Axons containing cocaine- and amphetamine-regulated transcript (CART) densely innervate the hypothalamic paraventricular nucleus (PVN). Recent data from our laboratory demonstrated that CART-immunoreactive (IR) neurons of arcuate nucleus origin innervate the PVN, but comprise only a portion of the total CART-IR input to this region of the brain. To identify sources other than the arcuate nucleus, retrograde transport studies were performed with cholera toxin B subunit (CTB), focally delivered into the PVN of adult rats. Neurons double-labeled for CTB and CART were visualized by immunofluorescence. The most prominent groups of double-labeled cells were identified in the retrochiasmatic area, arcuate nucleus, lateral hypothalamus, perifornical area, zona incerta, C1-3 regions, and the medial subnucleus of the nucleus tractus solitarius (NTS). In addition, scattered retrogradely labeled CART-IR neurons were found in the parabrachial nucleus. In the diencephalon, the majority of double-labeled neurons were localized ipsilateral to the injection site; however, in the medulla the CART/CTB-containing neurons were found bilaterally. By triple-labeling immunofluorescence, CART/CTB neurons in the perifornical area, zona incerta complex, and more medial portions of the lateral hypothalamus were found to co-contain melanin concentrating hormone (MCH), whereas CART/CTB neurons of the C1-3 regions of the brainstem but not medial subnucleus of the NTS were observed to express phenylethanolamine N-methyltransferase (PNMT). We conclude that the CART innervation of the PVN derives from multiple neuronal sources of the hypothalamus and medulla. These observations raise the possibility that CART serves multiple functions in the PVN and is utilized to transmit diverse physiological signals that contribute to the complex regulation of homeostatic functions of the PVN.
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