Traditional Japanese medicine Kamikihito ameliorates sucrose preference, chronic inflammation and obesity induced by a high fat diet in middle-aged mice.

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner.

Acquisition and expression of fat conditioned flavor preferences following dopamine D1, opioid and NMDA receptor antagonism in C57BL/6 mice.

Objectives: Inbred mouse strains differ in the pharmacology mediating sugar and fat intake and conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice are differentially sensitive to dopamine (DA) D1, opioid and muscarinic receptor antagonism of sucrose, saccharin or fat intake, and to DA, opioid, muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonism of acquisition of sucrose-CFP. DA D1, opioid and NMDA receptor antagonists differentially alter fat (Intralipid)-CFP in BALB/c and SWR mice. The present study examined whether naltrexone, SCH23390 or MK-801 altered acquisition and expression of Intralipid-CFP in C57BL/6 mice.Methods: In acquisition, groups of male food-restricted C57BL/6 mice received vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 µg/kg) before 10 training sessions in which mice alternately consumed two novel-flavored 5% (CS+) and 0.5% (CS-) Intralipid solutions. Six two-bottle CS choice tests followed with both flavors mixed in 0.5% Intralipid without injections. In expression, C57BL/6 mice underwent the 10 training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 µg/kg).Results: Fat-CFP acquisition in C57BL/6 mice was significantly though marginally reduced following naltrexone, SCH23390 and MK-801. Fat-CFP expression was similarly reduced by naltrexone, SCH23390 and MK-801 in C57BL/6 mice. Discussion: C57BL/6 mice were more sensitive to DA D1, opioid and NMDA antagonists in the expression of fat-CFP relative to sugar-CFP, but were less sensitive to DA D1 and NMDA antagonists in the acquisition of fat-CFP relative to sugar-CFP.

Additive Effects of L-Ornithine on Preferences to Basic Taste Solutions in Mice.

In addition to the taste receptors corresponding to the six basic taste qualities-sweet, salty, sour, bitter, umami, and fatty-another type of taste receptor, calcium-sensing receptor (CaSR), is found in taste-bud cells. CaSR is called the 'kokumi' receptor because its agonists increase sweet, salty and umami tastes to induce 'koku', a Japanese word meaning the enhancement of flavor characters such as thickness, mouthfulness, and continuity. Koku is an important factor for enhancing food palatability. However, it is not well known whether other kokumi-receptors and substances exist. Here, we show that ornithine (L-ornithine but not D-ornithine) at low concentrations that do not elicit a taste of its own, enhances preferences to sweet, salty, umami, and fat taste solutions in mice. Increased preference to monosodium glutamate (MSG) was the most dominant effect. Antagonists of G-protein-coupled receptor family C group 6 subtype A (GPRC6A) abolished the additive effect of ornithine on MSG solutions. The additive effects of ornithine on taste stimuli are thought to occur in the oral cavity, and are not considered post-oral events because ornithine's effects were confirmed in a brief-exposure test. Moreover, the additive effects of ornithine and the action of the antagonist were verified in electrophysiological taste nerve responses. Immunohistochemical analysis implied that GPRC6A was expressed in subsets of type II and type III taste cells of mouse circumvallate papillae. These results are in good agreement with those reported for taste modulation involving CaSR and its agonists. The present study suggests that ornithine is a kokumi substance and GPRC6A is a newly identified kokumi receptor.

Lycium barbarum polysaccharide attenuates emotional injury of offspring elicited by prenatal chronic stress in rats via regulation of gut microbiota.

