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Sedentary/inactive lifestyle leads middle-aged and older adults to metabolic syndrome and frailty. Capsinoids from nonpungent chili pepper cultivar have been reported to reduce body fat mass, promote metabolism, and improve unidentified complaints of chills. Additionally, they have an anti-inflammation effect; therefore, we hypothesized that continuous oral ingestion of capsinoids alleviates age-related inflammation in the brain and improves the physical activity (PA) in middle-aged and older adults. In our double-blind human study, 69 participants (17 male, 52 female; mean age: 74.1 ± 7.7 years; range: 52–87 years) were administered either 9 mg of capsinoids which were extracted from pepper fruit variety CH-19 Sweet (Capsicum anuum L.) (CP group), or a placebo (PL group) daily over a 3 month period. In an animal study, PA and inflammation-related mRNA expression in the brain were examined in 5-week (young) and 53-week (old) aged mice fed a diet with or without 0.3% dihydrocapsiate, a type of capsinoids, for 12 weeks. In a human study, capsinoids intake did not increase the amount of light-to-moderate PA less than 6.0 metabolic equivalents (METs) (CP: 103.0 ± 28.2 at baseline to 108.2 ± 28.3 at 12 weeks; PL: 104.6 ± 19.8 at baseline to 115.2 ± 23.6 at 12 weeks, METs × hour/week); however, in participants exhibiting an inactive lifestyle, it showed significant increase (CP: 84.5 ± 17.2 at baseline to 99.2 ± 24.9 at 12 weeks; PL: 99.7 ± 23.3 at baseline to 103.8 ± 21.9 at 12 weeks). The energy expenditure in physical activity also improved in the inactive CP group (CP: 481.2 ± 96.3 at baseline to 562.5 ± 145.5 at 12 weeks; PL: 536.8 ± 112.2 at baseline to 598.6 ± 127.6 at 12 weeks; kcal/day). In all participants, CP showed reduced waist circumference, percent body fat, and visceral fat volume; in addition, chills were eased in subjects aged 80 years and older. The older mice fed capsinoids showed increased locomotion activity, decreased inflammation, and oxidative stress in the brain. The results suggest that the continuous oral ingestion of capsinoids gains PA through anti-inflammation effect in the brain as well as reduces fat accumulation and chills in inactive and older humans.

In daily life, we encounter situations where we must quickly decide which hand to use for a motor action. Here, we investigated whether the hand chosen for a motor action varied over a short timescale (i.e., hours) with changes in arm dynamics. Participants performed a reaching task in which they moved a specified hand to reach a target on a virtual reality display. During the task, a resistive viscous force field was abruptly applied to only the dominant hand (DH). To evaluate changes in hand choice caused by this perturbation, participants performed an interleaved choice test in which they could freely choose either hand for reaching. Furthermore, to investigate the effect of temporal changes on arm dynamics and hand choice, we exposed the same participants to another condition in which the force field was introduced gradually. When the abrupt force was applied, use of the perturbed hand significantly decreased and not changed during the training. In contrast, when the incremental force was applied, use of the perturbed hand gradually decreased as force increased. Surprisingly, even though the final amount of force was identical between the two conditions, hand choice was significantly biased toward the unperturbed hand in the gradual condition. These results suggest that time-varying changes in arm dynamics may have a greater influence on hand choice than the amplitude of the resistant force itself.

Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [11C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol's transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [11C]PBR28 binding. [11C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [11C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [11C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [11C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [11C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.

Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.