A glucokinase-linked sensor in the taste system contributes to glucose appetite.

OBJECTIVES: Dietary glucose is a robust elicitor of central reward responses and ingestion, but the key peripheral sensors triggering these orexigenic mechanisms are not entirely known. The objective of this study was to determine whether glucokinase, a phosphorylating enzyme with known glucosensory roles, is also expressed in taste bud cells and contributes to the immediate hedonic appeal of glucose-containing substances. METHODS AND RESULTS: Glucokinase (GCK) gene transcripts were localized in murine taste bud cells with RNAScope®, and GCK mRNA was found to be upregulated in the circumvallate taste papillae in response to fasting and after a period of dietary access to added simple sugars in mice, as determined with real time-qPCR. Pharmacological activation of glucokinase with Compound A increased primary taste nerve and licking responses for glucose but did not impact responsivity to fructose in naïve mice. Virogenetic silencing of glucokinase in the major taste fields attenuated glucose-stimulated licking, especially in mice that also lacked sweet receptors, but did not disrupt consummatory behaviors for fructose or the low-calorie sweetener, sucralose in sugar naïve mice. Knockdown of lingual glucokinase weakened the acquired preference for glucose over fructose in sugar-experienced mice in brief access taste tests. CONCLUSIONS: Collectively, our data establish that glucokinase contributes to glucose appetition at the very first site of nutrient detection, in the oral cavity. The findings expand our understanding of orosensory inputs underlying nutrition, metabolism, and food reward.

A Subregion of Insular Cortex Is Required for Rapid Taste-Visceral Integration and Consequent Conditioned Taste Aversion and Avoidance Expression in Rats.

Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats' oromotor and somatic reactions to intraoral (IO) infusions of sucrose were periodically assessed over 45 min following lithium chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl injection. We further assessed whether the failure to integrate interoceptive feedback with ongoing taste-guided behavior impaired acquisition and/or expression of conditioned aversion and/or avoidance in these same rats. Although, as a group, LiCl-injected rats with IC lesions subsequently avoided the sugar in a 48-h two-bottle test, their preference for sucrose was significantly greater than that of the LiCl-injected neurally-intact rats. Overall lesion size, as well as proportion of the posterior gustatory and/or anterior visceral IC were each associated with impaired avoidance. These findings reveal new roles for the posterior gustatory and anterior visceral ICs in multisensory integrative function.

Lactiplantibacillus plantarum K8-based paraprobiotics prevents obesity and obesity-induced inflammatory responses in high fat diet-fed mice.

This study was conducted to investigate the effect of the paraprobiotics, lactic acid bacteria lysates (LAB-P) prepared from Lactiplantibacillus plantarum K8, on obesity and obesity-induced inflammatory responses in high-fat diet (HFD)-fed mice. LAB-P (100 mg/kg) significantly decreased the HFD-induced increase in weight by approximately 20% compared to that in the HFD control. This result was accompanied by a decrease in adipose weight/size. The white adipose tissue weight of epididymis, subcutaneous inguinal region, and mesentery were decreased by 36%, 20%, and 40%, respectively, in LAB-P (100 mg/kg)-administered mice. The size of the epididymal white adipose tissue-derived adipocytes was reduced by 41%. The LAB-P-mediated reduction in adipose tissues was associated with downregulation of adipogenic factors, such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα). In addition, LAB-P administration reduced total cholesterol and low-density lipoprotein levels by 23% and 42%, respectively, with a 55% reduction in lactate dehydrogenase levels. Stromal vascular fraction-derived adipose tissue macrophages were favorably regulated by LAB-P administration; the expression of CD11c, an inflammatory marker, was reduced by 30%, and that of CD206, an anti-inflammatory marker, was increased by 9-fold. These results were shown to correlated with the inhibition of proinflammatory cytokines (IL-1ß and IL-6) and downregulation of NF-κB expression. Furthermore, LAB-P administration suppressed HFD-induced fatty liver by activating AMPKα, an energy metabolic sensor. This study indicates that LAB-P effectively prevents HFD-induced obesity and obesity-induced inflammatory responses and serves a valuable basic work for utilizing LAB-P as functional food ingredient to preventing obesity and treating obesity-associated inflammatory diseases.

Medial preoptic area antagonistically mediates stress-induced anxiety and parental behavior.

