GLP-1 modulates the supramammillary nucleus-lateral hypothalamic neurocircuit to control ingestive and motivated behavior in a sex divergent manner

Abstract

ObjectiveThe supramammillary nucleus (SuM) is nestled between the lateral hypothalamus (LH) and the ventral tegmental area (VTA). This neuroanatomical position is consistent with a potential role of this nucleus to regulate ingestive and motivated behavior. Here neuroanatomical, molecular, and behavior approaches are utilized to determine whether SuM contributes to ingestive and food-motivated behavior control.MethodsThrough the application of anterograde and retrograde neural tract tracing with novel designer viral vectors, the current findings show that SuM neurons densely innervate the LH in a sex dimorphic fashion. Glucagon-like peptide-1 (GLP-1) is a clinically targeted neuro-intestinal hormone with a well-established role in regulating energy balance and reward behaviors. Here we determine that GLP-1 receptors (GLP-1R) are expressed throughout the SuM of both sexes, and also directly on SuM LH-projecting neurons and investigate the role of SuM GLP-1R in the regulation of ingestive and motivated behavior in male and female rats.ResultsSuM microinjections of the GLP-1 analogue, exendin-4, reduced ad libitum intake of chow, fat, or sugar solution in both male and female rats, while food-motivated behaviors, measured using the sucrose motivated operant conditioning test, was only reduced in male rats. These data contrasted with the results obtained from a neighboring structure well known for its role in motivation and reward, the VTA, where females displayed a more potent response to GLP-1R activation by exendin-4. In order to determine the physiological role of SuM GLP-1R signaling regulation of energy balance, we utilized an adeno-associated viral vector to site-specifically deliver shRNA for the GLP-1R to the SuM. Surprisingly, and in contrast to previous results for the two SuM neighboring sites, LH and VTA, SuM GLP-1R knockdown increased food seeking and adiposity in obese male rats without altering food intake, body weight or food motivation in lean or obese, female or male rats.ConclusionTaken together, these results indicate that SuM potently contributes to ingestive and motivated behavior control; an effect contingent on sex, diet/homeostatic energy balance state and behavior of interest. These data also extend the map of brain sites directly responsive to GLP-1 agonists, and highlight key differences in the role that GLP-1R play in interconnected and neighboring nuclei.

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.…”

“…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 …”

“…1 Similarly,GLP-1levelsincrease in the rat before food access in a model of scheduled feeding ofastandarddiet, 26 andmotivation-relatedbrainnucleiaresensitive to analogues of this hormone when administered centrally. 3 Weusedretrogradeandanterogradetracers,andCre-dependent viral-assisted mapping, to trace the afferent and efferent connec-tionsofSuMMneurones.Weidentifieddirectconnectionsbetween theSuMMandtheLHA,DMHandVTA;areaswhereFosexpression correlatedwiththatseenintheSuM.Theconnectionbetweenthe…”

“…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. Pharmacological studies have demonstrated that the SuM mediates reinforcement, revealing a potential role for the SuM in motivated behaviours.…”

Can GLP-1 Be a Target for Reward System Related Disorders? A Qualitative Synthesis and Systematic Review Analysis of Studies on Palatable Food, Drugs of Abuse, and Alcohol

“…Expression of supramammillary nucleus (SuM) GLP-1R is comparable with the expression in the LH and NAc, but lower than that found in the NTS (López-Ferreras et al, 2019 ). Activation of GLP-1R by infusion of Ex-4 (0.01 and 0.03 μg) into the SuM or AAV virus in male or female rats was found to be potently anorexigenic.…”