2008 — 2010 |
Carter, Matthew E |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
The Role of Hypocretins in the Regulation of Stress and Arousal
[unreadable] DESCRIPTION (provided by applicant): In response to a stressor that threatens to disrupt an organism's homeostasis, the brain activates various neuropeptide-secreting systems to attempt to maintain the health of the animal. These adjustments include changes in behavioral state, such as an increase in locomotor activity, as well as changes in physiological state, such as an increase in heart rate, blood pressure, and body temperature. If the stress response is excessive and prolonged, as frequently occurs in the busy lives of Americans, the altered behavioral and physiological states can be deleterious and harmful. An excessive stress response can weaken the immune system and increase the risk of illness, obesity, and heart attacks. The neurobiological basis of the stress response is poorly understood. The most studied stress inducing neuropeptide is corticotropin-releasing factor (CRF), which initiates a series of biological events that stimulate the stress response in mammals. Interestingly, a pair of novel neuropeptides, the Hypocretins (Herts), also causes a heightened arousal in animals. The precise role of Hcrt cells in initiating the stress response is unknown, primarily due to the difficulty in observing and manipulating this relatively small population of neurons in the inferior surface of the brain. However, specific manipulation of Hcrt cells is now possible using the novel technique of photostimulation, a method by which we can specifically excite Hcrt neurons with high temporal precision. The purpose of this proposal is to use photostimulation technology to study a causal role between Hypocretin cell activation and the stress response. Our specific hypothesis is that stimulation of Hcrt neurons induces behaviors and physiological processes associated with the response to acute stressors by stimulating the release of CRF. We will study this hypothesis in three aims: (1) To determine if stimulation of Hcrt neurons is sufficient to promote behaviors associated with acute stress; (2) To determine if stimulation of Hcrt neurons is sufficient to promote autonomic physiological processes associated with stress; (3) To determine if stimulation of Hcrt neurons alters CRF cell activity, gene expression, and peptide release. PUBLIC HEALTH RELEVANCE Research aimed at exploring the neurobiological basis of stress may lead to the development of drugs and other treatments to relieve the negative symptoms of stress disorders. Hypocretins have recently been the target of drug design, and elucidating the role of these neuropeptides in the stress response could lead to novel therapeutics for stress disorders and related illnesses, as well as identify potential side effects for drugs that target the Hcrt system for other disorders. [unreadable] [unreadable] [unreadable]
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1 |
2015 |
Carter, Matthew E |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Determination of How Orexigenic Agrp Neurons Anatomically and Functionally Interact With Anorexigenic Pbel Cgrp Neurons to Regulate Food Intake Behavior
? DESCRIPTION (provided by applicant): The motivation to eat depends on the relative balance of activity between orexigenic (appetite inducing) and anorexigenic (appetite suppressing) populations of neurons in the brain. An abnormal balance of activity in these systems can lead to substantial health problems with high associated economic costs. In the United States, over half the population is considered overweight, and the aggregate economic cost is estimated in excess of $60 billion per year. Undernourishment is also a substantial problem: abnormal appetite suppression, as can occur during infection, old age, or cancer, can lead to severely low body weight and malnutrition. However, despite obvious importance, the neural basis of hunger and appetite suppression continues to be poorly understood at a neuronal level. In recent years, two populations of neurons have emerged as key regulators of appetite and body weight. A group of neurons in the hypothalamus called AgRP neurons sense homeostatic signals from the body and increase appetite. When stimulated, AgRP neurons cause a robust increase in food intake. In contrast, a group of neurons in the parabrachial nucleus (PBN) called PBel CGRP neurons sense signals from the stomach and viscera and decrease appetite. When stimulated, PBel CGRP neurons cause a substantial decrease in food intake. The opposing roles of orexigenic AgRP neurons and anorexigenic PBel CGRP neurons raise important questions about how they interact. AgRP neurons release the inhibitory neurotransmitter GABA and project to the region where PBel CGRP neurons are located. However, it is unknown whether AgRP neurons directly inhibit PBel CGRP neurons, nor is it known whether this inhibition could overcome PBel CGRP neuron-mediated suppression of appetite. The purpose of this proposal is to determine how orexigenic AgRP neurons anatomically and functionally interact with anorexigenic PBel CGRP neurons to regulate food intake behavior. In Aim 1, we will test the hypothesis that AgRP neurons send direct, monosynaptic projections to PBel CGRP neurons. In Aim 2, we will test the hypothesis that inhibition of AgRP neurons or AgRP-to-PBN projections decreases food intake and increases activity in PBel CGRP neurons. In Aim 3, we will test the hypothesis that stimulation of AgRP neurons or AgRP-to-PBN projections inhibits PBel CGRP neurons and increases food intake during conditions when appetite is normally suppressed, such as during visceral malaise, illness, or satiety. To pursue these aims, we will use cutting edge viral gene delivery tools and genetically encoded tracers and neuromodulators in mice to provide new insights into how the brain balances orexigenic and anorexigenic information.
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1 |
2017 — 2022 |
Carter, Matthew |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Career: Bidirectional Control of Sleep and Wakefulness by the Hypothalamic Arcuate Nucleus
Despite the fact that sleep is universal across the animal kingdom and occupies a substantial portion of an animal's lifetime, the regulation of sleep and wakefulness by the brain is poorly understood. Additionally, national surveys show that sleep is poorly understood among the general public and that many Americans, particularly students, are extremely sleep deprived. Therefore, this project integrates a series of research and educational goals to impact our understanding of the brain mechanisms that control mammalian sleep. The PI will manipulate two populations of neurons (called AgRP neurons and POMC neurons) in rodent brains using powerful genetic technologies to determine their roles in regulating sleep/wake behavior. These groups of neurons are well-known for sensing the nutritional and caloric needs of the body, and so our research will study how food intake affects states of sleep and wakefulness. This work will thus increase our understanding of how the brain coordinates complex behavioral states, in this case hunger and sleep. The educational goals will broaden the impact of this project by including undergraduates in all aspects of this research and by implementing a new course at Williams College on the science of sleep. This course will produce educational materials on sleep that will be freely available and distributed. Together, the research and educational components of this award will increase the United States' competitiveness in science and technology, particularly in the field of neuroscience.
The goal of this project is to determine how neurons that regulate energy homeostasis also regulate sleep. Previous studies indicate that sleep/wake states are significantly affected by food need and availability, but the role of neurons that regulate food intake in sleep/wake behavior is unknown. The hypothalamic arcuate nucleus contains two populations of neurons that regulate food intake behavior: orexigenic agouti-related protein (AgRP)-expressing neurons and anorexigenic pro-opiomelanocortin (POMC)-expressing neurons. Preliminary evidence from our laboratory suggests that AgRP neurons can independently promote wakefulness and food intake and that POMC neurons maintain sleep states in addition to suppressing appetite. Previous data also suggest that AgRP and POMC neurons might influence sleep/wake states by projecting to hypocretin-expressing neurons and melanin-concentrating hormone-expressing neurons, respectively, in the lateral hypothalamus. This project will use cutting-edge optogenetic and chemogenetic methods in combination with electroencephalography (EEG) and behavioral analyses to increase our understanding of these systems in sleep/wake behavior and thus how the brain coordinates complex behavioral states. Undergraduate students will be involved in all aspects of this work, which will further impact the field of neuroscience through the hands-on training it will provide for the next generation of scientists and educators.
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