Neural circuitry at the intersection of feeding, reproduction, and emotion

Body weight is delicately controlled by circuitry in the brain that regulate food intake and energy expenditure. These circuits communicate closely with circuitry regulating reproduction and emotion (Figure 1) in a concerted effort to prioritize behavioral responses towards constantly changing internal and external needs. Impaired communication between metabolic circuitry and circuitry regulating reproduction and emotion is at the heart of multiple metabolic, reproduction, and psychiatric disorders, such as obesity, gestational diabetes, and anorexia nervosa. Thus to develop more effective pharmacological strategies for metabolic and reproductive disorders, it is critical to understand the basic neural circuitry linking energy state to circuitry regulating emotional and reproductive behaviors.

To study the neural circuitry linking energy homeostasis with emotion and reproduction we focus on the central melanocortin system, a well conserved circuitry in the brain with a critical role in controlling body weight and feeding behavior. The central melanocortin system is composed of "first-order" AgRP and POMC neurons located in the hypothalamic arcuate nucleus. These neurons detect short term post-meal satiety signals (PYY, CCK, etc.) and long-term hormonal signals of stored energy (i.e leptin and ghrelin), and communicate this information to a remarkably diverse group of downstream brain structures. Many of these downstream brain regions express the central melanocortin receptors, MC3R and MC4R, which directly respond to inputs from AgRP and POMC neurons. Current studies in the lab are focused on determining the function of these downstream MC3R and MC4R containing neurons in brain regions controlling motivation and emotion.

Publications

1. Lam BYH, Williamson A, Finer S, Day F, Tadross JA, Goncalves Soares A, Wade K, Sweeney P, Bedenbaugh MN, Porter DT, Melvin A, Ellacott KLJ, Lippert RN, Buller S, Rosmaninho-Salgado J, Dowsett GKC, Ridley KE, Xu Z, Cimino I, Rimmington D, Rainbow K, Duckett K, Holmqvist S, Khan A, Dai X, Bochukova EG, Genes & Health Research Team, Trembath RC, Matin HC, Coll AP, Rowitch DH, Wareham NJ, van Heel DA, Timpson N, Simerly RB, Ong KK, Cone RD, Langenberg C, Perry JRB, Yeo GS, O’Rahilly S. The melanocortin 3 receptor links nutritional state to growth, body composition and the onset of puberty. Nature.

2. Sweeney P, Bedenbaugh M, Maldonado J, Pan P, Fowler K, Williams SY, Gimenez LE, Ghamari-Langroudi M, Downing G, Gui Y, Hadley CK, Joy S, Mapp A, Simerly R.B, Cone R.D. (2021). The melanocortin 3 receptor is a pharmacological target for the regulation of anorexia. Science Translational Medicine.

3. Sweeney P, Chen C, Rajapakse I, Cone R.D. (2021). Network dynamics of hypothalamic feeding neurons. Proc. Natl. Acad. Sci. USA. 118(14).

4. Zhang J, Chen D, Sweeney P, Yang Y. (2020) An excitatory hypothalamus to paraventricular thalamus (PVT) circuit that suppresses food intake. Nature Communications. 11,6326.

5. Ghamari-Langroudi M, Cakir I, Lippert RN, Sweeney P, Litt MJ, Ellacott KLJ, Cone RD. (2018) Regulation of energy rheostasis by the melanocortin-3 receptor. Science Advances. Aug;4(8).

6. Sweeney P., Li. C, Yang. Y (2017). Appetite suppressive role of medial septal area glutamatergic neurons. Proc. Natl. Acad. Sci. USA. 114(52):13816-13821 (Featured in Nature)

7. Sweeney P., O’Hara. K, Xu. Z, and Yang. Y (2017). HFD-induced energy states-dependent bidirectional control of anxiety levels in mice. Int J Obes (Nature press; London). 41(8):1237-1245.

8. Sweeney P. & Yang. Y (2017). Neural circuit mechanisms underlying emotional regulation of homeostatic feeding. Trends in Endocrinology & Metabolism. 6(28), 437-448.

9. Sweeney P, Qi. Y, Xu Z, and Yang. Y (2016). Activation of hypothalamic astrocytes suppresses feeding without altering emotional states. Glia. 64 (12), 2263-2273.

10. Sweeney P and Yang. Y (2016). An inhibitory septum to lateral hypothalamus circuit that suppresses feeding. Journal of Neuroscience. 36 (44): 11185-11195. (Featured article)

11. Sweeney P, Levack. R, Watters. J, Xu. Z, and Yang. Y (2016). Caffeine increases food intake while reducing anxiety-related behaviors. Appetite 101, 171-177.

12. Sweeney P, and Yang. Y (2015). An excitatory ventral hippocampus to lateral septum circuit that suppresses feeding. Nature Communications. 6: 10188. (Featured by Faculty of 1000)

13. Saul. ML, Tylee D, Becoats KT, Guerrero BG, Sweeney P, Helmreich DL, Fudge JL (2012). Long-term behavioral consequences of stress exposure in adolescent versus young adult rats. Behav Brain Res. 229, 226-34.