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Proopiomelanocortin Neurons in Nucleus Tractus Solitarius Are Activated by Visceral Afferents: Regulation by Cholecystokinin and Opioids

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Proopiomelanocortin Neurons in Nucleus Tractus Solitarius Are Activated by Visceral Afferents: Regulation by Cholecystokinin and Opioids 3578 • The Journal of Neuroscience, April 6, 2005 • 25(14):3578–3585 Behavioral/Systems/Cognitive Proopiomelanocortin Neurons in Nucleus Tractus Solitarius Are Activated by Visceral Afferents: Regulation by Cholecystokinin and Opioids Suzanne M. Appleyard,1,2 Timothy W. Bailey,1 Mark W. Doyle,1 Young-Ho Jin,1 James L. Smart,2 Malcolm J. Low,2,3,4 and Michael C. Andresen1 1Department of Physiology and Pharmacology, 2Vollum Institute, 3Department of Behavioral Neuroscience, and 4Center for the Study of Weight Regulation and Associated Disorders, Oregon Health and Science University, Portland, Oregon 97239-3098 Thenucleustractussolitarius(NTS)receivesdenseterminationsfromcranialvisceralafferents,includingthosefromthegastrointestinal (GI) system. Although the NTS integrates peripheral satiety signals and relays this signal to central feeding centers, little is known about which NTS neurons are involved or what mechanisms are responsible. Proopiomelanocortin (POMC) neurons are good candidates for GI integration, because disruption of the POMC gene leads to severe obesity and hyperphagia. Here, we used POMC–enhanced green fluorescent protein (EGFP) transgenic mice to identify NTS POMC neurons. Intraperitoneal administration of cholecystokinin (CCK) induced c-fos gene expression in NTS POMC–EGFP neurons, suggesting that they are activated by afferents stimulated by the satiety hormone. We tested the synaptic relationship of these neurons to visceral afferents and their modulation by CCK and opioids using patch recordings in horizontal brain slices. Electrical activation of the solitary tract (ST) evoked EPSCs in NTS POMC–EGFP neurons. The invariant latencies, low failure rates, and substantial paired-pulse depression of the ST-evoked EPSCs indicate that NTS POMC–EGFP neurons are second-order neurons directly contacted by afferent terminals. The EPSCs were blocked by the glutamate antagonist 2,3- dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. CCK increased the amplitude of the ST-stimulated EPSCs and the frequency of min- iature EPSCs, effects attenuated by the CCK1 receptor antagonist lorglumide. In contrast, the orexigenic opioid agonists [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. These findings identify a potential satiety pathway in which visceral afferents directly activate NTS POMC–EGFP neurons with excitatory inputs that are appropriately modulated by appetite regulators. Key words: POMC; cholecystokinin; vagus; NTS; food intake; autonomic; enkephalin Introduction 2001; Ibrahim et al., 2003). However, little is known about NTS Obesity is a major health problem with multiple underlying eti- POMC neurons. ologies. Mutations in the proopiomelanocortin (POMC) and The NTS is the major portal through which visceral afferent melanocortin-4 (MC4) receptor genes produce severe obesity information for homeostatic reflexes enters the brain. Vagal af- (Clement et al., 2002). The POMC system comprises two groups ferents from the gastrointestinal (GI) tract synapse within subre- of neurons located in the arcuate nucleus of the hypothalamus gions of the NTS, and the activation of these afferents inhibits (ARC) and the nucleus tractus solitarius (NTS) in the medulla. food intake (Schwartz, 2000; Broberger and Hokfelt, 2001). The The ARC–POMC system regulates energy homeostasis via wide- NTS, in turn, is reciprocally connected to regions of the brain spread limbic, motor, and autonomic projections and is modu- integral to the regulation of feeding, such as the hypothalamus, lated by appetite-regulating hormones such as leptin and glucose amygdala, and nucleus accumbens (Schwartz, 2000; Broberger (Cone et al., 2001; Cowley et al., 2001; Spiegelman and Flier, and Hokfelt, 2001). The medial NTS, in which NTS POMC neu- rons are concentrated, contains highly fenestrated endothelial cells providing a permeant blood–brain barrier (Gross et al., Received Oct. 7, 2004; revised Feb. 18, 2005; accepted Feb. 24, 2005. 