Melanin-concentrating hormone projections to areas involved in somatomotor responses.

The lateral hypothalamic area (LHA) participates in the integration of sensory information and somatomotor responses associated with hunger and thirst. Although the LHA is neurochemically heterogeneous, a particularly high number of cells express melanin-concentrating hormone (MCH), which has been reported to play a role in energy homeostasis. Treatment with MCH increases food intake, and MCH mRNA is overexpressed in leptin-deficient (ob/ob) mice. Mice lacking both MCH and leptin present reduced body fat, mainly due to increased resting energy expenditure and locomotor activity. Dense MCH innervation of the cerebral motor cortex (MCx) and the pedunculopontine tegmental nucleus (PPT), both related to motor function, has been reported. Therefore, we postulated that a specific group of MCH neurons project to these areas. To investigate our hypothesis, we injected retrograde tracers into the MCx and the PPT of rats, combined with immunohistochemistry. We found that 25% of the LHA neurons projecting to the PPT were immunoreactive for MCH, and that 75% of the LHA neurons projecting to the MCx also contained MCH. Few MCH neurons were found to send collaterals to both areas. We also found that 15% of the incerto-hypothalamic neurons projecting to the PPT expressed MCH immunoreactivity. Those neurons preferentially innervated the rostral PPT. In addition, we observed that the MCH neurons express glutamic acid decarboxylase mRNA, a gamma-aminobutyric acid (GABA) synthesizing enzyme. We postulate that MCH/GABA neurons are involved in the inhibitory modulation of the innervated areas, decreasing motor activity in states of negative energy balance.

Connectivity pattern suggests that incerto-hypothalamic area belongs to the medial hypothalamic system.

The incerto-hypothalamic area (IHy) is a poorly defined diencephalic region located at the junction of the medial hypothalamus and zona incerta (ZI). This region is characterized by the presence of the A13 dopaminergic group and also cells expressing melanin-concentrating hormone (MCH) and cocaine- and amphetamine-regulated transcript (CART). The dopaminergic neurons appear to influence luteinizing hormone secretion, but the role of the MCH/CART-expressing cells is unclear. Even though IHy presents a singular neurochemistry, it has long been assumed that it is also part of the zona incerta. By injecting biotinylated dextran amine into the IHy and ZI of adult male Wistar rats, we analyzed the efferent projections from the IHy in comparison to the ZI. We have found that ZI projects mainly to laterally located brain stem structures, whereas the main efferents from the IHy are the reuniens thalamic nucleus, precommissural nucleus, posterior hypothalamic area and dorsolateral periaqueductal gray matter. The IHy projection pattern is quite similar to that of the anterior hypothalamic area and our hodological results suggest that IHy belongs to the medial hypothalamic system and might be part of the defensive behavior system. The IHy could be an integrative area associated with the regulation of neuroendocrine functions related to motivated behaviors, which are mediated by the medial hypothalamus.

Distribution of melanin-concentrating hormone neurons projecting to the medial mammillary nucleus.

The melanin-concentrating hormone and neuropeptide glutamic acid-isoleucine are expressed in neurons located mainly in the hypothalamus that project widely throughout the CNS. One of the melanin-concentrating hormone main targets is the medial mammillary nucleus, but the exact origin of these fibers is unknown. We observed melanin-concentrating hormone and neuropeptide glutamic acid-isoleucine immunoreactive fibers coursing throughout the mammillary complex, showing higher density in the pars lateralis of the medial mammillary nucleus, while the lateral mammillary nucleus showed sparse melanin-concentrating hormone innervation. The origins of these afferents were determined by using implant of the retrograde tracer True Blue in the medial mammillary nucleus. Double-labeled neurons were observed in the lateral hypothalamic area, rostromedial zona incerta and dorsal tuberomammillary nucleus. A considerable population of retrogradely labeled melanin-concentrating hormone perikaryal profiles was also immunoreactive to neuropeptide glutamic acid-isoleucine (74+/-15% to 85+/-15%). The afferents from the lateral hypothalamic area, rostromedial zona incerta and dorsal tuberomammillary nucleus to the medial mammillary nucleus were confirmed using implant of the anterograde tracer Phaseolus vulgaris leucoagglutinin. In addition, using double-labeled immunohistochemistry, we found no co-localization between neurons expressing melanin-concentrating hormone and adenosine deaminase (histaminergic marker) in the dorsal tuberomammillary nucleus. We hypothesize that these melanin-concentrating hormone projections participate in spatial memory process mediated by the medial mammillary nucleus. These pathways would enable the animal to look for food during the initial moments of appetite stimulation.