Dendritic Spines on AgRP Neurons as Communication Hubs Controlling Feeding

Summary

Principal Investigator: Dong Kong
Abstract: DESCRIPTION (provided by applicant): Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus are critical regulators of energy balance. AgRP neurons are anabolic: optogenetic or pharmaco-genetic stimulation of AgRP neurons drives intense feeding behavior and promotes obesity;disruption of these neurons in adult mice causes severe anorexia. Given the important roles played by AgRP neurons, there is great interest in understanding the factors that regulate their activity. Most previous studies have been placed on examining their direct regulation by circulating factors, such as leptin, insulin, and ghrelin. Their synaptic regulation by neurotransmitters released from other neurons in the brain, however, has been greatly overlooked. This is unfortunate because defective synaptic transmission on these neurons could also contribute to eating disorders. Furthermore, it is likely that the mechanism-of-action for hormonal regulation of AgRP neurons, for example by ghrelin, is modulation of afferent synaptic transmission. Through the recent work at Dr. Brad Lowell group (Prof of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School), the candidate has found that glutamatergic synaptic transmission plays a key role in AgRP neurons. In particular, he discovered that AgRP neurons but not the adjacent POMC neurons have dendritic spines, 1um3 protrusions where majority of glutamatergic synapses reside and within which glutamate NMDA receptors operate to control synaptic plasticity. In addition, he found that the fasting- induced activation of AgRP neurons and its related feeding behavior are paralleled (and likely caused) by a marked increase in the number of spines (i.e. spinogenesis), and this is dependent on postsynaptic NMDARs. Thus, glutamatergic transmission and its plasticity, as modulated by postsynaptic NMDARs, play critical roles in controlling AgRP neuron activity and their related feeding behaviors. These findings, which are recently published on Neuron, provide the candidate a unique opportunity to interrogate synaptic regulations in the feeding circuits. However, to pursue such studies, some state-of-art technologies (such as electrophysiology combined with 2-photon microscope imaging), which are beyond the scope of Dr. Lowell's lab and not available at BIDMC, are required. Toward these ends, the candidate is now trained by Dr. Bernardo Sabatini (Prof of Neurobiology, HHMI, Dept. of Neurobiology, Harvard Medical School), to use such advanced technologies to study structural and functional properties of spines. In this K01 mentored career development award, under the mentorship of Dr. Sabatini, and co- mentorship of Dr. Lowell, the candidate proposes to obtain acquisition in both scientific knowledge and in technologies (electrophysiology combined with 2-photon microscope imaging) related to synapse studies, and develop other necessary skills toward his career independence (immediate goal). The candidate is now Instructor in Medicine at BIDMC and Harvard Medical School. Once he finishes training with Dr. Sabatini, he will be transitioned to Assistant Professor at BIDMC and establish his own laboratory, become an independent investigator in the area of nutrition, obesity and neuroscience research, and apply multi- disciplinary methodology to understand synaptic plasticity in hypothalamic neurons controlling feeding, energy expenditure, and fuel metabolisms (long-term goal). Therefore, the K01 award will provide the candidate protected time to obtain necessary training before he becomes independent. At the same time, the proposed project in this award will greatly help the candidate to obtain subsequent R01 grant support.
Funding Period: 2013-07-15 - 2013-12-31
more information: NIH RePORT

Research Grants

  1. AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
    Bradford B Lowell; Fiscal Year: 2013
  2. TULANE NATIONAL PRIMATE RESEARCH CENTER
    L Lee Hamm; Fiscal Year: 2013
  3. Appetite-regulating Hormones and Neurocircuitry in Anorexia Nervosa
    ELIZABETH AUSTEN LAWSON; Fiscal Year: 2013
  4. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  5. The VMH and Molecular Control of Energy Balance
    Bradford B Lowell; Fiscal Year: 2013
  6. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  7. Sex Differences in the Cannabioid Regulation of Energy Homeostasis
    Edward J Wagner; Fiscal Year: 2013
  8. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
  9. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  10. Neurobiology of Anorexia and Bulimia Nervosa
    Walter H Kaye; Fiscal Year: 2013

Detail Information

Research Grants30

  1. AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
    Bradford B Lowell; Fiscal Year: 2013
    ....
  2. TULANE NATIONAL PRIMATE RESEARCH CENTER
    L Lee Hamm; Fiscal Year: 2013
    ..abstract_text> ..
  3. Appetite-regulating Hormones and Neurocircuitry in Anorexia Nervosa
    ELIZABETH AUSTEN LAWSON; Fiscal Year: 2013
    ..Lawson's training in clinical research, with the ultimate goal of becoming an independent investigator with an expertise in combining neuroendocrinology and neuroimaging technology to better understand pathophysiology of disease. ..
  4. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  5. The VMH and Molecular Control of Energy Balance
    Bradford B Lowell; Fiscal Year: 2013
    ....
  6. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  7. Sex Differences in the Cannabioid Regulation of Energy Homeostasis
    Edward J Wagner; Fiscal Year: 2013
    ....
  8. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  9. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  10. Neurobiology of Anorexia and Bulimia Nervosa
    Walter H Kaye; Fiscal Year: 2013
    ..Understanding biologic vulnerabilities in AN and BN is critical for developing effective treatment interventions for these often chronic and deadly disorders. This if the first resubmission of competing renewal MH042984 ..
  11. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  12. Regulation of Energy Homeostasis by BDNF
    Baoji Xu; Fiscal Year: 2013
    ..Findings from this proposed project would provide insights into the mechanism by which BDNF regulates energy balance as well as the role of structural changes in hypothalamic neural circuits in the development of obesity. ..
  13. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013
    ..This goal is also a function of the Biomedical Research Cores. ..