Prevailing models of the development of decision-making propose that peak risk-taking occurs in adolescence due to a neural imbalance between two processes: gradual, linearly developing cognitive ...control and rapid, non-linearly developing reward-processing. Though many studies have found neural evidence supporting this dual-systems imbalance model, its behavioral predictions have been surprisingly difficult to document. Most laboratory studies have not found adolescents to exhibit greater risk-taking than children, and public health data show everyday risk-taking to peak in late adolescence/early adulthood. Moreover, when adolescents are provided detailed information about decision options and consequences, they evince similar behavior to adults. Such findings point to a critical feature of the development of decision-making that is missed by imbalance models. Specifically, the engagement of cognitive control is context dependent, such that cognitive control and therefore advantageous decision-making increases when available information is high and decreases when available information is low. Furthermore, the context dependence of cognitive control varies across development, such that increased information availability benefits children more than adolescents, who benefit more than adults. This review advances a flexible dual-systems model that is only imbalanced under certain conditions; explains disparities between neural, behavioral, and public health findings; and provides testable hypotheses for future research.
It is not currently possible to measure the real-world thought process that a child has while observing an actual school lesson. However, if it could be done, children's neural processes would ...presumably be predictive of what they know. Such neural measures would shed new light on children's real-world thought. Toward that goal, this study examines neural processes that are evoked naturalistically, during educational television viewing. Children and adults all watched the same Sesame Street video during functional magnetic resonance imaging (fMRI). Whole-brain intersubject correlations between the neural timeseries from each child and a group of adults were used to derive maps of "neural maturity" for children. Neural maturity in the intraparietal sulcus (IPS), a region with a known role in basic numerical cognition, predicted children's formal mathematics abilities. In contrast, neural maturity in Broca's area correlated with children's verbal abilities, consistent with prior language research. Our data show that children's neural responses while watching complex real-world stimuli predict their cognitive abilities in a content-specific manner. This more ecologically natural paradigm, combined with the novel measure of "neural maturity," provides a new method for studying real-world mathematics development in the brain.
Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic ...site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.
Display omitted
•Metformin increases kidney GDF15 synthesis and plasma GDF15 levels•Knocking down kidney GDF15 synthesis negates metformin to increase plasma GDF15 levels•Knocking down kidney GDF15 synthesis negates metformin to lower feeding and weight•Knocking down GFRAL in the AP negates metformin to lower feeding and weight
Zhang et al. demonstrated that metformin induces kidney GDF15 synthesis to increase plasma GDF15 levels and activate GFRAL in the AP to lower feeding and weight in rats. This study highlighted the kidney as a novel metformin target to activate a circulating GDF15-dependent kidney-AP axis to lower feeding and weight.
The area postrema (AP) of the brain is exposed to circulating metabolites and hormones. However, whether AP detects glucose changes to exert biological responses remains unknown. Its neighboring ...nuclei, the nucleus tractus solitarius (NTS), responds to acute glucose infusion by inhibiting hepatic glucose production, but the mechanism also remains elusive. Herein, we characterized AP and NTS glucose-sensing mechanisms. Infusion of glucose into the AP, like the NTS, of chow rats suppressed glucose production during the pancreatic (basal insulin)-euglycemic clamps. Glucose transporter 1 or pyruvate kinase lentiviral-mediated knockdown in the AP negated AP glucose infusion to lower glucose production, while the glucoregulatory effect of NTS glucose infusion was also negated by knocking down glucose transporter 1 or pyruvate kinase in the NTS. Furthermore, we determined that high-fat (HF) feeding disrupts glucose infusion to lower glucose production in association with a modest reduction in the expression of glucose transporter 1, but not pyruvate kinase, in the AP and NTS. However, pyruvate dehydrogenase activator dichloroacetate infusion into the AP or NTS that enhanced downstream pyruvate metabolism and recapitulated the glucoregulatory effect of glucose in chow rats still failed to lower glucose production in HF rats. We discovered that a glucose transporter 1– and pyruvate kinase–dependent glucose-sensing mechanism in the AP (as well as the NTS) lowers glucose production in chow rats and that HF disrupts the glucose-sensing mechanism that is downstream of pyruvate metabolism in the AP and NTS. These findings highlight the role of AP and NTS in mediating glucose to regulate hepatic glucose production.
In response to energy abundant or deprived conditions, nutrients and hormones activate hypothalamic pathways to maintain energy and glucose homeostasis. The underlying CNS mechanisms, however, remain ...elusive in rodents and humans.
Here, we first discuss brain glucose sensing mechanisms in the presence of a rise or fall of plasma glucose levels, and highlight defects in hypothalamic glucose sensing disrupt in vivo glucose homeostasis in high-fat fed, obese, and/or diabetic conditions. Second, we discuss brain leptin signalling pathways that impact glucose homeostasis in glucose-deprived and excessed conditions, and propose that leptin enhances hypothalamic glucose sensing and restores glucose homeostasis in short-term high-fat fed and/or uncontrolled diabetic conditions.
In conclusion, we believe basic studies that investigate the interaction of glucose sensing and leptin action in the brain will address the translational impact of hypothalamic glucose sensing in diabetes and obesity.
Peer presence can elicit maladaptive adolescent decision-making, potentially by increasing sensitivity to the rewards one receives. It remains unknown whether peer presence also increases ...adolescents' sensitivity to others' outcomes, which could have an adaptive effect in contexts allowing pro-social behaviors. Here, we combine social utility modeling and real-time decision process modeling to characterize how peer presence alters adolescents' processing of self and other outcomes. We found that adolescents behaved selfishly when privately allocating monetary rewards for themselves and a peer in an incentive-compatible task. In peer presence, however, adolescents became more altruistic. Real-time decision process estimates collected using computer mouse tracking showed that altruistic behavior was associated with relatively earlier influence of peer-outcomes relative to self-outcomes, and that peer presence sped the influence of peer-outcomes without altering the time at which self-outcomes began to influence the decision process. Our results indicate a mechanism through which peer presence prompts greater prosocial behavior by altering how adolescents process prosocial outcomes.
Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 ...diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown.
We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel.
We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance.
Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.
Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we ...found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.
Display omitted
•DVC oleic acid infusion lowers hepatic secretion of VLDL-TG in chow but not HF rats•Inhibition of ACSL in the DVC negates lipid sensing•DVC glucose infusion lowers hepatic glucose production in chow but not HF rats•Inhibition of FXR in the DVC enhances oleic acid but not glucose sensing in HF rats
Biological Sciences; Physiology; Endocrinology