Colocalization Of Neurochemicals In Hcrt Neurons

Hcrt neurons contain several other neurotransmitters. Although the functional consequence of these additional neurotransmitters is not completely understood, phenotypic differences exist between the Hcrt ligand knockout mouse, in which only the Hcrt gene is deleted,16 and the transgenic Hcrt/ataxin-3 mouse, in which Hcrt-expressing neurons degenerate.17 Although a narcolepsy-like syndrome is seen in both animals, hypophagia and obesity occur only in the Hcrt/ataxin-3 mouse,17 suggesting that other factors in the Hcrt neurons contribute to regulation of energy metabolism.

Following the identification of Hcrt neurons, colocalization studies were performed to determine whether other functionally important neurotransmitters are expressed in these neurons. Substances reported to colocalize with Hcrt can be classified into three major categories: neuropeptides and other neurotransmitters, receptors for neuromodulators, and other cellular factors. The neuropeptide melanin-concentrating hormone (MCH), originally isolated from the salmon pituitary, does not colocalize with Hcrt,5,18,19 although it is expressed in a large population of perifornical and LHA neurons. Broberger et al. reported that the number of Hcrt neurons was equivalent to the number of MCH neurons at the level of the LH containing the Hcrt population, but that MCH neurons were more extensive in the rostral-caudal direction. The MCH neuron population extends rostrally to the level of the caudal suprachiasmatic nucleus (SCN) and caudally to the level of the mammillary recess.18 In contrast, the Hcrt neuron population extends rostrally only to the level of the paraventricular nucleus and caudally only to the level of the posterior hypothalamic area.5 Cocaine- and amphetamine-related transcript (CART), a neuropeptide found in a subpopulation of MCH neurons, also does not colocalize with Hcrt.20 The gaseous neuromodulator nitric oxide is likely not a significant colocalizing factor, as the enzyme nitric oxide synthase (NOS) has been detected in roughly 4% of Hcrt neurons in the Long-Evans rat,13 and no colocalization was seen in the Wistar rat.21 In fact, nNOS seems not to be colocalized with MCH either, as only NOS-immunoreactive, but not MCH or Hcrt neurons, express the neuropeptide Y (NPY) Y1 receptor.22

The neuropeptide galanin was reported to be colocalized with some Hcrt neurons,23 but the extent of colocalization among the Hcrt neuronal population was not reported. Hcrt neurons were found to be colocalized with prodynorphin (dyn)A mRNA. Double in situ hybridization and immunohistochemical experiments demonstrated a high degree (>94%) of correspondence between Hcrt- and DynA-expressing neurons,24 although dynA mRNA was also found in adjacent hypothalamic nuclei that did not express Hcrt such as the supraoptic nucleus, the paraventricular nucleus, ventromedial hypothalamic nucleus, and the compact region of the DMH. Hcrt neurons were found to correspond to a neuronal population that was previously recognized by an ovine prolactin antiserum (prolactin-like immunoreactivity).25 These prolactin-like immunoreactive neurons had been previously characterized as also containing bradykinin and dynorphin B.26 After Hcrt was discovered, it was demonstrated that dynorphin B colocalized with Hcrt.27 Hcrt neurons are likely to be glutamatergic as well, since glutamate28,29 and also the excitatory amino acid transporter EAAT330 and vesicular glutamate transporters VGLUT131 and VGLUT231,32 have been found in Hcrt neurons and/or terminals.

Neurotransmitter receptors that have been reported to colocalize in Hcrt neurons include the GABAa receptor epsilon subunit,33 the pancreatic polypeptide Y4 receptor,34 and the adenosine A1 receptor.35 In addition, the receptor for the adipose hormone leptin is found in Hcrt neurons.23 The significance of these colocalizations will be discussed in Chapter 7 on afferent innervation of Hcrt neurons. Other cellular factors reported to be expressed in Hcrt neurons includes precursor-protein convertase36, secretogranin II,27,37 the transcription factor Stat-3,23,38 and the neuronal pentraxin Narp, implicated in clustering of ionotropic glutamate receptors.39

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