Anxiety is a negative emotional state that is overly displayed in anxiety disorders and depression. Although anxiety is known to be controlled by distributed brain networks, key components for its initiation, maintenance and coordination with behavioral state remain poorly understood. Here, we report that anxiogenic stressors elicit acute and prolonged responses in glutamatergic neurons of the mouse medial preoptic area (mPOA). These neurons encode extremely negative valence and mediate the induction and expression of anxiety-like behaviors. Conversely, mPOA GABA-containing neurons encode positive valence and produce anxiolytic effects. Such opposing roles are mediated by competing local interactions and long-range projections of neurons to the periaqueductal gray. The two neuronal populations antagonistically regulate anxiety-like and parental behaviors: anxiety is reduced, while parenting is enhanced and vice versa. Thus, by evaluating negative and positive valences through distinct but interacting circuits, the mPOA coordinates emotional state and social behavior.

Changes in Lower Limb Muscle Activation and Degree of Weight Support according to Types of Cane-Supported Gait in Hemiparetic Stroke Patients.

This study was aimed at investigating the changes in the degree of weight support loaded on the cane and paretic-side lower limb muscle activation according to the types of cane and cane-supported gait using a weight-support feedback cane (WSFC). Eleven hemiparetic stroke patients were recruited from a local rehabilitation hospital. WSFC can measure the degree of weight support loaded on the cane during cane-supported walking in units of kg, through a force sensor installed inside the handle. This study measured the degree of weight support loaded on the cane and lower limb muscle activation under four conditions: two-point and three-point gait with mono and quadripod canes. In the two-point gait with mono and quadripod canes, subjects were asked to move the WSFC and paretic-side foot forward at the same time and then move the nonparetic-side foot. In the three-point gait with mono and quadripod canes, subjects were asked to first move the WSFC forward, then the paretic-side foot, and finally the nonparetic-side foot. The degree of weight support loaded on the cane was significantly higher in the three-point gait with WSFC than in the two-point gait with WSFC for both mono (P = .047) and quadripod canes (P = .002). Additionally, the paretic-side lower limb muscle activation during the stance phase was significantly higher in the two-point gait with WSFC than in the three-point gait with WSFC for both mono (P = .008 ~ .044) and quadripod canes (P = .008 ~ .026). Our results suggest that applying the three-point gait with high cane dependence in the early stages of training for stability and subsequently applying the two-point gait for the enhancement of lower limb muscle activation and training of normal gait pattern could be effective.

Interaction between lead and noradrenergic genotypes affects neurocognitive functions in attention-deficit/hyperactivity disorder: a case control study.

BACKGROUND: Lead is known to be associated with attention-deficit/hyperactivity disorder (ADHD) even at low concentrations. We aimed to evaluate neurocognitive functions associated with lead in the blood and the interactions between lead and dopaminergic or noradrenergic pathway-related genotypes in youths with ADHD. METHODS: A total of 259 youths with ADHD and 96 healthy controls (aged 5-18 years) enrolled in this study. The Korean Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version was conducted for psychiatric diagnostic evaluation. Blood lead levels were measured, and their interaction with dopaminergic or noradrenergic genotypes for ADHD; namely, the dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and alpha-2A-adrenergic receptor (ADRA2A) genotypes were investigated. All participants were assessed using the ADHD Rating Scale-IV (ADHD-RS). Participants also completed the continuous performance test (CPT) and Stroop Color-Word Test (SCWT). Analysis of covariance was used for comparison of blood lead levels between ADHD and control groups. A multivariable linear regression model was used to evaluate the associations of blood lead levels with the results of ADHD-RS, CPT, and SCWT; adjusted for intelligence quotient (IQ), age, and sex. A path analysis model was used to identify the mediating effects of neurocognitive functions on the effects of blood lead on ADHD symptoms. To evaluate the effect of the interaction between blood lead and genes on neuropsychological functions, hierarchical regression analyses were performed. RESULTS: There was a significant difference in blood lead levels between the ADHD and control groups (1.4 ± 0.5 vs. 1.3 ± 0.5 µg/dL, p = .005). Blood lead levels showed a positive correlation with scores on omission errors(r = .158, p = .003) and response time variability (r = .136, p = .010) of CPT. In the multivariable linear regression model, blood lead levels were associated with omission errors (B = 3.748, p = .045). Regarding the effects of lead on ADHD symptoms, hyperactivity-impulsivity was mediated by omission errors. An interaction effect was detected between ADRA2A DraI genotype and lead levels on omission errors (B = 5.066, p = .041). CONCLUSIONS: Our results indicate that neurocognitive functions at least partly mediate the association between blood lead levels and ADHD symptoms, and that neurocognitive functions are affected by the interaction between blood lead levels and noradrenergic genotype.

Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone.

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.

