Masashi Yanagisawa’s research while affiliated with University of Texas Southwestern Medical Center and other places

We developed CaliAli, a comprehensive suite designed to extract neuronal signals from one-photon calcium imaging data collected across multiple sessions in free-moving conditions in mice. CaliAli incorporates information from blood vessels and neurons to correct inter-session misalignments, making it robust against non-rigid brain deformations even after substantial changes in the field of view across sessions. This also makes CaliAli robust against high neuron overlap and changes in active neuron population across sessions. CaliAli performs computationally efficient signal extraction from concatenated video sessions that enhances the detectability of weak calcium signals. Notably, CaliAli enhanced the spatial coding accuracy of extracted hippocampal CA1 neuron activity across sessions. An optogenetic tagging experiment showed that CaliAli enhanced neuronal trackability in the dentate gyrus across a time scale of weeks. Finally, dentate gyrus neurons tracked using CaliAli exhibited stable population activity for 99 days. Overall, CaliAli advances our capacity to understand the activity dynamics of neuronal ensembles over time, which is crucial for deciphering the complex neuronal substrates of natural animal behaviors.

Bromocriptine, generally regarded as a dopamine D2 receptor agonist, has been used to treat patients with type 2 diabetes in the USA; however, its mechanisms of action including the receptors that mediate its anti-diabetic effects remain unclear. Therefore, we herein conducted pharmacological and genetic knockout experiments to investigate how bromocriptine improves glucose metabolism under type 2 diabetic conditions. Bromocriptine transiently increased blood glucose levels in both wild-type and dopamine D2 receptor-deficient mice. This glucose-elevating effect was blocked by the α2-adrenergic receptor antagonist yohimbine. On the other hand, when bromocriptine was administered daily for two weeks, glucose tolerance improved in wild-type mice fed a high-fat diet. Similar anti-diabetic effects of bromocriptine were observed in dopamine D2 receptor-deficient, dopamine D1 receptor-deficient, and orexin-deficient mice under the diet-induced obese condition as well as in genetically obese db/db mice. Bromocriptine-induced improvements in glucose tolerance were not affected by a pretreatment with the autonomic ganglion blocker hexamethonium, which suggested the involvement of the peripheral effects of bromocriptine. Given the biphasic properties of bromocriptine, we examined the drug effect on hepatic endoplasmic reticulum (ER) stress that dually regulates glucose metabolism. In the livers of diet-induced obese mice, the levels of ER stress markers, including C/EBP homologous protein (CHOP), were reduced by the daily administration of bromocriptine. In human hepatoma HepG2 cells, increases in CHOP expression by thapsigargin, a potent inducer of ER stress, were prevented by a pretreatment with low concentrations of bromocriptine, whereas high concentrations induced CHOP expression. These results suggest that low concentrations of bromocriptine caused beneficial ER stress preconditioning, which protected against subsequent severe ER stress in the liver. Therefore, bromocriptine may prevent obesity-induced glucose intolerance via peripheral mechanisms including promotion of hepatic ER homeostasis, but not central dopamine D2 receptor-mediated mechanisms.

Background Sleep is essential for physical and mental health. However, stress-related sleep disorders are common in Japan, and the gut–brain axis may play a role in sleep and stress management. This study investigated whether the consumption of granola containing multiple prebiotic ingredients could alleviate stress and improve insomnia in adults with stress-related sleep problems, regardless of individual differences in the gut microbiota. Additionally, we aimed to investigate the relationship between changes in gut microbiota and the observed improvements. Method A single-arm uncontrolled trial was conducted with 27 adults with high stress levels and sleep disturbance. The participants consumed 50 g of prebiotics-containing granola daily for 8 weeks. Subjective sleep quality was assessed using the Athens Insomnia Scale, Epworth Sleep Scale, and Oguri-Shirakawa-Azumi Sleep Inventory-Middle-aged and Aged version (OSA-MA). Stress levels were assessed by administering the Brief Job Stress Questionnaire and Profile of Mood States 2nd edition (POMS2). Gut microbiota composition was analyzed using 16S rDNA sequencing. Results After 8 weeks, subjective insomnia scores and sleep onset and maintenance improved significantly, whereas the stress and mood disturbance scores decreased significantly. Gut microbiota analysis showed that the relative abundance of Bifidobacterium increased, whereas that of Bacteroides decreased. Correlation analysis suggested a significant association between increased Bifidobacterium level and reduced stress (r = −0.39, p = 0.0035) and insomnia levels (r = −0.3, p = 0.026). Conclusion Prebiotics-containing granola improved subjective sleep quality and reduced stress in adults with stress-related sleep disturbances, which may be attributed to alterations in gut microbiota, particularly the increase in Bifidobacterium abundance.