Stress during pregnancy is not only detrimental to a woman's own physical and mental health, but can also cause changes in the intrauterine environment and even have an impact on later growth and development, this study was designed to understand the changes of gut microbiota in the maternal and offspring caused by prenatal chronic stress, and to explore the regulatory effect of LBP on gut microbiota, and then to improve the emotional damage caused by prenatal chronic stress in the offspring. A rat model of prenatal chronic stress was made and used LBP to intervene by gavage. Fresh feces of offspring were collected, the concentration of microbial metabolites were tested by ELISA. Illumina MiSeqPE300 sequencing technology was used to determine the sequence of 16S rRNA V3-V4 of microorganisms. On the PND 42, the emotional function of offspring were tested by open-field test (OFT), sucrose preference test (SPT) and tail of suspend test (TST). Results indicated that stress factors increased the plasma corticosterone level of rats during pregnancy and they appeared depressive behaviors. The body weight of offspring during prenatal chronic stress was lower than the control group, and the plasma corticosterone level was increased. Prenatal chronic stress had a significant impact on emotional performance of the offspring on OFT, SPT and TST. Alpha diversity of gut microbiota and microbiota composition in offspring of prenatal chronic stress was attenuated and some relationships existed between these parameters. LBP treatment reduced offspring's plasma corticosterone level and improved their body weight, changed the emotional function, increased the diversity of gut microbiota. Collectively, these findings disclose that prenatal chronic stress not only causes emotional injury on the offspring, but also changes the gut microbiota of the mother and offspring; LBP may regulate the intestinal flora of the mother, then reducing the influence of stress factors on the emotional injury of offspring.

Effects of Dopamine D1-Like Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys.

Although dopamine plays a prominent role in mediating cocaine's abuse-related effects, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2Rs) have been characterized, less is known about dopamine D1-like receptors (D1Rs). The present experiments examined the effects of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status influenced the behavioral effects of D1R-acting drugs. The high-efficacy D1R agonist SKF 81297, low-efficacy D1R agonist SKF 38393, and D1R antagonist SCH 23390 were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine-choice dose-effect curve was determined daily. To assess selectivity of behavioral effects on cocaine choice, effects of doses that did not disrupt responding (indicated by a ≥35% decrease in total reinforcers delivered) were analyzed. Neither SKF 81297 nor SCH 23390 affected cocaine choice in dominant or subordinate monkeys. However, the low-efficacy agonist SKF 38393 selectively decreased cocaine choice; this effect was larger and only reached statistical significance in subordinate monkeys. Increasing the time between D1-acting drug administration and the cocaine choice session did not affect these results. The results indicate that, like D2R-acting drugs, the behavioral effects of D1R-acting drugs on cocaine choice can vary according to intrinsic efficacy and social status. Moreover, they demonstrate that D1R-acting drugs affect behavior under a narrower range of conditions than D2R-acting drugs. SIGNIFICANCE STATEMENT: Cocaine use disorder represents an insidious public health concern with no Food and Drug Administration-approved medications. Although dopamine receptors have been strongly implicated in mediating the abuse-related effects of cocaine, the roles of dopamine receptor subtypes are incompletely understood. The present study in nonhuman primates found that cocaine choice was decreased only by a low-efficacy D1R agonist, and that this effect depended on the social status of the monkey.

A combination of cecum microbiome and metabolome in CUMS depressed rats reveals the antidepressant mechanism of traditional Chinese medicines: A case study of Xiaoyaosan.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS), a representative and classic prescription in traditional Chinese medicines (TCMs), has been used for thousands of years for treating depression. The anti-depression effect of XYS has been demonstrated both clinically and experimentally. However, it is still unclear that whether XYS could regulate the abnormalities of gut microbiota and metabolites of cecum induced by depression, and in which way. This study aimed to explore the underlying mechanism of the anti-depressant effects of XYS from the perspective of cecal microbiota and metabolites. MATERIALS AND METHODS: Chronic unpredictable mild stress (CUMS)-induced depression-like rats were used as the depression animal model. Various classic behavioral tests were performed to assess the anti-depressant effects of XYS. Additionally, the composition, the richness, and the diversity of the cecum microbiota were assessed by 16S rRNA gene sequencing technology. Besides, the metabolic profiling of cecum samples was analyzed by 1H-NMR metabolomics. Multivariate data analysis was then applied to screen the differential metabolites and to characterize the changes in cecum metabolites. Moreover, a correlation analysis between differential metabolites and crucial microbiota was conducted. RESULTS: XYS significantly improved depressive behaviors and the abnormal diversity of cecum microbiota induced by CUMS. At the phylum level, XYS could significantly increase the abundance of Firmicutes while decrease the abundance of Actinobacteria in depressed rats. XYS significantly regulated the abundances of 9 out of 13 potential microbial biomarkers at the genus level. Cecal metabolomics showed that XYS could also regulate the abnormal levels of alanine, proline, lactate, and valine of depression rats. CONCLUSIONS: This study revealed, for the first time, from the perspectives of microbiota and cecum metabolites, the anti-depression mechanisms of XYS. This study is of significance for not only comprehensively understanding the anti-depression effects and mechanisms of XYS, but also for providing a research approach for revealing the underlying mechanisms of action of TCMs, i.e. to apply a combination of 16S rRNA gene sequencing and metabolomics.

