Neuropeptide Y Variation Is Associated With Altered Static and Dynamic Functional Connectivity of the Salience Network.

Neuropeptide Y (NPY) is a neurotransmitter that has been implicated in the development of anxiety and mood disorders. Low levels of NPY have been associated with risk for these disorders, and high levels with resilience. Anxiety and depression are associated with altered intrinsic functional connectivity of brain networks, but the effect of NPY on functional connectivity is not known. Here, we test the hypothesis that individual differences in NPY expression affect resting functional connectivity of the default mode and salience networks. We evaluated static connectivity using graph theoretical techniques and dynamic connectivity with Leading Eigenvector Dynamics Analysis (LEiDA). To increase our power of detecting NPY effects, we genotyped 221 individuals and identified 29 healthy subjects at the extremes of genetically predicted NPY expression (12 high, 17 low). Static connectivity analysis revealed that lower levels of NPY were associated with shorter path lengths, higher global efficiency, higher clustering, higher small-worldness, and average higher node strength within the salience network, whereas subjects with high NPY expression displayed higher modularity and node eccentricity within the salience network. Dynamic connectivity analysis showed that the salience network of low-NPY subjects spent more time in a highly coordinated state relative to high-NPY subjects, and the salience network of high-NPY subjects switched between states more frequently. No group differences were found for static or dynamic connectivity of the default mode network. These findings suggest that genetically driven individual differences in NPY expression influence risk of mood and anxiety disorders by altering the intrinsic functional connectivity of the salience network.

Nanoconfinement Raises the Energy Barrier to Hydrogen Atom Exchange between Water and Glucose.

In bulk aqueous environments, the exchange of protons between labile hydroxyl groups typically occurs easily and quickly. Nanoconfinement can dramatically change this normally facile process. Through exchange spectroscopy (EXSY) NMR measurements, we observe that nanoconfinement of glucose and water within AOT (sodium bis(2-ethylhexyl) sulfosuccinate) reverse micelles raises the energy barrier to labile hydrogen exchange, which suggests a disruption of the hydrogen bond network. Near room temperature, we measure barriers high enough to slow the process by as much as 2 orders of magnitude. Although exchange rates slow with decreasing temperatures in these nanoconfined environments, the barrier we measure below ∼285 K is 3-5 times lower than the barrier measured at room temperature, indicating a change in mechanism for the process. These findings suggest the possibility of hydrogen tunneling at a surprisingly high-temperature threshold. Furthermore, differences in exchange rates depend on the hydroxyl group position on the glucose pyranose ring and suggest a net orientation of glucose at the reverse micelle interface.

Sex differences in the human reward system: convergent behavioral, autonomic and neural evidence.

Several studies have suggested that females and males differ in reward behaviors and their underlying neural circuitry. Whether human sex differences extend across neural and behavioral levels for both rewards and punishments remains unclear. We studied a community sample of 221 young women and men who performed a monetary incentive task known to engage the mesoaccumbal pathway and salience network. Both stimulus salience (behavioral relevance) and valence (win vs loss) varied during the task. In response to high- vs low-salience stimuli presented during the monetary incentive task, men showed greater subjective arousal ratings, behavioral accuracy and skin conductance responses (P < 0.006, Hedges' effect size g = 0.38 to 0.46). In a subsample studied with functional magnetic resonance imaging (n = 44), men exhibited greater responsiveness to stimulus salience in the nucleus accumbens, midbrain, anterior insula and dorsal anterior cingulate cortex (P < 0.02, g = 0.86 to 1.7). Behavioral, autonomic and neural sensitivity to the valence of stimuli did not differ by sex, indicating that responses to rewards vs punishments were similar in women and men. These results reveal novel and robust sex differences in reward- and punishment-related traits, behavior, autonomic activity and neural responses. These convergent results suggest a neurobehavioral basis for sexual dimorphism observed in the reward system, including reward-related disorders.

Neuropeptide Y and representation of salience in human nucleus accumbens.

Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring low NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.

Sweet Confinement: Glucose and Carbohydrate Osmolytes in Reverse Micelles.

The research presented here reports the surprising observation that adding glucose and other carbohydrate osmolytes to the polar phase of water-containing reverse micelles causes the particles to shrink. This apparent change in reverse micelle size is attributed to two factors: an increase in the surface area per surfactant molecule induced by the presence of carbohydrate and changes in the particle shape eccentricity. The studies reported here not only focus on glucose but also explore other carbohydrate osmolytes, specifically ethylene glycol, glycerol, erythritol, xylitol, sorbitol, myo-inositol, and trehalose, in the nanoconfined environments of reverse micelles. Through two-dimensional proton nuclear Overhauser enhancement nuclear magnetic resonance spectroscopy, the osmolytes were determined to reside solvated in the aqueous interior of the reverse micelles. This paper reports the loading limit of carbohydrates into AOT [sodium bis(2-ethylhexyl)sulfosuccinate] reverse micelles, demonstrates the location of the carbohydrates in the reverse micelles, and shows an unexpected effect where the carbohydrates add to the reverse micelle volume without causing an apparent increase in the reverse micelle diameter.

Nanoconfinement's Dramatic Impact on Proton Exchange between Glucose and Water.

Glucose nanoconfined by solubilization in water-containing AOT (sodium bis(2-ethylhexyl) sulfosuccinate) reverse micelles has been investigated using 1H NMR. NMR spectra reveal well-defined signals for the glucose hydroxyl groups that suggest slow chemical exchange between them and the water hydroxyl groups. Using the EXSY (ZZ-exchange) method, the chemical exchange rate from water to glucose hydroxyl groups was measured for glucose in reverse micelles as a function of size (water pool diameter of ∼1-5 nm) at 25 °C. The chemical exchange rates observed in the nanoconfined interior are dramatically slower (5-20 times) than those observed for glucose in bulk aqueous solution at the same concentration as the micelle interior. Exchange rate constants are calculated via a mechanism that accounts for these observations, and implications of these results are presented and discussed.

Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans.

Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.