An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger

Krashes, Michael J.; Shah, Bhavik P.; Madara, Joseph C.; Olson, David P.; Strochlic, David E.; Garfield, Alastair S.; Vong, Linh; Pei, Hongjuan; Watabe-Uchida, Mitsuko; Uchida, Naoshige; Liberles, Stephen D.; Lowell, Bradford B.

doi:10.1038/nature12956

Cited by 540 publications

(540 citation statements)

References 33 publications

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“…Activation of DRN in behavioral responses DJ Urban et al hM3Dq-positive DRN neurons (t(4) = 12.06, p = 0.0003, Figure 2b and c) but not in EGFP-expressing neurons (t(4) = 1.182, p = 0.3028)-in agreement with many previous studies (Alexander et al, 2009;Krashes et al, 2011Krashes et al, , 2014Garfield et al, 2015). Importantly, hM3Dq-expressing neurons had similar RMPs compared with EGFP-expressing control neurons (Figure 2d).…”

Section: Acute Activation Of Drn Serotonergic Neurons Induces Anxiogesupporting

confidence: 90%

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Urban

Zhu

Marcinkiewcz

et al. 2015

Neuropsychopharmacol

126

100

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Elucidating how the brain's serotonergic network mediates diverse behavioral actions over both relatively short (minutes-hours) and long period of time (days-weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility, and spatio-temporal control. Recently, we have demonstrated that our chemogenetic approach (eg, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) provides a reliable and robust tool for controlling genetically defined neural populations. Here we show how short-and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short-and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network activity via a recently developed non-invasive imaging technology DREAMM (DREADD Associated Metabolic Mapping). Our findings reveal a previously unappreciated brain network elicited by selective activation of DRN serotonin neurons and illuminate potential therapeutic and adverse effects of drugs targeting DRN neurons.

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Section: Acute Activation Of Drn Serotonergic Neurons Induces Anxiogesupporting

confidence: 90%

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Urban

Zhu

Marcinkiewcz

et al. 2015

Neuropsychopharmacol

126

100

View full text Add to dashboard Cite

show abstract

“…Similarly, when PACAP was administered centrally in the posterior region of the stria terminalis bed nucleus, weight loss was observed for 24 h postinjection in a dose-dependent manner (24). Recently, PACAP and thyrotropin-releasing hormone (TRH) were shown to be crucial in the ARC to the excitatory drive of the agoutirelated peptide-expressing neurons that control hunger (27). In the GI tract, PACAP and its PAC1 receptor have been shown to play major physiological effects in the GI tract.…”

Section: Discussionmentioning

confidence: 99%

PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin

Goyal

Luong

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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PM. PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin. Am J Physiol Gastrointest Liver Physiol 309: G816 -G825, 2015. First published September 3, 2015 doi:10.1152/ajpgi.00190.2015.-Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1Ϫ/Ϫ) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP 1-38 or PACAP 1-27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP 1-38 administration in fasted WT mice. PACAP 1-38/PACAP1-27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP 1-38 injected into PAC1Ϫ/Ϫ mice failed to significantly change food intake. Importantly, PACAP1-38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1Ϫ/Ϫ mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP 1-38/PACAP1-27 significantly reduced appetite and food intake through PAC1. In PAC1Ϫ/Ϫ mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.pituitary adenylate cyclase-activating peptide; PAC1 receptor; appetite; ghrelin; GLP-1; leptin PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) was originally isolated from the ovine hypothalamus and is highly conserved among vertebrates (1). PACAP, because of its protein structure, particularly in the first 27 amino acids, belongs to the secretin-glucagon superfamily of hormones, which includes vasoactive intestinal peptide (VIP), gastric inhibitory peptide, glucagon-like peptide (GLP)-1 and GLP-2, growth hormone-releasing hormone, peptide histidine methionine, peptide histidine isoleucine, and exendins (34). PACAP exists in two variant forms: PACAP 1-27 and the COOHterminally extended form PACAP 1-38 that originates from the same precursor and stimulates adenylate cyclase activity in pituitary cells (23,35). PACAP functions through its P...

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“…The next step was to identify which neurons triggered the AgRP neurons. By using a rabies virus expressing a reporter gene that makes active upstream neurons glow green, Lowell traced the AgRP neural circuit back to the hypothalamic paraventricular nucleus 6 -the region associated with satiety that Lowell had cut decades earlier.…”

Section: Circuits and Switchesmentioning

confidence: 99%

Neuroscience: Dissecting appetite

Trivedi¹

2014

Nature

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An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger

Cited by 540 publications

References 33 publications

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin

Neuroscience: Dissecting appetite

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