Background Few studies have explored the relationship between macronutrient intake and sleep outcomes using daily data from mobile apps. Objective This cross-sectional study aimed to examine the associations between macronutrients, dietary components, and sleep parameters, considering their interdependencies. Methods We analyzed data from 4825 users of the Pokémon Sleep and Asken smartphone apps, each used for at least 7 days to record objective sleep parameters and dietary components, respectively. Multivariable regression explored the associations between quartiles of macronutrients (protein; carbohydrate; and total fat, including saturated, monounsaturated, and polyunsaturated fats), dietary components (sodium, potassium, dietary fiber, and sodium-to-potassium ratio), and sleep variables (total sleep time [TST], sleep latency [SL], and percentage of wakefulness after sleep onset [%WASO]). The lowest intake group was the reference. Compositional data analysis accounted for macronutrient interdependencies. Models were adjusted for age, sex, and BMI. Results Greater protein intake was associated with longer TST in the third (+0.17, 95% CI 0.09-0.26 h) and fourth (+0.18, 95% CI 0.09-0.27 h) quartiles. In contrast, greater fat intake was linked to shorter TST in the third (–0.11, 95% CI –0.20 to –0.27 h) and fourth (–0.16, 95% CI –0.25 to –0.07 h) quartiles. Greater carbohydrate intake was associated with shorter %WASO in the third (–0.82%, 95% CI –1.37% to –0.26%) and fourth (–0.57%, 95% CI –1.13% to –0.01%) quartiles, while greater fat intake was linked to longer %WASO in the fourth quartile (+0.62%, 95% CI 0.06%-1.18%). Dietary fiber intake correlated with longer TST and shorter SL. A greater sodium-to-potassium ratio was associated with shorter TST in the third (–0.11, 95% CI –0.20 to –0.02 h) and fourth (–0.19, 95% CI –0.28 to –0.10 h) quartiles; longer SL in the second (+1.03, 95% CI 0.08-1.98 min) and fourth (+1.50, 95% CI 0.53-2.47 min) quartiles; and longer %WASO in the fourth quartile (0.71%, 95% CI 0.15%-1.28%). Compositional data analysis, involving 6% changes in macronutrient proportions, showed that greater protein intake was associated with an elevated TST (+0.27, 95% CI 0.18-0.35 h), while greater monounsaturated fat intake was associated with a longer SL (+4.6, 95% CI 1.93-7.34 min) and a larger %WASO (+2.2%, 95% CI 0.63%-3.78%). In contrast, greater polyunsaturated fat intake was associated with a reduced TST (–0.22, 95% CI –0.39 to –0.05 h), a shorter SL (–4.7, 95% CI to 6.58 to –2.86 min), and a shorter %WASO (+2.0%, 95% CI –3.08% to –0.92%). Conclusions Greater protein and fiber intake were associated with longer TST, while greater fat intake and sodium-to-potassium ratios were linked to shorter TST and longer WASO. Increasing protein intake in place of other nutrients was associated with longer TST, while higher polyunsaturated fat intake improved SL and reduced WASO.

Sleep need accumulates during waking and dissipates during sleep to maintain sleep homeostasis (process S). Besides the regulation of daily (baseline) sleep amount, homeostatic sleep regulation commonly refers to the universal phenomenon that sleep deprivation (SD) causes an increase of sleep need, hence, the amount and intensity of subsequent recovery sleep. The central regulators and signaling pathways that govern the baseline and homeostatic sleep regulations in mammals remain unclear. Here, we report that enhanced activity of calcineurin Aα (CNAα)—a catalytic subunit of calcineurin—in the mouse brain neurons sharply increases the amount (to ~17-h/d) and delta power—a measure of intensity—of non–rapid eye movement sleep (NREMS). Knockout of the regulatory ( CnB1 ) or catalytic ( CnAα and CnAβ ) subunits of calcineurin diminishes the amount (to ~4-h/d) and delta power of baseline NREMS, but also nearly abrogates the homeostatic recovery NREMS following SD. Accordingly, mathematical modeling of process S reveals an inability to accumulate sleep need during spontaneous or forced wakefulness in calcineurin deficient mice. Moreover, calcineurin promotes baseline NREMS by antagonizing wake-promoting protein kinase A and, in part, by activating sleep-promoting kinase SIK3. Together, these results indicate that calcineurin is an important regulator of sleep need and governs both baseline and homeostatic regulations of NREMS in mice.

Sleep insufficiency and sleep disorders pose serious health challenges. This study aimed to determine the potential discrepancy between subjective and objective sleep assessments, including the latter made by physicians, by analyzing a 421-participant dataset in Japan comprising multiple nights of in-home sleep electroencephalogram (EEG) data and questionnaire responses on sleep habits or subjective experiences. We employed logistic regression models to examine which subjective and objective sleep parameters physicians are paying attention to when assessing sleep insufficiency, insomnia, sleep quality, and sleep apnea. Questionnaire responses, including subjective sleep assessments, exhibited poor performance predicting physicians’ assessments, whereas objective data demonstrated good predictive performance, indicating a discrepancy between subjective and objective sleep assessments. Although the in-home sleep EEG measurements had minimal first night effects, incorporating measurements over multiple nights can improve the detection of objective insomnia. Moreover, we found that participants with severe sleep insufficiency overestimated their sleep duration, whereas those with subjective insomnia but without objective insomnia underestimated it. Additionally, subjective sleep quality reflected sleep efficiency but not the frequency of short awakenings or objective sleep depth. In particular, the effects of apnea on objective sleep quality were not subjectively perceived. Collectively, our findings suggest that subjective sleep assessments alone are insufficient for evaluating sleep health and that health checkups and advice based on sleep EEG measurements may be useful in improving sleep habits and for early detection of sleep disorders.