,88 In the latter study, triple immunofluorescence determining the extent of colocalization of leptin and HcrtRl receptors in NPY and alpha-MSH neurons revealed that alpha-MSH cells mainly contained both receptors, whereas NPY cells were more heterogeneous. HcrtRl localization in the LC and adjacent mesencephalic trigeminal nucleus was seen in several studies.89,90 HcrtRl-immunoreactivity was also confirmed in the tenia tecta, indusium griseum, septum, paraventricular thalamic nucleus, dorsal and median raphe,88 bed nucleus of the stria terminalis,88,89 medial septum and diagonal band, lateral septum, and substantia innominata,89 pontine reticular formation, motor trigeminal nucleus, superior olive, ventral cochlear nucleus, Barrington's nucleus, and cholinergic neurons of the laterodorsal tegmental nucleus.90 HcrtR2 receptor localization was confirmed in parvalbumin neurons in the medial septum,71 the motor trigeminal nucleus, pontine reticular formation, Barrington's nucleus, and the ventral cochlear nucleus.90 Both hcrtrl and hcrtr2 mRNA80 and immunoreactivity50 were found in the pineal gland.

The composite distribution of the two Hcrt receptors strongly resembles the distribution of the MCH receptor.91 MCH receptor mRNA distribution is similar to that of the HcrtRl in the LC, amygdala, and other brainstem noradrenergic groups, whereas in other brain regions such as the septum, hypothalamus, and much of the brainstem, the distribution of MCH receptor mRNA resembles that of the HcrtR2.91

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