Research Projects

Created by Dr. Kit-Yi Yam and Dr. Jose Maldonado

Circuits that control body weight develop under the influence of the adipocyte-derived hormone leptin during discrete temporal domains, suggesting that there are region-specific, hormonally directed mechanisms governing the assembly of homeostatic circuits. Moreover, leptin appears to exert these actions through direct cell autonomous neurotrophic influences on hypothalamic neurons that include promoting neurite extension, specifying patterns of axonal targeting, and influencing cell type specific alterations in synaptic density. Thus, leptin is a major developmental factor that may mediate metabolic programming of the hypothalamus by a variety of environmental factors, including nutrition, with direct implications for the developmental origins of obesity and diabetes. 

By using axonal labeling methods and organotypic explant cultures we provided the first evidence that leptin can direct formation of the very hypothalamic pathways it acts on later in life. Moreover, it does so by acting during a restricted neonatal critical period in much the same way that sex steroid hormones direct development of forebrain pathways involved in reproduction. Subsequent work established the relative importance of intracellular signaling pathways and demonstrated that in addition to promoting axon elongation, leptin influences targeting of ARH axons to functionally distinct populations of postsynaptic neurons, as well as postsynaptic transmission of viscerosensory information from the brainstem. Moreover, treatment of leptin deficient mice with exogenous leptin only during the postnatal critical period is sufficient to rescue food intake and various measures of autonomic function, as well as improve leptin sensitivity in adulthood. Recent work has defined the limits of the developmental critical period and suggests that maternal and neonatal nutrition alters patterns of hypothalamic circuitry, as well as the strength of pathways that convey viscerosensory information to the hypothalamus.

Created by Dr. Kit-Yi Yam and Dr. Jessica Biddinger

Perinatal exposure to maternal high fat diet (MHFD) causes significant changes in both levels and timing of postnatal leptin secretion in the offspring with adverse consequences for regulation of energy homeostasis. Restricting MHFD to the lactational period (MHFD-L) corresponds to the early postnatal leptin surge and is known to impair both metabolic physiology and hypothalamic circuitry (Vogt et al, 2014). Visceral sensory information is relayed to the hypothalamus by the nucleus of the solitary tract (NTS), which contains a population of preproglucagon (PPG) neurons that innervate the paraventricular nucleus of the hypothalamus (PVH), a region that integrates varied metabolic signals regulating energy balance. Glucagon-like peptide-1 (GLP-1) is expressed in these inputs to the PVH and signals through its receptor (GLP-1R). GLP-1R expressing PVH neurons, have been shown previously to respond to caloric state and acute feeding behavior suggesting that they play an important role in mediating satiety (Li et al., 2018). However, it remains unknown if MHFD-L impacts neuronal targeting of PPG neurons to the PVH, or if GLP-1 neuronal signaling is altered in the offspring. Recent experiments revealed that exposure to MHFD-L causes an increase in postnatal leptin levels and a permanent reduction in the density of GLP-1 inputs to the PVH. In addition, activation in PVH neurons following vagal activation by either i.p. injection of cholecystokinin (CCK) or stomach stretch induced by oral gavage was reduced in offspring derived from MHFD-L litters. 

Videos Created by Dr. Michelle Bedenbaugh

Our laboratory has a longstanding interest in forebrain circuits that control reproduction. Neural and hormonal systems conveying metabolic status communicate closely with reproductive circuitry to assure that adequate energy is available for the energetically demanding process of reproduction. Further, metabolic disorders associated with decreased body weight, such as anorexia nervosa, are associated with an increased likelihood of reproductive disorders and infertility. Likewise, reproductive state communicates with energy homeostasis circuits, driving the increase in food intake and adipose stores during pregnancy.

Melanocortin 3 receptor (MC3R) is an understudied member of the melanocortin receptor family, and through our longstanding collaboration with Roger Cone’s lab (at University of Michigan) we are evaluating the organization of circuits that express MC3R. Early results indicate that MC3R is ideally positioned, both anatomically and functionally, to mediate direct communication between reproductive and metabolic circuits. However, the cellular identity of MC3R-expressing neurons has not been determined in males and females, nor has the detailed organization of their central circuits been defined. 

We have begun to neurochemically map MC3R expression using RNAScope, immunohistochemistry, axonal labeling, tissue clearing and lightsheet microscopy. Using MC3R-GFP mice, we have found that MC3R is expressed in brain regions known to play a role in controlling reproductive and metabolic state, including the anteroventral periventricular nucleus (AVPV), arcuate nucleus (ARH), paraventricular nucleus of the thalamus (PVT), ventral tegmental area (VTA), and discrete regions of the caudal brainstem. Moreover, distributions of MC3R in several regions display striking sexual dimorphism. The projections of MC3R neurons, visualized through genetically targeted axonal labels, extend to a surprising variety of functional neuronal systems that include circuits known to control body weight, gonadotropin secretion, motivated behavior and reward. By using a variety of viral labeling strategies we are gaining new insight into the organization of neural circuits expressing MC3R in order to clarify how their regulation by MC3R signaling participates in altering a diverse set of homeostatic responses.