2013 |
Hommel, Jonathan Dean |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Neuromedin U as a Novel Mechanism Underlying Cocaine Addiction @ University of Texas Medical Br Galveston
DESCRIPTION (provided by applicant): Safe and effective approaches for the treatment of cocaine addiction are needed to address the tremendous burden of substance abuse disorders. An expanded mechanistic appreciation of the molecular, neural, and behavioral bases of reward is needed to identify integral pharmacotherapeutic targets for addiction. Interestingly, over 400,000 Americans are active cocaine users but are not considered cocaine dependent. These individuals have an underlying resilient neurobiology which makes them resistant to the development of addiction to cocaine. Studying this neurobiology of resilience may provide insight into the molecular, neural, and behavioral basis of addiction and lead to novel pharmacotherapeutic targets for cocaine addiction. An innovative prospect in this regard is neuromedin U (NMU), a highly conserved neuropeptide which has been shown to inhibit intake of food, a natural reward. These effects of NMU may be due to actions in the ventral tegmental area (VTA), the origin of the mesoaccumbens system. Little is known about the involvement of NMU in mesoaccumbens circuit, although recent data demonstrate that NMU administration increases neuronal activity in a terminal area of this circuit, the nucleus accumbens. Preliminary data indicates that expression is increased in the VTA in response to acute or chronic cocaine, a response which shows high levels of individual differences, with some animals in the range of controls while others are fivefold higher than controls. Also, we found that peripheral injection o NMU can block behavioral sensitization to cocaine. The goal of the present proposal is to explore NMU signaling in the VTA as a key mechanism that underlies behavioral responses to cocaine. To this end, it will be determined if changes in expression of NMU in the VTA can predict the magnitude of behavioral responses to cocaine. In addition, we seek to demonstrate a role for NMU in the behavioral effects of cocaine via use of RNAi-mediated knockdown of NMU in the VTA followed by assessment of locomotor sensitization to cocaine. Overall, linking NMU signaling in the VTA with the behavioral effects of cocaine will promote the idea that NMU signaling underlies behavioral responses to drugs of abuse, and support its potential as a novel therapeutic target to treat addiction.
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0.941 |
2016 — 2020 |
Hommel, Jonathan Dean |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Integration of Hypothalamic and Limbic Pathways to Regulate Motivation For Food @ University of Texas Medical Br Galveston
? DESCRIPTION (provided by applicant): Safe and effective approaches for the treatment of obesity are needed to address the tremendous burdens of this disease such as diabetes, cardiovascular disease, and even some cancers. Although studied as distinct pathways for decades, processes regulating eating and motivation are now thought to be driven by overlapping neural circuits. Studying this overlap may provide important insights into the basis of excess caloric intake and lead to the identification of novel pharmacological targets for treating metabolic diseases, the long-term goal of our research. A potential novel and innovative target in this regard is neuromedin U (NMU), a peptide shown to suppress food intake and cause weight loss. These effects of NMU are related to its actions at the NMU receptor 2 (NMUR2) in the hypothalamus, particularly in the paraventricular nucleus (PVN), which is enriched for NMUR2. We have previously found that selective depletion of NMUR2 in the PVN of rats potentiates the intake of a high-fat diet, increases weight gain, and enhances a dietary preference specifically for fat but not sucrose. The goals of the present project are to explore NMUR2 signaling as a key interface between the hypothalamic and mesolimbic systems, and to further evaluate the action of NMUR2 agonists on feeding behavior. Our preliminary data indicate that NMUR2 neurons in the hypothalamus are directly connected to the nucleus accumbens, a key region of the mesolimbic system that regulates reward and motivated behavior. We have, for the first time, evaluated small-molecule NMUR2 agonists in vivo. Our preliminary data indicate that these compounds suppress feeding on a high-fat diet. To accomplish our goals, our Specific Aims are 1) To evaluate the structural link between the hypothalamic and mesolimbic circuits, 2) To establish a functional link between these areas involving enkephalins and opioid signaling, and 3) To determine if NMUR2 is a target to inhibit motivation for high-fat food and regulation of metabolic physiology. These aims will be achieved using such innovative technologies as viral-vector tracers to map neural pathways in the brain, optical clearing with CLARITY visualize these pathways in clarified, intact brains, and virus-mediated RNA interference study the effects of the NMUR2 gene on food intake, body weight, and motivation for food. Overall, these studies will lay the foundation for understanding neural pathways that regulate motivation for food, and for future work developing NMUR2-based therapeutics for the treatment of obesity.
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0.941 |
2020 |
Hommel, Jonathan Dean |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hypothalamic-Striatal Control of Motivation For Obesogenic Food @ University of Texas Med Br Galveston
PROJECT ABSTRACT Obesity is an alarming chronic health crisis that currently affects 39.8% of the adult population (2015-2016) in the United States. Obese individuals present a challenging public health problem because they are at increased risk for several life-threatening and costly co-morbidities including diabetes, metabolic syndrome, cardiovascular disease, and cancer. Because the financial and health burdens of obesity are so pernicious, a more mechanistic appreciation of the feeding behavior(s) that contribute to obesity is critical to understanding the etiology of this disease and for identifying druggable targets. One feeding behavior that contributes to obesity is overconsumption of highly palatable food. Highly palatable food, including high-fat food, is an important driver of obesity and has demonstrated reinforcement value in rodents. Reinforcement is mediated in part by the nucleus accumbens shell (NAcSh), a key neuroanatomical substrate that regulates hedonic feeding. Another substrate governing food intake is the paraventricular nucleus of the hypothalamus (PVN). The PVN regulates food intake at the level of physiological energy requirements, and facilitates homeostatic feeding behavior. PVN neurons project to the NAcSh (PVN?NAcSh) and orchestrate social reward, but their role in motivation for high-fat food remains unknown. Preliminary data indicate that the neurotransmitter Glutamate (Glu) plays an integral role in PVN?NAcSh transmission. Pharmacogenetic stimulation of PVN?NAcSh neurons results in robust and sustained presynaptic Glu release in the NAcSh. Additionally, administration of Glu agonists directly to the NAcSh decrease feeding, while administration of Glu antagonists evoke an immediate and sustained increase in consumption behavior. Despite considerable evidence of Glu involvement in consumption behavior, the role of Glu in motivation for high fat food has not been explored. We propose that Glu signaling within PVN?NAcSh neurons is a critical neuromodulator of motivation for high-fat food. The objectives of this proposal are to (1) establish the neuroanatomical basis for Glu signaling in PVN?NAcSh and (2) manipulate presynaptic Glu release in PVN?NAcSh to test specific hypotheses concerning the role of Glu in the regulation of motivation for high-fat food. Completion of these objectives will provide the applicant with training in new concepts and methodologies, including the neurobiology of obesity, the design and interpretation of behavioral experiments, principles and methods of neuropharmacology, and the application of genetic technology. The outcomes of these studies will have a sustained, powerful impact on our field by identifying a key regulatory role for Glu transmission in PVN?NAcSh mediated motivation for highfat food, which will critically advance efforts to improve treatment outcomes in obesity and metabolic dysregulation.
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0.928 |