Critical role of lateral habenula circuits in the control of stress-induced palatable food consumption.

Chronic stress fuels the consumption of palatable food and can enhance obesity development. While stress- and feeding-controlling pathways have been identified, how stress-induced feeding is orchestrated remains unknown. Here, we identify lateral habenula (LHb) Npy1r-expressing neurons as the critical node for promoting hedonic feeding under stress, since lack of Npy1r in these neurons alleviates the obesifying effects caused by combined stress and high fat feeding (HFDS) in mice. Mechanistically, this is due to a circuit originating from central amygdala NPY neurons, with the upregulation of NPY induced by HFDS initiating a dual inhibitory effect via Npy1r signaling onto LHb and lateral hypothalamus neurons, thereby reducing the homeostatic satiety effect through action on the downstream ventral tegmental area. Together, these results identify LHb-Npy1r neurons as a critical node to adapt the response to chronic stress by driving palatable food intake in an attempt to overcome the negative valence of stress.

Within versus between group designs, and not timing of onset of puberty, influence sex and age differences in intake of palatable food in rats.

Understanding normative development of sensitivity to palatable food in adolescence is key to developing animal models for preclinical research of disorders of reward systems (e.g., eating disorders). Nevertheless, few studies have investigated changes in consumption of palatable food in both sexes and the role of the timing of onset of puberty as a factor. Here, we tested multiple ages of adolescence in both female and male Long-Evans rats and used both a within-group and between-group testing paradigm to compare effects of repeated testing on consumption of diluted sweetened condensed milk. In the within-group, female rats consumed more per body mass at postnatal day (P) 27 and declined in intake thereafter. Male rats also had the highest intake per body mass at P27 and declined thereafter, although a second peak was evident at P48, and the intake of females was greater than that of males from P41 on except at P48. In those tested at one age only (between-group design), there were no sex differences across ages, and the decline reached a plateau at P48 in both sexes. Further, intake per body weight was less in the between-group rats than in the within-group rats, suggesting that the within-group design used here as in previous studies may induce bingeing (excessive consumption in a discrete period of time). Thus, such a design may not capture normative development but rather sensitized intake akin to behavioural sensitization to drugs of abuse and/or binge-eating. There was no evidence of an effect of timing of puberty onset on intake in either design. The results show how methodological factors may compromise the interpretation of the development of, and sex differences in, the intake of palatable foods.

The orexinergic neural pathway from the lateral hypothalamus to the nucleus accumbens and its regulation of palatable food intake.

OBJECTIVE: To explore the orexinergic pathway from the lateral hypothalamus (LHA) to the nucleus accumbens (NAc) and its regulation on the palatable food intake. METHODS: Fluorescent gold retrograde tracing combined with fluoro-immunohistochemical staining were used to observe the projection of orexinergic neurons from LHA to NAc. The orexin-A expression in LHA and c-Fos in NAc were studied after electrical stimulation of LHA. The firing rates of neurons were monitored by single-unit extracellular electric discharge recording and the palatable food intake were measured after orexin microinjection in NAc or electrical stimulation of LHA. RESULTS: (1) Fluorescent gold retrograde tracing combined with fluoro-immunohistochemical staining showed some orexinergic neural projection from the LHA to the NAc shell. (2) Electrical stimulation of LHA significantly enhanced the expression of orexin-A in LHA and the expression of c-Fos in NAc (P < .05). (3) The results of single-unit extracellular discharge recording showed that the microinjection of orexin in NAc or electrical stimulation of LHA significantly increased the discharge activity of gastric distension responsive neurons in NAc, and the effect could be partly blocked by pretreatment of orexin-A receptor inhibitor SB334867 in NAc (P < .05). (4) Microinjection orexin-A in NAc or electrical stimulation of LHA significantly increased the palatable food intake in rats, and the effect also was partly inhibited by pretreatment of SB334867 in NAc (P < .05). CONCLUSION: There is an orexinergic pathway from LHA to NAc, which may have potential regulatory effects on food reward and obesity.