ALTERTASTE: improving food pleasure and intake of oncology patients receiving chemotherapy.

ALTERTASTE is a prospective study to evaluate changes in taste/flavor perception and food preferences in patients treated with adjuvant or neoadjuvant chemotherapy for breast or colorectal cancer. The study adopts a longitudinal approach. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and their psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors. Furthermore, the trial aims to develop an easy and reliable procedure to test smell, taste and food behavior alterations to allow a routine measure with patients. Clinical trial registration: NCT04495387 (ClinicalTrials.gov).

Lay abstract Malnutrition (under- or over-nutrition) is highly prevalent in cancer patients receiving chemotherapy and is an important predictor of morbidity, mortality, treatment response and toxicity. Alterations in taste and smell are frequently reported as side effects of chemotherapy and may contribute strongly to malnutrition through an impact on eating behaviors and to a worse quality of life. ALTERTASTE is a prospective longitudinal study to evaluate changes in taste/flavor perception and food preferences in patients treated with chemotherapy for breast, colon or rectal cancer. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors.

Protocatechuic acid attenuates chronic unpredictable mild stress induced-behavioral and biochemical alterations in mice.

Amelioration of oxidative stress via promoting the endogenous antioxidant system and enhancement of monoamines in brain were the important underlying antidepressant mechanism of protocatechuic acid (PCA). The aim of the present study is to explore the potential antidepressant mechanism(s) PCA in chronic unpredictable mild stress (CUMS) mice. Mice were subjected to CUMS protocol for 4 weeks, and administered with PCA (100 and 200 mg/kg) and fluoxetine (20 mg/kg) for 24 days (from day 8th to 31st). Behavioral (sucrose preference, immobility time, exploratory behavior), and biochemical alterations such as serum corticosterone, brain derived neurotrophic factor (BDNF), inflammatory cytokines, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and antioxidants parameters were investigated. Experimental findings revealed that CUMS subjected mice exhibited significant impairment in behavioral alterations, such as increased immobility time, impaired preference to the sucrose solution, BDNF levels and, serum corticosterone, cytokines, malondialdehyde (MDA) formation with impaired antioxidants in the hippocampus and cerebral cortex. Administration of PCA to CUMS mice attenuated the immobility time, serum corticosterone, cytokines TNF-α, and IL-6, MDA formation and improved sucrose preference, including restoration of BDNF level. Thus, the present findings demonstrated the antidepressant potential of PCA which is largely achieved probably through maintaining BDNF level, and by modulation of the oxidative stress response, cytokines systems, and antioxidant defense system in mice.

Diet Protein Content and Individual Phenotype Affect Food Intake and Protein Appetence in Rats.

BACKGROUND: A low-protein diet can induce compensatory intake of excess energy. This must be better evaluated to anticipate the obesogenic risk that may result from the dietary recommendations for reducing animal protein consumption. OBJECTIVES: We aimed to further characterize the behavioral and physiological responses to a reduction in dietary protein and to identify the determinants of protein appetite. METHODS: Thirty-two male Wistar rats [4 wk old, (mean ± SEM) 135 ± 32 g body weight] were fed a low-protein (LP; 6% energy value) or normal-protein (NP; 20%) diet for 8 wk. Food intake and body mass were measured during the entire intervention. During self-selection sessions after 4 wk of experimental diets, we evaluated rat food preference between LP, NP, or high-protein (HP; 55%) pellets. At the end of the experiment, we assessed their hedonic response [ultrasonic vocalizations (USVs)] and c-Fos neuronal activation in the olfactory tubercle and nucleus accumbens (NAcc) associated with an LP or HP meal. RESULTS: Rats fed an LP diet had greater food intake (24%), body weight (5%), and visceral adiposity (30%) than NP rats. All LP rats and half of the NP rats showed a nearly exclusive preference for HP pellets during self-selection sessions, whereas the other half of the NP rats showed no preference. This suggests that the appetite for proteins is driven not only by a low protein status but also by individual traits in NP rats. LP or HP meal induced similar USV emission and similar neuronal activation in the NAcc in feed-deprived LP and NP rats, showing no specific response linked to protein appetite. CONCLUSIONS: Protein appetite in rats is driven by low protein status or individual preferences in rats receiving adequate protein amounts. This must be considered and further analyzed, in the context of current recommendations for protein intake reduction.