1990) and the potential for neurohumoral integration with the This work was supported by National Institutes of Health Grants DK66604, DK63040, and HL41119. M.J.L. de- systemic circulation. However, despite their strategic location, it clares a financial interest in transgenic mouse models using the POMC neural regulatory regions, and this potential conflict of interest has been disclosed to and managed by the Oregon Health and Science University Office for is not known whether NTS POMC neurons are regulated by vis- Integrity in Research. ceral afferents or which satiety factors are involved. Correspondence should be addressed to Dr. Suzanne M. Appleyard, Vollum Institute, L474 and Department of Cholecystokinin (CCK) is released after a meal and inhibits Physiology and Pharmacology, Oregon Health and Science University, 3183 Southwest Sam Jackson Park Road, food intake in part by increasing the firing rate of vagal afferents Portland, OR 97239-3098. E-mail: [email protected]. M. W. Doyle’s present address: Department of Biology, George Fox University, Newberg, OR 97132-2697. projecting to the NTS (Moran et al., 2001). CCK may interact DOI:10.1523/JNEUROSCI.4177-04.2005 with the brainstem POMC system, because CCK-induced satiety Copyright © 2005 Society for Neuroscience 0270-6474/05/253578-08$15.00/0 is blocked by fourth-ventricle injection of a melanocortin antag- Appleyard et al. • Afferents, CCK, and Opioids Modulate POMC NTS Neurons J. Neurosci., April 6, 2005 • 25(14):3578–3585 • 3579 onist and is absent in MC4 receptor knock-out mice (Fan et al., 10 NaCl, 130 K-gluconate, 11 EGTA, 1 CaCl2, 2 MgCl2, 10 HEPES, 2 2004). However, the site of action of CCK, the role of the vagal ATP, and 0.2 GTP, pH 7.3 (295–299 mOsm). Neurons were recorded afferents, and the cellular mechanisms underlying CCK activa- from NTS within 200 ␮m caudal to obex and medial to the ST. Patch ⍀ tion of POMC neurons are not known. electrodes (3.0–4.5 M ) were guided to neurons using both fluores- Appetite stimulators are also important in energy homeosta- cence and differential interference contrast (DIC) optics illuminated sis, and, if NTS POMC neurons are involved, one would predict with infrared light (Axioskop FS2; Zeiss, Oberkochen, Germany). Voltage-clamp and current-clamp recordings were made with an Axo- that they would be targets of orexigenic drugs. Opioids are neu- patch 200B or Axoclamp 2A amplifier and pClamp software versions 8 romodulatory peptides that stimulate feeding when injected into and 9 (Axon Instruments, Union City, CA). Only neurons with holding the NTS (Kotz et al., 1997). Furthermore, NTS injections of opi- Ϫ currents not exceeding 100 pA at a Vh of 60 mV for the 15 min control oid antagonists inhibit food intake, consistent with a basal tone of period (input resistance, Ͼ150 M⍀) were studied further. Synaptic cur- endogenous opioid action within the nucleus (Kotz et al., 1997, rents were evoked with an ultrafine concentric bipolar stimulating elec- 2000). Because vagal afferent terminals express opioid receptors, trode (200 ␮m; FHC, Bowdoinham, ME) placed on the ST 1–4 mm from afferent regulation of NTS POMC neurons represents an inter- the recording electrode. Electrical stimuli were delivered from an isolated esting potential target for opioids (Aicher et al., 2000). programmable stimulator (Master-8; A.M.P.I., Jerusalem, Israel) trig- We used POMC enhanced green fluorescent protein (EGFP) gered to deliver a burst of stimuli (50–200 Hz). Voltage-clamp protocols Ϫ mice to identify NTS POMC neurons for both in vivo c-fos studies included 200 ms voltage-command steps ranging from 80 to 0 mV. and in a newly developed horizontal brain-slice preparation. Our 2,3-Dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline (NBQX) and bicuculline methiodide were obtained from Tocris Cookson (Ballwin, findings show that POMC–EGFP neurons are directly activated MO). CCK, met-enkephalin (ME), naloxone, [D-Ala(2), N-Me-Phe(4), by visceral afferent glutamatergic synapses and that CCK facili- Gly-ol(5)]-enkephalin (DAMGO), and lorglumide were obtained from tates, and opioids depress, glutamate release onto these neurons. Sigma (St. Louis, MO), and TTX was obtained from Alomone Labs Thus, NTS POMC–EGFP neurons lie in a key position in afferent (Jerusalem, Israel). All drugs were applied for a 5 min period. In the case reflex pathways and respond to signals from two opposing regu- of pretreatment with antagonists, the antagonist was applied alone for 5 lators of feeding behavior, supporting the hypothesis that these min, and then the agonist was coapplied for an additional 5 min. neurons regulate energy homeostasis. All data are presented as means Ϯ SEM. Differences in drug effects were tested by repeated-measures ANOVA (RMA) with Bonferroni’s post hoc test or Student’s t test. Cumulative distributions of miniature Materials and Methods synaptic current amplitudes and frequencies were compared using the Breeding, housing, and genotyping of mice. POMC–EGFP transgenic mice Kolmogorov–Smirnov (KS) nonparametric analysis. Differences were were housed on a 14/10 h light/dark cycle at an ambient temperature in considered statistically significant for p values Ͻ 0.05. the Department of Comparative Medicine murine-specific pathogen- free facility. Mouse chow (Purina Mills, St. Louis, MO) and water were provided ad libitum. Genotyping and breeding of mice were as described Results previously (Cowley et al., 2001). All animal procedures were conducted Selective distribution
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