Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals
Introduction
Food intake is the product of meal size and meal number [1]. Meal number is regulated by cortical, limbic, striatal, and hypothalamic forebrain circuits, and is modulated by signals that convey information about environmental events, learned associations, reward, and energy status between meals {see [2], [3] for reviews}. Conversely, meal size is controlled primarily at the level of the caudal brainstem [1], and is modulated by satiety signals arising from the gastrointestinal (GI) tract and related digestive organs during the ingestion and digestion of food; these signals are conveyed largely by vagal sensory inputs to the NST [4], [5], [6], [7], [8], [9], [10]. The NST relays feeding-related visceral sensory signals to the forebrain, as well as to brainstem pattern generators and pre-motor neurons that control the motoric components of feeding (i.e., licking, chewing, and swallowing [11], [12]). Thus, NST neurons are critically involved in receiving and processing GI satiety signals that terminate ingestive consummatory behaviors, thereby limiting meal size [13].
NST neurons that receive and process satiety signals are neurochemically diverse [13]. However, recent studies have implicated two intermingled but phenotypically distinct caudal NST neuronal populations in meal size control: noradrenergic (NA) neurons that comprise the A2 cell group, and preproglucagon-expressing neurons that are immunopositive for glucagon-like peptide-1 (GLP-1) [13], [14], [15]. Based on increased expression of the immediate-early gene product cFos, results in laboratory rats indicate that A2 and GLP-1 neurons are stimulated by experimental treatments that activate GI vagal sensory afferents with synaptic inputs to the caudal NST [16], [17], [18], [19], [20]. Such treatments include mechanical gastric distension [20] and systemic administration of cholecystokinin octapeptide (CCK) [17], [18], [21], [22]. A2 neurons also are activated in a meal size-dependent manner by voluntary food intake in rats that have been acclimated/entrained to a feeding schedule in which repeating cycles of overnight food deprivation are followed by a predictable morning re-feeding period [16]. Conversely, the same repeating schedule of food deprivation followed by a large anticipated meal does not activate GLP-1 neurons [17], although GLP-1 neurons are activated in rats after a variety of interoceptive stressors [17]. Feeding schedule entrainment is associated with anticipatory physiological adjustments that serve to limit the homeostatic challenge of consuming large meals, thereby reducing the interoceptive stress that would otherwise be produced by the meal, and permitting increased meal size [2], [23]. Since multiple lines of evidence support the view that central GLP-1 signaling suppresses food intake [5], [24], [25], [26], the lack of GLP-1 neuronal recruitment in meal-entrained rats that consume a large anticipated meal may reflect homeostatic adjustments that minimize interoceptive stress. Indeed, attenuated feeding-induced activation of GLP-1 neurons may contribute to the progressively larger meals consumed by rats during meal entrainment [2], [23]. In non-entrained rats, such anticipatory physiological adjustments are absent, and deprivation-induced food intake is more directly limited by GI distension and other sensory feedback generated by the acute homeostatic challenge of consuming a large unanticipated meal.
The present study was designed to test the hypothesis that both A2 and GLP-1 neuronal populations are recruited in non-entrained rats after voluntarily intake of a large, unanticipated meal. To challenge this hypothesis, we examined cFos activation among DBH- and GLP-1-positive caudal NST neurons in rats after deprivation-induced intake of unrestricted or restricted volumes of a palatable liquid diet (i.e., Ensure). We extended our analysis of feeding-activated neurons to include a specific caudal subset of DBH-positive A2 neurons that co-express prolactin-releasing peptide (PrRP) along with NA synthetic enzymes [27], [28]. Central PrRP signaling is implicated in stress responses and control of energy balance [29], [30], [31], [32], [33], [34], [35], [36], and PrRP neurons may participate in meal size regulation [37], [38], [39]. PrRP-positive neurons within the caudal NST are activated in experimentally naïve rats and mice after overnight food deprivation followed by re-feeding [40], although that report did not examine the potential relationship between the amount of food consumed and the extent of PrRP neuronal recruitment.
Section snippets
Animals and feeding protocol
Experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the University of Pittsburgh Institutional Animal Care and Use Committee. Adult male Sprague–Dawley rats (Harlan; n = 31; 200–270 g BW) were individually housed in hanging wire cages in a temperature-controlled room with lights on from 07:00–19:00 h. Food (Purina rat chow #5001) and water were available ad libitum, except as noted for each experiment. Rats were acclimated to
Results
The number of rats per feeding condition group is indicated in Table 1. ANOVA confirmed no significant between-group differences in post-deprivation, pre-meal BWs (Table 1).
Discussion
Results from the present study demonstrate that DBH-positive neurons within the caudal visceral NST (including primarily the A2 cell group, but also the caudal portion of the C2 cell group) are progressively recruited to express cFos in rats that consume progressively larger volumes of palatable liquid Ensure after first-time food deprivation. Among DBH-positive neurons examined in our study, the PrRP-positive subset was most sensitive to feeding-induced activation, although smaller proportions
Conclusions
Our results demonstrate that large satiating meals of palatable liquid Ensure recruit NA (especially PrRP-positive) and GLP-1-positive neurons within the caudal NST in rats that have not been acclimated/entrained to a feeding schedule. Conversely, we previously reported that large meals activate similar proportions of NA neurons but do not activate GLP-1 neurons in meal-entrained rats [16], [17]. Considered together, these findings support the conclusion that PrRP-positive A2 neurons are
Acknowledgments
This manuscript is based on work presented during the 2013 Annual Meeting of the Society for the Study of Ingestive Behavior held in New Orleans, LA.
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