Activation of the rat hypothalamic supramammillary nucleus by food anticipation, food restriction or ghrelin administration

Abstract

The circulating orexigenic hormone ghrelin targets many brain areas involved in feeding control and signals via a dedicated receptor, the growth hormone secretagogue receptor 1A. One unexplored target area for ghrelin is the supramammillary nucleus (SuM), a hypothalamic area involved in motivation and reinforcement and also recently linked to metabolic control. Given that ghrelin binds to the SuM, we explored whether SuM cells respond to ghrelin and/or are activated when endogenous ghrelin levels are elevated. We found that peripheral ghrelin injection activates SuM cells in rats, reflected by an increase in the number of cells expressing c‐Fos protein in this area, as welll as by the predominantly excitatory response of single SuM cells recorded in in vivo electrophysiological studies. Further c‐Fos mapping studies reveal that this area is also activated in rats in situations when circulating ghrelin levels are known to be elevated: in food‐restricted rats anticipating the consumption of food and in fed rats anticipating the consumption of an energy‐dense food. We also show that intra‐SuM injection of ghrelin induces a feeding response in rats suggesting that, if peripheral ghrelin is able to access the SuM, it may have direct effects on this brain region. Collectively, our data demonstrate that the SuM is activated when peripheral ghrelin levels are high, further supporting the emerging role for this brain area in metabolic and feeding control.

Neural connectivity between the hypothalamic supramammillary nucleus and appetite‐ and motivation‐related regions of the rat brain

“…We show that ORX/MCH/TH‐negative DMH neurones innervate the SuMM, and also show the existence of a potentially dopaminergic SuM output to the DMH. Taken together, these data support the concept that the SuM is part of the brain's appetite control and/or motivational system and open avenues to further work characterising the functional circuitry involved in these behaviours.…”

“…In our earlier electrophysiological study of the SuM, we did not determine the neuroanatomical connectivity of the cells we recorded in vivo. Approximately 40% of the cells we recorded were juxtacellularly labelled with neurobiotin but none of these neurobiotin‐labelled cells proved to be TH‐positive.…”

“…However, recent findings provide evidence indicating that the SuM may be involved in metabolic control. We previously showed that the activity of SuM neurones is sensitive to ghrelin administration or to physiological states where ghrelin levels are elevated, and that intra‐SuM ghrelin administration promotes feeding . This novel role for the SuM in ghrelin‐associated feeding behaviours raises the question of whether the SuM is a node in the networks involved in motivation and appetite.…”

“…Ghrelin is orexigenic when administered into the brain, and increases in ghrelin levels are also associated with anticipation of palatable schedule‐fed food in rats . We have previously shown that rat SuM neurones are sensitive to this hormone . Similarly, GLP‐1 levels increase in the rat before food access in a model of scheduled feeding of a standard diet, and motivation‐related brain nuclei are sensitive to analogues of this hormone when administered centrally …”

“…In the present study, we set out to examine the connectivity of the hypothalamic supramammillary nucleus (SuM), a region with an emerging role in metabolic control. We have previously shown that SuM Fos expression is increased with fasting and food anticipation, that peripheral administration of the orexigenic hormone ghrelin increases SuM Fos expression and also evokes an excitatory response in single SuM cells recorded electrophysiologically in vivo, and that intra‐SuM ghrelin injection induces feeding in rats . In addition, an anorexigenic glucagon‐like peptide 1 (GLP‐1)‐oestrogen conjugate molecule or a GLP‐1 receptor agonist have been shown to act at the SuM to reduce body weight and motivation for food reward.…”