Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons

Abstract

Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus and nucleus tractus solitarius (NTS) of the brainstem play important roles in suppressing food intake and maintaining energy homeostasis. Previous tract-tracing studies have revealed the axonal connection patterns of these two brain areas, but the intermingling of POMC neurons with other neuron types has made it challenging to precisely identify the inputs and outputs of POMC neurons. In this study, we used the modified rabies virus to map the brain areas that provide direct inputs to the POMC neurons in the ARC and NTS as well as the inputs to the ARC AgRP neurons for comparison. ARC POMC neurons receive inputs from dozens of discrete structures throughout the forebrain and brainstem. The brain areas containing the presynaptic partners of ARC POMC neurons largely overlap with those of ARC AgRP neurons, although POMC neurons receive relatively broader, denser inputs. Furthermore, POMC neurons in the NTS receive direct inputs predominantly from the brainstem and show very different innervation patterns for POMC neurons in the ARC. By selectively expressing fluorescent markers in the ARC and NTS POMC neurons, we found that almost all of their major presynaptic partners are innervated by POMC neurons in the two areas, suggesting that there are strong reciprocal projections among the major POMC neural pathways. By comprehensively chartering the whole-brain connections of the central melanocortin system in a cell-type-specific manner, this study lays the foundation for dissecting the roles and underlying circuit mechanisms of specific neural pathways in regulating energy homeostasis.

Tryptophan overloading activates brain regions involved with cognition, mood and anxiety

“…For instance, apart from its important role in stress regulation (Fekete and Lechan 2014), the Pa is also part of a neuronal circuitry that regulates food intake. The best-characterized neurochemical pathways related to energy consumption and food intake are the orexigenic neuropeptide Y/ Agouti-related protein and the anorexigenic proopiomelanocortin/cocaine-and amphetaminerelated transcript neurons in the Arc (Wang et al 2015), which also showed increases in Fos-ir in the present study. These neurons project from the Arc to other key hypothalamic nuclei, such as the Pa and the VMH (Kotagale et al 2014).…”

Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures

“…This fact clearly needs to be considered in our analysis. However, a recent elegant study, employing a dual viral vector tracing strategy, reported that POMC neurons in the Arc and Sol give rise to a very different set of axonal projections (Wang et al, 2015). Thus, axons from Sol POMC neurons were found to be mainly distributed in the caudal brainstem, although some Sol axons were additionally observed in rostral brain areas, including the hypothalamus (Wang et al, 2015).…”

“…However, a recent elegant study, employing a dual viral vector tracing strategy, reported that POMC neurons in the Arc and Sol give rise to a very different set of axonal projections (Wang et al, 2015). Thus, axons from Sol POMC neurons were found to be mainly distributed in the caudal brainstem, although some Sol axons were additionally observed in rostral brain areas, including the hypothalamus (Wang et al, 2015). On the other hand, in line with the present findings, the heaviest projections of Arc POMC neurons were found in the hypothalamus with a minor contingent innervating the mid-and hindbrain (Wang et al, 2015).…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…There are several subtypes of the melanocortin peptides, such as adrenocorticotrophin (ACTH) and alpha-melanocyte-stimulating hormone (α-MSH), which act at G-protein-coupled melanocortin receptors such as the MC 1-5 receptors [118,138,139]. In the brain, POMC is mainly expressed in the Arc [138,140], and projects to various regions of the hypothalamus [118,141]. Certain POMC gene mutations may contribute to obesity in healthy human populations [142,143], while mouse knockout for POMC also shows the obese phenotype [138,144].…”