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Control of feeding behavior by melanin-concentrating hormone

黑色素浓缩激素控制进食行为

基本信息

批准号：
10152596
负责人：
Scott Edward Kanoski
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-23 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152596
关键词：
3-Dimensional Affect Amygdaloid structure Anatomy Anti-Obesity Agents Appetite Stimulants Behavior Behavior Therapy Behavioral Behavioral Mechanisms Biological Body Weight Brain Brain Mapping Brain region Cerebral Ventricles Cerebrospinal Fluid Chronic Communication Consumption Cues Data Detection Eating Feeding behaviors Fluorescent in Situ Hybridization Food Food Intake Regulation Health Care Costs High Fat Diet Histologic Image Immunohistochemistry Impulsivity In Situ Hybridization Injections Intake Lateral Hypothalamic Area Medial Mediating Messenger RNA Methods Mus Neural Pathways Neurobiology Neuromodulator Neurons Neuropeptides Nucleus Accumbens Obesity Output Palate Pathway interactions Peptides Pharmacology Pharmacotherapy Phenotype Population Prefrontal Cortex Prevalence Rattus Regional Blood Flow Research Resolution Rest Rewards Rodent Role Route Signal Pathway Signal Transduction Slice Structure Sucrose Synapses System Techniques Testing Transgenic Organisms United States Ventricular Viral Virus adverse outcome awake bariatric surgery base brain pathway circadian conditioned place preference diet-induced obesity experimental study feeding hormonal signals hormone deficiency increased appetite innovation insight interest melanin-concentrating hormone melanin-concentrating hormone receptor multimodality neural circuit neural network neurochemistry neuroimaging novel obesogenic overexpression receptor relating to nervous system success

项目摘要

7. Project Summary: Melanin-concentrating hormone is an neuropeptide produced primarily in the lateral hypothalamic area of the brain that potently increases appetite, food intake, and body weight 1,2. Importantly, chronic central pharmacological blockade of MCH receptors (MCH1Rs) reverses diet-induced obesity in mice 3,4 and therefore there is recent interest in developing obesity pharmacotherapies targeting the MCH system 5-8. While MCH-producing neurons extensively project throughout the brain 9 and central MCH1Rs are widely distributed 10, very little is presently known about the neuronal pathways and behavioral mechanisms mediating the potent orexigenic effects of MCH. Our preliminary data reveal that central MCH signaling in rats increases both normal chow intake as well as conditioned reward-based feeding behaviors, including impulsive responding and conditioned place preference for palatable food. We further identify two novel signaling targets through which MCH neurons promote orexigenic effects: [1] “bulk flow” signaling through the cerebral ventricles following MCH release into the cerebral spinal fluid (CSF), and [2] synaptic signaling to the nucleus accumbens shell (ACBsh), a brain substrate critically associated with learned aspects of food reward 11,12. We hypothesize that MCH CSF- and ACBsh-signaling pathways differentially regulate normal vs. reward-based feeding, respectively. This hypothesis is supported by our preliminary data showing that chemogenetic activation of ACBsh-projecting MCH neurons increases palatable food (sucrose, high fat diet) intake without affecting intake of bland chow, whereas CSF MCH injections equally increase intake of a less- and more- preferred food (chow vs. sucrose), and endogenous MCH CSF levels are elevated prior to regular nocturnal chow intake. Our hypothesis will be examined in Aim 1, where we investigate the effects of chemogenetic activation of specific MCH neuronal populations that project to either the CSF or the ACBsh on various feeding behaviors (e.g., habitual, circadian, conditioned reward-based). Conditional virus-based neural pathway tracing strategies are used in Aim 2 in order to identify the collateral projections of CSF- and MCH-projecting MCH neurons, as well as the 2nd-order targets of MCH neurons that receive input from the medial prefrontal cortex and the basolateral amygdala, two brain regions that are critically involved in reward-based feeding 13. In conjunction with retrograde neural pathway tracing, neurochemical phenotyping of these populations of MCH neurons will be done using fluorescence in situ hybridization and immunohistochemistry techniques. Finally, Aim 3 utilizes a [14C]-iodoantipyrine-based autoradiographic brain mapping method to identify functional downstream neural systems through which MCH neurons elevate feeding. Results will reveal brain networks engaged by chemogenetic activation of ACBsh-projecting MCH neurons at resting state, during intake of palatable sucrose, and during presentation of a sucrose-conditioned cue. Neural networks engaged by activating CSF-projecting MCH neurons will also be identified, at resting state and during chow consumption. Overall, results from this proposal will identify the neurobiological pathways and behavioral mechanisms whereby MCH engages normal and reward-based feeding, thus contributing critical insight into feeding behavior, and advancing toward strategies to reverse excessive feeding.

7. 项目概述：黑色素浓缩激素是一种主要在外侧产生的神经肽