The basolateral nucleus of the amygdala mediates caloric sugar preference over a non-caloric sweetener in mice
Introduction
Caloric intake from sugar-sweetened foods and liquids in humans has increased for several decades (Saris, 2003, Bellisle and Drewnowski, 2007) despite the development and wide use of non-caloric artificial sweeteners. Increased intake of sweetened foods/fluids can disturb appetite control (Erlanson-Albertsson, 2005, Malik et al., 2006, Malik and Hu, 2012). Consumption of caloric sugar-sweetened beverages has been suggested to be a key factor for increased body weight (Ludwig et al., 2001, Hu, 2013). Moreover, an increased preference for caloric sugars over non-caloric sweeteners may contribute to increased caloric intake derived from caloric sugars in humans. Increased preference for caloric sucrose has been reported in rat studies with experimental manipulations such as stress loading, adrenalectomy, Roux-en-Y gastric bypass, and taste–nutrient learning (Dess, 1992, Sclafani, 1995, Sclafani, 2004, Laugero et al., 2001, Mathes and Spector, 2012, Mathes et al., 2012). However, the neural and behavioral mechanisms underlying shifts in preference for caloric sugars over non-caloric sweeteners remain unclear.
Although many brain areas that regulate taste-processing and feeding behavior may be involved in the sweetener preference shift, we assumed that the amygdala would be critical because of the following reasons: (1) The amygdala plays a role in the association between sensory cues and reinforcers (Balleine and Killcross, 2006, Dwyer and Iordanova, 2010, Mahler and Berridge, 2012) and (2) in the encoding of the reward value of food (Kenny, 2011); (3) the amygdala response to caloric sucrose is altered by habitual consumption of non-caloric sweeteners (Green and Murphy, 2012, Rudenga and Small, 2012). However, in rats, lesions of the whole amygdala fail to disrupt nutrient-conditioned preferences for taste mixture stimuli that are clearly different from each other (‘bitter-sweet’ versus ‘salty-sweet’) (Touzani and Sclafani, 2005). In this previous study, the salience of the taste mixtures may be strong enough to be associated with postingestive influences in the absence of amygdala function. It remains unclear whether the amygdala plays a role in the preference shift for a ‘simple’ oral caloric sucrose cue over that of an equally sweet-tasting non-caloric saccharin cue. The amygdala consists of subnuclei that have different roles. Thus, the question of which subnucleus was dominantly involved in the sweetener preference shift arose. We explored the role of the basolateral nucleus of the amygdala (BLA), because the BLA plays roles in learned preference changes for flavor through flavor–nutrient (Touzani and Sclafani, 2005, Dwyer and Iordanova, 2010) or flavor–taste (Gilbert et al., 2003, Dwyer, 2011) associations. The central nucleus of the amygdala (CeA) plays a role in feeding behavior including unconditioned feeding control (Hajnal et al., 1992, Bovetto and Richard, 1995) and an unconditioned preference–aversion shift toward a highly concentrated sodium solution in sodium-depleted animals (Galaverna et al., 1993). The CeA also has a relatively weaker contribution to flavor–nutrient learning (Touzani et al., 2009). To evaluate the roles of these subnuclei, we compared the effects of selective lesions of the BLA and CeA on the sweetener preference shift. For selective lesions of the CeA, we used a well-controlled microlesioning technique (Hernadi et al., 2000) to minimize and localize the lesioned area while preserving the BLA.
To examine the roles of the BLA and CeA, we used a novel behavioral model of the sweetener preference shift in mice. To develop the sweetener preference shift in the model, we selected an oral-simultaneous training method, i.e., alternating oral delivery of caloric sucrose and non-caloric saccharin (cf. Sclafani, 1995, Dwyer and Iordanova, 2010). During training, mice received both oral (e.g., sweet taste) and post-oral (postingestive consequences) cues that normally occur after the intake of each sweetener. To evaluate the effect of energetic state on the intake of and preference for the sweeteners (Sclafani, 1991, Sclafani and Ackroff, 1993), we first compared sweetener preferences between the two groups of mice in the presence or absence of food access prior to sweetener access.
We used the well-studied sweet-sensitive C57BL/6J (B6) mouse strain (Bachmanov et al., 2001, Sclafani and Glendinning, 2003, Glendinning et al., 2005, Pinhas et al., 2012). Since B6 mice are widely used as a control strain in transgenic mouse studies (e.g., de Araujo et al., 2008, Stratford and Finger, 2011), the behavioral model used herein is applicable to transgenic strains for the investigation of neurobiological and genetic mechanisms.
Section snippets
Animals
C57BL/6J male mice (10–12 weeks-old, weighing 18–20 g at the start of the study; n = 50) were obtained from CREA Japan (Osaka, Japan). Mice were divided into two groups: those receiving chow for only 4 h per day (Chow4h) (n = 41) or 20 h per day (Chow20h) (n = 9). A pellet diet (MF; Oriental Yeast, Japan) was delivered as normal chow. Seven days after arrival at our laboratory, mice were subjected to the experimental procedures described below. All behavioral procedures were conducted in their home
Sweetener preference shift for caloric sucrose after alternate training under food-deprived conditions
Before comparing the effects of lesions on the shift in sweetener preference, we examined the effects of food deprivation on changes in sweetener intake during the training blocks and on the two-bottle choice preference between sucrose and saccharin. Fig. 2A, C show the intake of 1.0 M sucrose and saccharin for six blocks in the Chow4h trained group (n = 10) and Chow20h group (n = 9), respectively. As shown in Fig. 2A, C, basal water intake during the pretraining period was significantly different
Discussion
The main findings of the present study were as follows: (1) the intake of and preference for caloric sucrose over non-caloric saccharin increased after alternating oral delivery training under food restricted conditions; (2) the BLA, but not the CeA, was involved in the shift in sweetener preference. Our data clearly suggest that development of preference shifts for sugar-sweetened substances is mediated by BLA function.
Conclusion
The present study demonstrates that a remarkable shift in preference for caloric sucrose over non-caloric saccharin can be induced via an alternating oral delivery training method in food-restricted mice. Our procedure provides a simple mouse model of increased intake of calorie-dense sweetened foods/beverages caused by an increased preference for caloric sugars as observed in humans. The present results, using well-controlled excitotoxic microlesions, also suggest that the BLA, but not the
Acknowledgments
We thank Prof. Takashi Yamamoto for his thoughtful comments on this manuscript. This work was supported by grants from the Bio-Imaging Center, Japan Women’s University (T.M.), and from the Mishima Kaiun Memorial Foundation, Asahi Group Foundation, and a Grant-in-Aid for Scientific Research (C) (JSPS KAKENHI Grant Number 24614006) (Y.Y.). We thank Ohkubo Lisa and Erina Yamaguchi for their technical assistance.
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