AgRP neurons: circadian control and interactions with the HPA axis AgRP neurons play a key role driving feeding. They are activated by feedback signals reporting low energy stores, and their activation promotes the seeking and eating of food. Remarkably, they are also regulated by feedforward cues that anticipate future needs and outcomes. The central role of AgRP neurons is further highlighted by their ability to cause many of the adaptive physiologic responses to fasting. Given the primacy of AgRP neurons, it is important that we understand how they are regulated, what processes they control, and how they bring about such control. With this in mind, this grant pursues the following two Aims:
Aim 1 : To study SCN / circadian feedforward activation of AgRP neurons and feeding. In this Aim, we extend the concept of feedforward anticipatory regulation by determining if the SCN engages AgRP neurons to proactively schedule daily feeding and prevent future energy deficits. While it is known that feeding is under circadian control, and that this is important because mis-timed feeding causes disease, it is entirely unknown how the circadian system does this. To investigate SCN control of AgRP neurons, we have developed the unique ability to continuously monitor AgRP neuron activity in vivo over many days, while simultaneously monitoring rhythms in feeding, body temperature (Tb), locomotor activity (LMA), and in other neurons. Using this approach, we have found that: i) AgRP neuron activity oscillates with a 24 hr cycle (peaking later in the day, falling later in the night) in both light/dark and constant darkness conditions, ii) that peaks and troughs in AgRP neuron activity are in-phase with SCN neurons, and iii) that with ?jet lag? (6 hr advancement of the light cycle), the AgRP neuron rhythm re-entrains gradually over 8 days in parallel with rhythms in feeding, Tb and LMA. Based on this and optogenetic stimulation studies, we propose that the SCN, by inhibiting an intervening GABAergic neuron, activates (disinhibits) AgRP neurons, and that this causes circadian control of feeding.
Aim 2 : To investigate reciprocal interactions between AgRP neurons and the HPA axis. In this Aim, we examine reciprocal interactions between AgRP neurons and the HPA axis. First, we follow up on our discovery that corticosterone directly activates AgRP neurons by establishing the electrophysiologic, transcriptional and epigenomic mechanism for this activation. Also, we determine if activation of AgRP neurons by corticosterone causes the metabolic consequences of Cushing?s syndrome and chronic stress. Second, we extend the role of AgRP neurons in causing brain-based adaptations to fasting by establishing their role in driving the HPA axis. We have discovered that AgRP neurons potently activate PVHCrh neurons and the HPA axis, and we propose that they do this by inhibiting GABAergic ?gateway? neurons that connect AgRP neurons to PVH-Crh neurons. Finally, linking Aims 1 and 2, we simultaneously assess rhythms in AgRP and PVH-Crh neurons, and investigate if SCN regulation of AgRP neurons drives circadian control of the HPA axis, or vice versa.

Public Health Relevance

This proposal, centered on AgRP hunger neurons, investigates circadian control of AgRP neurons and hunger (Aim 1), reciprocal interactions between AgRP neurons and the hypothalamic-pituitary-adrenal glucocorticoid (HPA) axis (Aim 2), and finally regulatory links between circadian control of AgRP neurons and the HPA axis. These studies will determine the mechanism by which eating is prompted to occur at the optimal time of day, how the stress hormone, corticosterone, activates AgRP neurons and if this is responsible for metabolic disease associated with Cushing?s syndrome and chronic stress, and finally how fasting causes adaptive activation of the HPA axis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK096010-09A1
Application #
10116601
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Cooke, Brad
Project Start
2012-07-01
Project End
2025-07-31
Budget Start
2020-09-13
Budget End
2021-07-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Todd, William D; Fenselau, Henning; Wang, Joshua L et al. (2018) A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 21:717-724
Ross, Rachel A; Leon, Silvia; Madara, Joseph C et al. (2018) PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse. Elife 7:
Mandelblat-Cerf, Yael; Kim, Angela; Burgess, Christian R et al. (2017) Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons. Neuron 93:57-65
Fenselau, Henning; Campbell, John N; Verstegen, Anne M J et al. (2017) A rapidly acting glutamatergic ARC?PVH satiety circuit postsynaptically regulated by ?-MSH. Nat Neurosci 20:42-51
Cheng, Longzhen; Duan, Bo; Huang, Tianwen et al. (2017) Identification of spinal circuits involved in touch-evoked dynamic mechanical pain. Nat Neurosci 20:804-814
Campbell, John N; Macosko, Evan Z; Fenselau, Henning et al. (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484-496
Resch, Jon M; Fenselau, Henning; Madara, Joseph C et al. (2017) Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling. Neuron 96:190-206.e7
Andermann, Mark L; Lowell, Bradford B (2017) Toward a Wiring Diagram Understanding of Appetite Control. Neuron 95:757-778
Livneh, Yoav; Ramesh, Rohan N; Burgess, Christian R et al. (2017) Homeostatic circuits selectively gate food cue responses in insular cortex. Nature 546:611-616
Kong, Dong; Dagon, Yossi; Campbell, John N et al. (2016) A Postsynaptic AMPK?p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons. Neuron 91:25-33

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