Cannabinoids modulate food preference and consumption in Drosophila melanogaster.

Cannabinoids have an important role in regulating feeding behaviors via cannabinoid receptors in mammals. Cannabinoids also exhibit potential therapeutic functions in Drosophila melanogaster, or fruit fly that lacks cannabinoid receptors. However, it remains unclear whether cannabinoids affect food consumption and metabolism in a cannabinoid receptors-independent manner in flies. In this study, we systematically investigated pharmacological functions of various cannabinoids in modulating food preference and consumption in flies. We show that flies display preferences for consuming cannabinoids, independent of two important sensory regulators Poxn and Orco. Interestingly, phyto- and endo- cannabinoids exhibit an inhibitory effect on food intake. Unexpectedly, the non-selective CB1 receptor antagonist AM251 attenuates the suppression of food intake by endocannabinoids. Moreover, the endocannabinoid anandamide (AEA) and its metabolite inhibit food intake and promote resistance to starvation, possibly through reduced lipid metabolism. Thus, this study has provided insights into a pharmacological role of cannabinoids in feeding behaviors using an adult Drosophila model.

Associations between opioid dependence and sweet taste preference.

RATIONALE: Past research suggests that people with opioid dependence show increased consumption of sweet food, but it is unclear if this is influenced by altered taste preference and/or taste perception. OBJECTIVES: We tested whether people prescribed opioid substitution therapy (OST) exhibited a shift in preference towards sweeter flavours, and altered perception of sweetness, and explored whether these measures of taste preference/perception were associated with measures of opioid use. METHODS: Three groups of participants (people prescribed OST, n=36; people with past opioid dependence, but now abstinent from all opioids, n=18; and controls with no history of substance dependence other than nicotine, n=29) provided ratings of "sweetness", "liking", and "desire" of 4 solutions with varying concentrations of sucrose. RESULTS: We did not find significant differences between groups in the effect of sucrose concentration on "sweetness", "liking", or "desire" ratings. However, among those prescribed OST, frequency of recent illicit opioid use was associated with reduced perception of "sweetness" of low sucrose concentrations. Higher methadone dose was associated with a shift towards liking sweeter concentrations. Among those with past opioid dependence, longer duration of abstinence from opioids was associated with a shift towards liking sweeter concentrations. CONCLUSIONS: Among people currently dependent on opioids, reduced sensitivity to low levels of sweetness and increased preference for sweeter flavours may be associated with increased dependence on opioids. Among those who have ceased opioid use, the association between preference for sweeter flavours and duration of abstinence is a novel finding that deserves further investigation.

Remifentanil-food choice follows predictions of relative subjective value.

BACKGROUND: Preclinical studies into drug vs. nondrug choice have emerged to better model and investigate the neurobehavioral mechanisms underlying drug preference. Current literature has suggested that drugs of abuse have inherently low value, thus promoting food preference. Herein, we examined remifentanil vs. food choice to test both the relative value hypothesis and the 'direct effects' (pharmacological effects of drugs on alternative reinforcers) hypothesis of opioid preference. METHODS: Adult male rats were trained under two choice procedures (controlled vs. uncontrolled reinforcer frequency) for remifentanil vs. food choice. Furthermore, a series of procedural manipulations known to affect drug reinforcement were tested under both choice procedures. Using remifentanil self-administration data, pharmacokinetic profiles were calculated and analyzed to determine if opioid intake was related to opioid preference. RESULTS: Both choice procedures produced dose-dependent preference. Moreover, procedural manipulations produced comparable changes in remifentanil preference under both choice procedures. In addition, calculated pharmacokinetic data revealed that preference was dissociable from intake under the controlled reinforcer frequency choice procedure. CONCLUSIONS: When compared to the 'direct effects' hypothesis, remifentanil preference was better predicted by the relative value hypothesis, formalized in generalized matching. Use of a controlled reinforcer frequency schedule successfully removed the drug preference-intake confound found in most drug-choice procedures. Importantly, drug preference under the controlled reinforcer frequency schedule remained sensitive to procedural manipulations known to affect drug reinforcement. Thus, given that differential drug intake itself affects neurobiological measurements, future use of controlled reinforcer frequency schedules may help to better isolate the neurobehavioral mechanisms that mediate opioid preference.