Reduced Medial Prefrontal Control of Palatable Food Consumption Is Associated With Binge Eating Proneness in Female Rats.

Binge eating is the core, maladaptive eating behavior that cuts across several major types of eating disorders. Binge eating is associated with a significant loss of control over palatable food (PF) intake, and deficits in behavioral control mechanisms, subserved by the prefrontal cortex (PFC), may underlie binge eating. Few studies, to date, have examined whether the PFC is directly involved in the expression of binge eating. As such, the present study investigated the functional role of the medial PFC (mPFC) in PF consumption, using an individual differences rat model of binge eating proneness. Here, we tested the hypothesis that binge eating proneness (i.e., high levels of PF consumption) is associated with reduced mPFC-mediated behavioral control over PF intake. In experiment 1, we quantified PF-induced Fos expression in both excitatory and inhibitory neurons within the mPFC in binge eating prone (BEP) and binge eating resistant (BER) female rats. In experiment 2, we pharmacologically inactivated the mPFC of BEP and BER female rats, just prior to PF exposure, and subsequently quantified PF intake and scores of feeding behavior. While most Fos-expressing neurons of the mPFC in both BEPs and BERs were of the excitatory phenotype, fewer excitatory neurons were engaged by PF in BEPs than in BERs. Moreover, pharmacological inactivation of the mPFC led to a significant increase in PF intake in both BEPs and BERs, but the rise in PF consumption was stronger in BEPs than in BERs. Thus, these data suggest that lower, PF-induced excitatory tone in the mPFC of BEP rats may lead to a weaker, mPFC-mediated behavioral "brake" over excessive PF intake.

Food craving, cortisol and ghrelin responses in modeling highly palatable snack intake in the laboratory.

Overeating of highly palatable (HP) foods in the ubiquitous HP food cue environment and under stress is associated with weight gain and contributes to the global obesity epidemic. However, subjective and biobehavioral processes that may increase HP overeating are not clear. Using a novel experimental approach, we examined HP food motivation and intake and neuroendocrine responses in the context of food cues, stress and a control neutral relaxing cue exposure in healthy individuals. METHODS: Twenty individuals (12 M; 8F; ages 18-45) with body mass index (BMI) in the lean (LN: N = 8; 3/8 female BMI: 18-24.9) or overweight/obese (OW: N = 12; 5/12 female; BMI: 25-37) range were enrolled in a controlled, hospital-based, 3-day laboratory experiment. On each day, subjects were exposed to a brief 5-min individualized guided imagery of stress, food cue or an active neutral-relaxing control cue script, followed by a food snack test (FST), with one imagery condition per day and order of imagery exposure randomized and counterbalanced across subjects. Subjective HP food craving and caloric intake, anxiety, cortisol and total ghrelin was assessed repeatedly during each test day. RESULTS: Significant condition and condition × group effects for food craving, anxiety and HP calorie intake were observed, with food cue relative to neutral condition increasing HP food craving and intake across all subjects (p < .001), but stress relative to neutral condition increased HP food craving and intake in the OW but not LN group (p < .01). Pre-snack increases in food craving after exposure to food cues and to stress predicted greater subsequent HP food intake (p's < 0.01). Furthermore, ghrelin increased in the food cue and stress conditions (p < .01), but stress-induced increases in ghrelin was associated with HP food intake only in the OW/OB condition (p < .01). Finally, cortisol increased during food cue exposure and increased cortisol responses were associated with greater HP food caving and with intake (p's < 0.05). CONCLUSIONS: These findings, while preliminary, validate a laboratory model of HP food motivation and intake and identify specific subjective and neuroendocrine responses that may play a role in HP snacking with implications for weight gain and obesity risk. (342 words).

The duration of intermittent access to preferred sucrose-rich food affects binge-like intake, fat accumulation, and fasting glucose in male rats.