Psychometric Properties and Factor Structures of the Korean Version of Children's Depression Rating Scale-Revised.

OBJECTIVE: The Children's Depression Rating Scale-Revised (CDRS-R) is a valid instrument for the assessment of depressive symptoms in youth, but this measure is yet to be validated in Korea. Thus, the present study aimed to evaluate the validity of the Korean version of the CDRS-R and to determine its factor structures. METHODS: This study included 66 youths between 12 and 17 years of age who participated as part of an ongoing study investigating biomarkers of the antidepressant response and suicidal events in depressed youth. At baseline, the participants were assessed using the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version (K-SADS-PL), CDRS-R, Children's Depression Inventory (CDI), Beck Depression Inventory (BDI), Clinical Global Impressions-Severity (CGI-S), Children's Global Assessment Scale (CGAS), and Child Behavior Checklist (CBCL). Based on their diagnosis, each participant was assessed either five (major depressive disorder [MDD], n = 36) or two (non-MDD, n = 30) more times with the CDRS-R, CDI, BDI, CGI-S, and CGAS; thus, 306 assessments were included in the final analyses of the present study. Pearson's r and Cronbach's α values were used to determine validity and internal consistency, and exploratory factor analysis was performed to determine the factor structures of the Korean version of the CDRS-R. RESULTS: The CDRS-R score was significantly correlated with scores on the K-SADS-PL depression subscale (r = 0.93, p < 0.01), CDI (r = 0.86, p < 0.01), BDI (r = 0.85, p < 0.01), CGI-S (r = 0.84, p < 0.01), and CGAS (r = -0.86, p < 0.01), indicating that this measure has strong criterion validity. In addition, the high correlation of the CDRS-R with the depression subscale of the CBCL (r = 0.67, p < 0.01) and lower correlations with the subscales of the CBCL that assess delinquent behavior, aggressive behavior, and externalizing problem support the discriminant validity of this instrument (rs ≤ 0.50, p < 0.01). Internal consistency was high, as evidenced by a Cronbach's α of 0.91, and the exploratory factor analysis revealed that the Korean version of the CDRS-R comprised three factors as follows: subjective depressed mood, daily functional impairment, and observed depressive affect. These factors differed from those used in previous studies, which were performed with the English version of the CDRS-R. CONCLUSIONS: This study of the Korean version of the CDRS-R provides initial promising data regarding its criterion validity, discriminant validity, internal consistency, and factor structures. These properties were significantly strong, which suggests that the Korean version of the CDRS-R is a valid and reliable instrument for the assessment of depressive symptoms in youth.

Selectivity of Neuromodulatory Projections from the Basal Forebrain and Locus Ceruleus to Primary Sensory Cortices.

UNLABELLED: Acetylcholine and noradrenaline are major neuromodulators that affect sensory processing in the cortex. Modality-specific sensory information is processed in defined areas of the cortex, but it is unclear whether cholinergic neurons in the basal forebrain (BF) and noradrenergic neurons in the locus ceruleus (LC) project to and modulate these areas in a sensory modality-selective manner. Here, we mapped BF and LC projections to different sensory cortices of the mouse using dual retrograde tracing. We found that while the innervation of cholinergic neurons into sensory cortices is predominantly modality specific, the projections of noradrenergic neurons diverge onto multiple sensory cortices. Consistent with this anatomy, optogenetic activation of cholinergic neurons in BF subnuclei induces modality-selective desynchronization in specific sensory cortices, whereas activation of noradrenergic LC neurons induces broad desynchronization throughout multiple sensory cortices. Thus, we demonstrate a clear distinction in the organization and function of cholinergic BF and noradrenergic LC projections into primary sensory cortices: cholinergic BF neurons are highly selective in their projections and modulation of specific sensory cortices, whereas noradrenergic LC neurons broadly innervate and modulate multiple sensory cortices. SIGNIFICANCE STATEMENT: Neuromodulatory inputs from the basal forebrain (BF) and locus ceruleus (LC) are widespread in the mammalian cerebral cortex and are known to play important roles in attention and arousal, but little is known about the selectivity of their cortical projections. Using a dual retrobead tracing technique along with optogenetic stimulation, we have identified anatomic and functional differences in the way cholinergic BF neurons and noradrenergic LC neurons project into primary sensory cortices. While BF projections are highly selective to individual sensory cortices, LC projections diverge into multiple sensory cortices. To our knowledge, this is the first definitive proof that BF and LC projections to primary sensory cortices show both anatomic and functional differences in selectivity for modulating cortical activity.