The antidepressant-like effects of the water extract of Panax ginseng and Polygala tenuifolia are mediated via the BDNF-TrkB signaling pathway and neurogenesis in the hippocampus.

ETHNOPHARMACOLOGY RELEVANCE: The water extract of Panax ginseng (GT) and Polygala tenuifolia (YT), the main constituents of the commonly used kai-xin-san formula of traditional Chinese medicine, represents SY. It possesses strong neuroprotective effects. Using behavioural tests, we have previously established that the SY formulation exerts superior antidepressant activity than that of GT or YT. AIM: To elucidate the impact of SY treatment on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours and the prospective mechanism related to hippocampal neurogenesis and the BDNF signaling pathway. METHODS: We exposed Sprague-Dawley rats (male; 180-200 g) to CUMS for 35 days. The rats in the experimental treatment groups were daily treated with either fluoxetine (10 mg kg-1d-1) or SY (67.5, 135, or 270 mg kg-1d-1) orally until the behavioural tests (tail suspension test [TST], novelty-suppressed feeding test [NSFT], sucrose preference test [SPT], and forced swim test [FST]) were completed. We assessed the modifications in the hippocampal neurogenesis and the BDNF signaling pathway post-treatment with CUMS and SY. Additionally, K252a, a tyrosine protein kinase inhibitor, was utilized to evaluate the antidepressant mechanisms of SY. RESULT: s: The results of SPT, NSFT, FST, and TST in CUMS-exposed rats confirmed the antidepressant actions of SY. Additionally, SY treatment induced the BDNF signaling pathway and reversed the hippocampal neurogenesis caused by CUMS. Moreover, we found that the TrkB antagonist K252a blocked SY effects on behavioural improvement, inhibited the incremental effects of SY on hippocampal neurogenesis, and eliminated the impact of SY on BDNF-TrkB signaling activation. Thus, the impact of SY treatment on BDNF signaling molecules (pAkt, pERK1/2, and pCREB) were significantly inhibited by K252a. CONCLUSIONS: This study showed that SY acted as an antidepressant in rats exhibiting CUMS-induced depressive-like behaviours, and was facilitated by promoting hippocampal neurogenesis and the BDNF signaling pathway activation. Thus, SY could act as a potential novel supplement or adjuvant to prevent or treat clinical depressive disorders.

Inactivation of the ventral hippocampus facilitates the attenuation of odor neophobia in rats.

Food neophobia is a behavior observed in rodents involving reduced consumption of a novel food or drink. In the absence of negative post-ingestive consequences, consumption increases with exposure (attenuation of neophobia), which is seen as an associative safe memory. Olfaction and gustation are sensory modalities essential for the development of a food preference. However, little is known about the neural mechanisms underlying neophobia to a food-related odor stimulus. In the present study, we examined the effect of pharmacological inactivation of the ventral hippocampus (vHPC) on neophobia to orally consumed solutions in rats using muscimol, a gamma aminobutyric acid type A receptor agonist. Two different types of solutions, almond odor (benzaldehyde) and sweet taste (saccharin), were prepared. In the results, microinjections of muscimol into the bilateral vHPC before the first odor and taste exposures did not alter the neophobic reactions of the rats to each stimulus. However, in the second odor, but not taste, exposure, the muscimol-injected rats showed higher consumption in comparison to that observed in the control rats, suggesting that the vHPC inactivation facilitates the attenuation of odor neophobia. On the other hand, intra-vHPC muscimol microinjections after the first odor and taste exposures did not facilitate consumption at the second exposures. These results indicate that neural activations within vHPC during orally consuming a novel odor, but not taste, solution play an inhibitory role in the subsequent attenuation of neophobia.

Phosphodiesterase-2 inhibitor reverses post-traumatic stress induced fear memory deficits and behavioral changes via cAMP/cGMP pathway.