Many people restrict their palatable food intake. In animal models, time-limiting access to palatable foods increases their intake while decreasing intake of less preferred alternatives; negative emotional withdrawal-like behavior is sometimes reported. In drug addiction models, intermittent extended access drives greater changes in use than brief access. When it comes to palatable food, the impact of briefer vs. longer access durations within intermittent access conditions remains unclear. Here, we provided male rats with chow or with weekday access to a preferred, sucrose-rich diet (PREF) (2, 4, or 8 h daily) with chow otherwise available. Despite normal energy intake, all restricted access conditions increased weight gain by 6 weeks and shifted diet acceptance within 1 week. They increased daily and 2-h intake of PREF with individual vulnerability and decreased chow intake. Rats with the briefest access had the greatest binge-like (2-h) intake, did not lose weight on weekends despite undereating chow, and were fattier by 12 weeks. Extended access rats (8 h) showed the greatest daily intake of preferred food and corresponding undereating of chow, slower weight gain when PREF was unavailable, and more variable daily energy intake from week to week. Increased fasting glucose was seen in 2-h and 8-h access rats. During acute withdrawal from PREF to chow diet, restricted access rats showed increased locomotor activity. Thus, intermittent access broadly promoted weight gain, fasting hyperglycemia and psychomotor arousal during early withdrawal. More restricted access promoted greater binge-like intake and fat accumulation, whereas longer access promoted evidence of greater food reward tolerance.

Fetal growth interacts with multilocus genetic score reflecting dopamine signaling capacity to predict spontaneous sugar intake in children.

BACKGROUND: We have shown that intrauterine growth restriction (IUGR) leads to increased preference for palatable foods at different ages in both humans and rodents. In IUGR rodents, altered striatal dopamine signaling associates with a preference for palatable foods. OBJECTIVES: Our aim was to investigate if a multilocus genetic score reflecting dopamine-signaling capacity is differently associated with spontaneous palatable food intake in children according to the fetal growth status. METHODS: 192 four-year old children from a community sample from Montreal and Hamilton, Canada, were classified according to birth weight and administered a snack test meal containing regular as well as palatable foods. Intrauterine growth restriction was based on the birth weight ratio below 0.85; children were genotyped for polymorphisms associated with dopamine (DA) signaling, with the hypofunctional variants (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10-repeat, Met/Met-COMT) receiving the lowest scores, and a composite score was calculated reflecting the total number of the five genotypes. Macronutrient intake during the Snack Test was the outcome. RESULTS: Adjusting for z-score BMI at 48 months and sex, there was a significant interaction of the genetic profile and fetal growth on sugar intake [߈ = -4.56, p = 0.04], showing a positive association between the genetic score and sugar intake in IUGR children, and no association in non-IUGR children. No significant interactions were seen in other macronutrients. CONCLUSIONS: Variations in a genetic score reflecting DA signaling are associated with differences in sugar intake only in IUGR children, suggesting that DA function is involved in this behavioral feature in these children. This may have important implications for obesity prevention in this population.

Extended vs. brief intermittent access to palatable food differently promote binge-like intake, rejection of less preferred food, and weight cycling in female rats.