Phosphodiesterase 2 is one of the phosphodiesterase (PDEs) family members that regulate cyclic nucleotide (namely cAMP and cGMP) concentrations. The present study determined whether PDE2 inhibition could rescue post-traumatic stress disorder (PTSD)-like symptoms. Mice were subjected to single prolonged stress (SPS) and treated with selective PDE2 inhibitor Bay 60-7550 (0.3, 1, or 3 mg/kg, i.p.). The behavioral tests such as forced swimming, sucrose preference test, open field, elevated plus maze, and contextual fear paradigm were conducted to determine the effects of Bay 60-7550 on SPS-induced depression- and anxiety-like behavior and fear memory deficits. The results suggested that Bay 60-7550 reversed SPS-induced depression- and anxiety-like behavior and fear memory deficits. Moreover, Bay 60-7550 prevented SPS-induced changes in the adrenal gland index, synaptic proteins synaptophysin and PSD95 expression, PKA, PKG, pCREB, and BDNF levels in the hippocampus and amygdala. These effects were completely prevented by PKG inhibitor KT5823. While PKA inhibitor H89 also prevented Bay 60-7550-induced pCREB and BDNF expression, but only partially prevented the effects on PSD95 expression in the hippocampus. These findings suggest that Bay 60-7550 protects mice against PTSD-like stress induced traumatic injury by activation of cGMP- or cAMP-related neuroprotective molecules, such as synaptic proteins, pCREB and BDNF.

Inefficient weapon-the role of plant secondary metabolites in cotton defence against the boll weevil.

MAIN CONCLUSION: Cotton genotypes displayed similar volatile organic compound (VOC) profiles, but major differences in terpenoid aldehyde (TA) content. The differences in VOC production were minor among genotypes, but these differences are crucial for boll weevil attraction. Weevils did not display any preference in feeding behaviour towards cotton genotypes, suggesting physiological adaptation to cope with cotton chemical defence mechanisms. Plant cultivar selection for resistance to herbivore pests is an effective, environmentally safe and inexpensive method to implement in integrated pest management programmes. In this study, we evaluated seven cotton genotypes with respect to the production of volatile organic compounds (VOCs) and non-volatile compounds [terpenoid aldehydes (TAs)], and the attraction and feeding preference of adult boll weevils. Chemical analyses of VOCs from BRS-293, BRS-Rubi, CNPA TB-15, CNPA TB-85, CNPA TB-90, Delta Opal, and Empire Glandless showed that there were few qualitative and quantitative differences across the range of genotypes. In contrast, major differences in TA content were observed, with CNPA TB-15 and CNPA TB-85 producing higher levels of TAs compared to the other genotypes. Our results showed that boll weevil attraction to cotton genotypes varied, suggesting that the ratios and quantities of emitted cotton VOCs are important for host location. However, boll weevil feeding behaviour was neither positively nor negatively influenced by the terpenoid content (non-volatile compounds) of cotton genotypes. The results in this study suggest that boll weevils have adapted physiologically to cope with cotton chemical defence mechanisms.

Optogenetic Stimulation of Type I GAD65+ Cells in Taste Buds Activates Gustatory Neurons and Drives Appetitive Licking Behavior in Sodium-Depleted Mice.