BACKGROUND: Palatable food access promotes obesity leading some to diet. Here, we modeled the roles of duration, intermittency and choice of access in bingeing, escalation of daily intake, and underacceptance of alternatives. METHOD: Female rats with ("Choice") or without continuous chow access, received chow or continuous (Chocolate), intermittent (MWF) long (24h, Int-Long), or intermittent short (30min, Int-Short) access to a sucrose-rich, chocolate-flavored diet (CHOC). RESULTS: Int-Long rats showed cycling body weight; they overate CHOC, had increased feed efficiency on access days and underate chow and lost weight on non-access days, the latter correlating with their reduced brown fat. Int-Short rats had the greatest 30-min intake upon CHOC access, but did not underaccept chow or weight cycle. Individual vulnerability for intermittent access-induced feeding adaptations was seen. Continuous access rats gained fat disproportionate, but in direct relation, to their normalized energy intake and persistently underaccepted chow despite abstinence and return to normal weight. Abstinence reduced the binge-like CHOC intake of Int-Short rats and increased that of continuous access rats, but not to levels associated with intermittent access history. Choice increased daily CHOC intake under Continuous access and binge-like intake under Int-Short access. CONCLUSIONS: Intermittency and duration of past access to palatable food have dissociable, individually-vulnerable influences on its intake and that of alternatives. With extended access, daily intake reflects the palatability of available food, rather than metabolic need. Ongoing restrictedness of access or a history of intermittency each drive binge-like intake. Aspects of palatable food availability, similar and different to drug availability, promote disordered eating.

Effect of adapted interpersonal psychotherapy versus health education on mood and eating in the laboratory among adolescent girls with loss of control eating.

OBJECTIVE: Interpersonal psychotherapy (IPT) is aimed at improving negative affect that is purported to contribute to the development and maintenance of loss-of-control (LOC) eating. Although youth who report LOC over eating tend to consume more snack-foods than those without LOC, it is unknown if IPT impacts objective energy intake. METHODS: To test if IPT improves mood and eating in the laboratory, we examined a sample of 88 girls with LOC eating who were randomized to either IPT (n = 46) or a standard-of-care health education (HE) group program. At baseline, and 6-month (follow-up 1) and 1-year (follow-up 2) following the initiation of the groups, girls consumed lunch from a multi-item meal with an instruction designed to model a LOC episode. Girls also reported mood state immediately before each meal. RESULTS: Girls in IPT experienced no significant changes in pre-meal state depressive affect, while girls in HE experienced a non-significant improvement by follow-up 1 and then returned to baseline by follow-up 2 (p < .04). We found no significant group difference for changes in total intake relative to girls' daily energy needs (p's ≥ .25). However, IPT reduced, while HE increased, the percentage of daily energy needs consumed from snack-foods by follow-up 2 (p = .04). Within-groups, HE increased their snack food intake from follow-up 1 to follow-up 2 (p = .01). CONCLUSIONS: In adolescent girls with LOC, IPT did not change total intake at the test meal and was associated with reduced snack-food intake. Data are required to determine if IPT effectively prevents excess weight gain in the longer-term. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:490-498).

Experience of Neonatal Maternal Separation May Lead to a Long-term Modulation in the Neuronal Activity of Nucleus Accumbens in the Offspring

Dysfunction of the nucleus accumbens (NAcb) is implicated in the development of anhedonia, a core symptom of major depressive disorder. In order to define the neural basis of depression-like behaviors induced by experience of neonatal maternal separation (MS), both basal and stress-induced neuronal activations in the NAcb of adolescent rats with MS experience were examined parallel with palatable food intake. Rat pups were separated from dam daily for 180 min during the first two weeks of age (MS), and non-handled control (NH) pups were left undisturbed. After weaning on postnatal day (PND) 22, a half of NH or MS pups were subjected to 1 h of restraint stress every even day during PND 28~40 (NH/R or MS/R), and then had free choices of chow and chocolate cookie for 1 h immediately after returned to home cage. The rest half of NH and MS pups (NH/C or MS/C) received free choices of chow and cookie in the same time schedule with stress group, just omitting restraint stress. Cookie intake was significantly decreased in MS/C, whereas c-Fos expression in the NAcb and plasma corticosterone increased, compared to NH/C. Restraint stress suppressed cookie intake and increased the NAcb c-Fos expression in NH/R, but not in MS/R. The plasma corticosterone of NH/R, but not of MS/R, increased following repeated restraint stress. These results suggest that the increased neuronal activation in the NAcb of MS/C may be implicated in the development of anhedonia by MS experience, perhaps, in relation with a blunted responsivity of the hypothalamic-pituitary- adrenal axis to stress.