Mammalian taste buds are comprised of specialized neuroepithelial cells that act as sensors for molecules that provide nutrition (e.g., carbohydrates, amino acids, and salts) and those that are potentially harmful (e.g., certain plant compounds and strong acids). Type II and III taste bud cells (TBCs) detect molecules described by humans as "sweet," "bitter," "umami," and "sour." TBCs that detect metallic ions, described by humans as "salty," are undefined. Historically, type I glial-like TBCs have been thought to play a supportive role in the taste bud, but little research has been done to explore their role in taste transduction. Some evidence implies that type I cells may detect sodium (Na+) via an amiloride-sensitive mechanism, suggesting they play a role in Na+ taste transduction. We used an optogenetic approach to study type I TBCs by driving the expression of the light-sensitive channelrhodopsin-2 (ChR2) in type I GAD65+ TBCs of male and female mice. Optogenetic stimulation of GAD65+ TBCs increased chorda tympani nerve activity and activated gustatory neurons in the rostral nucleus tractus solitarius. "N neurons," whose NaCl responses were blocked by the amiloride analog benzamil, responded robustly to light stimulation of GAD65+ TBCs on the anterior tongue. Two-bottle preference tests were conducted under Na+-replete and Na+-deplete conditions to assess the behavioral impact of optogenetic stimulation of GAD65+ TBCs. Under Na+-deplete conditions GAD65-ChR2-EYFP mice displayed a robust preference for H2O illuminated with 470 nm light versus nonilluminated H2O, suggesting that type I glial-like TBCs are sufficient for driving a behavior that resembles Na+ appetite.SIGNIFICANCE STATEMENT This is the first investigation on the role of type I GAD65+ taste bud cells (TBCs) in taste-mediated physiology and behavior via optogenetics. It details the first definitive evidence that selective optogenetic stimulation of glial-like GAD65+ TBCs evokes neural activity and modulates behavior. Optogenetic stimulation of GAD65+ TBCs on the anterior tongue had the strongest effect on gustatory neurons that responded best to NaCl stimulation through a benzamil-sensitive mechanism. Na+-depleted mice showed robust preferences to "light taste" (H2O illuminated with 470 nm light vs nonilluminated H2O), suggesting that the activation of GAD65+ cells may generate a salt-taste sensation in the brain. Together, our results shed new light on the role of GAD65+ TBCs in gustatory transduction and taste-mediated behavior.

Involvement of FGF-2 modulation in the antidepressant-like effects of liquiritin in mice.

It has been reported that liquiritin produced an antidepressant-like effect in rodents. However, little information is known regarding its antidepressant activity with the regulation of fibroblast growth factor 2 (FGF-2), a protein maintaining development and maturation of the nervous central system. Therefore, the aim of the present study was to investigate the underlying FGF-2 modulation involved in the antidepressant-like effects of liquiritin. In the present study, mice were orally administrated with liquiritin for 7 days prior to LPS injection. The depressive-like behaviors, levels of FGF-2, number of Iba1 positive cells, expression of proinflammatory cytokines and density of dendritic spines were evaluated. The results showed that liquiritin significantly ameliorated the depressive-like behaviors in mice response to LPS injection. Liquiritin reversed the reduction of FGF-2 levels in the hippocampus of LPS induced mice. In addition, the microglial activation caused by LPS was attenuated by liquiritin, in accordance with downregulation in mRNA levels of proinflammatory cytokines. Moreover, liquiritin also increased the density of dendritic spines in the hippocampus, which was suppressed by LPS. In conclusion, our findings demonstrated that liquiritin exerted the antidepressant-like effects in LPS-induced depression through FGF-2 enhancement by inhibiting neuroinflammation and maintaining synaptogenesis.

Food texture affects glucose tolerance by altering pancreatic ß-cell function in mice consuming high-fructose corn syrup.

The incidence of metabolic diseases, such as type 2 diabetes, has increased steadily worldwide. Diet, beverages, and food texture can all markedly influence these metabolic disorders. However, the combined effects of food texture and beverages on energy metabolism remains unclear. In the present study, we examined the effect of food texture on energy metabolism in mice administered high-fructose corn syrup (HFCS). Mice were fed a soft or hard diet along with 4.2% HFCS or tap water. Body weight and total caloric intake were not affected by food texture irrespective of HFCS consumption. However, caloric intake from HFCS (i.e., drinking volume) and diet were higher and lower, respectively, in the hard food group than in the soft food group. The hard food group's preference for HFCS was absent in case of mice treated with the µ-opioid receptor antagonist naltrexone. Despite increased HFCS consumption, blood glucose levels were lower in the hard-diet group than in the soft-diet group. In HFCS-fed mice, insulin levels after glucose stimulation and insulin content in the pancreas were higher in the hard food group than the soft food group, whereas insulin tolerance did not differ between the groups. These food texture-induced differences in glucose tolerance were not observed in mice fed tap water. Thus, food texture appears to affect glucose tolerance by influencing pancreatic ß-cell function in HFCS-fed mice. These data shed light on the combined effects of eating habits and food texture on human health.

The mood stabilizing properties of AF3581, a novel potent GSK-3ß inhibitor.

Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzymeand highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3ß has been linked to several disease conditions. There is now large evidence on the role of GSK-3ß in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3ß in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3ß inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3ß in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3ß activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 ß inhibitors in the management of bipolar disorders patients.